Journal of Clinical Oncology (JCO) Podcast

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Genetic Testing in Breast Cancer Patients: Striking the Balance Between Over Versus Undertesting Mar 11, 2020

Show notes

This podcast summarizes and provides commentary on the recent article by Yadav et al. in which the authors demonstrate that expansion of the current NCCN guidelines for genetic testing in breast cancer patients to include all women diagnosed at or below the age of 65 markedly improves the sensitivity for detecting pathogenic germline variants without requiring the testing of all breast cancer patients.

TRANSCRIPT

This JCO Podcast provides observations and commentary on the JCO article "Evaluation of Germline Genetic Testing Criteria in a Hospital-Based Series of Women with Breast Cancer" by Yadav et al. My name is Erin Cobain, and I am a Clinical Lecturer at the University of Michigan Rogel Cancer Center in Ann Arbor, Michigan United States. My oncologic specialty is breast cancer.

In this study, the authors sought to determine the sensitivity and specificity of current genetic testing criteria for the detection of pathogenic germline variants in women with breast cancer. Current national comprehensive cancer network (NCCN) guideline criteria, updated in January 2020, recommend that genetic testing be offered to all women diagnosed with breast cancer at age 45 or younger, those diagnosed with triple negative breast cancer at age 60 or younger as well as those with family history of breast, ovarian, prostate or pancreatic cancer that meet specific criteria. In addition, any patient with Ashkenazi Jewish ancestry is recommended to undergo testing. This most recent update to the guidelines also incorporates a recommendation to offer testing to individuals who have a greater than 5% risk of having a BRCA1 or BRCA2 mutation by prior probability models such as Tyrer-Cuzick or BRCAPro who would not otherwise meet criteria. Prior to the publication of the present study by Yadav and colleagues, several recent articles including those by Beitsch et al. and Yang et al. indicate that many patients with pathogenic or likely pathogenic germline variants in genes associated with hereditary breast and ovarian cancer syndromes are missed by current testing criteria. The Beitsch et al. study analyzed results from a prospective registry whereby patients with previously or newly diagnosed breast cancer were consented and underwent genetic testing with an 80-gene panel test. Approximately 1,000 patients were enrolled and approximately half met NCCN guideline criteria for genetic testing. Among the patients who met NCCN guideline criteria, 9.4% had a pathogenic or likely pathogenic variant identified. For those patients not meeting NCCN guideline criteria for testing, 7.9% had a pathogenic or likely pathogenic variant. This led the authors to conclude that nearly half of breast cancer patients with pathogenic germline variants would be missed by NCCN criteria. Similarly, Yang and colleagues examined a cohort of patients with personal or family history of breast or gynecologic cancer from a Medicare database undergoing genetic testing. Data from over 4,000 patients tested indicated that the rate of identifying a likely pathogenic or pathogenic germline variant was nearly identical in the cohorts that met NCCN guideline criteria for testing versus those that did not, with the rate of pathogenic germline variants being approximately 10% in both groups. Indeed, the results from these studies lead the American Society of Breast Surgeons to issue a recommendation in October 2019 that all patients with personal history of breast cancer undergo genetic testing. While this recommendation would undoubtedly identify more patients with genetic susceptibility to breast cancer and other malignancies, the implications of this recommendation must be considered. Large scale testing would more readily identify patients with moderate penetrance genes that are without established cancer risk reduction guidelines. More testing also leads to increased identification of variants of uncertain significance, presenting challenges both for patients and their providers attempting to best counsel individuals with an ambiguous result. Finally, inequities in access to testing and genetic counseling resources as well as increased healthcare costs that result from broad testing are of major concern. If cost of testing is not covered by insurance, paying out of pocket may not be feasible for many patients. In the present study, Yadav and colleagues attempted to address some of these apprehensions regarding the adoption of widespread genetic testing in breast cancer patients. The investigators enrolled patients with personal history of breast cancer over a 16 year period of time into a registry and evaluated for pathogenic germline variants in 9 cancer predisposition genes, including ATM, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, and TP53. These genes were selected because there are clear management recommendations in the NCCN guidelines when they are identified. The authors found that among almost 4,000 women tested, those meeting current NCCN guideline criteria for testing (comprising 48% of the cohort) were more likely to harbor a pathogenic germline variant than those women who did not meet criteria. The rate of detection of pathogenic germline variants was 9% and 3.5% in these groups respectively. Despite the updated NCCN guideline criteria identifying patients with pathogenic germline variants more readily, there are undoubtedly still patients missed by these criteria. The authors conducted subsequent analysis to include all women diagnosed with breast cancer at age 65 or younger, which achieved 90% specificity for the 9 cancer predisposition genes selected and greater than 98% specificity for identification of pathogenic germline variants in BRCA1 and BRCA2. Given this, the authors concluded that expanding the NCCN genetic testing criteria to include all women diagnosed with breast cancer at or before the age of 65 will markedly improve the sensitivity of genetic testing and avoid the need to evaluate all patients with personal history of breast cancer. The major limitations of this study were that cost-effectiveness of this approach was not analyzed, and the majority of the patients included in the registry were White, limiting the applicability of these findings to a diverse patient population. Despite these limitations, this study offers a promising and considered approach to genetic testing in patients with personal history of breast cancer. While validation of this approach in additional study cohorts would be of great value, this data strongly suggests that testing all patients at or below age 65 at the time of breast cancer diagnosis achieves a balance between the two current testing paradigms, identifying the vast majority of patients at risk, and avoiding unnecessary testing of many.

This concludes this JCO Podcast. Thank you for listening.

High Reward, High Toxicity: Combination Pembrolizumab and Lenvatinib in Advanced Endometrial Cancer Mar 01, 2020

Show notes

The combination of pembrolizumab and lenvatinib is a promising second line option for metastatic or recurrent MSS endometrial cancer, although there can be considerable toxicity and choosing appropriate patients is key.

TRANSCRIPT

This JCO Podcast provides observations and commentary on the JCO article "Lenvatinib and Pembrolizumab in Patients With Advanced Endometrial Cancer" by Makker et al. My name is Meghan Shea, and I am an Instructor of Medicine at Harvard Medical School at Beth Israel Deaconess Medical Center in Boston, Massachusetts. My oncologic specialty is gynecologic oncology.

Patients with advanced endometrial carcinoma have limited options after receiving the carboplatin and paclitaxel doublet for recurrent or metastatic disease. The study that accompanies this podcast evaluates the combination pembrolizumab and lenvatinib, providing a much needed second-line option for this patient population. The approval of single-agent pembrolizumab for tumors with microsatellite instability (from here on referred to as MSI high) does not have immediate relevance for the majority of patients with advanced endometrial carcinoma who have microsatellite stable disease (from here on referred to as MSS). Makker et al. now report the results of an ongoing phase 1b/2 study of pembrolizumab, an anti-PD1 antibody, and lenvatinib, an oral tyrosine kinase inhibitor that targets the VEGF-receptor, in patients with metastatic endometrial carcinoma. Eligibility criteria included patients with an ECOG 0 to 1 who had confirmed metastatic disease with less than or equal to 2 prior lines of systemic therapy. Notably the majority were not heavily pre-treated; 52.8% of patients in the study had only one prior line of systemic treatment.

Patients received lenvatinib 20 mg once daily orally continuously and pembrolizumab 200 mg intravenously every 3 weeks – with a maximum duration of 2 years for pembrolizumab. All patients had imaging at baseline and then every 6 weeks for first 24 weeks and then every 9 weeks thereafter. The primary end point was objective response rate at 24 weeks. Forty-one of the 108 patients, 38%, had a response at 24 weeks with a median follow up of 18.7 months. As expected, the MSI high tumors had a higher response rate of 63.6%, although this was a minority of the study population, only 11 patients. Most importantly, the patients with MSS tumors had a response rate of 37.2% with a median duration of response of 21.2 months. The histology did not appear to impact the response rate – the majority of patients had endometrioid (50.9%), although the study population also contained a reasonable proportion of serous and clear cell (38%) compared to the expected frequency in the general population of advanced uterine cancers. The PD-L1 status positive or negative did not correlate with response.

