Journal of Clinical Oncology (JCO) Podcast

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Role of Molecular Classification in Predicting Response to Radiation in Early Endometrial Cancer Nov 30, 2023

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Dr. Shannon Westin and her guest, Dr. Nanda Horeweg and Dr. Carien Creutzberg, discuss the paper "Molecular Classification Predicts Response to Radiotherapy in the Randomized PORTEC-1 and PORTEC-2 Trials for Early-Stage Endometrioid Endometrial Cancer" recently published in the JCO. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Shannon Westin: Hello everyone, and welcome to another episode of JCO After Hours, the podcast where we get in-depth on manuscripts published in the Journal of Clinical Oncology. I'm your host Shannon Westin, Social Media Editor for the JCO and GYN Oncologist by trade. And I'm so excited about today's topic because it is a GYN Oncologist dream. Before I start, please note that none of the authors have any conflict of interest. We are going to be discussing molecular classification predicts response to radiotherapy in the randomized PORTEC-1 and PORTEC-2 trials for early-stage endometrioid endometrial cancer. And this was published in the JCO on September 20th, 2023. And we're going to be speaking to two of the lead authors. First is Nanda Horeweg. She's a senior researcher in the Department of Radiation Oncology at the Leiden University Medical Center in the Netherlands. Welcome. Nanda Horeweg: Thank you. Happy to be here. Shannon Westin: And Dr. Carien Creutzberg. She's professor at the Department of Radiation Oncology at the Leiden Medical Center as well. Carien Creutzberg: Thank you. Shannon Westin: So, let's get into it. And I want to really level set because we have a mixed audience here. So, why don't you start by speaking about the incidents and mortality of endometrial cancer? Nanda Horeweg: Yes, of course. Endometrial cancer is the sixth most common cancer in women with around 400,000 new diagnoses made globally each year. And a woman's lifetime risk to get endometrial cancer is around 3%, and the median age, the diagnosis is 61 years. Most of the women who are diagnosed with endometrial cancer are diagnosed at an early stage, around two thirds, and they have an excellent prognosis. Actually, the five-year survival rates are around 92%. For stage 2 disease, this is actually already going down a bit to 74%. Therefore, stage 3 disease is only 48%. Women that are diagnosed with advanced disease have only a five-year survival, 15%. Shannon Westin: So, given that we know the majority of endometrial cancers are diagnosed at this early stage, prior to your evaluation, what was known about the optimal way to treat this early-stage patient population? Carien Creutzberg: Well, of course, the PORTEC trials were done … were started PORTEC-1 in the 19th of the last century, and PORTEC-2 in 2002. So, at that time, there were still many, many women treated adjuvantly with external beam radiation therapy. And we just developed risk factors to decide on their risk and the incidents for radiotherapy. And in PORTEC-2, because in PORTEC-1 we had seen that most of the recurrences in these early stage cancers were in the vaginal fold, we compared local vaginal brachytherapy only three sessions within full course of pelvic radiotherapy and showed that it had similar pelvic control and survival. Of course, this study, which Nanda conducted, was a long-term analysis with many new factors known from the translational research in the tissue samples of these patients who participate in PORTEC-1 and 2. And in the meantime, we've developed much more knowledge on the molecular factors and other important factors such as LVSI, which tell us much more about the individual prognosis to patients. So, the treatment has been developing greatly in the past 20 years. Shannon Westin: Yeah, and I think this is a great case of less is more, right? We were doing so much for so many people that really didn't need it. And so, really tailoring who needs less treatment, who doesn't need any treatment, and then also, conversely, who may need more treatment that would be missed by the traditional risk factors that you're speaking of. So, I think that brings us right into my next question, which is just bringing the audience up to date on the cancer genome atlas and how that's changed the way we classify endometrial cancer. Nanda Horeweg: Yes, I think the molecular classification of the TCGA has shaped the way we think about endometrial cancer, and has huge impact on decisions on adjuvant treatments in the years to come. The TCGA performed an extensive characterization of the endometrial cancers and found that in fact, this disease exists of four different groups. And the first of the groups I'd like to discuss is the ultra-mutated group, which is characterized by POLE mutations. And this group is shown to have an excellent prognosis in many independent studies. A second group that also has a high mutational burden is characterized by microsatellite instability, and mismatch repair deficiency and has shown to have an intermediate prognosis. Then there's another group that has a low mutational burden with high copy number alterations and frequent TP53 mutations, and these have a poor prognosis. And then lastly, there's a group that does not have any of the classifying features and is often called non-specific molecular profile or TP53 wild type. And this group also has an intermediate prognosis. And then finally, there's a small group of cancers that has more than one of these classifying features, the so-called multiple classifiers. And the WHO 2020 has developed an algorithm which can be used to classify them into the four groups. And that's first on the POLE status. And for the POLE wild type tumors, they are assigned according to mismatch repair deficiency status. And for those that are mismatch repair proficient than POLE wild type, they are classified according to the TP53 status into NSMP or p53 abnormal. Carien Creutzberg: Yeah, that is because of in the ultra-mutated and hyper mutated groups, many of the other mutations are secondary mutations in the context of the ultra-mutated stage, and they behave like the first molecular group. Shannon Westin: Yeah. So, that POLE mutation is going to trump anything else, and it's so important. And I will just say as a sidebar, it's been challenging with the price of next gen sequencing sometimes to get that for everyone. So, sometimes for us when we see a p53 mutation, we actually go back and do the full next gen sequencing to make sure that we're not going to act on that core prognostic feature when it really is in the setting of that more simplistic or that more positive prognostic place. So, this is great, we already kind of highlighted a little bit PORTEC-1 and 2, but if you don't mind, I would love to get the audience a little bit more information just maybe about the populations that were included as we were figuring out how aggressive to be with radiation just to remind people of that, or to teach them that if they haven't gotten a chance to look at those studies. Carien Creutzberg: Yeah, that's important to know because PORTEC-1 was still in the era that we also treated intermediate risk stage 1 endometrial cancer patients. So, deep invasion with grade 1 and 2 or superficial invasion with grade 2 and 3. That's what we defined at that point. Then we compared external beam radiation or no further treatment, showing no survival difference, but a higher risk of recurrence with higher risk being older age over 60, grade 3 for deep myometrial invasion. And we kept those high intermediate risk factors as also similarly found by GOG-99 at the time to do PORTEC-2. So, at the time, about 50% of patients did not have an indication for adjuvant therapy anymore, and with a high intermediate risk population for PORTEC-2, we compare external beam or vaginal brachytherapy and found the benefit of vaginal brachytherapy. A simple outpatient treatment, very short with almost no side effects ensuring local control. And nowadays, using the molecular classification of PORTEC-4a, we've compared achieving treatment with or without use of the molecular factors to designated treatment. So, the standard arm is vaginal brachytherapy and investigational arm is first, a molecular risk profile. And then we give no radiotherapy for those with a favorable profile, then a brachytherapy for the intermediate ones, and for the small group is either extensive LVSI or TP53 mutation or L1 chem overexpression external beam. And we hope to show that less overtreatment and less undertreatment will benefit these patients. Shannon Westin: Yeah, I'm very much looking forward to the results of PORTEC-4a. But let's circle back and talk a little bit about your amazing work here. So, how did you leverage those patient populations from PORTEC-1 and 2 for the current study? Nanda Horeweg: Yes. Well, the PORTEC-1 and 2 study provided a unique opportunity to look into differential treatment effects for radiotherapy. And that is because these are randomized trials, so the groups are comparable, and we have long-term follow-up data that's of very high-quality. In addition, as Carien said earlier, she had the vision already back in the nineties to directly ask the patients permission for the collection of the tissue. So, we have a broader complete biobank for both of these trials, which is quite unique. And our colleagues, Professor Smit and also Charlene Goseff from the pathology department, they have done extensive work on molecular classification, and have molecularly characterized all these cases. So, this allowed us to include 880 patients in this study, which is the largest so far. And besides like the very good starting point that we have of PORTEC-1 and 2 is that we also chose a design that was optimized to conduct like real causes, the causal effects of the molecular class on radiotherapy response. So, we tried to preserve this randomization effect, the exchangeability of the groups as much by working with the intention to treat population and not excluding any patients, except for when they did not have the molecular classification assessed. And also, we looked at areas in the body that were irradiated in one group and not in the other one to really observe the effect of radiotherapy as much as possible. So, looking to the entire pelvis, so local and regional recurrences in PORTEC-1 and looking at pelvic recurrences in PORTEC-2. Shannon Westin So, how were the intervention outcomes in this study different based on the TCGA classifiers? Nanda Horeweg: Before I tell you the results of biomolecular group, I think it's good to have the starting point of the analysis here. So, the no hypothesis of my study was to see whether there was any difference, and no hypothesis is that there's no difference. So, if we find a significant effect, then we can actually say that we found something. And if we start with the POLE group, we did not find any significant difference between the groups allocated to radiotherapy or not. But we did see not a single recurrence in any of the patients that we included from both of these trials. So, technically speaking, we did not find a predictive effect of the molecular classifier, but a prognostic effect. There's no one's having recurrence, so we can deduct from that, that radiotherapy is probably over treatment. Then for the MMRd group, we did observe some recurrences, but these were not significantly different between these three groups. So, based on this study, we cannot draw conclusions on which type of radiotherapy we should give to the patients or whether we should give radiotherapy at all. This was very different for the p53 group. There, the patients had lots of recurrences, unfortunately, as we expected, but we saw a big difference in outcome compared between no radiotherapy at all if it's vaginal brachytherapy where we still had lots of recurrences, and EBRT where we hardly saw any recurrences in the pelvis. And that difference was significantly different. So, that's an indication that these patients need more than just vaginal brachytherapy, even though it's only stage 1 endometrioid endometrial cancer. And then in the last group, the NSMPs, we saw even a different pattern where patients who had had external beam radiotherapy or vaginal brachytherapy, both had an excellent local regional control, and the ones that did not receive any treatments had more recurrences. And this was also very significant. So, there, you would conclude that both therapies are appropriate, but of course, the toxicity profile for vaginal brachytherapy is much more favorable than that of EBRT. Shannon Westin: We really are getting kind of consistent data around p53 needing more treatment. And I think the natural question that comes here, for me at least, and I know we can't answer it with the work, is would chemo be — would that be that extra treatment, when we saw with PORTEC-3 that the group needed the chemotherapy the most. So, I think we'll have to continue to work through that and determine is any more treatment what we need or specific treatments really the best. So, this is so intriguing and it's nice that it's consistent, that we're seeing that across these different studies that really kind of lends strength and validity, I think to what we're finding. So, one of the actions that we're kind of moving towards and that you advocate certainly in your paper is omitting therapy for patients with POLE mutations. Are there any ongoing studies around that that will help us confirm that this is safe for our patients? Nanda Horeweg: Yeah, that's a very good point. I think the evidence is strong enough now to conduct prospective trials. And of course, these are ongoing, the PORTEC-4a trial was already briefly mentioned there. The patients with poor mutations will be randomized between observation and vaginal brachytherapy. So, that will give us a good indication whether in this high intermediate risk early-stage group omission is safe. And in addition to that, we are also conducting with the RAINBO Consortium, the RAINBO-BLUE trial, wherein patients also with high-risk features, so non-endometrioid isotypes, LVSI and higher stages are included. And also in those patients, we investigate whether the de-escalation of treatment is safe. So, we're definitely looking forward to those results to be able to transfer this knowledge to clinical practice later on. Carien Creutzberg: And maybe it's nice to add that RAINBO BLUE is connected to the Canadian Taper trial. Taper being a general de-escalation trial where the POLE patients in that trial are also feeding into the RAINBO-BLUE. And I know that in North America, many centers will participate in the Taper trial. Shannon Westin: Yes, I think everyone is very excited and I think it'll be nice to have these two very strong studies that will help us really confirm that that is 100% a test that needs to be done, cost are not — and that will help avoid overtreatment of patients. So, in line of that, have you all experienced any challenges with implementing molecular testing across patients with endometrial cancer? Any thoughts on how we could potentially simplify? You talked about the rational promise algorithm, which I think is excellent, but I'm just curious to hear your thoughts on this. Nanda Horeweg: The implementation of the molecular classification can be challenging. We have to be honest about that. And usually, it's the assessment of the POLE status that's causing the problems because that's usually done with NGS, which is quite expensive. It requires a lot of knowledge in the laboratory and it's also a bit time-consuming. So, that is the bottleneck for most laboratories and for most settings. But this is already changing in a couple of places, lik…

Full show notes at the publisher

JCO Article Insights: Impact of Physical Activity on Mortality and of BMI on Treatment-Related Adverse Events Nov 27, 2023

Show notes

In this JCO Article Insights episode, Davide Soldato provides summary on two articles published in the November issues of the Journal of Clinical Oncology. The first article provides data on the prognostic effect of physical exercise on overall mortality and cancer-related mortality in a pan-cancer analysis of the PLCO study. The second article provides data regarding the impact of BMI on treatment-related adverse events and adherence to Palbociclib in the PALLAS trial. Overall, results of these study support the need to conduct studies investigating lifestyle behavioral factors and their impact on outcomes in survivors of and patients diagnosed with cancer.

TRANSCRIPT

The guest on this podcast episode has no disclosures to declare.

Davide Soldato: Welcome to the JCO Article Insights episode for the November issue of the Journal of Clinical Oncology. This is Davide Soldato, your host, and today, I will be providing a summary on two articles focused on the impact of exercise on cancer prognosis and of BMI on treatment side effects.

In the first article titled Pan-Cancer Analysis of Postdiagnosis, Exercise, and Mortality, Lavery and colleagues investigated whether higher exercise was associated with a reduced risk of mortality among individuals diagnosed with cancer. The authors conducted a pan-cancer analysis using data from the Prostate, Lung, Colorectal, and Ovarian cancer screening study or PLCO, using data from a questionnaire that was administered to participants in the study at a median of nine years after initial randomization.

