Researchers Forge Ahead Amid Setbacks in Advanced Gastric Cancer

David H. Ilson, MD, PhD

Progress in advanced gastric cancer has been modest due to a string of negative trials that suggest the need for more targeted strategies, explained David H. Ilson, MD, PhD, a medical oncologist at Memorial Sloan Kettering Cancer Center.

“Gastric cancer has an aggressive biology. We’re not seeing the same benefits we see in melanoma or non—small cell lung cancer. We’ve made progress, but it’s why we need randomized trials. We get a signal from a phase II trial and then the phase III trial shows that the drug shouldn’t move forward,” said Ilson.

In an interview during the 2020 OncLive^® State of the Science Summit™ on Gastrointestinal Cancer, Ilson discussed the treatment landscape of advanced gastric cancer and the research being done to define a role for novel agents in this space.

OncLive: What is the role of chemotherapy in advanced gastric cancer?

Ilson: Fluorinated pyrimidine and platinum is standard of care. We usually use a regimen like FOLFOX. Data have suggested that adding a taxane, particularly in the docetaxel, cisplatin, and 5-fluorouracil regimen might improve responses and survival. However, there aren't a lot of randomized data to support that. A recent trial from Japan of over 700 patients with metastatic gastric cancer evaluated fluorinated pyrimidine and platinum with or without docetaxel. The trial was negative; we didn’t see a difference in response or survival, reinforcing that 2-drug chemotherapy is better for these patients.

What data do we have regarding the use of novel agents in this space?

In terms of novel agents, we know that the addition of the anti-VEGF therapy ramucirumab (Cyramza) to second-line chemotherapy with paclitaxel improves outcomes. A recent publication showed no benefit when ramucirumab was added to chemotherapy in the frontline setting. We’re interested in [other] TKIs that target the VEGF pathway, and the two that are being studied now are regorafenib (Stivarga) and apatinib. Apatinib was approved in China based on a survival benefit versus best supportive care. Unfortunately, the phase III trial that was conducted in the West was a negative trial, so that drug will likely not move forward. Regorafenib remains the subject of ongoing randomized trials versus best supportive care in refractory gastric cancer. There’s also some provocative, albeit preliminary, data for the combination of TKIs and checkpoint inhibitors. There may be a role for these drugs in combination with checkpoint inhibitors.

We recently received negative results from two randomized trials. One trial evaluated napabucasin which we think might be a stem cell inhibitor. It's a STAT inhibitor and may inhibit beta-catenin. The trial, which was conducted in the second-line setting, randomized patients to paclitaxel and napabucasin or paclitaxel alone. Because the trial was negative, the drug will not move forward. Similarly, a matrix metalloproteinase inhibitor, which looked promising in combination with FOLFOX in a frontline phase II trial, was negative [in the larger phase III trial].

One interesting drug on the horizon that is under investigation in an ongoing phase III trial is a claudin-directed antibody. Claudin is a gap junction protein that’s overexpressed in 70% of gastric cancers. We saw provocative phase II data with zolbetuximab and chemotherapy in claudin-positive cancers. The combination resulted in significant survival benefit, particularly in patients with high expression of the protein. There are now two ongoing randomized trials with zolbetuximab in advanced gastric cancer. One is the ILUSTRO trial which is evaluating FOLFOX with or without zolbetuximab in patients with high claudin expression. The other is the Spotlight trial which is evaluating capecitabine and oxaliplatin with or without zolbetuximab in claudin-positive patients.

Could you discuss some of the data with immunotherapy?

The recent data with immunotherapy have largely been negative. I highlighted the results from the phase II KEYNOTE-059 trial which showed a most signal of activity with pembrolizumab (Keytruda) in patients with PD-L1—positive refractory gastric cancer and significant activity in microsatellite instability-high (MSI)-H cancers. Based on that phase II data, pembrolizumab was approved for patients with refractory gastric cancer who are MSI-H or PD-L1–positive.