One might question, before accepting a complicated regimen with both oral and IV chemotherapy as a new second-line standard option, whether anyone has studied the activity of either single agent lenvatinib or single agent pembolizumab in a similar population, especially for those with MSS disease. With the caveats of cross study comparisons, it appears that neither single agent is as active as the current combination. For instance, Vergote et al reported results of a phase 2 study of lenvatinib monotherapy for advanced endometrial cancer, where the response rate was only 14.3% with median progression free survival of 5.4 months. Likewise, Ott et al studied single agent pembrolizumab in endometrial cancer with 18 of 19 patients having MSS cancer, resulting in only a 13% response rate and progression free survival of 1.8 months.

So you may be wondering, what's the catch? The issue is the potential toxicity of this doublet regimen, with 66.9% or 83 of 108 patients, having a grade 3 or 4 treatment-related adverse event. Overall 17.7% of the patients discontinued one or both drugs. Notably, pembrolizumab was never dose reduced - only dose held or discontinued. Most strikingly, 62.9%, roughly two thirds of patients, required a dose reduction of lenvatinib. Only 11 patients (that is 8.9%) stayed on full dose 20 mg of lenvatinib for greater than 6 months. The average dose for lenvatinib was 14.4 mg daily. The toxicity profile of lenvatinib may be related to the fact that it is a multi-targeted tyrosine kinase inhibitor that targets not only vascular endothelial growth factor receptors, but also fibroblast growth factor receptors, platelet-derived growth factor receptor alpha, RET and KIT.

There were 51 deaths during this study; the majority occurred during follow up due to progression of disease. However, there were 16 deaths while on study, 4 considered treatment emergent adverse events and 2 judged to be treatment related. The four deemed treatment emergent were due to gastrointestinal perforation, intestinal obstruction, general health deterioration and metabolic encephalopathy. The two deemed treatment related were from septic shock and intracranial hemorrhage.

The National Comprehensive Cancer Network (NCCN) guidelines have added the combination of pembrolizumab and lenvatinib to their list of second line therapeutic options, and it also has been approved by the Food and Drug Administration (FDA). This recognizes the fact that this combination has the highest response rate of the available drugs listed, and thus should be a strong consideration for second line therapy for patients with MSS endometrial carcinoma. However, ensuring that this treatment is appropriate for a given patient is of the utmost importance. First the patient must be a candidate for immunotherapy – ideally not on chronic prednisone and/or have an active autoimmune disease. In contrast to prescribing single agent anti-PD-1 or anti-PD-L1, a performance status of 0 to 1 is important with this combination. The most appropriate patient should have controlled blood pressure prior to initiating drug, be able to monitor their blood pressures, take their oral chemotherapy as prescribed, and readily report any new symptoms. I avoid prescribing this drug combination if the patient has a bleeding disorder, recent clotting, uncontrolled hypertension, or is at high risk of a fistula or bowel obstruction. Lenvatinib is a renally-cleared drug, and thus patients with a reduced glomerular filtration rate (GFR) require renal dosing. This is especially relevant for patients with recurrent uterine cancer, whose kidney function is dynamic, especially in the setting of hydronephrosis. In my practice, I consider starting patients with normal renal function at 14 mg lenvatinib daily, given that the vast majority of patients on study were eventually dose-reduced. Furthermore, I might start the lenvatinib dosing even lower for patients with dynamic renal function and for those who have a baseline GFR lower than 30.

Overall this study provides a promising second line option for metastatic or recurrent MSS endometrial cancer, with responders having a durable response. Patient selection and dose adjustments are key considerations to avoiding and managing toxicity.

This concludes this JCO Podcast. Thank you for listening.

Optimizing Treatment Strategies for Germline BRCA/PALB2 Mutant Pancreatic Adenocarcinoma Jan 21, 2020

Show notes

This podcast will discuss the findings from a phase II trial of gemcitabine, cisplatin and PARP inhibitor therapy in germline BRCA/PALB2 mutant pancreatic cancer and discuss an optimal treatment strategy in this setting.

TRANSCRIPT

This JCO Podcast provides observations and commentary on the JCO article "A Randomized, Multi-Center, Phase II Trial of Gemcitabine, Cisplatin with or without Veliparib in Patients with Pancreas Adenocarcinoma and a Germline BRCA/ PALB2 Mutation" by O'Reilly et al. My name is Daniel Renouf, and I am a medical oncologist at the BC Cancer Vancouver Centre in Vancouver, Canada. My oncologic specialty is pancreatic cancer.

In this podcast, we will be discussing an important and evolving area that is changing our standard treatment strategies for pancreatic cancer. Progress has been slow for pancreatic adenocarcinoma, which is now the third leading cause of cancer-related death in North America and is projected to become the second leading cause of cancer-related death within the next decade. Modest gains in our treatments have been achieved with new chemotherapy combinations, including FOLFIRINOX and gemcitabine and nano-albumen bound-paclitaxel, yet still the majority of patients diagnosed with advanced disease will live for less than one year.

There is a critical need for improved treatment options as well as clinically relevant predictive markers to guide our therapeutic decision making. The first clinically important predictive marker in pancreatic cancer is germline BRCA/PALB2 mutation status, which is present in 5-9% of pancreatic adenocarcinomas. Multiple translational studies and case series have demonstrated distinct molecular features of these tumors, as well as unique clinical characteristics. Germline BRCA/PALB2 mutant pancreatic adenocarcinomas have been noted to be sensitive to platinum agents and be associated with a better prognosis. Despite this data, and a general acceptance within the community that platinum agents are the preferred therapies in this setting, there is minimal prospective trial data specifically assessing the activity of platinum combinations in germline BRCA/PALB2 mutant pancreatic adenocarcinoma.

At a plenary session at ASCO 2019 and its subsequent publication, the POLO trial assessed the role of maintenance therapy with a poly-ADP ribose polymerase (PARP) inhibitor (olaparib), compared to placebo, in patients with metastatic pancreatic adenocarcinoma and germline mutations in BRCA/PALB2 who had responded or had stable disease after initial therapy with FOLFIRINOX. This was a positive trial, demonstrating that maintenance olaparib significantly improved progression-free survival compared to placebo. There was no difference noted in overall survival, but this data was not yet mature. The role of combining a PARP inhibitor with platinum-based chemotherapy as upfront treatment in this patient population is yet to be defined. A previous Phase I trial of gemcitabine, cisplatin and the PARP inhibitor veliparib determined a recommended phase II dose for velipirib in this combination and demonstrated promising efficacy in germline BRCA-mutant pancreatic adenocarcinoma.

In the article that accompanies this podcast, Dr. O'Reilly and colleagues report on the results of a phase II prospective trial comparing gemcitabine and cisplatin versus gemcitabine, cisplatin and veliparib in patients with advanced pancreatic adenocarcinoma with germline aberrations in BRCA/PALB2. In the trial, patients with locally advanced or metastatic pancreatic cancer who had not received chemotherapy in the advanced setting, had a good performance status, and who harbored germline aberrations in BRCA/PALB2 were randomized.

