Show notes
Dr. Lakshmi Rajdev and Dr. Manish Shah join the podcast to discuss the updated guideline on immunotherapy and targeted therapy in unresectable locally advanced, advanced, or metastatic gastroesophageal cancer. They share first-line and subsequent-line recommendations for both gastroesophageal adenocarcinoma and esophageal squamous cell carcinoma based on actionable biomarkers including PD-L1 expression, MMR and/or MSI, CLDN18.2 expression, and HER2 status. They note the importance of the algorithms and tables in the guidelines that provide visual illustrations and quick reference guides of the evidence-based recommendations. They also comment on ongoing and recently presented trials that may impact future guidelines in this space. Read the full guideline, "Immunotherapy and Targeted Therapy for Advanced Gastroesophageal Cancer: ASCO Guideline Update" at www.asco.org/gastrointestinal-cancer-guidelines" TRANSCRIPT This guideline, clinical tools and resources are available at www.asco.org/gastrointestinal-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-25-02958 Timestamps · 00:00 – 02:15 Introduction and Overview · 02:16 - 08:20 First-line treatment for patients with pMMR/MSS, HER2-negative gastroesophageal adenocarcinoma · 08:21 –10:29 First-line treatment for patients with pMMR/MSS, HER2-positive gastroesophageal adenocarcinoma · 10:30 – 14:39 First-line treatment for patients with dMMR/MSI-H, gastroesophageal adenocarcinoma · 14:40 – 18:03 First-line treatment for ESCC · 18:04 – 22:04 Second- and third-line therapy for gastroesophageal adenocarcinoma and ESCC · 22:05 – 24:38 Importance of guideline · 24:39 – 27:45 Outstanding questions and future research Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today I am interviewing Dr. Lakshmi Rajdev from the Icahn School of Medicine at Mount Sinai and Dr. Manish Shah from Weill Cornell Medicine, co-chairs on "Immunotherapy and Targeted Therapy for Advanced Gastroesophageal Cancer: ASCO Guideline Update." Thank you for being here today, Dr. Rajdev and Dr. Shah. Dr. Lakshmi Rajdev: Thank you. Dr. Manish Shah: Thank you for having us. It is wonderful. Brittany Harvey: And then just before we discuss this guideline, I would like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Rajdev and Dr. Shah, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So then to dive into what we are here today to talk about, Dr. Shah, I would like to start first with what prompted the update to this guideline, which was previously published in 2023, and what is the scope of this updated guideline? Dr. Manish Shah: Yes, terrific. So even in the last few years, the pace of drug development in gastroesophageal cancers has just been astounding. So, what prompted this guideline is actually the practice-changing results for a new biomarker, CLDN18.2 hat was based on the GLOW and SPOTLIGHT studies, as well as a practice-changing study in HER2-positive disease where we added pembrolizumab to trastuzumab and chemotherapy for tumors that are HER2-positive and PD-L1 CPS 1 or greater. And then there were also new studies and new approvals in esophageal squamous cell cancer that you will hear about as well. So there were several studies, overall more than 5,000 patients were reported on, and that led to several new therapies, new indications, and it really necessitated this guideline. Brittany Harvey: Excellent. It is great to hear about all of these exciting updates in this space. So then to next review the key recommendations of this guideline by clinical question that the expert panel addressed. So, Dr. Rajdev, what is the recommended first-line treatment for patients with proficient mismatch repair, microsatellite stable, HER2-negative gastroesophageal adenocarcinoma? Dr. Lakshmi Rajdev: Thank you for that question. So historically, we have sort of used fluoropyrimidine and platinum doublets, which yielded a survival of about one year. More recently, immunotherapy and targeted therapy options have improved outcomes in patients with advanced esophageal and gastric adenocarcinoma, as well as squamous cell carcinoma. Patients with gastric and GE junction adenocarcinoma have a high rate of actionable alterations, so it is imperative that physicians test the following biomarkers upfront so that it can help guide therapy. The markers recommended by the ASCO panel are HER2, MMR or MSI, CLDN18.2, and PD-L1. And also, it was recommended to use NGS if feasible in this patient population. HER2, as we know, is expressed in about 15% to 25% of patients; PD-L1 expression occurs in about 80% of patients; MSI-high, deficient MMR is present in about 5% to 8% of patients; and CLDN18.2 expression is present in about 40% of patients. There is, of course, biomarker overlap. About 13% to 22% of CLDN18.2 patients are also PD-L1 positive. For patients with pMMR or microsatellite stable HER2-negative disease with PD-L1 expression greater than 1 and absence of CLDN18.2, the panel recommended a first-line therapy with fluoropyrimidine and platinum-based therapy in combination with immunotherapy. These