The questionnaire including 12 questions related to physical activity, both occupational and non-occupational. Of these 12 questions, four were used to assess the prognostic impact of moderate and strenuous exercise evaluated both in terms of frequency, so a number of sessions per week, and duration of exercise sessions.

The exposure to exercise was defined according to international guidelines, and patients were so divided among those who had a moderate intensity exercise defined as at least four days per week with each session on average for 30 minutes in duration, and strenuous intensity exercise equal or more to two days per week with each session on average of at least 20 minutes in duration.

So, based on this definition, the patients were categorized as either exerciser, if they were meeting the recommendation or non-exercisers. Additionally, to assess the existence over those response relationship between exercise and mortality, the authors further categorize patients on a four level scale as reporting no exercise, exercise, not meeting recommendation, meeting recommendation, or exceeding recommendation.

The primary endpoint of the study was all-cause mortality, and secondary endpoints included cancer mortality and mortality from other causes. This study included more than 11,000 patients diagnosed with cancer. 38% of them reported meeting guidelines recommendation with a median of 44 and 19 minutes spent in moderate and strenuous exercise respectively.

Individuals belonging to the group of exerciser were more frequently male, non-smokers, and with a lower prevalence of cardiovascular diseases. The most common cancer diagnosis were prostate cancer, breast cancer, and colon cancer observed respectively in 37%, 20%, and 7% of the participants.

Patients who died within six months from the completion of the questionnaire were excluded from this study. A median follow-up time between this landmark point and the last follow-up was 11 years. More than 4,500 deaths were observed in this period, and less than half were related to cancer meeting.

Meeting exercise recommendation was associated with a 25% risk reduction in all-cause mortality, a 21% risk reduction in cancer mortality, and a 28% risk reduction in mortality from other causes. In particular, five-year cancer mortality rate was 12% among exerciser and 16% among non-exerciser.

Interestingly, the positive prognostic effect of exercise was observed starting within the first five years of observation, but persisted up to 20 years afterwards. An inverse to those response relationship between exercise and mortality was observed, so increasing exercise was overall associated with incremental reduction in the risk of death.

The authors compared patients reporting no exercise with those reporting exercise under at the recommendation or over the recommendation. For all-cause mortality, the risk reduction was equal to 25% among those reporting exercise below the recommendation, and increased to 35 and 36% among those meeting and exceeding recommendation respectively.

Similar results were observed for cancer mortality, risk reduction ranged from 19% in those reporting exercise below recommendation, up to 33% for those exceeding recommendation. Finally, the authors investigated the effect of exercise on mortality by cancer type, and observed a significant reduction in cancer mortality only for head and neck cancer and renal cancer.

While reduction all-cause mortality and mortality from other causes were observed across a wide range of cancer, including breast, endometrial, and hematopoietic and prostate. The study confirms previous findings by showing an inverse relationship between higher level of exercise and lower risk of all-cause mortality, and provides novel insights on the topic by reporting that those response association, data on other causes of death, and edited analysis by cancer site diagnosis.

All limitation of the study is related to the generalizability of the findings. The study included only patients that were alive at a median of 4.5 years after cancer diagnosis, which might have applied to selection of patients with good prognosis, and thus, reducing the number of cancer mortality events. Additionally, these patients were willing to complete an additional questionnaire in the context of the trial, which might be related to a higher motivation in engaging in healthy lifestyle behaviors.

The study did not replicate previous findings observing a reduction in cancer mortality for breast, colon, and prostate cancer, among those reporting higher exercise. Although this might be related to the inclusion of long-term survivors in the study.

In the second article titled Impact of BMI in Patients With Early Hormone Receptor-Positive Breast Cancer Receiving Endocrine Therapy With or Without Palbociclib in the PALLAS trial, Dr. Pfeiler and colleagues investigated the impact of BMI on side effects, adherence to treatment, and efficacy of palbociclib in the PALLAS trial.

Just as a reminder, PALLAS is a randomized clinical trial that investigated whether the addition of two years of palbociclib to standard endocrine therapy in patients treated for stage two, three hormone receptor-positive HER2-negative breast cancer could improve invasive disease-free survival. Previous report of the trial showed that palbociclib did not improve invasive disease-free survival compared to endocrine therapy alone.

More than 5,500 patients were included in this analysis, and among them, more than two third at a BMI equal or over 25 diagnoses with 32% being overweight and 30% obese. Overweight and obese patients were more frequently older and coming from North America rather than from Europe.

In line with the age difference, normal weight patients were treated more frequently with Tamoxifen alone or in combination with ovarian function suppression or with aromatase inhibitors in combination with ovarian function suppression.

No differences in tumor characteristics was observed according to BMI. However, there were some minor differences regarding the type of surgery and administration of chemotherapy. The authors observed that side effects of palbociclib were significantly different according to BMI and in particular, they observed a lower incidence of a hematological toxicity among overweight and obese patients.

Conversely, higher rates of arthralgia, nausea and diarrhea were observed among overweight and obese patients, both in the palbociclib and in endocrine therapy alone. In particular, regarding hematological toxicity, the authors observed that overweight and obese patients experienced a significantly lower incidence of overall neutropenia, grade 3 and grade 4 episodes of neutropenia.

For example, looking at grade 3 neutropenia, the incidence was equal 44% in the obese population versus 64% in the normal weight cohort. Differences in incidence of neutropenia remains significant even when adjusting for confounding factors, including previous administration of chemotherapy, age, ECOG performance status, and race ethnicity.

Furthermore, a lower incidence of overall thrombocytopenia was observed in the overweight and obese cohort. The lower incidence of hematological toxicity led to significant differences in those reduction, early discontinuation, and relative dose intensity for palbociclib. At six months, only 29% of obese patients reduced to those of palbociclib compared to 50% in the normal weight cohort. Similarly, only 20% of obese patients permanently stopped palbociclib compared to 35% in a normal weight group.

Finally, the risk of palbociclib early discontinuation was 25% lower for each additional 10 units of BMI, even when accounting for additional potential co-founders. As a consequence of a lower dose reduction and lower rates of early discontinuation, the relative dose intensity for palbociclib was significantly higher among overweight and obese patients compared to normal weight ones. Efficacy of palbociclib was not different according to BMI, neither in the palbociclib bar, nor when assessing patients in both arms. However, these analyses are performed with a relatively short, medium follow-up time, and a low number of events.

So, in conclusion, this report from the PALLAS trial shows that higher BMI was associated with a more favorable safety profile, especially regarding hematological toxicity, and a lower risk of treatment discontinuation. These findings are in line with previous data obtaining the metastatic setting with other CDK4/6 inhibitors, and support the existence of a different pharmacodynamic profile influenced by BMI that translates in a more favorable toxicity profile.

At present, differences in BMI do not seem to affect palbociclib efficacy, but further analysis with additional follow-up time and events, as well as by type of endocrine therapy administered are planned in the PALLAS study. That concludes this episode of JCO Article Insights.

In these episodes, we summarized findings from two studies, the first titled, Pan-Cancer Analysis of Postdiagnosis, Exercise and Mortality by Lavery and colleagues. This trial shows that higher level of exercise are associated with lower risk of all-cause cancer specific and other cause mortality, although with some differences according to cancer site.

The second article titled Impact of BMI in Patients with Early Hormone Receptor-Positive Breast Cancer Receiving Endocrine Therapy With or Without Palbociclib in the PALLAS trial by Dr. Pfeiler and colleagues observed a significant different side effect profile for palbociclib according to BMI, but no differences in efficacy.

This is Davide Soldato, thank you for your attention and stay tuned for the next episode of JCO Article Insights.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions.Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Durvalumab Plus Carboplatin/Paclitaxel Followed by Maintenance Durvalumab With or Without Olaparib as First-Line Treatment for Advanced Endometrial Cancer: The Phase III DUO-E Trial Nov 05, 2023

Show notes

In this "Podcast Takeover," Dr. Lidia Schapira guest hosts to discuss with Dr. Shannon Westin her own JCO paper, which reports on the DUO-E Trial. Dr. Ramez Eskander also joins in this lively discussion. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in depth on manuscripts published in the Journal of Clinical Oncology. I am your host, Shannon Westin, Social Media Editor of the JCO and Gynecologic Oncologist by trade. And actually, I'm super excited today because we are going to have a podcast takeover because we are discussing my own work, which was simultaneously presented at the European Society of Medical Oncology 2023 Congress and published in the Journal of Clinical Oncology on October 21st, 2023. And this was the DUO-E trial, "Durvalumab Plus Carboplatin/Paclitaxel Followed by Maintenance Durvalumab With or Without Olaparib as First-Line Treatment for Advanced Endometrial Cancer." Because we're discussing this work and we wanted you to have an unbiased podcast discussion, Dr. Lidia Schapira, who is a Professor of Medical Oncology at Stanford University and an Associate Editor of JCO and the Art of Oncology podcast host, is going to take over this podcast and really just pepper me with questions about this exciting work. Welcome, Dr. Schapira. Dr. Lidia Schapira: Thank you so much. It's such a pleasure to be with you. Dr. Shannon Westin: And before I turn over the reins, I also want to introduce one of my colleagues, who's going to be providing quite a bit of insight on this topic, Dr. Ramez Eskander, who is Professor of Obstetrics, Gynecology, and Reproductive Sciences at the University of California, San Diego. And you will know he's the principal investigator of the GY-018 study, which established pembrolizumab and chemotherapy as the new standard of care in endometrial cancer. Welcome, Ramez. Dr. Ramez Eskander: Thank you. Thank you, Dr. Westin. It's a pleasure to be here. And congratulations again to you and your study team for this exceptional work. Dr. Shannon Westin: Thank you. And congratulations to you. Dr. Schapira, thank you for being here and please do take it away. Dr. Lidia Schapira: So let's start by having you tell us a little bit about the standard of care for women with endometrial cancer and advanced endometrial cancer prior to this study. Ramez, I'm going to direct this question to you first. Dr. Ramez Eskander: For many years, actually since about 2012, carboplatin and paclitaxel, which ironically is a chemotherapy backbone really across all of our gynecologic tumors, emerged as the preferred doublet chemotherapy regimen for the management of advanced-stage metastatic or recurrent endometrial cancer. It evolved through a series of different clinical trials, in fact taking us from whole abdominal radiation, systemic chemotherapy, comparing single agents to doublets and then triplet regimen of TAP to carboplatin and paclitaxel, which ultimately, then, following the presentation of GOG Protocol 209 and its publication, as the chemotherapy backbone, being carboplatin and paclitaxel. And it's been that way for many, many years. Dr. Lidia Schapira: And how effective is the regimen? Dr. Ramez Eskander: The response rates to carboplatin and paclitaxel are actually quite reasonable in the patients who have advanced-stage disease, particularly if they haven't had prior systemic chemotherapy. Response rates in the 50% to 60% range. The issue is that the responses tend to be limited and disease recurrence is an expectation in these patients who have advanced-stage disease. And so that really highlighted the importance of trying to continue to advance therapeutic opportunities in these patients to improve long-term outcomes. Dr. Lidia Schapira: As we think about improved long-term outcomes, we're thinking about a better treatment and also a kinder treatment, perhaps one that is also less toxic. Can you talk a little bit about the population of women with endometrial cancer? Are these older women? Do they have comorbidities? Dr. Ramez Eskander: What we're seeing is, interestingly, there has been an evolution a bit in this space. Historically, we used to think about endometrial cancer as—the phrases we used to use are type I and type II. These type I tumors, we would say, are estrogen-driven malignancies; they tend to be seen in overweight or obese patients. And we would identify them in a theoretically younger patient population. And then we had these type II, or what we termed estrogen-independent malignancies, that we would see in an older patient population. Of course, with obesity came metabolic syndrome and other cardiovascular comorbidities, etc. But really, that narrative has evolved dramatically, and that's really something that will be highlighted in, I think, our discussion of these studies today, where the nomenclature that we used to historically use has evolved because of our understanding of the molecular characterization of this disease. So we've really gone away from that, and now we understand that we're seeing all of these different heterogeneous endometrial cancer types amongst patients of different ages, different comorbidities, different races and ethnicities. And so it's created a more complex picture for us. But certainly, there are comorbidities that these patients face, and that's important as we look to identify treatments strategies that are both effective and tolerable. Dr. Lidia Schapira: My final question before we jump into this very exciting study is about the Cancer Genome Atlas work. Can you tell us how that's changed the thinking and the design of the studies? Dr. Ramez Eskander: It was a seminal publication, really, back in 2012/2013 looking at an assessment of endometrial cancers to try and determine whether or not all of these "endometrial cancers" that we used to enroll on a single study are similar or divergent. And it's important because the study I referenced that really established the standard of care, GOG Protocol 209, as carboplatin and paclitaxel, there was no real consideration of molecular characterization at all. We enrolled all patients onto this study without thinking about these variables, of course, because it was designed, conducted, and completed before the TCGA data emerged. But what we learned from the TCGA is there appeared to be four distinct molecular subgroups. There were the POLE-mutated patient population. There was the mismatch repair deficient or MSI-high endometrial cancer population. There was the copy number-high or what we say are the p53-mutated. And then the last cohort was called the NSMP (no specific molecular profile). But now, that's even evolved; some people term it TP53 wild type. That's a bit of even a heterogeneous cohort amongst itself. So we're going to take these subsets, independent of POLE and an MSI-high, and we're going to look at TP53 or copy number-high, and that will probably be divvied out further, and the NSMP, and that will probably be subdivided. But really, it gave us these four components, which has then evolved. Many of you may have heard of the ProMisE algorithm or ProMisE Plus, which looked to take the data from TCGA so that we can start to really look at it in clinical practice. So it's really revolutionized how we think about these patients, how we think about the disease, and how we design trials. Dr. Shannon Westin: And I just want to add to that because I think that it's so important, what Ramez said about the way we were developing trials, the way we were designing trials. We knew that these classifiers—we were learning these classifiers are prognostic. Now what we're really trying to hone in on is how predictive they are. And certainly, one of the major classifiers that we're going to talking about today is mismatch repair status, and that is most definitely predictive of response to therapies. But we're still learning about the other classifiers and how we might adjust the way we treat people, even deescalating care for certain patients. That is still being proven in clinical trials, although we suspect that it's going to be borne out as other clinical trials report. Dr. Lidia Schapira: It's a perfect segue to this current trial. Tell us a little bit about the objectives and the design of DUO-E. Dr. Shannon Westin: As Ramez said, the standard of care was chemotherapy. And so we wanted to see if there was a way to improve outcomes for these women with advanced and recurrent endometrial cancer in a really clinically relevant, meaningful fashion for patients. And so we knew that this TCGA classifier, the mismatch repair, was so important, and we thought that the addition of immunotherapy to chemotherapy would most certainly work in that population but could even work in the entire population because, generally, endometrial cancer seems to be a little bit more responsive to immunotherapy and to activation of the immune system than, say, some of our other gynecologic malignancies. And so we set out to see what the addition of durvalumab, which is a PDL-1 inhibitor, would add to chemotherapy. And this was two chemo as well as followed by durvalumab maintenance. But even further, we had some really kind of exciting science data from our lab that said that if we combined a PARP inhibitor with immunotherapy that we could accentuate on the response to therapy and we could get more benefit. And there's kind of a lot behind that, but essentially, what we thought was that the damage that's caused by the PARP inhibitors would create an activation of different immuno-pathways, like STING pathway and activating cytokine release, and that we would get this synergistic activity. So one of the other objectives was to see if the addition of the olaparib, the PARP inhibitor, to durvalumab in that maintenance setting could even further improve benefit. So we had a dual primary endpoint looking at progression-free survival, so the amount of time people live without their cancer coming back. And that endpoint was first, the durvalumab-alone arm to control, and then the second portion of that was the durvalumab/olaparib arm back to control. Dr. Lidia Schapira: So before you tell us about the results, tell us a little bit about the study itself. I mean, I was very impressed that you did it in so many different locations. Tell us about that effort. Dr. Shannon Westin: This was a huge collaborative effort both with the GOG Foundation, the Gynecologic Oncology Group Foundation, as well as ENGOT, which is our European colleagues that do amazing clinical trials. But in addition to that, we really worked very closely with our industry partner to really make sure we spanned the globe. And so we had groups from all over the world that participated and really were exceptional. The care that was taken and the hard work that went into this type of study across the world really can't be overstated. We were very lucky to have a wonderful infrastructure group. We met weekly for a long time, just keeping an eye on the data and making sure that everything was as positive as possible and, of course, that we were watching the outcomes of the patients very closely and making sure that there was no evidence of harm or issue. And so it really did take a village, truly, to run this study and to ensure that at the end of it, we got really great data that we can trust. Dr. Lidia Schapira: So tell us the results. Dr. Shannon Westin: So DUO-E was positive for both of its primary endpoints, which was very thrilling. So for the first analysis, which is the durva-alone arm to control, we saw a reduction in the risk of progression of 29%, so a hazard ratio of 0.71. And then the addition of olaparib seemed to further enhance this benefit, so a 45% reduction in the risk of progression for a hazard ratio of 0.55. But what's really exciting is our follow-up time was pretty long; it was about 17 months, so we were able to look at a couple of different analyses, including an 18-month landmark analysis where we saw approximately 50% of the patients were still alive progression free at 18 months, as compared to only 21% of patients being alive progression free in the control arm. So there was a doubling in that progression-free survival time point at 18 months, which is thrilling. Dr. Lidia Schapira: So Ramez, as an expert in the field, what was your reaction when you read or heard these results? Dr. Ramez Eskander: It's exciting, honestly. So we have gone a long time without seeing really significant successes in the endometrial cancer space, a testament to the fact that we hadn't yet developed our understanding of how we could move this needle forward. But Dr. Westin and the DUO-E team conducted an exceptional clinical trial, as you mentioned, international study, rational and important hypothesis to adjudicate. And what we saw here was both now we had other studies—the RUBY trial, the GY018 trial, the AtTEnd—and now here DUO-E, which added this hypothesis of PARP maintenance in addition to checkpoint to try to augment response and consistent, really provocative data, exciting, in line with what we've seen and hopefully will continue to drive the science in this space, most importantly. Dr. Lidia Schapira: So let me ask you a follow-up question to that. What kind of scientific questions are in the air now as a result of this trial and what the trial found? Dr. Ramez Eskander: Oh, goodness. Shannon and I could both take this, I'm sure. But I think in the dMMR population, we recognize that there's a ton of data that is supportive of the fact that these tumors are immune responsive, particularly in dMMR endometrial cancer, whether it's an epigenetic promoter hypermethylation, or a mismatch repair gene mutation. I think the data has emerged that immunotherapy is here to stay for these patients in the newly diagnosed advanced stage, even chemo naïve, who need adjuvant therapy. The pMMR population, this is where we're seeing more and more questions emerge because we realize that that may be a cohort of different cancers. And I'll let Shannon speak to this briefly, but even the incorporation of the PARP inhibitor, in addition to the checkpoint, there's a biologic rationale for combining those two together to augment response. And to see the benefit in that trial—arm three and arm two, we can look at descriptively and look at the differences, but who are those patients? Where is the PARP and the checkpoint most effective? How do we expand that to a larger population of patients potentially? These are questions that emerged because, as Dr. Weston will allude to, I know we also talk about HRR mutations, which are captured, but we even have a lot to understand about that in endometrial cancer, where we've had more research in the ovarian cancer space. Dr. Shannon Westin: Being mindful of time, because I have, like, 1,000 hypotheses that have been generated by this study, which, I think, shows it's a great study, right? Because you get some answers, and as our colleague Brad Monk says, "The only definitive study is the negative studies." This most certainly was not that. But just kind of expanding on what Ramez said, the interesting thing about DUO-E is that really the biggest benefit for the combination of the durvalumab and olaparib was in that mismatch repair proficient group. And I personally thought that we were going to see accentuation of the impact in the mismatch repair deficient group based on the science, but that just wasn't borne out by the data. It doesn't seem that the combination has that much to add in that mismatch rep…