A total of 50 patients were enrolled, and the results demonstrated good efficacy in both arms, with a response rate of 74.1% in the veliparib arm and 65.2% in the control arm. Median progression-free survival was 10.1 months and 9.7 in the veliparib and non-veliparib arms respectively, and median overall survival was 15.5 and 16.4 months. Of note, for the entire cohort, 2-year overall survival was notably high at 30.6%, and 3-year overall survival was 17.8%. Grade 3-4 toxicities, including neutropenia, thrombocytopenia, and anemia were greater in the veliparib arm.

The authors concluded that gemcitabine and cisplatin demonstrated significant activity in BRCA/PALB2 germline mutant pancreatic adenocarcinoma, and the addition of concurrent veliparib did not improve efficacy. Given this promising data, it was concluded that gemcitabine and cisplatin should be considered a standard treatment for BRCA/PALB2 germline mutant pancreatic adenocarcinoma.

This is an important trial, as it is one of the first to specifically assess platinum chemotherapy prospectively in this patient population and has important implications for treatment strategies for pancreatic cancer, the first of which is that testing for germline BRCA/PALB2 mutations should now be considered standard of care for all newly diagnosed pancreatic adenocarcinomas. Not only does this have important treatment implications for the patient; it also has strong relevance to the patients' family members, as it was found to also harbor a germline BRCA/PALB2 mutation. Screening and potential prevention strategies could be considered for other cancers, such as breast and ovarian.

Secondly, if a patient is found to have a germline BRCA/PALB2 mutation, the data from this trial in combination with the body of literature in this setting would suggest that first line therapy with a platinum agent should be considered. In this setting, one could consider either FOLFIRINOX or gemcitabine and cisplatin. The efficacy of gemcitabine and nano albumen bound-paclitaxel in this patient population is not clearly defined, but in the context of data from other disease sites also demonstrating increased sensitivity to platinum in this patient population, and given many patients with advanced pancreatic adenocarcinoma are often not well enough to received multiple lines of therapy, a first line platinum combination should be strongly considered. Thirdly, this trial demonstrates that there is no additional benefit from adding a PARP inhibitor to chemotherapy in this setting, but there is added toxicity, and thus this strategy should not be considered at this time.

Finally, given that toxicity from platinum-based chemotherapy is cumulative, the question of an optimal maintenance strategy remains. The POLO trial demonstrated that there is activity and a progression-free survival benefit when using olaparib as a maintenance post upfront platinum-based chemotherapy when compared to placebo, and therefore this represents one potential strategy. One criticism of the POLO trial is that many centers do not stop treatment and instead continue therapy without the platinum after an initial response. In patients responding to initial treatment with FOLFIRINOX, maintenance FOLFIRI is often considered. Data from a second line trial of FOLFIRI with or without veliparib presented as a poster discussion at ASCO 2019 by Dr. Chiorean and colleagues noted that BRCA/PALB2 mutant tumors also appear to have increased sensitivity to FOLFIRI. At this time, the optimal maintenance strategy after upfront platinum therapy is yet to be fully defined, and further research in this setting is needed. In addition, to what extent these strategies should be applied to patients with pancreatic adenocarcinomas that are germline BRCA/PALB2 wildtype but have other homologous recombination deficiency defects requires further investigation.

In summary, this is an exciting time in pancreatic adenocarcinoma as we now have a clinically important biomarker to guide treatment strategies. This important trial by Dr. O'Reilly and colleagues further solidifies the importance of BRCA/PALB2 germline testing in pancreatic adenocarcinoma and that first line platinum-based chemotherapy should be considered in these patients.

This concludes this JCO Podcast. Thank you for listening.

Immune Checkpoint Inhibitor Use in Patients With Inflammatory Bowel Disease: A Closer Look Jan 08, 2020

Show notes

Towards improved characterization of immune-related adverse events in the setting of pre-existing autoimmune disease.

TRANSCRIPT

This JCO Podcast provides observations and commentary on the JCO article "Immune Checkpoint Inhibitor Therapy in Patients with Preexisting Inflammatory Bowel Disease", by Abu-Sbeih et al. My name is Katy Tsai, and I am Assistant Professor of Medicine in the Division of Hematology/Oncology at the University of California, San Francisco. My oncologic specialty is the treatment of advanced melanoma and non-melanoma skin cancers.

Immune checkpoint inhibitors, referred to as ICIs in this podcast, have transformed the landscape of treatment options in oncology. While ICIs were first approved for the treatment of advanced melanoma in 2011, since that time, ICIs have shown activity in a variety of other histologies. Anti-PD-1 or anti-PD-L1, with or without anti-CTLA-4, are now approved for the treatment of lung cancer, head and neck squamous cell carcinoma, renal cell carcinoma, and many others. While ICIs can result in durable responses, their continued use can be limited by the development of immune-related adverse eventsimmune-related adverse events. Because these events are believed to be autoimmune in nature, there are intuitive safety concerns about ICI use in patients with known autoimmune disease. Can patients with pre-existing autoimmune disease be safely treated with ICI? Are these patients more likely to experience immune-related adverse events related to their autoimmune disease? Is this risk increased if their autoimmune disease is severe, with a history of required immunosuppression? These are all important questions faced by healthcare providers, questions which are not well studied due to the exclusion of patients with known autoimmune disease from pivotal ICI clinical trials.

To address these questions, Abu-Sbeih and colleagues chose to focus on ICI use in patients with pre-existing inflammatory bowel disease. This is a clinically relevant population of interest, given the relatively high incidence of immune-related diarrhea and colitis with ICI use; these immune-related adverse events occur in almost half of patients receiving combination anti-CTLA-4 and anti-PD-1 or PD-L1, about one-third of patients receiving anti-CTLA-4, and less frequently in patients receiving anti-PD-1 or PD-L1 alone. Abu-Sbeih and colleagues conducted a retrospective, multicenter study in which 102 patients – half with Crohn's disease, half with ulcerative colitis – received ICI between 2010 and 2019. 17 patients received anti-CTLA-4, and 85 received anti-PD-1 or anti-PD-L1. This is a notable cohort of patients, as previous meta-analyses have reported on the safety of ICI use in much smaller numbers of patients with inflammatory bowel disease, and with less detailed clinical characterization of their inflammatory bowel disease. Univariate and multivariate logistic regression were used to assess the risk of gastrointestinal, or GI, adverse events, and was compared to a control population of 11,377 ICI-treated patients without inflammatory bowel disease, from the same participating institutions.

An important observation made by the authors was that the rate of GI immune-related adverse events in the inflammatory bowel disease cohort was significantly higher at 41%, compared to 11% in the non-inflammatory bowel disease cohort. Univariate analysis identified anti-CTLA-4 (given as monotherapy or in combination) as a risk factor for GI immune-related adverse events compared to anti-PD-1/L1 therapy but showed only a tendency toward significance in multivariate analysis, as did inflammatory bowel disease involving the colon. Although none of the collected clinical variables reached significance in multivariate analysis, the authors' analysis of outcomes in the inflammatory bowel disease cohort is illuminating. Of the 41 inflammatory bowel disease patients who developed diarrhea, 51% had peak grade 3 or 4 diarrhea, 76% received glucocorticoids, and 29% required additional immunosuppression with infliximab or vedolizumab. 4% developed colonic perforation, with half of those patients requiring surgical intervention. Also of note, patients who were identified as having active inflammatory bowel disease within 3 months of ICI start had higher grade diarrhea compared to patients with inactive inflammatory bowel disease. Endoscopy data were also available for 48 inflammatory bowel disease patients. Interestingly, of the 41 patients who were noted to have normal or mild inflammatory findings, 18 (43%) developed any GI immune-related adverse events, 5 (12%) of which were grades 3-4. In the 7 patients with moderate/severe inflammatory findings, 5 (71%) had GI immune-related adverse events of any grade, 2 (29%) of which were grades 3-4.

