Dr Ilson Talks Current Role of Immunotherapy in GEJ, GI Cancer- Part I

In part one of this video series, David Ilson, MD, PhD, Memorial Sloan Kettering Cancer Center, reviews the recent immunotherapy treatment updates in esophageal/gastric cancer, presented at the 2021 Great Debates and Updates in GI Malignancies Annual Meeting.



Hi, I am Dr. David Illson. I am a GI medical oncologist at Memorial Sloan Kettering Cancer Center where I am attending physician and professor of medicine. I am going to comment today on an update on immunotherapy treatments in esophageal gastric cancer.

This is an area where we have made significant progress in the last several years, where we now see the usage of immunotherapy agents not only in refractory esophageal gastric cancer but the potential for these drugs to move into earlier line of treatment as well as adjunct therapies.

Also, I will comment a little bit about agents targeting other pathways like HER2 and the FGF receptor that are also trying to capitalize on immunotherapeutic mechanisms.

What I will review briefly is the current approval for immunotherapy drugs which in the United States is the use of pembrolizumab in PD‑L1‑positive chemotherapy‑refractory gastroesophageal adenocarcinomas. That is based on the expansion Phase II cohort from the KEYNOTE‑059 trial.

We also have regulatory approval in the second‑line setting for pembrolizumab in metastatic squamous cancer of the esophagus and patients whose tumors are CPS 10% or higher. Also, we recently saw a regulatory approval for the use of the drug nivolumab in metastatic squamous cancer of the esophagus and second‑line treatment of this disease in patients irrespective of PD‑L1 status.

The important new data which is still awaiting regulatory review and approval is earlier line use of checkpoint inhibitors. From the recent CheckMate trial, we had very positive data for the use of first‑line nivolumab combined with FOLFOX chemotherapy in gastroesophageal junction and gastric adenocarcinomas.

The trial specifically showed improvements in survival, response rate, duration of response, and progression‑free survival, the primary target population of this trial which was patients whose tumors were CPS 5% or higher, clear benefit for this primary endpoint of the trial which was PFS and overall survival adding nivolumab to first‑line FOLFOX.

What is less clear is whether there is a benefit in patients whose CPS scores are less than 5% or negative. The trial did show benefits for those subpopulations, but it is not clear whether that was driven by the primary endpoint population, which is the CPS 5% or higher.

I suspect we will hear about regulatory approval for nivolumab in first‑line treatment of metastatic GE junction and gastric adenocarcinoma plus FOLFOX in the near future.

The other positive results were for pembrolizumab in esophageal cancer looking at esophageal squamous cancer and esophageal adenocarcinoma extending to the GE junction. This was a trial combining pembrolizumab with infusional 5‑FU and cisplatin chemotherapy and first‑line treatment compared to chemotherapy alone.

This trial was also focusing mainly on a higher CPS population, although they enrolled patients that were both CPS 10% or higher or less than 10%. The endpoint of the trial was to demonstrate superiority for adding pembrolizumab to chemotherapy in CPS 10% or higher, and that trial met that endpoint.

Overall survival was significantly improved by 4-5 months, as was response rate, duration of response, and progression‑free survival indicating a potential role for first‑line pembrolizumab combined with fluorinated pyrimidine and platinum‑based chemotherapy in esophageal squamous cell and potentially adenocarcinoma.

Again, the benefit for CPS less than 10% is less clear, although there were trends. Again, the primary endpoint of the trial was to demonstrate superiority for adding pembrolizumab to CPS 10% or higher, and they achieved that endpoint. Again, we await consideration for regulatory approval of first‑line pembrolizumab in metastatic esophageal cancer.

Lastly, in terms of checkpoint inhibitors, we saw a very provocative data from the CheckMate trial looking at the use of adjuvant nivolumab in esophageal squamous cell and adenocarcinomas in patients undergoing chemotherapy and radiation followed by surgery. The trial focused on the adjuvant treatment of patients if they had any residual disease at surgery, so they either had residual disease in the primary or in lymph nodes.

The trial excluded pathologic complete response patients, and the primary endpoint was to improve disease‑free survival. They saw a rather striking improvement in disease‑free survival from 11 months - 22 months which was highly statistically significant and met the primary endpoint of the trial.

Although overall survival was not commented on, such a degree of improvement in disease‑free survival is almost certainly going to translate into an overall survival benefit, and the trial met the primary endpoint.

Another aspect may be the use of adjuvant nivolumab for a year in patients with esophageal squamous cell and adenocarcinoma after chemo, radiation, and surgery in patients who have residual disease remaining a surgery that did not achieve a pathologic complete response.

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