Immunotherapy Shakes Up Gastric/GEJ Cancer Space, Alongside Angiogenic, Cytotoxic Agents

J. Stuart Salmon, MD

Within gastric and gastroesophageal junction (GEJ) adenocarcinoma, strategies such as angiogenesis inhibition, cytotoxic therapy, and most recently, immunotherapy, are all beginning to have more refined roles in the treatment paradigm, explained J. Stuart Salmon, MD.

In February 2019, the FDA approved TAS-102 (trifluridine/tipiracil; Lonsurf) as a third-line therapy for adult patients with metastatic gastric or GEJ adenocarcinoma who were previously treated with ≥2 prior lines of chemotherapy that included a fluoropyrimidine, a platinum, either a taxane or irinotecan, and HER2/neu-targeted therapy, if appropriate.

Although the approval garnered much excitement, as TAS-102 is the first agent to demonstrate a survival benefit in the third-line setting, Salmon explained that the results of the KEYNOTE-181 trial sparked renewed interest in the use of immunotherapy in gastric/GEJ cancer.

In the study, pembrolizumab (Keytruda) monotherapy induced a median overall survival (OS) of 9.3 months in patients with advanced/metastatic esophageal cancer and a PD-L1 combined positive score (CPS) ≥10 compared with 6.7 months with physician’s choice of chemotherapy (HR, 0.69; 95% CI, 0.52-0.93; P = .0074).

“The most important research moving forward is going to be with immunotherapy. It’s clearly a paradigm shift in oncologic care,” said Salmon. “We need to do a better job of identifying the patients who are going to benefit from these therapies. Patient selection for these studies is going to be key.”

He added that there is a subset of patients who seem to significantly benefit from this approach. “Those patients may need to get immunotherapy earlier in the disease,” he said. “There's also a subset of patients who do not seem to benefit at all, and they may never be appropriate for immunotherapy.” For those patients, ramucirumab (Cyramza) and paclitaxel remain viable second-line options.

OncLive: What does the treatment landscape of gastric/GEJ cancer look like right now?

In an interview during the 2019 OncLive^® State of the Science Summit™ on Gastrointestinal Cancers, Salmon, a medical oncologist at the Levine Cancer Institute, highlighted first-, second-, and third-line treatment options for patients with gastric and GEJ cancer following recent clinical trial findings and regulatory approvals.Salmon: There were several seminal papers in the past year. The first one was the TAGS study, in which investigators looked at the use of TAS-102 in patients with advanced gastric adenocarcinoma in the third-line setting. It was a positive stud; patients had improved OS and the treatment was found to be well tolerated.

We then moved on to discuss anti-HER2 therapy, which included negative studies with the addition of pertuzumab (Perjeta) to trastuzumab (Herceptin) with platinum and fluoropyrimidine-based therapy in patients with HER2-overexpressing gastric cancer. Unfortunately, the JACOB study was a negative study. The addition of pertuzumab did not improve OS. [However], there was a statistically significant improvement in progression-free survival (PFS), and there was improvement in response rate. There may be a signal of activity, although it did not meet the standard of statistical significance. At this point, there is no role for pertuzumab in the treatment of those with HER2-amplified gastric cancer.

We then discussed the role of antiangiogenic therapy in advanced gastric and gastroesophageal carcinoma. We have one antiangiogenic agent approved by the FDA for the treatment of patients with gastric cancer in the United States; that's ramucirumab. The approval was based on positive data from 2 large phase III registration studies published in 2014: REGARD and RAINBOW. These studies demonstrated improvement in OS. In REGARD, patients who were randomized to receive ramucirumab versus placebo in the second-line setting experienced an OS benefit. In RAINBOW, patients who were given paclitaxel with ramucirumab in the second-line setting [experienced a benefit in OS]. Both studies met their primary endpoint. Now, ramucirumab is approved and has become a standard part of our armamentarium in the United States.

There has been 1 other positive phase III study that was published with the VEGFR2 TKI apatinib; this drug improved OS as a single agent in the third-line setting. However, the study was performed in Asia only. Therefore, the FDA, understanding that there are big differences in Asian patients and North American patients, has not approved the agent. It is approved for third-line treatment in China. We now have antiangiogenic therapies available in the United States in the second-line setting, which raises the question of whether they could be used in the first-line setting. Data from AVAGAST was published several years ago. This was a negative study testing bevacizumab (Avastin) in the frontline setting of advanced gastric cancer. As of about 2 weeks ago, a publication came out [on research in which investigators] tested ramucirumab in the same setting. The studies were very similar, and both studies were negative. Therefore, at this point, there is no role for antiangiogenic therapy in the first-line setting.