Despite the higher rate of GI immune-related adverse events and associated complications in the inflammatory bowel disease cohort compared to the non-inflammatory bowel disease cohort, there were no fatalities. Additionally, 48% of patients in the inflammatory bowel disease cohort were identified as having complete response, partial response, or stable disease to ICI therapy, a clinical benefit rate similar to those reported in ICI clinical trials. It seems, then, that the benefits of ICI therapy in this population may well outweigh the risks, particularly for patients with inflammatory bowel disease who may have no viable alternative therapy available for their malignancy.

Overall, despite the inherent limitations of retrospective analysis, this work represents the largest study to date investigating the risk of GI immune-related adverse events in patients with cancer and comorbid inflammatory bowel disease who were treated with ICIs. It provides evidence for increased incidence and severity of GI immune-related adverse events, and complications thereof, in a well-annotated cohort of patients with inflammatory bowel disease. As these patients continued to receive clinical benefit from their ICI therapy, these findings can help better inform pre-ICI treatment counseling in patients with preexisting inflammatory bowel disease, and better prepare them for expected risks of treatment. At the same time, this work also raises a number of questions for further investigation. Is anti-CTLA-4 truly safe to use in this population, or was this limited by the small number of patients receiving anti-CTLA-4 in this study? Should ICI therapy be delayed to allow for optimal treatment of active inflammatory bowel disease, to decrease the risk of severe GI immune-related adverse events? What additional guidance can be given to providers regarding when to initiate additional immunosuppressive therapy, and should this be driven by endoscopic findings? These questions and more can and should be investigated in future larger-scale prospective studies. For the time being, based on the data presented, I would certainly be more cautious about giving a more aggressive immunotherapy regimen – that is, combination anti-CTLA-4 and anti-PD-1/L-1 – in a patient with highly symptomatic inflammatory bowel disease. Also, while numbers in this study were small, it seems that endoscopic evaluation prior to ICI start could be helpful in risk stratifying for severe GI IRAE. While inflammatory findings on endoscopy may not necessarily be an absolute contraindication to use of ICI, it seems these results would certainly be helpful in shared decision-making with the patient regarding their risk of developing GI IRAE and weighing other potential treatment options. Finally, and most importantly, this data demonstrates that some patients with inflammatory bowel disease who receive ICI for their malignancy can derive clinical benefit with manageable toxicities, suggesting that the mere presence of comorbid inflammatory bowel disease should not be a blanket exclusion criterion for ICI clinical trials.

This concludes this JCO Podcast. Thank you for listening.

The High Prevalence of Exercise Intolerance in Adult Survivors of Childhood Cancer Is Predictive of All-Cause Mortality Jan 08, 2020

Show notes

This podcast describes a study examining aerobic capacity in a cohort of over 1200 adult survivors of childhood cancer and related impairments of cardiac, pulmonary and neuromuscular body systems, to understand how aerobic capacity influences all-cause mortality.

TRANSCRIPT

This JCO Podcast provides observations and commentary on the JCO article 'Exercise Intolerance, Mortality, and Organ System Impairment in Adult Survivors of Childhood Cancer' by Ness et al. My name is Kristin Campbell, and I am a licenced physical therapist and associate professor in the Faculty of Medicine at the University of British Columbia in Vancouver, Canada. My oncologic specialty is in rehabilitation, primarily related to breast cancer.

Exercise intolerance is a global measure of functional capacity that reflects the complex integration of body systems. It is well established in the general population that exercise intolerance is predictive of future cardiovascular health and mortality. Whether this relationship also existed for adult survivors of childhood cancer was examined by Ness and colleagues in the article that accompanies this podcast. . In the largest study to date of its kind, this manuscript reports on a comprehensive and methodologically rigorous examination of exercise intolerance measured by a gold standard maximal cardiopulmonary exercise test in over 1200 adult survivors of childhood cancer who are part of the St. Jude's Lifetime Cohort Study.

The first main finding is the low levels of exercise capacity in this sample of childhood cancer survivors despite a relatively young mean age of 35 years. The observed maximal aerobic capacity, or VO2peak, ranged on average between 25-27 ml/kg/min, which fall into the "poor" or "very poor" categories of age and sex matched normative values. Compared to 285 community controls who were friends or family members of the cohort patients, the observed maximal aerobic capacity values for childhood cancer survivors were on average 22% lower. In fact, these values are actually more consistent with values seen in healthy adults in their seventies or eighties. Furthermore, the low value of maximal aerobic capacity may also be an underestimate. Thirteen percent of individuals in the St. Jude's cohort who agreed to participate in the study were not cleared to undertake the maximal cardiopulmonary exercise test due to recent diagnosis of cardiac or pulmonary disease, or lab values and symptoms indicating cardiac or pulmonary issues. This suggests that the prevalence of exercise intolerance may be even greater in a real-world clinical setting than that observed in this cohort.

To examine the association between exercise intolerance and mortality, the authors defined exercise intolerance as a maximal aerobic capacity of

A unique feature of this study is that the authors also undertook comprehensive measures of host, treatment, and lifestyle factors to better understand how these factors influence exercise intolerance. These additional measures included cardiac imaging at rest, autonomic response, measured by blood pressure response to the maximal graded exercise test, standard pulmonary function testing, quadriceps strength testing, and peripheral sensorimotor function using the modified total neuropathy scale. This data provides a rare look into the acute and chronic responses to exercise of the cardiovascular, pulmonary, autonomic and neuromuscular systems in those exposed or not exposed to cardiotoxic agents and will appeal to those an interest in exercise physiology. Odds of exercise intolerance were highest with reporting

Of note, the type of treatment received impacted the presentation of exercise intolerance. Lower exercise tolerance was observed in individuals who received >350 mg/m2 of anthracyclines, >30 Gy of chest radiation, >20 Gy of cranial radiation and receipt of carboplatin. As a result, the authors suggest that even asymptomatic childhood cancer survivors who have received these treatments be screened by medical providers for any required medical management prior to recommending or implementing an exercise program. Furthermore, while ejection fraction of 1.5 SD above age- and sex-predicted increased the odds of exercise intolerance with an odds ratio of 1.71 in those exposed to cardiotoxic agents and an odds ratio of 1.29 in those not exposed to cardiotoxic agents. The authors suggest that the use of echocardiology derived strain be expanded from current published guidelines from the American Society of Clinical Oncology on Prevention and Monitoring of Cardiac Dysfunction to identify early cardiac dysfunction in childhood cancer survivors with exercise intolerance and normal ejection fraction.

The study does have some key limitations. It is cross-sectional in design, making it difficult to assign temporal relationships between impairments in body systems and exercise tolerance. For example, is it the treatment that causes impairments in body systems that then limit exercise tolerance, or does situational inactivity due to side-effects of cancer treatment drive exercise intolerance and this in turn negatively impacts the exercise response of body systems? Furthermore, while there was a high participation rate and participants did not differ from non-participants by age, race or sex, not all eligible survivors enrolled. This may over or underestimate the prevalence of exercise intolerance or impact on mortality.

In considering the implications of these findings to clinical oncology, the authors acknowledge that adult survivors of childhood cancer face unique challenges in engaging in physical activity. In light of the high prevalence of exercise intolerance in childhood cancer survivors and the association to all cause mortality, the authors suggest that survivors may require referral to trained exercise specialists to learn how to accommodate specific impairments and deficits in order to reap the benefits of engaging in exercise. In the United States, the appropriate exercise specialists could include physical therapists, occupational specialists, certified exercise physiologists or physical medicine and rehabilitation specialists. Oncology providers are encouraged to include these individuals on their care teams and establish a connection to available programming in their healthcare facility or community to provide adult survivors of childhood cancer with greater access to appropriate exercise programming aimed at improving exercise tolerance.

This concludes this JCO podcast. Thank you for listening.