The second-line trial, which compared paclitaxel with pembrolizumab, was negative. Pembrolizumab was not superior. Arguably, pembrolizumab was inferior in patients with low PD-L1 expression. Whether patients with a combined positive score (CPS) of 10 can receive pembrolizumab versus paclitaxel is still debatable.

The phase III KEYNOTE-062 trial evaluated fluorinated pyrimidine and platinum with or without pembrolizumab in the first-line setting. The addition of pembrolizumab to chemotherapy did not improve outcomes. Investigators claimed noninferiority in the head-to-head comparison of pembrolizumab versus chemotherapy. However, the trial really wasn't powered to look at that. There were more deaths in patients who received pembrolizumab early on in the first six months to a year of treatment. These results showed that the combination of pembrolizumab and chemotherapy is no better than chemotherapy alone. We also probably shouldn’t use pembrolizumab in a symptomatic patient if even if their CPS is 10 because of the higher mortality rate versus chemotherapy alone. The exception is MSI-H patients. Those patients may benefit from up front pembrolizumab [with the potential for] improved responses, and better progression-free survival and overall survival. It's not clear whether adding chemotherapy to a checkpoint inhibitor provides additional benefit, so there may be a role [for the combination in the frontline setting] in MSI-H patients.

At the 2020 Gastrointestinal Cancers Symposium, we heard about the phase III JAVELIN Gastric 300 study, in which patients who were stable following 3 months of fluorinated pyrimidine and oxaliplatin were randomized to continue chemotherapy or receive maintenance therapy with avelumab (Bavencio). It was a superiority trial. However, the trial was negative. We didn't really see an advantage [with avelumab maintenance]. Though, there may have been less treatment-related adverse events [with avelumab]. Collectively, the data support later-line use of checkpoint inhibitors in more refractory disease, particularly in patients with a CPS of 10 versus a CPS of 1. However, the FDA approval [for pembrolizumab] is in patients who are refractory to chemotherapy with a CPS score ≥1. Though, MSI-H patients have a more substantial benefit. Arguably, checkpoint inhibitors could be used earlier in the first- or second-line setting rather than waiting for patients to become refractory to chemotherapy.

We’ve made progress. For example, we know that HER2-targeted agents improve outcomes in the first-line setting. We know that MSI-H patients benefit from checkpoint inhibitors, and we know that PD-L1—positive patients may derive benefit from checkpoint inhibitors in the refractory setting. Additionally, we’ve seen success with VEGF inhibitors. We know ramucirumab is a valuable part of second-line treatment.

What are some emerging strategies in this space?

There's a lot of active research in this space. We’re still waiting for the first-line trial results with FOLFOX and nivolumab (Opdivo). It's a much larger trial than KEYNOTE-062, so we may see a greater signal of benefit in the study with nivolumab. The study enrolled patients with PD-L1—positive and PD-L1–negative disease. There was an arm with ipilimumab (Yervoy) plus nivolumab, but it closed early due to adverse events. The data suggest that checkpoint inhibitors play a role [in gastric cancer]. [They will probably] play a role earlier on in MSI-H patients. Though, they should probably still be reserved for more refractory settings in patients with PD-L1–positive disease. There's active interest in trying to study ways we can make a relatively cold immune environment hotter with specific antibodies.

In the HER2 space, we have several drugs that are moving forward. Trastuzumab deruxtecan (T-DXd; DS-8201), for example, which is the conjugate antibody of trastuzumab (Herceptin) and a topoisomerase I inhibitor. That drug [is approved] in HER2-positive breast cancer. It's being tested in randomized trials in the second-line setting in patients with metastatic HER2-positive gastric cancer. A press release announced that trastuzumab deruxtecan met its primary end point in a clinical trial of patients with trastuzumab-refractory disease. That drug will likely be studied in the first-line setting. Margetuximab is another promising drug that's being tested in combination in frontline randomized trials in HER2-positive patients. The drug is a combination of trastuzumab elements and natural killer-cell recruiting antibodies. The data largely [supported] margetuximab plus pembrolizumab, so there is interest in looking at this drug in combination with a checkpoint inhibitor.