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JCO Article Insights: Safety and efficacy of a Novel ADC Targeting TROP-2 in Metastatic Non-Small Cell Lung Cancer (NSCLC) Oct 30, 2023

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In this JCO Article Insights episode, Davide Soldato interviews Dr. Jacob Sands, medical oncologist at Dana Farber Cancer Institute (Boston, MA) and Assistant Professor at Harvard Medical School, on their paper "First-in-Human, Phase I Dose-Escalation and Dose-Expansion Study of Trophoblast Cell-Surface Antigen 2-Directed Antibody-Drug Conjugate Datopotamab Deruxtecan in Non-Small-Cell Lung Cancer: TROPION-PanTumor01". The interview offers a deep dive into the safety and efficacy data of this novel drug and puts these data in the context of the current treatment landscape of NSCLC and of the revolution that ADC are bringing into the oncology world. TRANSCRIPT Davide Soldato: Welcome to this JCO Article Insights episode for the October issue of Journal of Clinical Oncology. This is Davide Soldato, and today I will have the pleasure of interviewing Dr. Jacob Sands, co-author of the manuscript titled, "First-in-Human, Phase I Dose-Escalation and Dose-Expansion Study of Trophoblast Cell-Surface Antigen 2-Directed Antibody-Drug Conjugate Datopotamab Deruxtecan in Non-Small-Cell Lung Cancer: TROPION-PanTumor01." Dr. Sands is a Medical Oncologist working at Dana-Farber Cancer Institute in Boston and Assistant Professor at Harvard Medical School. His main field of research and clinical interests revolve around improving screening and diagnosis of lung cancer and also on developing novel therapeutic agents for this disease. So, welcome Dr. Sans, and thank you very much for accepting our invitation today. Dr. Jacob Sands: Happy to join. Thanks for having me. Davide Soldato: I just wanted to start with a very general question because I think that we are going to discuss a very important study and the manuscript that you co-authored is going to look at the safety and the efficacy of this novel ADC datopotamab-deruxtecan that is targeting TROP2. But I just wanted to have a little bit of context before starting to discuss the safety and efficacy data. So the population that was included in the study included more or less 60% of patients that received three or more lines of therapy and also 20% of patients who received five or more lines of therapy. So I think that this is a very particular population, especially considering that we are speaking about non-small cell lung cancer. And so I wanted to get from you like a general context, like what are the therapeutic options for these patients normally in clinical practice and what do we expect in terms of outcomes and in terms of toxicity? Dr. Jacob Sands: Yeah, so as you point out, this is a highly pretreated population in general, which is to say that they've really gotten the most effective lines of treatment up to this point. Now, we certainly do see some efficacy from some of the later lines of therapies in some patients, but inherently there is a decreasing response rate and decreasing durability of these responses as patients get further along in their treatment courses as far as lines of therapy. So it's generally considered to be a challenging clinical scenario, which is part of what makes the data that we're going to discuss, I think, so meaningful. Davide Soldato: Yeah, I think that especially if we look at the population that was included first, I think that the very particular thing is that included both oncogene-addicted and non-oncogenic addicted patients, and also the great majority of these patients received the most effective treatments that are available because they all received more or less immunotherapy and platinum-based chemotherapy, if I'm not mistaken. Dr. Jacob Sands: That's right. And that's an important distinction that you're drawing in the patients with oncogenic drivers and, of course, there's plenty of data with this compound with Dato-DXD in that population as well. But broadly speaking, in the non-oncogenic actionable alterations where they've gotten chemo-immunotherapy, those really are the most meaningful. Of course, docetaxel has been a long-standing second line that I'd say there is less and less enthusiasm about that as a line of treatment as we've seen some of these other more novel therapies that have just a better toxicity profile in particular, but also some with really durability that we don't quite see with docetaxel as well. And so once you're getting past that, you're really now reaching a bit deeper to then have something that is well tolerated and has efficacy. That's a setting where we really need it even more. Davide Soldato: So, going back to the results of the study, as we kind of pointed out, this was a very standard classic with a Bayesian design, phase I dose escalation and dose expansion study of this novel ADC datopotamab-deruxtecan. So I just wanted to go over with you and to provide our listeners a little bit with some data regarding the doses that were explored and then what were the doses that were selected for the expansion. And also to discuss a little bit the safety data. We were discussing the tradeoff between risk and benefit, especially in patients that are very pretreated, searching for these kind of sweet spots between the toxicity and the efficacy. So I just wanted to put in context a little bit the data that you reported in the manuscript. Dr. Jacob Sands: Yeah, that's right. So, like phase I's go, we started with a low dose at 0.27 milligrams per kilogram, and dose escalations occurred up to 10 milligrams per kilogram. The 10 milligram per kilogram dose did have toxicities that really made it not considered to be tolerable, and that mostly being mucositis and skin. And so it was then back down to 8 milligrams per kilogram. And then there was a dose expansion at 4, 6, and 8 milligrams per kilogram. The 4 and 6 milligram per kilogram doses had 50 patients enrolled within those cohorts and 80 patients within the 8 milligram per kilogram cohort to then get much more data, of course, for efficacy and tolerability within those levels. Ultimately, each of them really demonstrated some efficacy as well as general tolerability. The 6 milligram per kilogram dose was really the one selected overall for further testing and future trials based upon the data out of this one that we're going to discuss further. Davide Soldato: What were the main side effects that you observed in the trial? And particularly, do you think that there is some kind of special toxicity that should be looked at when using this novel type of ADC? Dr. Jacob Sands: Certainly there are some novel toxicities to really pay attention to. And maybe I'll just point out before diving into the toxicities, that this is in many ways chemotherapy. The antibody drug conjugates, as listeners probably know, are an antibody that has a linker bound to chemotherapy, what's called the payload. And in this case, it's a topoisomerase I inhibitor with the antibody, the TROP2. So the cells on the surface, when there's TROP2 expression, the drug binds to that, gets pulled into the cell and releases that chemotherapy intracellular, but it is still chemotherapy. And so some of the toxicities are things that we commonly see with chemotherapy drugs. Although, broadly speaking, I would say we're able to deliver higher doses of that chemo to the cells in this kind of targeted dosing of chemotherapy to give the chemo intracellular. Now, that being said, some of the toxicities that we see from this drug in particular that are a bit different is the stomatitis, mucositis. That is something that has occurred. Now, I've found that if it's really severe, then with a dose reduction that has really substantially improved any toxicities with future dosing. And at a 6 milligram per kilogram dose, a dose reduction to 4 milligram per kilogram is still within a dose range where we saw plenty of efficacy within the trial that we're discussing. That being said, if one can help patients tolerate it better, if it's more mild symptoms, if it's not severe, then that's better in maintaining that dose. And interesting things like ice chips at the time of infusion, so cold within the mouth, kind of like the cold caps to try to reduce alopecia at the time of infusion of the chemo may help some steroid rinses also can be helpful. But really these are things to help prevent stomatitis from being severe. It's harder when that occurs, then the treatment for improving it is a bit different. We do know, though, that that does improve with time. So even when it was severe with that infusion, it does improve as patients get further out from those doses. Of course, another one is dry eyes or irritation within the eyes. And if that is severe, then or even mild actually, I'd say when there's any known toxicity like this is to involve ophthalmology. Now, within this trial, ophthalmology was involved and patients had to get a baseline eye exam and they would get checked at different time points throughout the course of the trial. And so they were being monitored. I did not have anyone who needed to stop the drug because of this. The patient I had with the longest standing response to therapy did have some dry eye. It was not bothering him so much. And he had this real aversion to using eyedrops. It was very hard for him to make himself use these. But when I told him, "Look, if this gets worse, you might have to come off the trial, that it might not be our decision just by the way the trial describes it, if this gets worse." And so for him, the fear of having to come off the drug was really the thing that helped him to then start using his eyedrops, which really helped to control that a bit more. And so that is something to monitor for. But the biggest thing really is interstitial lung disease. This is something that is a complex topic, I think because it's something that we need to be very aware of and monitor for. At the same time, a diagnosis of interstitial lung disease can be challenging. There really were not cases where we had pathologic confirmation of this diagnosis. These are clinical diagnoses in the cases on this. Now there was an adjudication committee that would review all of the data and come to a determination of whether this looked like drug related ILD or not. But for clinicians, when you see a patient whose scan shows some inflammatory markings or inflammatory appearing markings on a scan, we see that all the time with other drugs too. And so determining what is potentially incidental versus drug related, I think in most cases on a trial when we're unsure, we lean toward drug related. And in some cases there are reported out severe cases of drug related ILD. I think the really difficult thing that I'd want people to take away from all of this, though, the bottom line is, yes, we need to be very aware of the potential for drug related ILD while at the same time, we need to not reflex, just call things drug related ILD and really make sure that we're doing a workup when feasible rather than just that bottom line conclusion. We see it at a rate related to the drug, and I do think it's real. But we also need to, when treating individuals, try to identify any other potential etiology. I did have one patient that really looked absolutely classic for this diffuse drug related ILD that ended up ultimately really being what looked more like tumor progression in just a radiographic pattern that looked more like an inflammatory process than it did the way we would typically see cancer progression. And so this has really, for me, I think, highlighted this as a topic where I'm diving a bit more into that description. Davide Soldato: And I also think that in the population of lung cancer patients, as you were saying, this is even more complicated because frequently these are patients who had a history of smoking, who can have concomitant infections where progression is easier in the lung. If I think, for example, other ADC that have already been tested, for example, in breast cancer, it might be far easier to detect and to adjudicate an ILD to the drug that we are using compared to what could be, for example, for lung cancer patients. So if I understood correctly, the toxicity that in your opinion as a clinician, they are more complicated to treat, let's say on a more daily basis, are more stomatitis and inflammation, but maybe the one that you experience as potentially more severe are always related to lung toxicity. Dr. Jacob Sands: Well, I think the scary thing about the ILD is that we have higher grades of ILD, and this is a toxicity that then can become life threatening. When we see a grade I or a grade II ILD reported in numbers, where we see, okay, this looks like it's really happening, and then see some really higher grade toxicities, I think the concern amongst clinicians then is if they're seeing lower grade, which of those can potentially progress to those higher grade, which then becomes life threatening toxicities. Whereas dry eyes certainly can become a nuisance, we didn't see any blindness or something like this, and the stomatitis resolves as you hold the drug, and in some cases, really before the next cycle even comes, it's just more a matter of controlling the discomfort, which can be severe. I'm not minimizing that. I think that's why ILD stands out so much, is that that becomes a potentially life threatening thing. And to your point exactly, these patients with a smoking history on other drugs, we see these inflammatory findings. Now, in some cases, we know it can be from the drug. In other cases, we see it and know that it's essentially incidental. And I'll say to patients, "Hey, we see this. It's something we'll monitor on future scans, and these can wax and wane." When you have a patient on a drug with a high attention towards something like ILD, there can be- what I'm cautioning against is a reflex attribution to that drug. In all cases. I'd urge clinicians to individually assess each of these patients to get a sense of whether they think that that's going on for that person, knowing that it's often not possible to say with 100% certainty in any of these cases. But we often see waxing and waning inflammatory findings. And in many of these patients with heavier smoking histories, in particular, there can be waxing and waning respiratory symptoms. So the question is, are there instances where there is what really is an incidental inflammatory findings and incidental respiratory waxing and waning that then suddenly we call a grade II? At the same time on the other part of that, if there is something that seems like it really may be drug related ILD, is doing that work up and really evaluating and diagnosing that before it progresses to a point that really there are severe symptoms. And it's kind of trying to do both of those things on the opposite ends of the spectrum that I'm speaking toward at the same time. Davide Soldato: Just on a personal note, do you think that, as we continue the development of these drugs that are associated potentially with lung toxicity, do you think that we also need to pay attention to the drugs that were immediately previously received by the patients? What I mean is, do you have the feeling that the previous treatment could potentially impact on the risk of developing this type of toxicity in the lung? Dr. Jacob Sands: I don't know that we yet have data to draw any real conclusions around that. But you raise an important question within this, and what potential toxicities could be related to prior treatments or synergy across those. Of course, we see inflammatory findings within the lungs and pneumonitis with prior immune-related therapies, and that it would be a good prompt to the question you're asking. And that in…