Leptomeningeal Disease in EGFR-Mutated Lung Cancer: Can We Finally Define a Standard Treatment? Jan 08, 2020

Show notes

This podcast describes the results of the BLOOM study, evaluating the efficacy of osimertinib in EGFR-mutated lung cancer with leptomeningeal disease after failure of prior EGFR TKI therapy.

TRANSCRIPT

This JCO Podcast provides observations and commentary on the JCO article "Osimertinib In Patients With Epidermal Growth Factor Receptor Mutation-Positive Non-Small-Cell Lung Cancer and Leptomeningeal Metastases: The BLOOM Study" by Yang et al. My name is Jürgen Wolf and I am the medical director of the Center for Integrated Oncology at the University Hospital of Cologne in Germany. I am a medical oncologist with expertise in personalized lung cancer care.

About 10% of patients with advanced EGFR-mutated lung cancer suffer from leptomeningeal disease. While this disease manifestation in non-small-cell lung cancer is generally associated with a particularly poor prognosis, with survival times of only a few months, the question arises whether treatment with specific tyrosine kinase inhibitors might enable a better disease control. Most studies evaluating the efficacy of 1st and 2nd generation EGFR-TKIs in leptomeningeal disease were retrospective and difficult to interpret, given the heterogeneity of the disease as well as of the preceding treatment procedures. Small prospective studies with patient numbers below 20 tested standard dose erlotinib or afatinib as well as high-dose pulsatile EGFR TKI treatment and reported disappointing results with survival times of around 4 months only.

The 3rd generation EGFR TKI osimertinib initially was approved for T790M positive failure of 1st and 2nd generation EGFR TKIs and is now commonly regarded as 1st line standard treatment for EGFR-mutated lung cancer based on a superior progression-free survival, overall survival and toxicity profile. In studies with primates and healthy volunteers, osimertinib has been shown to exert a higher blood-brain barrier permeability and a higher brain exposure compared with other TKIs. In the AURA clinical development program for osimertinib, 22 patients with T790M-positive relapse after EGFR TKI treatment and leptomeningeal disease were retrospectively identified, and an impressive median overall survival of 18.8 months was reported. A small prospective Japanese trial evaluated osimertinib in 13 patients with T790M-positive leptomeningeal disease which, however, could be confirmed only in 5 patients. Responses were seen in some patients, and the median progression free survival for all patients was reported with 7.2 months.

The BLOOM study part B, which is discussed in this podcast, is a multicenter phase I study evaluating osimertinib in EGFR-mutated lung cancer patients with leptomeningeal metastases and failure of previous EGFR TKI treatment. Study objectives were the assessment of clinical parameters like response, overall survival neurological status, and safety but also pharmacokinetics in blood and cerebrospinal fluid. Main inclusion criteria included confirmed diagnosis of EGFR Exon 19 deletion or L858R mutation and confirmation of leptomeningeal disease by positive cytology of cerebrospinal fluid and at least one leptomeningeal site assessable by MRI. There were two sequential cohorts, one unselected for the T790M mutation and with stable non-CNS disease at enrollment, and one for T790M positive patients without the requirement for stable non-CNS disease. Osimertinib dose was 160 mg once daily, which is twice the approved dose. Besides investigator-based response assessment, according to RECIST, leptomeningeal disease was also assessed by a neuroradiological blinded central review according to the RANO-LM working group criteria, which integrates clinical examination, cerebrospinal fluid cytology and neuraxis MRI.

41 patients from South Korea and Taiwan were included, 20 in the unselected and 21 in the T790M-positive cohort. About 70% of the patients had co-existing brain mets and about 50% prior radiotherapy. For 4 patients, no response data from the independent review were available.

The confirmed overall response rate for leptomeningeal disease was impressive at 62% as assessed by blinded independent review and nearly identical between both cohorts. By comparison, the overall response rate was only 27% by investigator assessment, which, in turn, revealed a higher stable disease rate. Prior brain radiotherapy had no influence on efficacy. Median duration of response was comparable between blinded independent review and investigator, with 15.2 and 18.9 months, respectively. In about one third of the evaluable patients confirmed CSF clearance could be observed. PK analysis indicated that plasma concentration of osimertinib and its active metabolites reached steady state by day 15; the ratio for osimertinib exposure in cerebrospinal fluid vs. plasma was around 16%.

Surprisingly, only half of the patients had an abnormal neurological baseline assessment, most of them with mild symptoms. Symptom stabilization occurred in 54% during treatment; only 5% showed regression of neurological functions.

Overall, median progression-free survival, as assessed by the investigators, was 8.6 months and median overall survival 11 months. Progression-free survival and overall survival differed markedly between both cohorts. For instance, overall survival was 16.6 months in the unselected and 8.1 months in the selected group. Possibly, the requirement for stable non-CNS disease in the unselected group was partly responsible for the better survival outcome in this subset . However, this has to be interpreted cautiously in view of small patient numbers and large confidence intervals.

Osimertinib 160mg was well tolerated in the majority of patients with the known osimertinib side-effect profile. However, 24% of the patients suffered from adverse events grade 3 or more—possibly related to osimertinib, according to the investigators' assessment. Dose reduction had to be performed in 12% and discontinuation of treatment in 22% of the patients due to adverse events. 17% of the patients had fatal events that did not appear to be causally related to osimertinib.

What can we learn from this study? This is the largest prospective study so far in this setting and osimertinib clearly shows clinical efficacy. The study methodology was sound, with response assessment by blinded independent review and based on RECIST criteria as well as on the RANO criteria established in particular for leptomeningeal disease. The overall response rate of leptomeningeal disease of around 60% and the duration of response of around 15 months is clinically relevant in particular, as it is correlated with improvement or at least neurological stabilization in most patients. Although the toxicity of the treatment is substantially higher than reported in osimertinib trials so far, it is manageable, and the risk/benefit ratio appears to be favorable.

What are the limitations of the study? Patient numbers are small, and the patients are heterogeneous with respect to several important factors such as pretreatment whole-brain radiotherapy, occurrence of simultaneous CNS metastases and neurological symptoms. Thus, absolute values for efficacy have to be interpreted cautiously, and comparison with already published trials remains difficult. Also, unfortunately in view of the toxicity, the question remains open whether the 160mg dose, which is not approved, is actually necessary. Finally, since osimertinib increasingly becomes the first-line treatment standard in EGFR-mutated lung cancer, the number of patients with failure of 1st- or 2nd-generation EGFR TKI treatment will decrease.

Despite these limitations, the trial provides the most convincing data so far in this special patient population and, in my opinion, defines an important new option to consider for patients with EGFR-mutated lung cancer and leptomeningeal disease after failure of previous EGFR TKI treatment.

This concludes this JCO Podcast. Thank you for listening.

Advancing Treatment Options for Mismatch Repair-Deficient Metastatic Colorectal Cancers Jan 08, 2020

Show notes

This podcast reviews the results of KEYNOTE 164 investigating the use of pembrolizumab for mismatch repair deficient metastatic colorectal cancer, the place of this agent in the current clinical paradigm, and future directions to identify which patients are most likely to benefit from this treatment strategy.

TRANSCRIPT

This JCO Podcast provides observations and commentary on the JCO article 'A Phase II, Open-Label Study of Pembrolizumab in Treatment-Refractory, Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: KEYNOTE-164' by Le et al. My name is Dustin Deming, and I am an associate professor at the University of Wisconsin Carbone Cancer Center in Madison, Wisconsin. My oncologic specialty is gastrointestinal oncology.

