Expert Discusses Continued Growth of Immunotherapy in Gastric/GEJ Cancer

Harry H. Yoon, MD

Following the FDA approval of the PD-1 inhibitor pembrolizumab (Keytruda) in September, the field of gastric cancer and gastroesophageal junction (GEJ) adenocarcinoma is buzzing when it comes to immunotherapies.

“Immunotherapy, in terms of biomarker-unselected populations, is probably the most promising [treatment] that we have identified in gastric/GEJ cancer,” said Harry H. Yoon, MD, co-chair, Esophageal/Gastric Cancer Disease Group, at Mayo Clinic.

Pembrolizumab was approved for patients with PD-L1—positive recurrent or advanced gastric or GEJ adenocarcinoma who have received 2 or more lines of chemotherapy, including fluoropyrimidine- and platinum-containing chemotherapy, and, if appropriate, HER2/neu-targeted therapy.

OncLive: Please provide an overview of your discussion on gastric cancer.

During a lecture at the 2017 OncLive® State of the Science Summit^TM on Gastrointestinal Cancers, Yoon proposed the use of PD-1 inhibitors in earlier lines of therapy. In an interview at the meeting, Yoon discussed the promise of immunotherapy and emphasized the importance of mismatch repair (MMR) deficiency testing.Yoon: I spoke about the most updated information that affects our standard practice, and what the most promising developments are on the horizon for gastric cancer.

A couple of interesting things have come out. The most interesting thing is with the PD-1 inhibitors, specifically pembrolizumab and nivolumab (Opdivo). It was recently demonstrated that nivolumab was better than placebo in the third-line or higher setting in an Asian study. The degree of benefit seen with nivolumab is higher than what has been [observed] with other biologic agents in that setting. That is a very promising thing.

Pembrolizumab is very interesting, as well. In a single-arm, phase II study conducted in the United States, pembrolizumab showed a very similar level of benefit or response that nivolumab did. These are 2 different agents targeting the same molecule—PD-1.

The other thing that is interesting is the fact that PD-1 inhibition seems to be more efficacious in earlier lines of therapy. Recently, there were specific data that were reported looking at the combination of pembrolizumab plus cytotoxic therapy in the frontline setting, with a response rate of 60%. That is higher than what we have seen in other trials in the chemotherapy-alone setting. Hopefully, those will be affecting our practice relatively soon. I have good experience with those agents, but they have to be in properly selected patients and we have to watch out for the side effects.

What is the future treatment for patients with this disease? Is it strictly immunotherapy?

Pembrolizumab was approved for all tumors that are MMR deficient. It seems that about 9% of gastric cancers are MMR deficient, and about 4% of GEJ adenocarcinomas are. I tend to perform MMR testing in all of my patients with gastric cancer and GEJ adenocarcinoma patients.There are other pathways that are promising, such as angiogenesis. Ramucirumab (Cyramza) was recently identified in a global frontline study to [have a] benefit with progression-free survival; it was combined with cisplatin and fluoropyrimidine. We don't know the full results or the magnitude of benefit, but that is an interesting pathway.

What is one of the biggest unmet needs in this landscape?

What is the take-home message from your presentation?

Going along with angiogenesis, the VEGFR tyrosine kinase inhibitors are really interesting. There are good preliminary data and those are now being evaluated in phase III studies. The other one is anti-Claudin (CLDN) 18.2, which is a gastric-specific cell-surface marker. There are interesting randomized phase II data showing that it may have promise. There are other areas, but immunotherapy is an area of very high interest.There are so many. Patients tend to do rather poorly no matter what type of therapy that we give—even in the so-called "curative-intent" setting. The unmet need is basically anyone with disease that is something more than purely local disease—which is the vast majority of patients—maybe 85% to 90%. All that need is unmet.The big thing is to understand and appreciate the role of MMR testing and to consider that in at least the second- or third-line setting, and maybe even earlier than that. Even if a patient has MMR proficiency, consider a PD-1 inhibitor in earlier lines of therapy—in something like a patient-assistance program. What I am talking about now is relevant to a US-based practice, where something like that may be available.

There are data from lung cancer suggesting that PD-1 inhibition in earlier lines of therapy could improve response to subsequent cytotoxic therapy exposure. We would lose that if we reserved PD-1 inhibition for later lines of therapy. These patients generally don't have many good options, so I would consider using PD-1 therapy in earlier lines of therapy if it is possible, through a patient-assistance program, and definitely through clinical trials.

Right now, we have many trials in every one of these settings. There are a lot of immunotherapy trials available, and those should be seriously considered in every line of therapy.