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Economic Evaluation of a Non-Medical Financial Assistance Program on Missed Treatment Appointments Among Adults With Cancer Oct 28, 2023

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Dr. Shannon Westin, Dr. Stephanie Wheeler, and Dr. Caitlin Biddell discuss the paper "Economic Evaluation of a Non-Medical Financial Assistance Program on Missed Treatment Appointments Among Adults With Cancer," a simultaneous publication, podcast, and presentation at the ASCO Quality Care Symposium. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in-depth on manuscripts published in the Journal of Clinical Oncology. I'm your host, Shannon Westin, Social Media Editor of the JCO and GYN Oncologist. And I am so excited that today we have a simultaneous publication in JCO and presentation at the 2023 ASCO Quality Care Symposium here on 10/28/2023. And this is going to be the manuscript "Economic Evaluation of a Nonmedical Financial Assistance Program on Missed Treatment Appointments Among Adults With Cancer." Very exciting work. And I'm thrilled to tell you I have two of the authors here with me today. First is Dr. Caitlin Biddell. She's a Health Services Researcher at Mathematica Policy Research. Welcome, Caitlin. Dr. Caitlin Biddell: Thank you. Happy to be here. Dr. Shannon Westin: And we also have Dr. Stephanie Wheeler. She is the Michael S. O'Malley Distinguished Professor in the Department of Health Policy and Management at the University of North Carolina, Chapel Hill, as well as being the Associate Director of Community Outreach and Engagement at UNC Lineberger Comprehensive Cancer Center. Welcome. Dr. Stephanie Wheeler: Thank you. Happy to be here as well. Dr. Shannon Westin: Please note that our authors and participants have no conflicts of interest. Let's get started. So first I would love to level set. Can you speak a little bit about what financial toxicity is and how common it is among patients with cancer? Dr. Stephanie Wheeler: Sure, Shannon. I'm happy to take that one. This is Stephanie. So we know that financial hardship is often reported by patients and survivors who've experienced cancer. And as many as 50% of people with cancer have trouble with financial toxicity. There has been prior work that has conceptualized financial toxicity in three domains. So there's the material hardship, kind of the out-of-pocket material costs associated with cancer, which include both medical and nonmedical expenses. There is the stress and the psychosocial effects of that material hardship. And then there's coping behaviors that patients and their caregivers may employ to help deal with the high cost of cancer care. And as we've seen, cancer care increases in cost over time, and these expenditures really have very burdensome effects on patients and their families. We've been interested in looking at ways that we can try to mitigate that harm and really thinking about interventions in addition to the health policy changes that are needed to really ensure that this doesn't become a barrier to patients seeking and receiving the best quality care that they can. Dr. Shannon Westin: I think that kind of leads pretty nicely into my next question, which is really: How does this toxicity potentially impact equitable cancer care delivery? Dr. Stephanie Wheeler: Yeah, I'm happy to talk about that a little bit as well. So we know from prior research, including some of our own, that patients of color, those from rural areas, and those who are uninsured or underinsured face the largest financial burdens associated with their cancer care. So to the extent that those financial hardships influence people's ability to seek and continue with and complete their cancer care that's been recommended, this actually is directly in the pathway and a mechanism through which patients are not able to get recommended treatment and therefore can contribute to differences in cancer outcomes. So there's direct health impacts in terms of their ability to receive and respond to cancer treatment. In addition to that, we know that this financial hardship contributes to household-level harms both economic and psychosocial in nature. And in some other work, this financial hardship has translated to worse quality of life, worse economic outcomes, things like being able to stay employed and seeking changes in employment or remaining within a particular position because you don't want to lose your insurance—this is referred to as "job lock"—or can also contribute to higher mortality. So there's been some really important work showing that financial toxicity is directly linked with cancer mortality. And so, as we think about ways that we need to address this, it's really key to ensuring cancer health equity that we are thoughtful about multiple solutions implemented at multiple levels that can deal with not only the contributors to high cancer costs but that can also start to affect both the nonmedical and the medical components of this cost burden. And by nonmedical, I mean things like the cost associated with transportation and seeking care, accommodations for people who need to receive radiation therapy multiple days in a row at a different healthcare facility than where they live, childcare costs. These things really start to add up in addition to the medical costs associated with cancer treatment. Dr. Shannon Westin: I really was intrigued by the intervention here that you all are studying around this Cancer Patient Assistance Fund. Can you tell me a little bit more about exactly what that was or is? Dr. Caitlin Biddell: Yeah, absolutely. So this is a program at the North Carolina Basnight Cancer Hospital, located within the Lineberger Comprehensive Cancer Center, and it started back in 2013, actually, and has really grown in size. But the main goal of this program is to ensure that patients do not face the nonmedical financial barriers to care that Dr. Wheeler was just talking about. So thinking about giving patients gas cards so that they are able to drive to and from treatment. Lineberger has a catchment area of the entire state, so many people are coming a long distance to come for cancer treatment. They also provide things like lodging and accommodations, as Stephanie mentioned, and then even paying patients' utility bills, things to keep them housed with electricity, the lights on, while they're undergoing cancer treatment. So just last year, in 2022, they distributed almost $350,000 to over 700 patients, and most of this is funded by philanthropic grants to ensure that patients can access the care they need. And it is a program that's really targeted to patients with low incomes. So they target patients with household incomes less than 250% of the federal poverty level. Dr. Shannon Westin: And how does a patient get connected to the fund? How do they find it and get hooked up? Dr. Caitlin Biddell: Yeah, there's a couple different ways. So one path is through the outpatient social work team. So they often perform distress screening for new cancer patients. So they use the Distress Thermometer, which was developed by the National Comprehensive Cancer Network. And it measures a variety of different factors that may be contributing to distress, but that does include financial stress, job stress, and the expense of daily living stress. And so, when a patient scores a certain amount on that thermometer, a social worker will meet with them for a full assessment. And then part of the referral pathway from that assessment includes the Cancer Patient Assistance Fund. Patients who are in inpatient will often be screened with the Social Determinants of Health Module, which is housed in the electronic health record. And so that can also generate referrals for assistance. And then beyond the kind of standard pathways, there's also many other ways that a patient may express concerns to a nurse, a care coordinator, an oncologist, and then that provider can reach out directly to the Cancer Patient Assistance Fund. Dr. Shannon Westin: Your objective was to basically try to formally assess the impact of this fund on missed radiation or chemotherapy appointments. And so what was kind of your rationale for choosing this endpoint? And kind of take us through the design. Dr. Caitlin Biddell: Yeah, absolutely. So the idea for this study actually came about from the program coordinator of the Cancer Patient Assistance Fund several years back. We were just having a conversation about the program. I was commenting how important I thought it was, how interesting it was. And she was saying, "You know, I know anecdotally that this program makes a difference, but we've never really known how to quantify that." And that's becoming increasingly important as they apply for philanthropic grants and really need to show that their program is having an impact. So that's what originally started our plan for evaluating the program. And then, in thinking about endpoints, of course we imagined this program could have an impact on a range of different endpoints. So missed appointments is quite practicable. We also imagine it could influence patient health-related quality of life, patient symptoms associated with their cancer treatment, even potentially other long-term outcomes like mortality. But for the purposes of this evaluation, we needed to identify an endpoint that we believed could be measured, the association could be measured, in the data we had. And so we had electronic health record data. Missed appointments is something that is routinely captured in the electronic health record data because it's an endpoint that matters financially to health systems. So they are regularly tracking missed or no-show appointments. And it's also an outcome that matters financially to the health system, so they want to reduce this. So we thought if we measure the impact of this program on missed appointments, there's potentially an opportunity to kind of align financial incentives so that if we show that the program has an impact on missed appointments, then that could be something that could get decision makers at the health system level to say, well, that's also an endpoint that we want to reduce, and so let's think about ways that we can align resources to reduce missed appointments through potentially the Cancer Patient Assistance Fund and other mechanisms. Dr. Shannon Westin: It's interesting because it definitely caught my eye because we give radiation, obviously, for gynecologic malignancies, and there's some pretty decent data that longer treatment duration for radiation has worse outcomes, with the implication that patients have missed appointments and so then, to finish their work, it takes longer, or to finish their treatment plan, it takes longer. So I definitely would be really intrigued to see the cancer-related outcomes. But I completely agree, like something practical, straightforward, and something easily obtained was the right way to start. I was just curious. So that's really interesting. So why don't you just walk us through the design of how you laid this out? Dr. Caitlin Biddell: Yeah, absolutely. So we conducted a retrospective evaluation between 2015 and 2019, and we chose that time point to end before the COVID-19 pandemic since we know that had many impacts on missed appointments. And we compared the proportion of missed appointments in the six months following treatment initiation between patients who were receiving Cancer Patient Assistance Fund assistance and then propensity-weighted comparators. And this is really just a method to make the pool of potential comparison patients look as similar to those receiving Cancer Patient Assistance Fund assistance as possible so that we can really tease apart that direct effect of the Cancer Patient Assistance Fund and separate it out from other characteristics that may be influencing missed appointments. So we had stratified our analysis by treatment type. We looked at radiation therapy, and then we also looked at oncology infusion, so specifically immunotherapy and chemotherapy. And to evaluate these endpoints, we used a couple of different data sources that we linked together. So the first and the primary data source was the electronic health record. So at UNC, we have EHR data for research purposes stored in a data warehouse that we were able to pull from. And then we also linked in UNC Health's portion of the North Carolina Cancer Registry to get that really important information on cancer stage, cancer type, and treatment start date. And then, of course, we pulled in program records from the Cancer Patient Assistance Fund to identify which patients were receiving assistance, how much, and at what time points. And so, essentially, using that data and thinking about missed appointment outcomes in those six months following treatment initiation, we created a couple different models. So we looked at the high versus low no-show proportion using a logistic regression. And then we also looked at just the continuous no-show proportion in the sample to see if there was an effect on that as well. Dr. Shannon Westin: And what did you find? What was the impact of the fund's support on your outcomes? Dr. Caitlin Biddell: For radiation therapy, which I'll start with, the radiation therapy had a higher number of encounters, as we might expect, than immunotherapy/chemotherapy. There were a mean of 37 total radiation therapy encounters in the six-month follow-up period, and about 53% of the sample had one or more no shows. And so, then, when we looked at the impact the Cancer Patient Assistance Fund on radiation therapy missed appointments, we found that receipt of any assistance was associated with an eight-percentage-point decrease in the probability of having a no-show proportion in the highest quintile. And then, when looking at continuous no-show proportion, we found it was associated with a 2.1-percentage-point decrease in the overall proportion of no shows, which corresponds to a 51% decrease in the overall mean no-show proportion. So a really substantial effect on radiation therapy missed appointments. And unsurprisingly, when we stratified the analysis by the amount of assistance received, we did see a greater impact of the program among patients receiving higher amounts of assistance. Moving on to the oncology infusion cohort, this sample had a lower number of encounters in the follow-up period and less no shows, so only about 14% had one or more no shows. And so it potentially wasn't as surprising that we did not see an impact of the Cancer Patient Assistance Fund on infusion oncology missed appointments, though, of course, with the additional power and alternative analyses, it's not to say that there wasn't an effect, but in our population, we were not able to detect that. Dr. Shannon Westin: Yeah, and that makes a lot of sense. I mean, radiation is so much more time intensive and having to come back and forth. And when you were describing the fund and saying, like, housing assistance, I was like, "Oh, well, there you go." Because that, I feel like, is one of the major issues. At MD Anderson, we also kind of take care of a very large catchment area, and it can be a huge burden for patients to have to come for that 15-minute appointment every day. So, yeah, when I saw your results, I thought that was likely what you were hypothesizing was the reason. And certainly, the impact on radiation is so impressive. It's just a hugely successful study and a hugely successful fund. So congratulations. So, I guess, any other variables? You spoke a little bit about the amount of financial assistance received. Was there anything else that impacted the number of missed appointments in your study? Dr. Caitlin Biddell: Yeah,…