Then, immunotherapy is an exciting new therapy that has become available and has transformed oncology across the board. In GI cancer, we felt neglected for a long time, but now we are getting some positive data. It appears that patient selection is the most important thing. At the 2019 Gastrointestinal Cancers Symposium, we saw the results of the randomized phase III KEYNOTE-181 study testing pembrolizumab versus chemotherapy. The study was done in the second-line setting in patients with esophageal cancer, which included those with GEJ carcinoma.

What is the impact of the recent FDA approval of TAS-102 on the landscape?

The study had 3 coprimary endpoints. The investigators looked at patients with squamous cell carcinoma, patients with high levels of PD-L1 with a CPS score ≥10, and the intent-to-treat population. The study was positive in patients with high PD-L1 expression; these patients seem to benefit more from pembrolizumab than chemotherapy in the second-line setting. In the squamous cell carcinoma population, there was a nonstatistically significant improvement in survival with pembrolizumab compared with chemotherapy. The standard for statistical significance was much more rigorous than what we usually consider.The drug appeared to be well tolerated. We saw the conventional adverse events that we are used to dealing with in oncology, which primarily includes hematologic toxicity. The study tested the agent in the third-line setting, so these were heavily pretreated patients. It’s good to have an option for those patients. Prior to this, we had no data for third-line treatment. If you look at the landscape, patients are going to be treated with a platinum and fluoropyrimidine in the first-line setting; that's become a de facto international standard. Some physicians will use oxaliplatin or cisplatin. You can also use capecitabine or fluorouracil as long as a platinum and a fluoropyrimidine are given. For patients with HER2 overexpression, they will also receive trastuzumab along with it.

In the second-line setting, for those who do not express very high levels of PD-L1, we recommend ramucirumab and paclitaxel. Ramucirumab and paclitaxel is the standard second-line treatment. If you have very high levels of PD-L1 expression, then we recommend pembrolizumab with the caveat that it was compared with single-agent paclitaxel in the study, not the combination of ramucirumab and paclitaxel.

Is there any rationale to explore TAS-102 with other therapies?

If angiogenic therapy is combined with cytotoxic chemotherapy, could that become a frontline option?

What other research is important to highlight?

In the third-line setting, TAS-102 is the only good option that we have data available for. Patients had a good performance status in that study, so that needs to be kept in mind. The drug did seem to be well tolerated. It also appeared to have a broad spectrum of activity with early separation of the Kaplan Meier curves in terms of OS.It's a cytotoxic agent, and we routinely combine cytotoxic agents together as well as with antiangiogenic therapy. We're also studying cytotoxic agents in combination with immunotherapy. There are clear advantages for TAS-102 compared with other cytotoxic agents that we have. Primarily, it's an oral agent, so there's less chair time [for patients] and less of a need to go to the infusion room regularly. It is going to be very interesting to test it in combination with platinum-based agents in future studies. There may even be a rationale to try combining it with fluoropyridines, although I would be worried about toxicity in that population. Of course, targeted therapies and TAS-102 may become an option, including antiangiogenic therapies and, eventually, immunotherapy.Right now, we have no positive data for the use of antiangiogenic therapy in the first-line setting. That's an important thing to note. It's current role right now is only in the second-line setting, either as a single agent or in combination with paclitaxel. There was some modest signal to suggest that there may be undiscovered benefit in the first-line setting. However, at this point, we don't have any positive data, so I do not feel that there is a role for first-line antiangiogenic therapy.We now have data with immunotherapy as a single agent. We still don’t have robust data in gastric or gastroesophageal cancer with combination immunotherapy, although it is being tested in combination with chemotherapy. Immunotherapy is also being tested in the adjuvant setting, and in combination with antiangiogenic therapy—really, in all elements of the treatment paradigm.

There is a large subset that falls in between. We have to try to identify how we can sensitize patients to immunotherapy. That might mean combining checkpoint inhibitors together. For example, combining PD-L1 inhibition with CTLA-4 inhibition or, LAG3 inhibition. Moreover, [we mays want to think about] utilizing chemotherapy to try to increase neoantigen exposure, which may then sensitize the tumors to checkpoint inhibition.

Kojima T, Muro K, Francois E, et al. Pembrolizumab versus chemotherapy as second-line therapy for advanced esophageal cancer: phase III KEYNOTE-181 study. J Clin Oncol. 2019;37(suppl 4; abstr 2). doi: 10.1200/JCO.2019.37.4_suppl.2.