PD-1 Regimens Lead Charge Against Gastrointestinal Cancers

April 25, 2021
Courtney Marabella
Courtney Marabella

Senior Editor, OncLive®
Courtney Marabella joined the MJH Life Sciences team in 2021 and is Senior Editor for OncLive®. Prior to joining the company she worked as the Audience Development Editor for the Asbury Park Press, part of the USA Today Network. Email: cmarabella@onclive.com

With immunotherapy options expanding for patients with a range of gastrointestinal cancers to include combination strategies with chemotherapy, their use in the treatment course should come sooner rather than later for those with high PD-L1 expression.

With immunotherapy options expanding for patients with a range of gastrointestinal cancers to include combination strategies with chemotherapy, their use in the treatment course should come sooner rather than later for those with high PD-L1 expression, explained Aravind R. Sanjeevaiah, MD.

“We should be looking at PD-L status upfront, just like we already knew, but we should also be looking at PD-L1, and if [the combined positive score is (CPS)] greater than 5, we should introduce immunotherapy sooner rather than later,” Sanjeevaiah said. “Previously we used to order the PD-L1 [testing] later because it was only approved in the third-line setting, but the paradigm has [since] shifted.”

In January 2021, nivolumab (Opdivo) was granted priority review status for use as an adjuvant treatment for patients with resected esophageal or gastroesophageal junction (GEJ) cancer following neoadjuvant chemoradiation. The FDA will make a decision on the supplemental biologics license application (sBLA) by May 20, 2021.

Also that month, the FDA granted a priority review to an sBLA for nivolumab (Opdivo) in combination with a fluoropyrimidine- and platinum-containing chemotherapy for use in patients with advanced or metastatic gastric cancer, GEJ cancer, or esophageal adenocarcinoma.The agency is expected to make a decision by May 25, 2021.

In an interview with OncLive® during a 2021 Institutional Perspectives in Cancer Webinar on gastrointestinal malignancies, Sanjeevaiah, an assistant professor in the Department of Internal Medicine at UT Southwestern Medical Center, discussed how immunotherapy has altered treatment for patients for gastrointestinal cancers, both as monotherapy and in combination with chemotherapy.

OncLive®: How has the addition of immunotherapy impacted the way you treat your patients with gastrointestinal cancers?

Sanjeevaiah: Many immunotherapy agents have been studied in gastrointestinal cancers, not just nivolumab, but also pembrolizumab [Keytruda], durvalumab [Imfinzi], atezolizumab [Tecentriq], and others. The first major study was the phase 2 KEYNOTE-059 [NCT02335411] trial, in which there was clear evidence of benefit with immunotherapy in metastatic gastroesophageal cancers.

The benefit appeared to be mostly in PD-L1-positive cancers in the third-line setting, and that is where it was approved and has lived, so to speak, for the last 2 to 3 years. Now, we have phase 3 data from CheckMate-649 [NCT02872116], which shows that, in patients with a CPS of 5 or higher, the introduction of nivolumab plus 5-fluorouracil [5-FU], leucovorin, and oxaliplatin [FOLFOX] would result in significant clinical benefit in terms of overall survival [OS]. That has been practice changing. There are further studies that are looking to see if that space can be further elaborated on, but the best evidence we have right now is from CheckMate-649.

How do you explain the discordant results between the CheckMate-649 and KEYNOTE-062 [NCT02494583] trials?

Let’s look at the differences between these 2 studies. Of course, the immunotherapy agent being used was different. In KEYNOTE-062, we used pembrolizumab, while in CheckMate-649 we used nivolumab. There was also a difference in the chemotherapy regimens. CheckMate-649 used FOLFOX, whereas KEYNOTE-062 used 5-FU and cisplatin.

Additionally, the sample sizes were different. CheckMate-649 was a larger study with about 790 patients in each arm, [while] KEYNOTE-062 had about 240 patients. That might have been a factor. Also, we need to gather more data about how many of the patients who progressed after chemotherapy [crossed over to receive] immunotherapy. We still do not have data regarding the crossover that influenced the survival in those patients.

How would you describe the clinical implications of the phase 3 CheckMate-577 (NCT02743494577) trial?

This is probably the most important study in the gastrointestinal cancer space. What the study did was examine patients who received chemoradiation followed by surgery. For patients who had residual disease after chemoradiation therapy, they were given adjuvant nivolumab. [There were] approximately 532 patients in that arm [with nivolumab], which was a 2:1 randomization, and [patients received] nivolumab every 2 weeks for 16 weeks, followed by 418 mg every 4 weeks for 1 year, or placebo.

CheckMate-577 showed that survival was drastically different for patients who received adjuvant nivolumab, and the median disease-free survival was 22 months compared with 11 months [for placebo]. That is impressive. There are other studies being conducted right now to answer the same question—whether there is a role for immunotherapy in the perioperative setting. In particular, the phase 2/3 EA2174 [NCT03604991] study [is looking at this question with] nivolumab and ipilimumab. That will be another study to look out for in the next few years.

What emerging agents in this space are of interest?

There are all sorts of studies looking into the use of immunotherapy agents along with docetaxel, oxaliplatin, leucovorin, and 5-FU [FLOT], which is not a standard perioperative chemotherapy. Those recent studies should be looked at going forward and could show that we can improve upon the current success rate in curing patients with resectable gastroesophageal cancers.