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.
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.
OncLive: What advancements have we seen in gastric/GEJ cancers?
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.
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.
What targeted therapies are being investigated?
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.