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Disparities in End-of-Life Cancer Care Oct 12, 2023

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Shannon Westin speaks with Holly Prigerson and Alfred Neugut about their thought-provoking editorial, "You Get (Offered) What You (Can) Pay For: Explaining Disparities in End-of-Life Cancer Care." TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Shannon Westin: Hello, everyone, and welcome to another episode of the JCO After Hours podcast. And this is where we get in-depth on manuscripts and editorials that have been published in the Journal of Clinical Oncology. As always, I am your host, Shannon Westin, Gynecologic Oncologist and Social Media Editor for the Journal of Clinical Oncology, and I'm so excited to be here today. We are going to be talking about a very compelling editorial that is called "You Get (offered) What You (can) Pay for: Explaining Disparities in End-of-Life Cancer Care." And this was published on June 20th, 2023, in the Journal of Clinical Oncology as an editorial on an article entitled the "End-of-Life Systemic Oncologic Treatment in the Immunotherapy Era: The Role of Race, Insurance, and Practice Setting." So a very timely topic and very exciting for us to discuss today. I'm joined by two of the authors of the editorial, Dr. Holly Prigerson, Professor of Sociology and Medicine, the Irving Sherwood Wright Professor in Geriatrics Medicine at the Weill Cornell Medical College and the Director of Cornell Center for Research on End-of-Life Care. Welcome, Dr. Prigerson. Dr. Holly Prigerson: Great to be here. Dr. Shannon Westin: And also accompanied by Dr. Alfred Neugut, the Myron M. Studner Professor of Cancer Research and Professor of Medicine and Epidemiology at Columbia University and the former Associate Director for Population Science and Racial Disparities Program for the Herbert Irving Comprehensive Cancer Center at Columbia. Welcome, Dr. Neugut. Dr. Alfred Neugut: Thank you very much. Dr. Shannon Westin: Very excited to talk about this topic today, and I like to always start with a little bit of level setting. So I'd love for one of you to discuss: How common is the use of systemic anticancer treatment at the end of life? Dr. Holly Prigerson: So, based on the article, it looks like the rates within the last 30 days of death, it was 34% on average overall. So that was sort of the—you say level setting—the base statistic. Within 14 days of death, it dropped to 13% overall. So all the associations that are described are really disparities from that level. Dr. Neugut: Speaking as an oncologist, I don't think any of my clinical colleagues will be surprised that it's that high. There is an effort made really to, in desperation, try to help. Patients want it. Families want it. So there really is efforts made to try to do that to prolong life or palliate or whatever. Dr. Holly Prigerson: The design also, which is probably going to be a question that's coming up, does raise a question for me that I'm wondering if Al could enlighten at least me on. They did select patients who were getting treatment for metastatic or advanced cancer starting in 2011 and then who died four years later. Does the selection for the fact that they were getting treatment initially—because everyone, that's how they sampled the study—does that increase the likelihood that they'll get treatment later on so that the rates are somewhat inflated is my question. Dr. Alfred Neugut: Yeah, no, for sure. People who start chemo tend to continue partially because there is a certain amount of those who do well do well. If you respond to chemo initially, you tend to respond to the second-line therapy, you tend to respond to third-line therapy. If you didn't do well on first-line chemo, you're not likely to respond to a second line or a third line, so you don't have the enthusiasm to continue with it, and the patient certainly tends to lose interest in it. So you're right; there is a certain, call it, momentum or inertia in going forward with chemo once you've started. Dr. Shannon Westin: I mean, I think this just always highlights some of the issues we have, right, with any kind of retrospective data is how well can we design a population without—because we can't always do randomized control trials, and certainly not in this kind of setting. That would not be acceptable, I think, to providers nor patients. And I do agree that it can be tricky. Any other kind of, maybe just to help the listeners if they haven't gotten a chance to read this Canavan study, about the design, exactly what they were looking at in this population? Dr. Holly Prigerson: Basically, they took these patients who were getting systemic therapy and had advanced metastatic cancer prior, and then who died. So there's always a question about the sampling on death issue, that they had to have died to be in the sample. So those are methodological issues, but there's really very little way around that. If you want to know what treatments people received in the last month of life, they have to die for there to be a last month of life. So then the treatments were divided into chemotherapy alone, chemotherapy with immunotherapy, and then immunotherapy with and without targeted therapy. So there were three types of treatment, which is sort of an important update because Al and I had published something in 2015 on chemotherapy and the outcome of what was called palliative chemotherapy at that time. And this was sort of a very refreshing–well, not—I shouldn't say refreshing, but important update to our study, which had said that there are questionable outcomes of palliating someone with palliative chemotherapy so far along in the disease. And then the question became, well, is it different? Is it different with immunotherapies? Is it different with targeted therapies? And that's why I was delighted to see this paper, because it answered… Dr. Alfred Neugut: I'd have to say there are probably differing views on this, but Holly and I are probably relatively nihilistic in terms of thinking that chemotherapy in late stages or near terminal patients is probably not all that helpful. Third-line, fourth-line therapy probably not going to get you very far. And maybe it's best to be thinking more about hospice care and supportive care. And now we have terrific palliative care programs at most or all cancer centers, and we really should be taking advantage of this. I think a real benchmark study was the Temel study from 2010 or 2011, which really—for those of your listeners who haven't read it or seen it, they should really take a look at it. It really changes the playing field and makes you realize that treatment is not really always the best thing for patients, and there are other options. And we go to hospice care or palliative care really, I think, too late in the game a lot of the time, and we really should be thinking otherwise. Dr. Holly Prigerson: That is one of the outcomes that we had looked at before. So we had looked at palliative chemo, and not only does it not palliate, and we didn't show that it significantly enhanced survival; we also showed that it resulted in a lower likelihood of earlier enrollment in hospice, a higher likelihood of not dying where your family members thought you would have wanted to die, a higher likelihood of dying in the ICU or getting some kind of aggressive care. So it's not only what the chemo does or doesn't do in terms of treatment or survival or quality of life; it also seems to exacerbate and put someone at risk for very burdensome interventions that having avoided it might have enabled patients to avoid getting very burdensome care that's largely futile. But as Al said, we are probably more the nihilistic type. Dr. Shannon Westin: Well, I think you bring up a couple of good points because you've got objective data, and these studies that you're mentioning are just some of them that show that early hospice care and early enrollment and even just a palliative care program or a supportive care program or whatever terminology we want to use, people do better, right? They live longer actually from that piece rather than necessarily the more "aggressive measures" of chemotherapy and things. Dr. Holly Prigerson: When there was an extra analysis of the Temel data, I believe they had shown that some of the survival advantage was explained by avoiding toxic chemo. So that's directly relevant. Dr. Alfred Neugut: There is an on the other hand, as always, which is that patients and families often don't want to do that. I mean, they realize that doing that is giving up, so they're reluctant to take hospice care or palliative care as an alternative to another cycle of chemo or another type of chemo. And as you say, you never know; maybe the next one is going to be the winner and there'll be a miracle or there'll be at least some substantial benefit. And then there's always experimental therapy, and now immunotherapy, which is the topic of this article, is the new winner on the block. And it has bright lights around it, and everybody has great hope for it. And it's the new kid on the block, and everyone hopes that that's going to be the big savior. Dr. Shannon Westin: Right, and I think everyone knows of a story of somebody that was "on death's door" and got immunotherapy or the newest targeted therapy or the newest ADC, so that definitely colors it. And that also colors, I think, the physicians that are offering it, right? Because, yes, I've definitely heard this, and I'm sure you guys have too: nobody should die with such and such cancer without receiving immunotherapy once or without receiving such and such targeted therapy. I hear people say this all the time, and I don't necessarily disagree. It's more that when are we giving it, right? So we should be thoughtful about when we're placing those things. But you're right; there's so many factors that go into these decisions, and it's not cut and dry around what the patients and the family members and the physicians are going to decide. Dr. Holly Prigerson: And I think that Al hits on a really key issue when he used the word "hope" because that seems like what the negotiation appears to be all about. You don't want to disparage someone or not offer them hope if there might… No one wants to say that there isn't hope. No one wants to be the bearer of that kind of bad news. And I guess it leads to—I think that that's part of the driver that ends up providing the gas that drives people to getting more aggressive therapies is because no one wants to be the person to be the wet blanket and disparage hope. And so it might affect how treatments are sold to patients or at least communicated to patients. There was this one finding in this report that was curious, and it was that patients with undocumented performance status were the ECOG group most likely to get treatment. And so, in terms of what could be done going forward to make people more realistic and not offer hope where it's really, really unlikely, maybe employing more decision rules about requiring the documentation of performance status and ensuring that it's what the ASCO guidelines permit for administering another line of treatment. Because that might be a way to sort of use data to help correct what in psychology we call cognitive distortion, so correct the distortion of this hyper-optimism. It might help correct some of that. We don't want to overcorrect and make people hopeless or depressed, but we want to offer realistic options. I think that's part of why this paper is so important, and it sort of informs future research to try to unpack some of the findings that they didn't have data on physician characteristics or communication discussions between patients and their oncologists. And maybe that's where the money is. Maybe that's where offering hope in a realistic way or different forms of hope, what to hope for, might be better communicated through more effective communication strategies and ways to enhance patients' abilities to understand what they're agreeing to or not agreeing to. Dr. Alfred Neugut: And I would add that it's easy for us to sit here and be dispassionate or scientific interlocutors and saying, you know, "It doesn't work, and therefore we're not going to offer it or you shouldn't get it or go on to hospice." But it's different when you're on the other side of the table. And even us doctors or healthcare professionals or scientists, when you're sitting on the other side of the table and you're the one who's got the cancer or your mother or child, you're not going to be so easily dismissive of getting third-line chemotherapy and having your 5% chance that the tumor will respond to some cocktail of who knows what and you never know. I don't want to say anybody's wrong or that it's stupid. Everybody has to do what they have to do, and we at least have to think about it and know what we're doing and have realistic—at least some idea of the realism of what we're putting people through and the costs and the toxicities and what to expect. Dr. Shannon Westin: I think you guys brought up some really great points, and I do think that there is a huge impact around the communication piece. And we actually just did a podcast on discussion of goals of care at the end of life for adolescents and young adults and how those conversations can be different. I think the other thing that really caught my eye and, of course, caught your eye when you did the editorial around the Canavan study was this idea that the patients with insurance—with all other things being equal, that the patients with insurance were more likely to receive end-of-life systemic treatment. And it's interesting because typically I feel like we think having insurance and having that support is always a positive thing and has a positive impact on our health, and it most certainly does. So that's not up for grabs. But then this particular study showed that it could potentially have been negative because of all the things that you all just said about the negative impact of care in this 30 days or even 14 days near the end of life. What are the opportunities for intervention at the insurance level? You talked a little bit about provider level and communication. Are there opportunities at the insurance level that we could address? Dr. Holly Prigerson: It does seem like having insurance companies determine what is reasonable and not reasonable to reimburse for. So including things, I would think, like having performance status factored in. What are the criteria for determining whether it's high value care or not? And I'm not an oncologist, so I really am going out on a limb, and I really want Al to respond to that question. But from my perspective, it seems like the ASCO guidelines determine when it's—"low-value care" is how they put. It's wasteful and futile and burdensome. And they have guidelines of performance status, having not responded to multiple lines of chemotherapy, so that there could be guidelines for when there is value and when there isn't and that it could be more values driven in terms of guidelines of what they would reimburse. Because, as our title implicated, it seems like you get offered what insurance companies are willing to pay for, and that leads to potential disparities in equity if you have different insurance than other people and fairness and justice. Those seem like valid questions to raise. Dr. Alfred Neugut: I mean, I think if we're following randomized trials and evidence-based medicine, then I think we're in a reasonable…