recommendations stem from large phase 3 trials, and the agents approved in the United States are pembrolizumab, nivolumab, and tislelizumab. It has been shown that immunotherapy benefit is greater in patients with higher PD-L1 expression, and it is not possible to comment on the individual PD-L1 cutoff scores and sort of identify the optimal PD-L1 cutoff score that sort of balances benefits and harms. But what is recommended is that immunotherapy-based treatments can be offered in patients with a CPS score of greater than 1. With regard to the choice of immunotherapy agents, that is pembrolizumab, nivolumab, or tislelizumab, these agents are considered to have similar efficacy, and the selection of an agent could be based on dosing schedule, cost considerations, toxicity, and the method of administration. Typically, clinicians should avoid withholding the start of chemotherapy while awaiting biomarker testing, depending on the clinical scenario. Now, for patients with pMMR microsatellite stable disease that is HER2-negative with PD-L1 expression less than 1 and positive CLDN18.2 expression, zolbetuximab-based treatments or in combination with chemotherapy is recommended, and this is based on two global phase III randomized controlled trials, the GLOW and the SPOTLIGHT. And across both studies, the hazard ratio for the overall survival was 0.78, and similarly, there was also an improvement in progression-free survival favoring the zolbetuximab group compared to the chemotherapy group alone. An important note is that nausea, vomiting is commonly associated with zolbetuximab-based treatments, and the panel recommended prophylactic antiemetics, adjusting zolbetuximab infusion rates, pausing infusion temporarily, using non-prophylactic antiemetics, and hydration intravenously prior to discontinuation of zolbetuximab-based chemotherapy. So effective handling of the GI-related symptoms with zolbetuximab is recommended prior to discontinuation of therapy. Now, for patients with pMMR microsatellite stable HER2-negative gastric, GE junction adenocarcinoma with PD-L1 expression greater than 1 and CLDN18.2 positivity, the ones with the dual expression with CLDN18.2 as well as PD-L1 chemotherapy, the choice of therapy can be based on the degree of PD-L1 expression, the toxicity profile, the burden of symptoms, and the anticipated improvement in symptoms associated with response to treatment, the patient comorbidities, the prior medical and treatment history. So this decision needs to be made on a case-by-case basis, and these are some of the factors that we suggested that could potentially influence the choice of therapy. For patients with pMMR microsatellite stable disease that is HER2-negative and a PD-L1 expression less than 1 and an absence of CLDN18.2 expression, first-line therapy with fluoropyrimidine and platinum-based chemotherapy is recommended. So you can see we have segmented out patients based on PD-L1 expression, pMMR and microsatellite stable disease expression, and also based on CLDN expression. Brittany Harvey: Absolutely. And that first point you noted, I think is really important, that biomarker testing is really critical for treatment decision-making in this space. So then the next subgroup of patients that the panel looked at, Dr. Shah, what first-line therapy is recommended for patients with proficient mismatch repair, microsatellite stable, HER2-positive gastroesophageal adenocarcinoma? Dr. Manish Shah: So this was an update from a few years ago. So we have known for 15 years now that if you are HER2-positive, you should get trastuzumab plus chemotherapy. That was based on the ToGA trial. And the update now is based on a trial called KEYNOTE-811, where it examined the addition of pembrolizumab to trastuzumab and chemotherapy versus trastuzumab and chemotherapy, and there was a progression-free and overall survival benefit. And again, here, the biomarkers are important. If your CPS PD-L1 is less than 1, we would not recommend Pembrolizumab in that setting, so you would still get trastuzumab and chemotherapy. But if it is 1 or greater, the PD-L1 CPS score, then we do recommend pembrolizumab unless there is a contraindication to immunotherapy. The take-home message really is from the onset of diagnosis, please check your biomarkers. And I will just, it is worth repeating, it is important to check your PD-L1 status, HER2 status, mismatch repair status, and CLDN18.2 status. And then the optimal therapy, and it is outlined in the publication, is really biomarker-driven. We know that if we are able to hit the target that is overexpressed, we are going to have a better outcome. And Dr. Rajdev did mention where there is overlap, there can be a lack of data, and that is where we are with both PD-L1 positive and CLDN positive. Here we do have data in HER2-positive cases where if you are both HER2-positive and PD-L1 positive, you would combine trastuzumab and pembrolizumab for the best outcomes. Brittany Harvey: Understood. I really appreciate you detailing what is most important for each individual biomarker combination