Microsatellite instability high status or mismatch repair deficiency is found in approximately 15% of early stage colorectal cancers, but only 3-4% of metastatic colorectal cancer. The mechanisms by which these cancers acquire their DNA repair aberrations can vary, including germline mutations, somatic mutations and promoter methylation, which is often observed in the setting of the hypermethylation phenotype associated with BRAF mutations. This distinct colorectal cancer subtype is of particular interest for immunotherapy strategies as the lack of adequate mismatch repair can lead to 1000s of mutations and also fusions leading to the potential for expression of more neoantigens.

This world-wide phase 2, open-label study enrolled 124 patients with microsatellite instability high or metastatic mismatch repair deficient colorectal cancer following 2 or more lines of standard therapy in cohort A and following 1 or more lines of therapy in cohort B. Patients received pembrolizumab 200 mg every 3 weeks, up to 2 years, until progression, unacceptable toxicity, or withdrawal. The primary endpoint was objective response rate by Response Evaluation Criteria in Solid Tumors version 1.1 by independent central review and secondary endpoints included duration of response progression-free survival, overall survival, safety and tolerability.

At the time of this report the median follow-up for cohort A was 31.3 months and 24.2 months for cohort B. The objective response rate was 33% for both cohorts. This includes 7 patients who achieved a complete response. The median PFS was 2.3 months for cohort A and 4.1 months for cohort B. For those patients that developed an objective response the duration of response was quite prolonged with the median duration of response not reached in either cohort. The median overall survival was 31.4 months for cohort A and not reached in cohort B. This treatment was well-tolerated in this population with the most common toxicities being fatigue, pancreatitis, and increased alanine aminotransferase or lipase.

Overall pembrolizumab is an exciting addition to the treatment strategy for patients with metastatic mismatch repair deficient cancers. Based on these results, in part, this agent is now FDA approved for patients with previously treated microsatellite instability high or mismatch repair deficient metastatic colon cancers after fluoropyrimidine, oxaliplatin, and irinotecan, and for patients also for non-colorectal solid tumors following at least one prior therapy, regardless of tumor type or origin. This was the first FDA approval of a tumor histology agnostic anticancer therapy.

Long-term follow-up from this, and similar cohorts, is required to further define the duration of response for these patients, as there is hope that some of these patients could even be cured. Unfortunately, it is only a minority of patients that seem to benefit from this approach as demonstrated by the short median progression free survival in both cohorts. A better understanding of which patients are likely to benefit from immunotherapy approaches are clearly needed.

The presence of Lynch syndrome was not captured in this study to evaluate for differential response in this setting. The BRAF mutation status was collected and across both cohorts 14 patients had BRAF mutant cancers. The response rate for these patients was 43%. A similar benefit was also observed in KRAS or NRAS mutant and wild-type cancers. This study was limited in its ability to further assess those factors that could influence pembrolizumab response given the relatively small sample size and limited biospecimen collection.

Further clinical trials are investigating the use of anti-PD1 therapies for these patients in the first-line and adjuvant settings, in combination with chemotherapy and with other immune checkpoint agents, such as CTLA4 and LAG3, among others. This includes Checkmate 142, which is a phase II study that is examining nivolumab and ipilimumab in a cohort of 46 patients with microsatellite instability high or mismatch repair deficient colorectal cancer in the first-line setting. Preliminary results were presented at the 2018 European Society of Medical Oncology meeting demonstrating a 60% objective response rate and a 12 month progression free survival of 77%. These early results are promising, but further investigation is needed.

As we look forward to which factors could be leading to a lack of clinical benefit from these agents it is important to consider those factors that are intrinsic to the cancer cells, tumor microenvironment, and patient specific factors. Tumor cell intrinsic factors include important cell attributes for the immune response such as the tumor mutation burden, MHC class I expression, including beta-2-microglobulin expression, the mutation profile, including alterations in WNT signaling shown to be important for immunotherapy resistance in metastatic melanoma, and tumor heterogeneity. There is also a growing understanding of factors that are important within the tumor microenvironment for tumors to be permissive to immune cell infiltration. These factors include differences in the immune and fibroblast cell subtypes present and also the presence of certain matrix proteins. This includes a matrix proteoglycan called versican that my laboratory and others have demonstrated has immunosuppressive properties, but can be cleaved by ADAMTS proteases to an immunostimulatory fragment. Additionally, patient specific factors need to be considered such as the microbiome, immunosuppression and adverse event management.

In summary, the results of KEYNOTE 164 are a significant advance for patients with microsatellite instability-high and mismatch repair deficient cancers. Long-term follow-up from this study and further studies into the most efficacious clinical setting to use these agents will continue to advance the clinical use of immunotherapy options for these patients.

This concludes this JCO Podcast. Thank you for listening.

Keeping Mycosis Fungoides in Check: A Study of Pembrolizumab for Relapsed/Refractory MF and Sezary Syndrome Jan 06, 2020

Show notes

This podcast evaluates results from a phase II clinical trial of pembrolizumab for relapsed Mycosis Fungoides and Sezary Syndrome in the context of the current systemic treatment landscape for this disease.

TRANSCRIPT

This JCO Podcast provides observations and commentary on the JCO article "Pembrolizumab in Relapsed and Refractory Mycosis Fungoides and Sezary Syndrome: A Multicenter Phase II Study" by Khodadoust et al. My name is Jennifer Amengual, and I am an Assistant Professor of Medicine at the Columbia University Irving Medical Center in New York, New York, USA. My oncologic specialty is lymphoma.

Mycosis fungoides, otherwise known as MF, and Sezary Syndrome, its leukemic variant, are rare subtypes of cutaneous T-cell lymphoma. Although most patients with MF have indolent disease, those with advanced stage MF often experience resistance to systemic therapy with a persistent and progressive disease course, which has a negative impact on overall well-being and survival. Patients may have intense pruritus, which can then put them at increased risk for staphylococcus infection, sepsis and in turn can trigger disease flare.

Advanced-stage MF is a chronic disease that is not considered curable; therefore, it is necessary to consider management strategies that provide symptom relief and can be maintained over a long period of time. Most patients cycle through a multitude of therapies, often including skin-directed and, later, systemic therapies. Many of the acceptable therapies are derived from retrospective studies or single-arm trials; therefore, it is not possible to objectively compare outcomes and toxicity. In order to put the outcomes of pembrolizumab in context of other acceptable treatment modalities, I will discuss some of these treatments now.

Systemic retinoids, such as bexarotene, are taken orally and can induce an overall response of 45-55%. The drug is well tolerated but can lead to hypertriglyceridemia and hypothyroidism, requiring monthly monitoring and frequent treatment with lipid-lowering agents and thyroid hormone replacement.

Low-dose methotrexate, administered either orally or by intravenous infusion weekly, can lead to response rates between 30 and 50%. Common side-effects include mucositis, cytopenias and gastrointestinal upset. Pralatrexate is a novel antifolate drug that when studied using half the dose of that which is approved for PTCL , induced a 45% response rate for patients with MF. The treatment is also well tolerated, with the most common side-effects being mucositis and thrombocytopenia.

There are 2 histone deacetylase inhibitors approved for use in MF and Sezary Syndrome. Both romidepsin and vorinostat have overlapping toxicity profiles, including gastrointestinal disturbances, fatigue, anorexia, and cytopenias. Romidepsin is also associated with ECG abnormalities. In patients with cutaneous T cell lymphoma, romidepsin has demonstrated a response rate of 34% and is associated with a median duration of response of 15 months. Vorinostat, an oral drug, has demonstrated a response rate of 30%.

