Ahn Recaps Advances and Challenges in Gastric/GEJ Cancers

Daniel H. Ahn, DO

Although research in the field of gastric and gastroesophageal (GEJ) cancers is focusing on targeting CLDN18.2 and VEGF, Daniel Ahn, DO, explained that the area that has piqued everyone’s interest is immunotherapy.

Ahn, an oncologist and internist at Mayo Clinic, said that immunotherapy’s relevance currently resides in the refractory setting, specifically in PD-L1—positive patients with gastric or GEJ cancers. To date, both positive and negative findings have been reported, including, most recently, negative results from the phase III KEYNOTE-061 study.

In KEYNOTE-061, pembrolizumab (Keytruda) did not improve survival as a second-line treatment for PD-L1—positive patients with advanced gastric or GEJ adenocarcinoma. Results showed that the hazard ratio for overall survival (OS) was 0.82 (95% CI, 0.66-1.03; one sided P = .042). Pembrolizumab also did not demonstrate a statistically significant improvement in progression-free survival.

Nevertheless, physicians are still searching for the optimal use of pembrolizumab and other PD-1 inhibitors in gastric/GEJ cancer, noted Ahn.

He specifically mentioned the phase III KEYNOTE-585 trial, which is studying the combination of pembrolizumab and chemotherapy in the neoadjuvant and adjuvant settings for patients with gastric/GEJ cancer, and the phase III CheckMate-577 trial (NCT02743494), which is investigating nivolumab (Opdivo) as an adjuvant treatment following chemoradiation and surgery for patients with resectable esophageal and GEJ cancer.

In the realm of targeted therapies, researchers continue to explore the VEGFR2 inhibitor ramucirumab (Cyramza), the multikinase inhibitor regorafenib (Stivarga), and the investigational VEGFR2 inhibitor apatinib, which was granted an orphan drug designation by FDA for the treatment of patients with gastric cancer.

OncLive: What advancements have we seen in gastric/GEJ cancers?

In an interview during the 2018 OncLive^® State of the Science Summit™, Ahn discussed advances and challenges with targeted and immune-based therapies in the treatment of patients with gastric and GEJ cancer.Ahn: A lot has changed in the way we treat gastric and GEJ cancers. We've had a lot of recent updates, in both the perioperative setting with the FLOT4 data and the metastatic setting with RAINFALL and JACOB. There are a lot of new emerging therapies specifically looking at targeting CLDN18.2, as well as looking at T-cell bispecific antibodies.

The area that everybody is interested in is immunotherapy. How do immune checkpoint inhibitors play into treating gastric and GEJ cancers? We've had 1 positive phase III study with ATTRACTION-2. We've had positive data from CheckMate-032 and KEYNOTE-059. However, we’ve also recently had negative data from KEYNOTE-061, as well as JAVELIN Gastric 300.

What targeted therapies are being investigated?

I would say there is a role for immune checkpoint inhibitors. The question is, “In what role of therapy?” Right now, immune checkpoint inhibitors are a relevant treatment in the refractory setting, specifically in PD-L1—positive patients in treating metastatic gastric or GEJ cancers. In patients who are PD-L1 negative or [low PD-L1 expression], we know that there is activity for pembrolizumab, but [there are] concerns for toxicities. There are also 2 negative phase III studies, so I would be very hesitant [to use it] right now, though it was still considered as a treatment option. I wouldn't move it into the second-line or earlier-stage setting. Other clinical trials are currently investigating that.There are 3 relevant targets right now, including VEGF. There are positive data with using ramucirumab in the refractory setting. However, the positive data from the RAINFALL study did not manifest into clinical significance. The difference was about 0.3 months. In terms of its role in the first-line setting, ramucirumab should be avoided and primarily [used] in the refractory setting, so second-line setting or beyond—depending on what patients received in the first-line setting.

Other agents that target VEGF include regorafenib and apatinib. Both agents are oral, tyrosine kinase inhibitors (TKIs). Both agents are currently being investigated in ongoing phase III trials.

Regorafenib is being investigated in Integrate II in which patients are randomized to receive either regorafenib or best supportive care with a primary endpoint of OS. This is an international phase III study, so hopefully, this study will accrue rapidly and give us a better idea about looking at patients receiving anti-VEGF therapies—even after the failure of prior ramucirumab therapy.

What are the data surrounding GS-5745 and FOLFOX?

Will immunotherapy ever be moved to the frontline setting?

Are different methods of administering chemotherapy being explored in clinical trials?

How do clinicians determine who will derive the most benefit from targeted therapy?

What is an area of research you would like to see addressed?

Is there anything else you would like to emphasize?

Apatinib was a study in Asia looking at targeting VEGFR2. This agent already [resulted in positive findings] in a randomized phase III trial, though only in a Chinese patient population. Right now, the ANGEL study is an international randomized phase III trial being conducted through the United States, European sites, and East Asia. This should give us a better idea of whether or not the signal that was seen in the study published in the Journal of Clinical Oncology in the Chinese patient population also holds true for the rest of the world. That’s a very interesting drug. Right now, it's too early to understand how that drug really works. Further studies need to be validated before understanding that target. That's a good question. Yes [it will], but in specific cohorts of patients. While we know that immune checkpoint inhibitors can work in all patient populations, based on what we've seen from The Cancer Genome Atlas, we know that there are certain molecular subtypes that are more likely to respond to immune checkpoint inhibitors. These are those that are MSI-high, those with PD-L1 positivity, or specifically those that have Epstein-Barr virus. Most of the data for intraperitoneal (IP) chemotherapy in treating advanced gastric and GEJ cancers is from Japan. They looked at giving IP paclitaxel as well as with tegafur/gimeracil/oteracil (S1). This is something that we have done occasionally, but there's no data to support it. We know that S1 is very different from capecitabine and IP paclitaxel, which is mainly given in gynecologic malignancies—not as much in gastric and gastroesophageal cancers. It is an area of interest, but for specific patient populations. Those who have a low peritoneal cancer index are likely to respond to it. It’s similar to the way we give heated intraperitoneal chemotherapy.We know that for some of these, specifically HER2, there’s a biomarker-driven strategy. We know CLDN18.2 will be a potentially relevant biomarker-driven strategy, as well as PD-L1. For the vast majority of patients—you're talking about 70% of patients—they're not going to have a biomarker-driven strategy. Studies that have tried to look at VEGF as biomarkers have shown only prognostic but not predictive [indications]. Unfortunately, time will tell for the vast majority of patients.Specifically, [we need to focus on] how we treat the non-biomarker treated patient population, since this usually makes up the vast majority of patients. It's very easy to combine certain agents where we know there's efficacy in certain biomarker-driven strategies, such as HER2 and PD-L1. However, research needs to be focused on the majority of patients who are left out, specifically on targets that may be overexpressed. These may be proteins or extracellular membrane receptors that are prevalent in certain tumor types, such as CLDN18.2.There is a lot of interest in how we give these TKIs. We've seen the data from ReDOS and how this applies to all of our patients with gastrointestinal malignancies. There are a lot of targeted [agents] or TKIs that are used, such as everolimus (Afinitor), regorafenib, sunitinib (Sutent), lenvatinib (Lenvima), etc. Should we [look for] more of a practical application? Should we look at dose-escalation strategies versus giving everybody a one-size-fits-all dose?