that patients may have. So then following that, Dr. Rajdev, what does the expert panel recommend for first-line treatment for patients with esophageal squamous cell carcinoma that is not amenable to definitive chemoradiation? Dr. Lakshmi Rajdev: There are three phase III randomized clinical trials that have influenced practice in patients with esophageal squamous cell carcinoma examining the benefit of immunotherapy in this patient population. The RATIONALE-306 was a randomized trial of tislelizumab plus chemotherapy with platinum and fluoropyrimidine or paclitaxel versus placebo with chemotherapy. And then you have the KEYNOTE-590, which compared pembrolizumab plus chemotherapy versus chemotherapy alone. And then you have CheckMate-648, which included comparisons of nivolumab plus chemotherapy versus nivolumab plus ipilimumab or chemotherapy. And the primary endpoints for these studies were overall survival, and they did look at subgroups with PD-L1 expression. They used TPS score greater than 1% in CheckMate-648 and PD-L1 CPS greater than 10 in KEYNOTE-590. The bottom line is that the overall hazard ratio for overall survival across this patient population was 0.72. So clearly, there is benefit in patients that express PD-L1 CPS greater than 1 for benefit for the addition of immunotherapy. Now, the benefit again in patients with a PD-L1 expression less than 1 remains limited, and so the panel has made a recommendation for using immunotherapy in combination with platinum-based chemotherapy in patients with a PD-L1 greater than 1. Again, we know that it is hard to make recommendations on what PD-L1 cutoffs are recommended in this patient population, meaning that should it be limited to patients with a PD-L1 of 1 to 4 or greater than 10? I think that the general consensus that has been gleaned from the data is that the higher the PD-L1 expression, the greater the benefit. I do want to comment on another option that is available in patients with squamous cell carcinoma compared to adenocarcinoma, and that is the combination of nivolumab and ipilimumab. Now, in CheckMate-648, nivolumab with ipilimumab was also recommended as a treatment option in patients that have a PD-L1 score of greater than 1. There was a survival benefit demonstrated with this combination compared to chemotherapy alone. And an important observation in this study is that, although there was a slightly increased rate in early death, but there was really no significant difference in PFS and OS compared to chemotherapy alone. Importantly, the treatment appeared to be pretty well tolerated by the study population. There was a notable difference in the objective response rate, which was 35% in the nivolumab plus ipilimumab group compared to patients receiving nivolumab and chemotherapy, where it was 53%. So superiority is, so the importance of chemotherapy in patients with esophageal squamous cell carcinoma is to be noted. However, there is no difference in overall survival and progression-free survival when using the combination of nivolumab and ipilimumab, and thus it affords a chemotherapy-free option for this patient population with esophageal squamous cell carcinoma and a CPS with a score of greater than 1. Brittany Harvey: Understood. I appreciate you reviewing the evidence underpinning those recommendations as well. So then the next patient population that the guideline panel addressed, what first-line therapy is recommended for patients with deficient mismatch repair, microsatellite instability-high, gastroesophageal adenocarcinoma or esophageal squamous cell carcinoma? Dr. Lakshmi Rajdev: The rate of MSI-high expression is about 3% to 7% across different studies. Now, the KEYNOTE-158 was a tumor-agnostic study in patients with non-colorectal cancers, and again, the problem with the MSI-high population, given that it is so rare, the numbers in the individual studies are fairly small. But consistent outcomes do emerge, indicating high response to immunotherapy. So in KEYNOTE-158, a response rate of about 46% was noted. The number of patients was small, it was about 24. In CheckMate-649, which is a study of chemotherapy plus or minus nivolumab in patients with advanced gastric adenocarcinoma, there was again a very small number of patients, and patients that were MSI-high or deficient MMR did experience substantial benefits with the addition of immunotherapy, with hazard ratios in the order of about 0.38. In KEYNOTE-062, again, it was a very small number of patients, again about 6% or so, and similar to CheckMate-649, a substantial benefit was noted in combination with chemotherapy, but also there were benefits noted with pembrolizumab alone. The RATIONALE-305 again was a study of tislelizumab in combination with chemotherapy and similarly showed benefits to the combination of chemotherapy plus immunotherapy in this patient population. I think that we are all aware of the dramatic benefits of immunotherapy in this particular subset of patients, deficient MMR MSI-high, and also we have se…
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