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Advance Care Planning in Adolescents and Young Adults with Cancer Sep 28, 2023

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A variety of perspectives are explored as Dr. Westin speaks with Dr. Jennifer Mack, Dr. Chun Chao, and Mallory Casperson about end-of-life care planning in adolescent and young adult cancer. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get down and dirty with manuscripts that are being published in the Journal Clinical Oncology. And I am your host, Shannon Westin, GYN Oncologist and Social Media Editor of the Journal of Clinical Oncology. I am so very excited to have a number of guests with us today to discuss a very important paper entitled "Discussions About Goals of Care and Advanced Care Planning Among Adolescents and Young Adults with Cancer Approaching the End of Life." And I'm joined by several of the authors of this important paper. The first is Dr. Jennifer Mack. She is the Associate Chief in the Division of Population Sciences, an Associate Professor at Harvard Medical School and Senior Physician in Pediatric Hematology Oncology at the Dana-Farber Cancer Institute. Welcome, Dr. Mack. Dr. Jennifer Mack: Thank you. Dr. Shannon Westin: We also have Mallory Casperson. She is the cofounder and CEO of the Cactus Cancer Society. They provide online support programs and resources to young adult cancer survivors and caregivers in the comfort of their own homes. Welcome. Mallory Casperson: Thanks for having me. Dr. Shannon Westin: And then, finally, last but not least, Dr. Chun Chao. She is a Senior Research Scientist in the Division of Epidemiologic Research in the Department of Research and Evaluation at Kaiser Permanente Southern California. Welcome. Dr. Chun Chao: Thank you. It's a pleasure being here. Dr. Shannon Westin: So I want to get right into this. I think that there certainly has been a lot of discussion, at least at our institution as well as at the ASCO level, around advanced care planning across all patients with cancer and anyone with a diagnosis of cancer. And I would love to just start and level set and make sure all of our listeners are all on the same baseline around the incidence and prevalence of cancer in adolescents and young adults. Like, first, define what are the age groups that we're looking at here? How common is cancer in this population? Dr. Jennifer Mack: Right. For this study, we defined adolescents and young adults as individuals aged 12 to 39. And right now, about 90,000 adolescents and young adults are diagnosed with cancer in the United States each year. Those numbers are also rising, so more and more are diagnosed each year, and because of that, we think it's increasingly important to pay attention to the needs of this population. This population really experiences a whole range of different cancer types, some of which are more common in children, some of which are more common in adults, but the most common ones include breast and gastrointestinal cancers, sarcomas, germ cell tumors, leukemias, lymphomas, and brain tumors. Dr. Shannon Westin: And your manuscript notes that adolescents and young adults seem to receive medically intensive measures at the end of life. Now, how common is this across this group? And do you all have a sense of some of the reasons that we see this increased use of these measures? Dr. Jennifer Mack: That's a great question. We and others—actually, the early work that led to this study was done with Chun. We had previously found that most adolescents and young adults receive at least some kind of medically intensive care at the end of life. And that includes things like being hospitalized, being in the intensive care unit, receiving chemotherapy, and spending time in the emergency room near the end of life. And so, if you take all of those together, about two-thirds of adolescents and young adults receive at least one of these near the end of life. And we don't know the reasons for this. There are probably complex reasons. Some adolescents and young adults may actually want to receive these kinds of measures, maybe because they're young and they want to do everything they can to live as long as they can. And some patients in this age group are parents to young children, and they may be making choices to prolong life and be there for their kids. But we also know that if we look at older adults, most people who know they're dying don't want to receive this type of care, which is also associated with more suffering and with poorer quality of life. So it's also possible they're making these choices because they don't fully recognize they're approaching the end of life or because they haven't had opportunity to plan for this time through conversations with their medical teams. Mallory Casperson: I think the conjecture, too, that a young adult is likely to focus on extending life, even in a situation where palliation is the stated goal, is a really great conjecture. This population is really burdened by these unique psychosocial issues that are driven by the extreme disruptions that cancer has on major life milestones. Like Jenny said, they may have young children at home, they may have a new spouse at home, still be trying to advance at work, you name it. So this period of young adulthood is really characterized by constant change. And it's possible that these young adults are being driven to stay present in their lives for really as long as possible to reach some of these goals or even just to support their young families as they reach their own goals. Dr. Shannon Westin: I really appreciate that context, and I'm going to always bring it back to what I know as a provider of gynecologic cancer care, where we see quite a bit of young people at the beginning of their life, at the beginning of their fertility. And I think it is so important to keep that context in mind as we're designing interventions and studies and things like that. So I really appreciate that, having the ability to kind of see from that standpoint. So I think you guys have convinced me this is important. We know the reasons. So why don't we just lay out the objectives of this particular study and give our listeners a brief review of how it was designed? Dr. Jennifer Mack: Great. We wanted to know how often adolescent and young adult patients with incurable cancer have discussions about prognosis and end-of-life care planning before they die. And a secondary goal was to understand whether having earlier discussions would change the type of care that's delivered. So, for example, having those discussions about goals of care earlier in their illness, could that make them less likely to receive intensive measures? So, to do the study, we conducted a retrospective review of health records for nearly 2,000 adolescents and young adults who died between 2005 and 2019 after receiving care in one of three centers—the Dana-Farber Cancer Institute, Kaiser Permanente Southern California, Kaiser Permanente Northern California—and looked for documentation of discussions about care planning. For this study, we focused on patients who either had stage IV disease at diagnosis or who had experienced a recurrence because we wanted to ensure that we had a population of young people who were living with advanced disease and not people who might have died suddenly and unexpectedly during treatment, because they might not have had the same opportunity for end-of-life care planning. So we really wanted to focus on those who had the poorest prognoses. Dr. Shannon Westin: It's a really large group of people and, I think, hopefully fairly representative. I guess my question is, when you're looking at the group that you were able to kind of pull from in this retrospective database, which I think can sometimes be limited, do you feel like it was fairly representative of the population that's out kind of across the States, let's say? Dr. Chun Chao: So I think it's a real strength that we included two different care settings in this study, so a tertiary cancer center and community-based cancer care. Therefore, patients who seek care in each of these settings are representative in our study. I think this design really increased the generalizability of our findings. And on a further note, in this study, we actually observed very similar care patterns across all three study settings. So that was quite reassuring. Dr. Shannon Westin: So reassuring. And I think it brings up a point that I wanted to make, and I also agree was a strength of your study, is having that across the academic center and then a large integrated health plan. And I guess I'm just curious how your collaboration came to be to kind of come across different groups and, of course, the inclusion of Mallory from the patient advocate side. I think this is a testament to your powers of collaboration. I'd just be interested in how that kind of came to be. Dr. Chun Chao: So this goes back to almost 10 years ago. I think, at that time, people started to really recognize that adolescent and young adults with cancer were a very understudied group, but they are also very challenging to study. So, for example, AYA cancers, adolescent and young adult cancers, are fortunately not very common. Although the number is increasing, you do need a large population base to study them. So, at that time, researchers at Integrated Health Systems started to really see that we had an opportunity here to really contribute to this knowledge gap, leveraging the resources that we had at these health systems, especially the ones that have a very large membership and a long-term retention of these members and also a comprehensive electronic medical record system. At that time, my colleague and I published a study that demonstrated the feasibility of using these resources to do follow-up studies of long-term health outcomes of AYAs with cancer. And I think that we might have attracted people's attention to utilizing the resources at these health systems to do such studies. So Jenny was the one who really saw the need or the lack of data or the need of high-quality data to really improve care for our AYAs who are at that end-of-life stage. So she reached out to a research network called the Cancer Research Network, who I think that the people there connected Jenny with me because I was also starting to work on long-term health outcomes of AYA cancer survivors, adolescent and young adults. After we talked, we were like, "We have to get this funded. We have to get these questions answered. These questions are so important." So, as Jenny mentioned, we did a pilot study that really showed there is a lot of burden of medical intensive care at the end of life for our young patients. And, as often is true with research, this opens up a lot more additional questions that we needed answers for. So we have been working together since then. Mallory Casperson: I came into this group sort of by accident. My background is in engineering. I was about halfway through a PhD when I needed to leave a couple years outside of my first cancer diagnosis. And I was at ASCO staffing a booth for my organization and just happened to meet a researcher from Kaiser Permanente Northern California, and the rest is history. That introduction sort of got me into this world, and, once you know one person, you get to meet others. And it's just been a really, really wonderful opportunity to help, I think, insert the patient voice. But also, for me, I just love research and data. And so getting to help advance the conversations happening around adolescent and young adult care in this research setting and in these settings where we are getting to look at very large datasets has just been really, really wonderful. Dr. Shannon Westin: These are my favorite parts of these podcasts, these stories of how things kind of came to be. And, at the risk of taking too much time there, I love the story, and I'm so in awe of you guys. I guess, let's get to the bottom line. What did you guys find? Did you find what you expected in regards to advanced care planning and goals of care in this population? Dr. Jennifer Mack: So we felt that most patients had documented discussions about prognosis, about goals of care, about palliative care, hospice, and their preferred location of death before they died. Dr. Shannon Westin: So I was actually kind of impressed at that. It seemed like a lot. I was expecting—I don't know what I was expecting, but I think I was expecting less documented discussions because, in my own practice, I don't necessarily think I do a great job of this. So was that in line? Were you expecting to see such kind of high levels of documentation? Dr. Jennifer Mack: I really agree with you. I was impressed with the fact that most patients had these discussions. Many of them had more than one discussion about their goals of care. So their providers were going back and having follow-up discussions, making sure that their goals of care were the same and weren't changing over time. So I agree. I was pleasantly surprised with how often these were happening. I would say I'd love to see these discussions either happening with everyone or at least offered to all patients so that they can say whether they want to have them or not. So, in this study, 17% of patients never had a discussion about goals of care. And non-white and Hispanic patients had lower rates of discussions than white patients. So there are some potentially important gaps here that need attention. But I also think you're right; there's a lot of good news here. Clinicians are making consistent efforts to talk with patients about their wishes for care, and then they're documenting them, which is an important thing because it allows those wishes to be known by everybody on the care team and helps to ensure that they're going to be carried out. Dr. Shannon Westin: I was also intrigued by the finding of the younger patients having earlier discussions around advanced care planning and hospice and goals of care. Any thoughts as to why that might be? Again, I felt like it was a little bit opposite of what I was expecting, not having a ton of background in the area. Dr. Jennifer Mack: I was surprised, too. We had to check the numbers a couple of times just to be sure because it wasn't what I was expecting. And we don't know for sure what the reason for this is, but I think one possibility is that some of these discussions with the youngest patients, or for the youngest patients, are happening with family members, maybe their parents. And it's possible that clinicians are a little more comfortable or more likely to talk with parents than with the young patients themselves. And so that could actually increase rates of discussions for that group. One thing we didn't assess was who was there for the discussions. It's not always documented. There's more to learn there about who was there and more about what was discussed. But that was our guess is that these may be family discussions more so than patient discussions. Dr. Shannon Westin: That really makes a lot of sense. And then I guess the next natural question is when we have these earlier goals-of-care discussions or when we have these discussions at all, what did you guys see on the impact of those kind of medical interventions that happened after? Dr. Jennifer Mack: Yeah. We found that when goals-of-care discussions happened earlier, more than a month before death, that adolescents and young adults were less likely to receive some of these intensive measures that we've talked about, so less likely to receive late-life chemotherapy, care in the intensive care unit and emergency room, and less likely to be hospitalized in the last month o…

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JCO Article Insights: Improving Lung Cancer Screening Using Blood-Based Biomarkers Sep 25, 2023

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In this JCO Article Insights episode, Davide Soldato summarized finding from the original article published in the September JCO issue: "Mortality Benefit of a Blood-Based Biomarker Panel for Lung Cancer on the Basis of the Prostate, Lung, Colorectal, and Ovarian Cohort". The summary provides information regarding the ability of a blood-based panel of 4 biomarkers in improving the identification of individuals at risk of developing lethal lung cancer and potential of combined screening strategies to improve trade-off between potential harms and benefit of the screening process.

TRANSCRIPT

The guest on this podcast episode has no disclosures to declare.

Davide Soldato: Welcome to the JCO Article Insights episode for the September issue of the Journal of Clinical Oncology. This is Davide Soldato, your host, and today I will be providing a summary on one article focused on the refinement of screening strategies for lung cancer. The article, titled "Mortality Benefit of a Blood-Based Biomarker Panel for Lung Cancer on the Basis of the Prostate, Lung, Colorectal, and Ovarian Cohort" by Dr. Irajizad and colleagues, investigated the ability of a panel of circulating blood biomarkers in improving the identification of individuals at risk of developing lethal lung cancer. We already know that lung cancer screening based on the use of low dose CT is associated with a reduction in mortality, as already demonstrated by the National Lung Cancer Screening Trial and the NELSON Trial. Furthermore, the US Preventive Task Force has recently recommended an expansion of screening criteria for lung cancer.

Currently, based on this recommendation, screening strategies are recommended for individuals 50 years of age and older with a smoking history of at least 20 pack-years and who are current smokers at the moment of the screening time or have quit within the past 15 years. Despite this positive data and this recommendation, the uptake of lung cancer screening in the US is still low, with reported uptake rates below 15%. The risk of false positive results, the unnecessary follow-up procedures, uneven access to lung cancer screening programs, and fear of cancer diagnosis and treatment have all been identified as potential barriers to optimal implementation and uptake of lung cancer screening. And so, in order to overcome some of these barriers, several efforts have been made in the last years to develop lung cancer screening prediction models with the aim of selecting a higher risk population who would derive higher benefit from lung cancer screening.

