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Immunotherapy Arrives in Gastric Cancer

Angelica Welch
Published: Friday, Mar 30, 2018

Manish A. Shah, MD
Manish A. Shah, MD
In the past year, immunotherapy has emerged as one of the more promising approaches for the treatment of patients with gastric and gastroesophageal junction (GEJ) adenocarcinoma. Specifically, pembrolizumab (Keytruda) and nivolumab (Opdivo) have demonstrated strong clinical activity in this patient population.

In September 2017, the FDA approved pembrolizumab for the treatment of patients with PD-L1–positive recurrent or advanced gastric/GEJ adenocarcinoma who have received 2 or more lines of chemotherapy, including fluoropyrimidine- and platinum-containing chemotherapy, and, if appropriate, HER2/neu-targeted therapy.

Although nivolumab is not yet approved in this indication, there have been promising data in the third-line or later with this PD-L1 inhibitor. Treatment with nivolumab was found to reduce the risk of death by 37% versus placebo for patients with advanced gastric/GEJ cancer following second or later-line chemotherapy, as seen in the phase III ONO-4538-12 trial.

Immunotherapy continues to be used in later lines of therapy for this patient population, as previous efforts to move it up in the treatment sequence have fallen flat, says Manish A. Shah, MD. There are currently 2 frontline immunotherapy studies ongoing—one with pembrolizumab, and one with nivolumab and ipilimumab (Yervoy). Results of these studies will read out in the next few years.

In an interview during the 2018 OncLive® State of the Science Summit™ on Gastrointestinal Cancers, Shah, director of gastrointestinal oncology and chief of Solid Tumor Service at Weill Cornell Medicine/NewYork-Presbyterian Hospital, discussed the advancements being made in the treatment of patients with advanced gastric and GEJ cancer.

OncLive: Please provide an overview of your lecture.

Shah: I spoke about immunotherapy in stomach cancer and foregut [carcinoid] tumors like esophageal/GEJ cancers. This is obviously a new treatment for stomach and esophageal cancers, and it has demonstrated some activity in the advanced or third-line setting. Some of the key questions that I addressed were, “Who should be tested for immunotherapy? What is the best test? What is the best marker?”

Of course, we would test for PD-L1 expression, but that is something unique to the way that pembrolizumab was approved, where they look at the total number of positive cells—not just tumor cells—and the immune infiltrate as well. They call this a combined positive score (CPS) or total count. The way that this is defined is the total number of positive cells over the total number of tumor cells, and then they take that as a percentage. In stomach cancer, a CPS of 1 or greater would make a patient eligible for pembrolizumab in the third-line setting. The data are coming out this year in esophageal cancer, but it is likely that the CPS score might be a little bit different. That leads to questions of why that would be.

The other thing I talked about is how we make the immune response even better. We know that the PD-1 inhibitors pembrolizumab and nivolumab work in 10% to 15% of patients with advanced stomach cancers and GEJ tumors. The question is, can you augment that with chemotherapy, radiotherapy, or other immune agents? 

What are your thoughts on moving immunotherapy into earlier settings?

Whether immunotherapy can move up to an earlier setting is a great question. Those studies are being done now. Pembrolizumab was examined against a taxane in the second-line setting, and unfortunately, that was a negative study. Avelumab (Bavencio) was tested in the third-line setting against chemotherapy, which was also negative. In the first-line setting, avelumab was tested as a maintenance approach, in which patients who received chemotherapy were then randomized to receive either chemotherapy or avelumab, and the results of that trial are pending. 

The first-line pembrolizumab as well as and the first-line nivolumab and ipilimumab studies are ongoing, and we should get the results of those in 2019 or 2020. They are also being tested in patients who have locally advanced disease. There is a large registration study looking at chemotherapy with or without pembrolizumab for advanced gastric cancer in the perioperative setting. There are many studies looking at nivolumab with or without ipilimumab in patients with esophageal cancer who received chemotherapy and radiation.

What is the prevalence of microsatellite instability (MSI) in patients with gastric cancer?

Another key area of immune activity is in patients who have a MSI-high (MSI-H) phenotype. That means that they have a high mutation burden. This is also known as Lynch syndrome. Many people don't realize that Lynch syndrome is also associated with gastric cancer. It is most commonly known for [its association with] colon cancer, but it also increases the incidence of gastric cancer.




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