Recently, 2 biologics have been in used for patients with MF. Brentuximab vedotin is an antibody drug conjugate which targets the surface marker CD30 and brings monomethyl auristatin E into the cell. It is associated with a response rate of 70% in MF. Responses are significantly better in those with greater than 5% of CD30 expression. The most common side-effect is peripheral neuropathy. Mogamulizumab is a humanized antibody directed against the chemokine receptor CCR4. This agent was studied in a randomized trial compared to vorinostat, where it led to a PFS of 7.7 months and response rate of 28%. The most common adverse events were attributed to infusion reactions, rash, diarrhea, and fatigue. There was also an increased risk of graft-versus-host disease in patients who subsequently went on to allogenic transplant, which needs to be considered when using this treatment strategy. As you can see, there are many different approaches to the treatment of advanced-stage MF and Sezary Syndrome, and the drugs I have discussed do not encompass an exhaustive list.

Immune checkpoint antibodies against Programmed cell death protein 1 otherwise known as PD-1 interfere with inhibitory signaling pathways expressed on exhausted T-cells and wake up these cells allowing them to perform anti-tumor activities. The investigators rationalize the use of PD-1 inhibitors in MF and Sezary syndrome given PD-1 dysfunction and altered expression on MF cells and the skin microenvironment.

The Cancer Immunotherapy Trials Network performed a multicenter phase II single-arm study of pembrolizumab in 24 patients across 8 centers with relapsed or refractory MF or Sezary Syndrome. Of the 24 patients enrolled, 9 had MF and 15 had Sezary syndrome. Most had advanced disease represented by tumor stage disease, erythrodermic presentation, or were stage IIIB or higher. Patients received a median of 4 prior lines of systemic therapy. In addition, 4 patients had evidence of histologic large cell transformation. These represent some of the most challenging clinical situations.

Pembrolizumab was administered every 3 weeks for 24 months or until withdrawal of consent, adverse reactions or investigator's decision. The therapy was well tolerated, with no grade 4 or 5 immune-related adverse events. There were, however, 11 immune-related adverse events observed among 9 patients. This led to discontinuation of treatment in 4 patients, all due to grade 3 events including pneumonitis, duodenitis, hepatitis, and a corneal ulcer.

Interestingly, over half of the patients with Sezary Syndrome experienced a flare of their symptoms early in their treatment course. This manifested as increased erythema, pruritus, and peripheral edema. Patients were managed with topical steroids and close observation. Only 1 patient had a prolonged reaction requiring systemic therapy, and no patients were discontinued from therapy due to flare of their disease. Patients with MF did not experience any skin toxicity. The authors investigated the relationship of this reaction to response and found that 3 of 8 Sezary patients who experienced a skin flare went on to achieve a response, whereas only 1 of the 7 Sezary patients who did not have a flare achieved a response. Using mass cytometry profiling of PBMCs, the authors observed a sevenfold increase in PD-1 expression on circulating Sezary cells in patients who experienced a flare. Although these observations were made across a small number of patients, it will be worthwhile to pay attention to this in future studies to determine if this is a true predictor for flare reaction or response.

Pembrolizumab demonstrated significant clinical responses in 9 of 24 patients, leading to an overall response rate of 38%. This falls right into the range with other acceptable treatment options. Patients were heavily pretreated, yet the number of prior lines of therapy did not impact the response to pembrolizumab, possibly owing to non-overlapping mechanism of action. In addition, responses were seen in both MF and Sezary patients and those with erythrodermic and tumor stage presentations. There was a trend toward better outcomes in the MF patients. Responses were durable, and the median duration was not reached within a follow-up period of 58 weeks. The 1-year PFS was 65%, and OS was 95%. Two responding patients relapsed 8 to 12 weeks after discontinuation of treatment. The authors discuss that this may indicate the need for continuous treatment in this patient population, which is contrary to the general treatment strategy used for checkpoint inhibitors in other malignancies.

Although this study only enrolled 24 patients, pembrolizumab appears to have similar outcomes as other drugs used in advanced-stage MF and Sezary Syndrome, with an acceptable toxicity profile. It produces a long duration of response, making it an attractive addition for patients suffering from this disease. Pembrolizumab does not have overlapping mechanism of action with most of the drugs used today and can therefore be easily integrated into the sequence of treatment for patients with MF and Sezary Syndrome. Finally, it is possible that pembrolizumab's effects will enhance those seen with other agents. We should look forward to confirmatory clinical trials of pembrolizumab for the management of patients with MF or Sezary Syndrome.

This concludes this JCO Podcast. Thank you for listening.

What's in a Name? An Introductory Guide Dec 26, 2019

Show notes

This podcast discusses the results and implications of a recent study on gender bias in speaker introductions at an international oncology conference.

This JCO Podcast provides observations and commentary on the JCO article "Evaluating Unconscious Bias: Speaker Introductions at an International Oncology Conference" by Duma et al. My name is Dr. Tatiana Prowell. I am an Associate Professor of Oncology at Johns Hopkins Kimmel Cancer Center and Breast Cancer Scientific Liaison at the U.S. Food and Drug Administration in Silver Spring, Maryland. My oncologic specialty is breast cancer.

In the article that accompanies this podcast, Duma and colleagues report the results of a retrospective observational study of speaker introductions at two consecutive years of ASCO Annual Meetings. The investigators hypothesized that female speakers in oral sessions would be introduced with a professional form of address less frequently than male speakers. For the purposes of the study, they defined a professional address as use of a title such as Professor or Doctor, followed by the speaker's full name or last name, or the speaker's full name followed by doctoral degree. A team of four male and four female reviewers analyzed 781 video recordings of oral sessions from the 2017 and 2018 ASCO Annual Meetings and recorded the gender of the introducer and speaker and how the speaker was introduced. They found that female speakers received a professional form of address 62% of the time whereas male speakers were introduced professionally 81% of the time, a difference that was statistically significant. Duma and her colleagues also assessed whether the gender of the introducer was associated with a difference in the likelihood of receiving a professional introduction. They found that male moderators introduced female speakers professionally a little more than half the time, whereas they introduced men professionally in 80% of cases. Interestingly, when serving as introducers, women were more likely than men to include a professional form of address, which they did about three-quarters of the time, regardless of whether they were introducing men or women. Perhaps the most striking result of the study was that one in six female speakers was introduced by her first name only, a surprising degree of informality for a high-profile conference like the ASCO Annual Meeting, which draws more than 40,000 attendees per year. By comparison, male speakers were introduced by first name alone in just 3% of presentations. In a multivariate analysis that included gender, degree, academic rank and geographic location of the speaker's institution, male speakers were 2.5 times more likely to receive a professional introduction compared to female speakers.

This study adds to a growing body of literature in medicine investigating the prevalence of gender bias in speaker introductions. For example, previous studies of speaker introductions over a 3 year period of Mayo Clinic Internal Medicine Grand Rounds and at an American Society of Colon and Rectal Surgeons Annual Meeting reported similar findings. In both cases, female speakers were less likely than men to be introduced using a professional form of address, and women introducers more consistently referred to speakers by a professional title, regardless of whether the speaker they were introducing happened to be a man or a woman.

This study raises two key questions: why do we see this, and how can we fix it? A speaker introduction, especially at an international conference, is by definition a formal ritual, and yet one so familiar to us that we may have lost sight of its purpose. It would be easy enough for speakers to introduce themselves. Every speaker has an opening slide that shows his or her name and institutional affiliation. So why choose someone, and often someone well-known within the field, whose role is to introduce the speakers at all? What leads us to say, "Dr. Carol Greider is Bloomberg Distinguished Professor, Director of Molecular Biology and Genetics at Johns Hopkins University, and a recipient of the 2009 Nobel Prize in Medicine"? I believe we do this for two reasons. First, formal introductions provide a moment, however brief, to demonstrate our collective respect for the speaker and his or her scientific contributions. Second, the information in the introduction signals to any who are not familiar with the speaker that the person is credible, knowledgeable, and worthy of our attention. Although more than 50% of medical school matriculants and about 40% of medical school faculty are women, they remain underrepresented at higher academic ranks and in leadership roles. Only about one-quarter of full professors are women, and fewer than 1 in 5 department chairs are women. Women are also less likely than men to be the first or senior author of manuscripts and thus less likely to be standing at the podium. As a result, the names and work of women in medicine may well be less familiar to the audience. Female introducers may therefore be more likely to assign value to use of a professional form of address. If this were true, one might expect to see women more consistently use a professional form of address when introducing speakers, and this is in fact what Duma and her colleagues observed.

