Immunotherapy in Patients with Locally Advanced Esophageal Carcinoma: ASCO Guideline Rapid Recommendation Update

An interview with Dr. Manish Shah from New York Hospital and Weill Cornell Medicine, co-chair on "Immunotherapy in Patients with Locally Advanced Esophageal Carcinoma: ASCO Guideline Rapid Recommendation Update." He discusses the results of the Checkmate 577 trial and the updated recommendation of the Treatment of Locally Advanced Esophageal Carcinoma Guideline. For more information, visit www.asco.org/gastrointestinal-cancer-guidelines.

TRANSCRIPT

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SPEAKER: 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. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines Podcast Series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at ASCO.org/podcasts.

My name is Brittany Harvey, and today I'm interviewing Dr. Manish Shah from New York Hospital and Weill Cornell Medicine in New York, NY, co-chair of the Locally Advanced Esophageal Carcinoma guideline expert panel and lead author on the Immunotherapy in Patients with Locally Advanced Esophageal Carcinoma: ASCO Guideline Rapid Recommendation Update. Thank you for being here, Dr. Shah.

MANISH SHAH: Absolutely. Thank you very much for having me.

BRITTANY HARVEY: First, I'd 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 full conflict of interest information for this guideline is available online. Dr. Shah, do you have any relevant disclosures that are directly related to this guideline?

MANISH SHAH: Yes, so I do have relationships with many of the companies that make checkpoint inhibitors. And in fact, we are being supported by Bristol Myers Squibb on a first-line study of chemotherapy with nivolumab. We've also been supported by Merck on a pre-operative study of chemotherapy with radiation and pembrolizumab.

BRITTANY HARVEY: Thank you for that information. Then so what prompted this rapid update to the Treatment of Locally Advanced Esophageal Carcinoma: ASCO Guideline?

MANISH SHAH: Yes, so recently there was a landmark study that was practice-changing in the space, published in the New England Journal of Medicine by Ronan Kelly and colleagues. And this was the report of CheckMate 577, the use of adjuvant nivolumab in resected esophageal or gastroesophageal junction carcinoma. And this was a positive study that led to important changes in practice. And we felt that this was worthy and worthwhile of getting it out there to the community.

BRITTANY HARVEY: Great. Then based off this new data from CheckMate 577 on nivolumab, what is the updated recommendation?

MANISH SHAH: Sure. So previously, the data available was that patients who receive chemotherapy and radiation and then went on to receive surgery, that those patients with esophageal cancer had no further treatment recommendations. This study, CheckMate 577, actually examined nivolumab in that context. So patients who received chemotherapy and radiation and then underwent surgery, if they had some residual disease at the time of the surgical resection, even if they had a major response but there was some residual cancer in the surgical specimen, patients were eligible for randomization. And about 800 patients were randomized, 2 to 1, to receive nivolumab versus placebo in this context.

And the primary endpoint in the study was disease-free survival. And patients who received nivolumab had a median disease-free survival of 22.4 months compared to placebo, which was the previous standard of care. The median disease-free survival in that group was 11.0 months, so almost a doubling of the disease-free survival. The hazard ratio was 0.69. And that was highly significant, with a p value of 0.001. So there was a 31% improvement in reducing the risk of recurrence with adjuvant nivolumab. So based on that trial, we have updated the guideline to recommend adjuvant nivolumab for patients who have received chemotherapy and radiation and surgery, and then had some residual disease in the surgical specimen.

A key distinction is that about 20% to 30% of patients will have had a pathologic complete response. These patients were not eligible for the trial. And so at this time, patients who have had a complete response, the current guidelines remain the same, where there's no further treatment indicated.

BRITTANY HARVEY: OK, it seems like this study provided a strong signal to update that recommendation. I appreciate you going through the details of that study, and particularly the patients that were eligible to participate. So then, how will this guideline impact patients with locally advanced esophageal cancer?

MANISH SHAH: Yeah, I think that this is a key thing. Because 70% to 75% of patients have residual disease at the time of resection. And still, even if you've had a major pathologic response, the risk of recurrence for many patients is still high, greater than 50%.

Of note also I'd highlight that the study included adenocarcinoma and squamous cell cancer. And the results were positive in both groups. So based on that, I think that this will be highly impactful for a majority of patients with esophageal cancer, both adenocarcinoma and squamous cell cancer, who, as I said, underwent chemoradiation and surgery and had residual disease in the surgical pathologic specimen.

BRITTANY HARVEY: That's good to hear that this will have a positive impact for these patients. So then what are the outstanding clinical questions regarding treatment of these patients?

MANISH SHAH: Yeah, so I think that there are a lot of outstanding questions. I think one question which is currently being studied is the use or integration of checkpoint inhibition therapy prior to surgery. So that's being examined in an inter-group study in the United States, as well as several company-sponsored studies across the globe. And a concept there is that, if you're giving chemotherapy with radiation and a checkpoint inhibitor all combined, you might be able to have even the higher benefit from activation of the immune system against the cancer than in the adjuvant setting where you're trying to treat microscopic minimal disease. So that's one question.

And the other key question, which was actually raised by the clinical trial itself was the CPS scoring system. So CPS means Combined Positive Score. This is a way to examine the level of PD-L1 expression in the tumor and its microenvironment. And it's not a great biomarker, but it's the best biomarker available. And it is predictive of who would benefit. So patients who have a higher CPS score are more likely to benefit from a checkpoint inhibitor. A post hoc analysis of this study suggested that tumors that had a CPS score of less than 5 had less benefit. So although the FDA approval for adjuvant nivolumab was independent of the CPS score, I think, with time, we'll have more information on the potential impact of CPS or other biomarkers on which patients really may benefit from adjuvant therapy.

So I think, on the positive end, patients now have options. And I think they're clinically significant and meaningful. But it does, as you point out, highlight new questions that will be answered in due course.

BRITTANY HARVEY: Great. And we'll look forward to the results of those studies that address some of those questions. So thank you for your efforts to issue this rapid update and for taking the time to speak with me today, Dr. Shah.

MANISH SHAH: Oh, absolutely. It was a pleasure to be here. Thanks so much, Brittany.

BRITTANY HARVEY: And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast Series. To read the full guideline, go to www.ASCO.org/gastrointestinal-cancer-guidelines. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

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