In the present manuscript, the author builds on their previous work where they developed and tested a clinical prediction model and a blood-based prediction model in the context of the PLCO cohort. The Prostate, Lung, Colon and Ovarian Cancer Screening Trial was a randomized, multicenter trial in the US which aimed to evaluate the impact of early detection procedures on disease-specific mortality for the aforementioned cancers. Two lung cancer screening prediction model had already been developed and tested in the cohort. The PLCOm2012 model is based on several clinical and demographic characteristics, including age, race and ethnicity group, education, BMI, chronic obstructive pulmonary disease, personal history of cancer, family history of lung cancer, smoking status and intensity, duration and quit time. In a previous study, this model demonstrated a higher sensitivity and positive predictive value with no loss in specificity for lung cancer diagnosis compared to the National Lung Screening Trial criteria.

Additionally, in the same cohort, the 4MP was a blood-based panel that included the precursor form of surfactant protein B, cancer antigen 125, carcinoembryonic antigen, and cytokeratin-19 fragment. In a previous study, a combination of this blood-based panel and the PLCOm2012 model was associated with a better identification of patients at high risk of developing lung cancer that would consequently benefit from lung cancer screening. In the manuscript that was published in the current issue of the JCO, the authors aim to expand on these previous results and test the ability of the combined 4MP and PLCO model to identify individuals at high risk of developing lung cancer death. The study used prediagnostic sera of 552 individuals that were diagnosed with lung cancer within one year from the blood draw and 2000 non-cases.

In the study, the authors assessed the performance of this combined four 4MP and PLCO model at a risk threshold of 1% and 1.7% of developing lung cancer at six years. Among the more than 500 individuals who were diagnosed with lung cancer, 70% died from it and 18% died of other causes, and the median survival times for lung cancer cases was 2.7 years. The combined 4MP and PLCO model had an area under the curve (AUC) of 0.88 for the prediction of lung cancer-specific mortality. The performance of this combined model using both clinical demographic and also a blood-based panel was higher than the ones of the two models considered alone. Furthermore, the model had similar predictive performance for both non small cell lung cancer and small cell lung cancer-related deaths.

Subsequently, the authors compared the performance of the combined 4MP and PLCO model with the 2013 and 2021 US Preventive Task Force criteria and observed that the combined model had improved sensitivity, specificity, and positive predictive value for the prediction of lung cancer-specific mortality compared to both types of criteria. Finally, the authors assessed whether the combined 4MP and PLCO model were able to determine the survival probability among individuals who had a smoking history of at least 10 pack-years. Cases and non-cases were classified as either test positive or negative according to model scores at the 1.7 and 1% risk threshold at six years. For both thresholds, the combined 4MP and PLCO model identified a significantly higher number of lung cancer deaths in test positive individuals compared with test negative ones.

So, in conclusion, these studies identify patients who are at higher risk of developing lung cancer-specific mortality using a combination of blood-based biomarkers and clinical demographic characteristics. The combined models showed higher sensitivity and specificity and positive predictive value compared to the standard US Preventive Task Force criteria. The results of this study are important because the identification of individuals at higher risk of lung cancer diagnosis and death offers the opportunity for a more favorable tradeoff between potential harms and benefits of the screening process. And so these results could assist in the design of future screening and intervention studies as well as facilitate the uptake of lung cancer screening, especially for those test-positive patients that have a higher risk of lung cancer death. Application of this model could potentially lead to a higher number of patients diagnosed in earlier stages and thus eligible for curative intent treatment.

That concludes this episode of JCO Article Insights regarding a summary of the article "Mortality Benefit of a Blood-Based Biomarker Panel for Lung Cancer on the Basis of the Prostate, Lung, Colorectal, and Ovarian Cohort" by Dr. Irajizad and colleagues.

This is Davide Soldato. Thank you for your attention and stay tuned for the next episode of JCO Article Insights.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Impact of Smoking Cessation on Mortality From Kidney Cancer Sep 14, 2023

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Dr. Mahdi Sheikh and Dr. David Zaridze join Dr. Shannon Westin to discuss how quitting smoking after diagnosis may impact survival in kidney cancer. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Shannon Westin: Hello everyone, and welcome to another episode of JCO After Hours. This is the podcast where we get in-depth on manuscripts that have been published in the Journal of Clinical Oncology. As always, I'm your host, Shannon Westin, Gynecologic Oncologist and Social Media Editor for the JCO. And I am so excited to be here today. We are going to be discussing the paper, "Smoking Cessation After Diagnosis of Kidney Cancer Is Associated With Reduced Risk of Mortality and Cancer Progression: A Prospective Cohort Study," which was published in the JCO on March 29, 2023. And this very intriguing paper, I have two of the major authors from this paper. First is Mahdi Sheikh, who is a scientist and epidemiologist at the International Agency for Research on Cancer, the World Health Organization in Lyon, France. Welcome, Dr. Sheikh. Dr. Mahdi Sheikh: Thank you very much, Dr. Westin, and thanks for having us. Dr. Shannon Westin: And then with Dr. Sheikh is Dr. David Zaridze. He is the Director of the Department of Clinical Epidemiology at the N.N. Blokhin Russian Cancer Research Center in Moscow and also the President of the Russian Cancer Society. We are with greatness today. Dr. David Zaridze: Thank you. Thank you very much. Nice to be with you. Dr. Shannon Westin: Very nice to be with the two of you. So, let's get started. I first wanted to just level set. Could one of you review just the overall incidence of kidney cancer and what proportion of patients with kidney cancer are known to be smokers at diagnosis? Dr. David Zaridze: The figures I'm going to present are rates. They are adjusted to standard world population. Why am I saying that? Because in America you sometimes use adjustment to the US population. These figures will be different from what you are accustomed to see. Okay, incidence of kidney cancer in Russia, in men, 14.1 per 100,000. I compare this with the United States of America, men, 16.5. Very small difference. Women in Russia, 8 per 100,000. In the United States of America, 8.8 per 100,000 of population. Exactly the same. Very close. These rates are sort of high-ish, but there are very high rates, for example, in the Czech Republic, where rates are more than 20 and other Central European countries. In Russia, kidney cancer mortality in men is 6 per 100,000. In USA, 3 per 100,000. In women in Russia, 1.9. In the United States, 1.3. I would say that there is a difference in mortality in men, not much in women. The incidence of kidney cancer is increasing in Russia sharply, sharply. Since 1990 it has increased - it's tripled. It increased from 5 per 100,000 in 1990 to 14 per 100,000 in 2019. Mortality is stable or declining. This is suggesting that kidney cancer is overdiagnosed in Russia and probably elsewhere. But this is not a problem of our discussion now. The frequency of the prevalence of smoking in kidney cancer patients. It is estimated that 15% to 20% of patients with kidney cancer smoke. In Russia, we have results only from our study. 18% of patients smoked at admission to our cancer center. Dr. Shannon Westin: Got it. Okay, good. Well, that's really helpful, especially to those of us that don't take care of patients with kidney cancer every day. It helps us just understand. And I guess the next question is what do we know about the impact of tobacco cessation on the risk of kidney cancer? So you were talking about that increasing incidence. How does tobacco cessation impact that? Dr. Mahdi Sheikh: Tobacco smoking is a known risk factor for kidney cancer and an estimated 17% of the kidney cancer burden worldwide can be attributed to tobacco smoking. There is a recent meta-analysis of 56 studies that was published a few years ago that clearly showed a dose-response relationship between smoking and kidney cancer, meaning that the more cigarettes a day you smoke, the risk of kidney cancer will go up. For example, the risk that was shown for five cigarettes per day was 20%. It goes up until 70% for 30 cigarettes per day. And also with a duration, the more years you smoke, the risk for kidney cancer will go higher. However, the good news is that when you quit smoking, there is strong evidence that the risk for developing kidney cancer will be lower compared to if you continue smoking. And there is some evidence that shows again dose-response relationship, meaning that the more years you spend in quitting smoking, the lower your risk would be for developing kidney cancer compared to if you continue smoking. So this is not only about renal cancer or kidney cancer but also true about many other cancer sites as well. Dr. Shannon Westin: Okay, that's super helpful. And then I guess prior to your study that we're about to talk about, did we have any information on what happens when patients quit smoking after their diagnosis? Any limitations to those data that were available? Dr. David Zaridze: You mean the data which was prior our study? You know, the negative effect of smoking after diagnosis has been shown nearly three decades ago. The information exists already for thirty years, but it was largely ignored not only in clinical practice but also in clinical trials. And I have to stress that in clinical trials this information is still ignored. I came across these studies and decided to review them some time ago. All they were case-control studies and to my knowledge, none of them assessed the effect of quitting smoking. I decided to review these studies and included this review in my book, Smoking: A Major Cause of Cancer, which was published in 2012 and was dedicated to Professor Richard Doll's anniversary. In fact, this was a stimulus for the study we are discussing. And in fact, the component of this study we are discussing today was built in and baked into the existing cohort study to which we added the active follow-up component for assessing the changes in smoking habit and disease status. Dr. Mahdi Sheikh: If you review the evidence, before publishing this study just like a few years ago, we find that there are many studies published talking about the effects of smoking cessation on cancer survival. However, as David mentioned when you go deep into these studies, you'll find a lot of limitations. First of all, most of these studies are retrospective studies, which means that either case-control or retrospective course that patients developed the outcome, and then some investigators came to see their records to assess or ask family members before they developed the outcomes. There are a lot of biases with these types of studies. And with the epidemiologic study, perspective study that we did, has less limitations compared to retrospective ones. Another one is that when we go into the study you see, they only assess a small number of patients, small sample size. Some studies just assess 10 smokers, some assess like 30. By this study we try to assess a large number of smokers who quit smoking after diagnosis. Another limitation is that– First, let's see what exposure and what setting we are talking about. We're talking about smoking which is a very dynamic behavior. People quit smoking and they relapse smoking and they quit smoking and so on. So if you access this exposure for only a limited time, for example, for one year, then you may miss what happens after that which results in misclassification of some of the participants. So repeated assessment was not done in other studies that we did here in this study. Another one, you are talking about special setting patients who are diagnosed with cancer. These patients have special circumstances, they have treatments, they have family support, they might go under the stress of cancer, and all these different stages at diagnosis. And most studies that are available, they didn't account for this. They didn't adjust or they didn't try to understand the role of these compounding factors, as we call it in epidemiology, on that, the thing that we're trying to address. And a prospective study, as I said, long follow-up time. Even the very few prospective studies that were available for other cancer sites that have only one year or maximum two years of follow-up with this type of exposure, so it is important to follow them for a long time. Another thing I would say was exposure assessment. Not only did we repeatedly try to assess exposure among participants, but try to call the people– David and his team who did the study in the field, called the participants and tried to ask the family members and sometimes their physicians about their smoking behaviors. When you go to current evidence you see, mostly smoking behavior was assessed using the record that is available like treatment records or patient records, which again has some limitations if you do not assess exposure among qualified participants. Finally, we're talking about a dynamic behavior in the follow-ups. Some people might change smoking. But there is a very important thing, in this study, we also collect at the time of quitting smoking. There's a very important thing in statistics we call Survivorship Bias, meaning that, if you were assessing an exposure doing the follow-up and if you do not pay attention to this, you will assess an exposure that is a proxy of people who lived longer. Meaning that people have enough time, they have a long time, and those who have longer time, will have more time to quit smoking. And then you will be assessing this, actually, not the exposure, but you're only assessing people who quit smoking, and then whatever you assess, you would end up with a beneficial effect. But if you have the time of quitting smoking and follow up and all these statistical things and lower sample size, you are able to account for this very very important bias in epidemiology. Dr. Shannon Westin: Before we go further, I'd love for just a bit of a description of exactly how you laid out your study to really add to where this data are so limited around survival and tobacco cessation. So maybe review the primary/secondary objectives, basic design, just to make sure our listeners are all on the same page. Dr. David Zaridze: The study has classical prospective cohort design that the study, which was basically a basic study, in which the new component was built in. This study used a user's questionnaire-based exposure assessment and molecular epidemiologic approach. I mean that, in addition to the questionnaire approach, we collected blood and tumor tissues for molecular studies. All patients with kidney cancer admitted to the cancer center were interviewed at admission before receiving any treatment. A structured lifestyle questionnaire was used. Participants were asked about their lifetime smoking history which included questions about the duration and frequency of smoking cigarettes, the average number of cigarettes smoked every day. They were also asked about their lifetime history of alcohol drinking. The questions included questions about exposures to carcinogens other than smoking, and health conditions, including chronic kidney diseases, hypertension, diabetes and so on. Height and weight were measured. Today, this study generated and continues to generate plenty of results and papers published in most prestigious journals such as Nature Genetics, for example. So, as you know, we started from 2012, we started the follow up of the cohort members, we were focusing on Moscow residents and the follow-up includes regular annual contacts with the patients personally or via telephone or with patients' household members, etc. Again, we collected information about changes in smoking behavior and disease status. We also used information from the regional cancer registry to confirm the information obtained from patients. The average period of follow up was eight years. And this is quite a long follow-up. Repeated assessment of smoking status reduces the likelihood that exposure to smoking was misclassified. However, regrettably, the self-reported information on smoking was not supported by biochemical tests, for example, by blood cotinine testing. To my knowledge, this is the only prospective cohort study in patients with cancer, not only with kidney cancer that have collected data on participants' smoking status prospectively for quite a long time. The average follow-up time was eight years. Dr. Shannon Westin: That was incredible. That definitely caught my eye. And I was looking, I was like, "Oh, how many did they lose?" And you guys kept 80-100% of the patients. I just was so impressed by that. And now hearing the mechanisms in which you did that, it makes sense. You were very diligent, multiple ways to contact patients and confirm the data. So you really are to be congratulated for the work that you're able to achieve. Dr. Sheikh, I'd love to hear, you talked a little bit about how some of the studies didn't really think about confounding variables. Can you kind of highlight some of the confounding variables that you all controlled for in order to really assess the impact of the cessation on survival? Dr. Mahdi Sheikh: Thanks to the high-quality data and also the large sample size and the way the study was designed, we were able to adjust for a lot of confounding. So we tried to adjust for all these things. So we used three approaches. The first approach was adjustment. When you ran this in the analysis, we tried a statistical model, we tried to adjust for these confounders like age, sex, treatment, socioeconomic status, smoking intensity, alcohol, and other factors. This is one effect, one approach. The second approach was stratification, meaning that we come and see the effect within people who have been diagnosed with only earlier stage tumors to see if the effect among people with earlier stage tumors differs with the effect that we see among people with higher stage tumors. But again, if you read the paper, you see that we saw the protective effects of smoking cessation on both groups of people, those who were diagnosed at earlier stages and those who were diagnosed at later stages. And also heavy smokers or mild to moderate smokers, again, we tried stratified analysis excluding those heavy smokers and saw the effect, again, among those who were light smokers or moderate smokers and also with the heavy smokers. I want to say that we tried all these types of analytical approaches and we really saw the protective effects across all patient subgroups. Finally, I talked again about the survivorship bias. So we used really strict statistical approaches to address this confounding, and because we had the time of quitting, we had the follow up time and all these things. And, again, whatever we did in the study we still could see the effects of smoking and all this is due to the good design, the large sample size, and the good questionnaire data that we have. Dr. Shannon Westin: That's awesome. I think, of course, now let's get to the bottom line. 40% reported that they quit smoking after diagnosis with none relapsing during the time period. And what did you see was the impact on overall survival as well as cancer-specific survival? Dr. Mahdi Sheikh: So we tried several outcomes - overall survival, cancer-specific survival, but also progression-free survival. And then because we had the large sample size we could assess all this. Interestingly, we saw the effect on all the three outcomes that we assessed. So the overall survival was better among those during the quitting time and also the cancer-specific survival was also better and also progression-free survival was better among all these…