The more troubling question is why men approached the introduction of male and female speakers so differently and why male speakers were 2.5 times more likely to be introduced with a professional title than women. I believe that most moderators, if presented with data from their own sessions, would be surprised to learn that they introduce men and women differently. This is called unconscious bias, and we are all susceptible to it. While the root causes of unconscious gender bias are numerous, one of these is surely the dearth of women occupying senior positions in medicine. As a community, we have tremendous power to remedy this source of unconscious bias. But while we can all re-commit ourselves to mentoring and sponsoring women in order to create more visible examples of female leaders in medicine, these efforts will not change the face of medicine, nor eliminate our unconscious gender bias, overnight. And yet, this is a change that needs to be made now. A male colleague of mine described introducing a woman at the podium by her first name as the verbal equivalent of rubbing the shoulder of a female professional acquaintance, then extending a handshake to a male professional acquaintance, that is to say, an inappropriate degree of familiarity with the woman. However, even in circumstances where the introducer and speaker are well-known to one another, formal settings call for formality. I call my physician husband "honey" at home, but if I were moderating an ASCO Annual Meeting session in which he was a panelist and said "Honey, why don't you take that question?" it would of course be ridiculous. Using respectful forms of address in formal settings like conference sessions is ultimately a mark of professionalism and, in 2019, non-negotiable.

The good news is that, unlike many problems in medicine, this one has a couple of solutions that we can implement immediately. We can provide a simple standardized script at the podium that ensures all speakers receive an equitable introduction. All conferences should implement this now, and in fact, motivated by Duma and her colleagues' work, session chairs will receive such a script for introductions at the 2020 ASCO Annual Meeting. Perhaps more importantly, though, we can appreciate the formal introduction as a ritual that has been conserved through generations of scientists for a reason. Regardless of our gender, all of us as physicians remember that feeling when were July interns and the attending said of us on rounds something like, "Dr. Smith will be back to explain the plan to you in more detail." In that moment, when we were called Doctor before an audience of our patients and our peers, we felt respected, capable, confident, and proud. Let's commit to ensuring that all of our colleagues have that feeling every time they take the podium.

This concludes this JCO Podcast. Thank you for

Resuming Life After Cancer Therapy: Treatment-Free Survival Dec 10, 2019

Show notes

Treatment-free survival is a novel endpoint in immunotherapy.

TRANSCRIPT

This JCO Podcast provides observations and commentary on the JCO article "Treatment-Free Survival: A Novel Outcome Measure of the Effects of Immune Checkpoint Inhibition—A Pooled Analysis of Patients With Advanced Melanoma" by Regan et al. My name is Adil Daud, and I am Professor of Medicine and Dermatology and Director of the Melanoma Program at the University of California, San Francisco. My oncologic specialty is medical oncology.

Cancer therapy has achieved great success in the last 40-50 years. Where treatment with chemotherapy required inpatient hospitalization and gut-wrenching toxicity, therapy today can often be achieved with lower grade side effects and limited time in the hospital or outpatient infusion center. While these changes have brought enormous benefit to patients, many patients feel that the tug of ongoing therapy for metastatic or advanced cancer and long for a time where therapy is not continuing, and the word "cure" is not completely out of mind.

Allied to these concerns is the rise and expansion of immunotherapy for cancer. The growth and spread of neoplasm often triggers the immune system, which mobilizes in response. While cancers can use a variety of adaptive mechanisms to evade the immune system, blocking these evasive mechanisms can produce lasting responses and, in some cases, durable tumor-free intervals. Cytokine therapy as exemplified by IL-2 offered this benefit since its approval in the 1990's for renal cell cancer and for melanoma for approximately 10-20% of patients treated. The CTLA4 antibody, ipilimumab has had a similar long-term disease control rate with a better toxicity profile. However, it is the anti-PD-1 monoclonal antibodies, used by themselves or with ipilimumab that have made treatment-free survival a tangible and achievable goal for many patients with cancer especially those with cutaneous melanoma.

Measuring the effect of treatment is traditionally done with measures of disease control. These include tumor shrinkage as measured by an agreed upon method such as RECIST or irRECIST or by lengthening of time-either lifespan or time without progressive disease (progression-free survival). However, it is possible that a similar lifespan could be achieved in one of 2 different ways-either continuous treatment with a drug or a shorter-term treatment that stops within a few months and then the patient has no further treatment. Comparing these treatments that are profoundly different for a patient but similar in terms of standard time or disease control measures demands new measures that can help describe the benefit of one or the other treatment.

In the JCO article that accompanies this podcast, Regan et al, in an analysis of 1077 patients across 2 different randomized trials, attempt to provide such a measure. They define treatment-free survival as interval between time to ICI cessation to the time to subsequent therapy or death. With this measure, the shorter the therapy and the more delayed the need for subsequent therapy (or death) the longer this interval is. Combination immunotherapy is notoriously toxic and while treatment duration can be short, the side effect duration can be prolonged. Could TFS be contaminated with toxicity ? to answer this question, Regan et al introduce another endpoint, TFS with and without toxicity and partition this with persistent and late onset grade ≥3 toxicity.

These endpoints are illustrated in Figure 1. Below the familiar Kaplan-Meier overall survival curve is a slice showing survival after subsequent therapy initiation (so factoring in progression). Below this is the TFS without toxicity. Below this slice is the TFS with toxicity and below this is the time on IO therapy. With this division, the familiar KM curve gives a lot more information and illustrates the difference between nivo-ipi combination therapy and nivolumab monotherapy. While the overall survival is not statistically different between these 2 treatments (as shown in previous publications) the TFS lets us see what is going on with patients. In Figure 4 we can see that in the combination nivo-ipi arm the TFS (mean) is 11.1 months vs 4.6 months for nivo alone and 8.7 months for ipi alone. These numbers indicate that TFS alone does not convey the full picture as ipi beats nivo in this measure due to the short duration of ipi treatment while extensive previous data including from keynote 006 show us that pd-1 therapy exceeds ctla4 therapy in virtually every other measure of health.

If we look at TFS subtracting toxicity, again ipi nivo beats nivo handily with 10 months vs 4 months but again ipi with 8.5 months slots in the middle. Figures 5A, 5 B and 5C show us the TFS partitioned by grade ≥3 treatment-related adverse events, grade ≥2 TRAEs or by the use of immune suppressants.

To summarize this interesting manuscript, overall survival can be subdivided into TFS and time on therapy and time following subsequent therapy. The TFS can be further subdivided into TFS with or without toxicity (≥2 or ≥3 TRAE or use of immune suppressants). These additional measures give some granularity to the survival and let us see what exactly survival constitutes, time off treatment and toxicity or time on treatment and with side effects.

These measures have several limitations: one of the important ones is introducing differences between treatment arms which by primary outcome measures have no difference by standard PFS or OS and by favoring short duration high toxicity treatments (such as ipi) over low toxicity, low intensity chronic treatments (such as nivo). These are value judgements which matter to many patients but need to be understood as such. In oncology, we need to make these value judgements explicit and make the tradeoffs clear. Ultimately though, the importance of TFS and similar outcome measures may be that they encourage this conversation and help our field open up to what matters.

This concludes this JCO Podcast. Thank you for listening.

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