Immunotherapy Arrives in Gastric Cancer

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.

OncLive: Please provide an overview of your lecture.

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.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.

What are your thoughts on moving immunotherapy into earlier settings?

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? 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.

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

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.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.

When is the best time for a patient with gastric cancer to undergo genetic testing?

What targeted therapies are you excited about in gastric cancer?

It is estimated that between 15% and 30% of gastric tumors may be MSI-H. It is one of the 4 genomically defined subtypes by The Cancer Genome Atlas, so it is relatively prevalent and needs to be tested for. Patients who have MSI-H tumors should receive pembrolizumab in the second- or third-line setting; that is the FDA indication. It is quite active—about 50% of patients will respond, and it can be life-altering because the responses are quite durable. This is a key question. In my approach, [testing should be done] the earlier the better. It takes 3 to 4 months for genetic testing results to come in, and sometimes you don't know that you don't have enough tissue until you ask for it. I end up testing for precision medicine or genetic profiling while patients are in their first line of therapy.There have been thousands of patients enrolled on targeted therapy clinical trials in the last 5 years alone in gastric cancer. We examined MET inhibition with rilotumumab, but [that was a] negative finding. We examined the STAT3-targeted stemness inhibitor napabucasin (BBI-608) against paclitaxel, which was also a negative study.

What challenges remain in the treatment of patients with gastric cancer?

Is there anything else that you would like to highlight?

What I am most excited about are 2 studies. One is in the first-line setting, which is with GS-5745, an MMP-9 antibody. That study is based on a phase Ib study that we performed, in which patients with advanced gastric cancer received FOLFOX with GS-5745, and the response was quite remarkable. In fact, in my own experience, 8 out of 9 patients had a major response. That led to quite a lot of excitement. The phase III study has completed and we are waiting for the results.Now that we have more lines of therapy available and are getting more drugs approved in the past few years with pembrolizumab, ramucirumab (Cyramza), and trastuzumab (Herceptin), our biggest challenge is tailoring therapy to individuals so that they receive all the treatments available to maximize their potential benefit. One of the key things about stomach cancer that is unique is the carcinogenesis develops with the bacteria helicobacter pylori (H. pylori). Half of the world's population have H. pylori and it is hard to get stomach cancer without having an H. pylori infection. H. pylori is immunologically active. People may have heard of the Th17 immune response, which is a pro-inflammatory immune response. That actually begets carcinogenesis, and H pylori stimulates Th17 immune response.

We are working on the microbiome and how that affects carcinogenesis, but also immunotherapy. There have been recent papers that have stated that a microbiome is required to develop an immune response. There will be a very important interplay that will be discovered in the next few years.

Kang Y-K, Satoh T, Ryu M-H, et al. Nivolumab (ONO-4538/BMS-936558) as salvage treatment after second or later-line chemotherapy for advanced gastric or gastro-esophageal junction cancer (AGC): A double-blinded, randomized, phase III trial. J Clin Oncol. 2017; 35 (suppl 4S; abstract 2).