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HER3-DXd in EGFR-Mutated NSCLC: HERTHENA-Lung01 Sep 10, 2023

Show notes

Dr. Shannon Westin and her guest, Dr. Helena Yu discuss the paper "HERTHENA-Lung01, a Phase 2 Trial of Patritumab Deruxtecan (HER3-DXd) in EGFR-Mutated NSCLC Following EGFR TKI Therapy and Platinum-Based Chemotherapy" published in the JCO during the World Conference on Lung Cancer in Singapore. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in-depth on manuscripts that are published in the Journal of Clinical Oncology. I am your host, Dr. Shannon Westin, GYN Oncologist and Social Media Editor of the JCO. And as always, it's my pleasure to review an incredibly exciting manuscript. Today, we're going to be talking about "HERTHENA-Lung01: A Phase II Trial of Patritumab Deruxtecan (HER3-DXd) in EGFR-mutated NSCLC Following EGFR TKI Therapy and Platinum-based Chemotherapy." And this is exciting. This is a simultaneous publication in the JCO on September 10th, 2023 at the same time it's being presented at the World Conference on Lung Cancer in Singapore. I am joined today by the first author and overall outstanding physician, Helena Yu. She's an Associate Attending Physician, Thoracic Oncologist, and Early Drug Development Specialist at Memorial Sloan Kettering Cancer Center in New York, New York. Welcome, Dr. Yu. Dr. Helena Yu: Thank you. I'm glad to be here, and thanks for having me. Dr. Shannon Westin: So we're so excited to have you, and we love doing these simultaneous podcasts because I think not everyone can go to Singapore and be with you today. So it's awesome that we'll be able to give people the data that they want to see as soon as possible. So first, let's just level set. Coming from the GYN Oncology standpoint, I always like to get down to the basics of the cancer. So, can you speak just a little bit about the incidence and mortality of lung cancer overall and what have been some recent trends in the treatment of this disease? Dr. Helena Yu: Everyone knows somebody that has been touched by lung cancer. It's the second most common cancer that is diagnosed in men and women in the US today. It is the leading cause of cancer-related deaths, with 25% of cancer deaths really being attributable to lung cancer. Historically, prognosis with lung cancer has been poor, with five-year survivals around 10%. What's really interesting is over the last couple of years, there have been some improvements in survival with lung cancer. And I think that that can largely be attributed to the advent of immunotherapies as standard of care, as well as targeted therapies for driver mutation-positive lung cancer. Dr. Shannon Westin: So that leads right into the next question: What is the role of the EGFR pathway in lung cancer? How common are these aberrations and how successful have prior treatments targeting this pathway been? Dr. Helena Yu: Yes. So we, in lung cancer, have this mutation pie, which really describes the different oncogenes that we see in lung cancer. And probably now two-thirds of patients actually have a detectable driver mutation when their tumors undergo next generation sequencing. EGFR is probably one of the first mutations that was identified. About 15% to 20% of patients diagnosed with lung cancer in the US have mutations in EGFR. It is both activating and sensitizing. So, obviously mutations in EGFR cause cancer and they are sensitizing to different EGFR targeted therapies we have. Right now, the standard of care for first-line treatment for EGFR mutant lung cancer are EGFR tyrosine kinase inhibitors. And those are oral therapies that actually are very successful at managing EGFR mutant lung cancer. They're not curative, but they do kind of control disease for a long period of time. But unfortunately for all patients, at some point their cancer does progress on these targeted therapies. And the most common one we use today is one called osimertinib, which is a third-generation EGFR TKI. And we do not have any approved targeted therapies after osimertinib. And so that kind of is the setting for this new drug, patritumab-deruxtecan. Dr. Shannon Westin: So tell us a little bit about HER3-DXd and why you prioritize targeting this particular part of the EGFR pathway in this population. Dr. Helena Yu: Yes. So HER3 is actually part of the HER EGFR family, and it is a protein that, when expressed, really portends a poor prognosis. It kind of tells us cancers that are more likely to recur and cancers where overall survival is shorter. So HER3-DXd is an antibody drug conjugate. There are a slew of new medicines in lung cancer that are ADCs. Historically, we looked at HER3 monoclonal antibodies in EGFR mutant lung cancer and they actually were not successful, not efficacious. And so it's really interesting that using these antibodies as part of an ADC construct has led to better efficacy. The HER3-DXd has that HER3 monoclonal antibody, there is a linker and then there is a chemotherapy payload. So for the deruxtecan family of which there are a few ADCs has a topoisomerase 1 chemotherapy, and in part, we know that HER3 is sort of more significantly expressed in these EGFR mutant lung cancers. And because HER3 is part of the EGFR family and heterodimerizes with EGFR, it was sort of a natural initial population to study this drug. Dr. Shannon Westin: Why don't you briefly highlight the design of the trial and your key eligibility for our listeners? Dr. Helena Yu: So this phase II study came off the heels of an initial phase I study that helped us identify the appropriate dose of HER3-DXd for patients with EGFR mutant lung cancer. And so this study enrolled patients with metastatic EGFR mutant lung cancer. All patients had to have received EGFR TKI, most of them received osimertinib and that's first line standard of care globally. And then also patients had to receive platinum doublet chemotherapy, which is really our second line standard of care treatment. The initial study randomized patients to two cohorts. One, which was all patients received 5.6 milligrams per kilogram every three weeks intravenous. The other cohort was an uptitration cohort, where they actually started with lower doses and then kind of sequentially over cycles increased the dose to see if that mitigated toxicity based on emerging phase I data that really showed that the 5.6 milligram per kilogram had the better efficacy as well as better toxicity profile. Pretty soon after the study started, all patients received that 5.6 mg per kilogram. And I think the other important thing to say is that patients with asymptomatic brain metastases were allowed. Lung cancer, in general, has a very high incidence or frequency of brain metastases. But in EGFR mutant lung cancer that number is north of 50%. So having a therapy that is effective in the CNS is especially important for this population. Dr. Shannon Westin: So let's talk a little bit more about this population. The group that you enrolled and treated, is it representative of the general population that we might see in the community? Dr. Helena Yu: Yes, I think so. I think that one thing to highlight are these patients were pretty heavily pretreated. The median prior lines of therapy were three lines prior to study enrollment, but I think that went up to eleven for certain patients. And so that is one thing that I think is unique about this population, where they're able to sort of receive several sequential therapies. I think it was unique in allowing those asymptomatic brain metastases and then EGFR mutant lung cancer has certain demographic tendencies. And so we see women, Asian, never smokers, which may not kind of represent the typical demographic for lung cancer, but certainly is the typical demographic for EGFR mutant lung cancer. Dr. Shannon Westin: Got it. And let's hear about your primary results. What did you discover? Dr. Helena Yu: To set the stage, this is really an unmet need where post EGFR TKI and post chemotherapy, we really don't have exciting efficacious therapies. When you look at real world studies, the response rate to third line and beyond treatments are less than 10% PFS less than three months. And so really searching for something in this treatment landscape. And so for the study, the primary endpoint was confirmed overall response which was 30% for this patient population. Duration of response was 7.4 months and the median progression free survival was 5.5 months. Looking at sort of prespecified subgroups, there really did not seem to be a particular subgroup that had enhanced benefit. Dr. Shannon Westin: So that is a really impressive improvement in the expected standard of care results. So I congratulate you and I'm so excited. I was also really excited to see that you included patients with the asymptomatic brain meds for the recent ASCO-Friends guidelines. Can you speak a little bit about the efficacy in this population specifically? Dr. Helena Yu: Absolutely. As I mentioned before, for these novel targeted therapies, we really do need to look specifically at CNS efficacy because that is absolutely an area where we often see disease progression. And so having studies that allow those patients really is more representative, of course, of the clinical practice that we actually treat. And so when you look at the subgroup that had a history of brain metastases, which in this group was actually, I believe, 51%, so the majority of patients, the response rate was really similar to the patients that did not have brain metastases. I believe it was 29% response rate for patients with brain metastases and 30% for patients without. And I think what is especially useful that we did was we had specific neuroradiologist look for measurable target lesions within the CNS that had not received prior radiation or prior local therapy to look at intracranial response rate. And so there were a subgroup of patients, 30 patients that had measurable target lesions within the CNS and the confirmed intracranial response rate was 33.3% in those patients with measurable target lesions in the CNS and disease control rate was 77%. So, I think, it's really exciting to see that the response rate in the CNS was really comparable to what we see with systemic disease. Dr. Shannon Westin: That is awesome. I don't think I've ever seen anything quite like that. So really, you and your co-authors are to be congratulated for including this really important population. I guess the next natural question is, how was HER3 expression? Did you look at that? How was it associated with response to therapy? And did you find any other intriguing genomic alterations associated with benefit from the HER3-DXd? Dr. Helena Yu: That is a super interesting topic because I think in lung cancer we are well familiar with these driver mutations that really are the biomarker for targeted therapy. It is less clear what the appropriate biomarkers are for some of these antibody drug conjugates. We absolutely looked at HER3 expression, pretreatment tissue was required for this point specifically. And actually within EGFR mutant lung cancer, almost all patients have some degree of HER3 expression. And so we're already looking at a population that is enriched for potential response. But we actually looked at H-scores, looking at membrane HER3 expression and really did not find differences in the degree of HER3 expression when you compare patients with response versus stable disease versus progressive disease. So I don't think the degree of HER3 expression really is an appropriate biomarker. And I think we're still figuring out with ADCs, I think you actually might need very little of the surface protein for these ADCs to be internalized and be effective. So, right now, the disease population of interest is EGFR mutant lung cancer, where we think there's reasonable efficacy. Dr. Shannon Westin: And that makes sense. And with this particular drug, is there a bit of bystander effect as well, like we've seen with some of the other ADCs? Dr. Helena Yu: There absolutely is a little bit. And I think what is interesting for this drug too is there are a few ADCs that are in development. So there is trastuzumab-deruxtecan, which is already approved for HER2 positive lung cancer; and then there is also datopotamab-deruxtecan, which is a TROP2 ADC. And so I think there really will be a wave of these different ADCs which are studied in slightly different populations. But I think understanding what the biomarker is for these and then, will there be cross resistance because of the similar chemo backbone, is something that we will need to find out in the future. Dr. Shannon Westin: Yeah, these are definitely unmet needs in this space. I guess one other question just around safety signals, anything unique for this particular agent? Kind of take us through the dose interruptions and dose reductions? Dr. Helena Yu: Absolutely. So I think that it is important to remember, and I do remind all of my patients that have consented to this study, that ADCs are a hybrid chemotherapy agent. So they will have some of the typical chemotherapy adverse events like cytopenias. We did see a little bit of alopecia with this as well. So I think there's thrombocytopenia and neutropenia that actually is more front-loaded and actually weren't necessarily associated with significant clinical sequelae like bleeding or neutropenic fever. The rate of treatment discontinuation from adverse events was actually pretty low at 7%; but about 20% of patients did require a dose reduction, and many of the side effects do appear to be dose-dependent. So I think those dose reductions are helpful. And then a really important side effect of this class of drugs is ILD or interstitial lung disease or pneumonitis. And we've seen kind of varying ranges of pneumonitis with these drugs. So far it really looks to be the highest with trastuzumab-deruxtecan with an ILD rate north of 15%; but with this drug, the independently adjudicated rate of ILD was 5%. So present, but maybe not as high as some of the other drugs in this class. Dr. Shannon Westin: Well, that's great news. Well, congratulations on these exciting results and your presentation and your paper. The last question I have for you is what's next for this agent? What do you see? Where do you see it going? Dr. Helena Yu: Absolutely. So I hope that with these promising results in an area of unmet need, that we will get approval for this drug so that we can get access to our patients. The other interesting thing that we are looking at is combining HER3-DXd with osimertinib, which is the standard of care EGFR inhibitor. So the idea of combining this novel therapy with the standard targeted therapy for this type of cancer, I think, is really interesting to see if we'll get even sort of greater efficacy and in particular greater CNS efficacy by combining two CNS active agents. So those are results that I'm looking forward to seeing, too. Dr. Shannon Westin: That's great. Well, thank you so much for being here, Dr. Yu. And congratulations again on these incredible results and your incredible success in the lung cancer space. And thank you all of you for listening in to JCO After Hours, again, discussing the "HERTHENA-Lung01: Phase II Trial of of HER3-DXd in EGFR Mutated Non-Squamous Cell Lung Cancer." We are always excited to have you. Please check out our other podcasts, reach out and let us know how we did. And until then, we'll see you next time. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own…

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