Global Perspectives on Sequencing in Gastroesophageal Cancers - Episode 10

Shortfalls in Recent Gastroesophageal Clinical Trials


Johanna C. Bendell, MD: We’ve seen a few negative studies. Yelena and I were talking this morning, saying what a disappointing year this is at ASCO for the gastroesophageal cancers. We talked about KEYNOTE-061; there’s also the avelumab data, the JAVELIN trial. Eric, can you tell us a little bit about this maintenance concept?

Eric Van Cutsem, MD, PhD: There are two JAVELIN trials. We have seen results of one JAVELIN trial—that’s JAVELIN Gastric 300—which was a study in later lines, where patients were randomized between avelumab, which is a PD-L1 antibody, versus any choice of chemotherapy; a taxane, irinotecan, or best supportive care. That study did not show a benefit. The other study, the JAVELIN Gastric 100, is a study in the maintenance phase, which is still ongoing. We don’t have yet any results, and that’s a study where patients are started with chemotherapy in the first-line, and then in the maintenance phase—after a certain period of chemotherapy, in those patients without progression—there is a randomization between avelumab or continuing a maintenance chemotherapy. That study is still recruiting today, and we hope to see the results, of course, in the future.

But the JAVELIN 300 study was indeed a study in later lines. The difference with the nivolumab study was, here the control arm was chemotherapy, irinotecan or taxane in later lines. While in the nivolumab Japanese study, it was nivolumab versus placebo, which is a different design and a different set up. This just teaches us that we have to better select, as Yelena said, our patients to come up with predictive biomarkers. In the avelumab study, all-comers were included with no enrichment for a certain biomarker. There was no enrichment for PD-L1, or for EBV (Epstein-Barr virus), or MSI, so it was just all-comers. That’s an important message. That’s probably not the way to go in gastric cancer with checkpoint inhibitors; you have to select patients.

Johanna C. Bendell, MD: Yes, and then we saw also the thought of a stem cell inhibitor. Dr Enzinger, tell us a little bit about what are these stem cell inhibitors in this BRIGHTER study that was done.

Peter C. Enzinger, MD: This is the agent BBI608. Basically, this is a stemness cell inhibitor, and the idea behind this is, that cells are actively dividing in general. These are cells that can be killed with a cell cycle poison, which is what most chemotherapy is. The idea is that there are certain cells that are quiescent or stem cells that are much harder to kill. The idea with this agent was that it affected this and there’s various ideas of exactly how the agent works, Wnt signaling or other mechanisms. But the bottom line was that this agent was combined with paclitaxel in second-line; so, paclitaxel with or without this agent. Unfortunately, based on the data that’s available to us at this point, the top-line result was negative with this study, and there was no benefit to adding this agent to paclitaxel in the second-line setting.

Johanna C. Bendell, MD: Then we have another negative study, the RAINFALL study. Peter, this is yours.

Peter C. Enzinger, MD: RAINFALL was the biggest disappointment, in particular to Yelena and myself as well, because we had a follow-up study that we had planned that fell through. But the bottom line is that we now have another study that shows no benefit for an angiogenesis inhibitor in the frontline setting. This was a study that looked at a platinum 5-FU frontline regimen, with or without ramucirumab, given in a different way actually, thkan given in subsequent lines of therapy. The idea was to give higher doses of ramucirumab, so it was given on day 1 and day 8 on this 3-week cycle. Although there was a small, statistically significant improvement in progression-free survival, there was no improvement in overall survival in this trial. Unfortunately, for that reason, the company that makes this agent is not pursuing a frontline indication for this agent.

We now have studies that show no benefit in the frontline setting; the AVAGAST study, the AVATAR study, and the RAINFALL study. There is no real proof right now that in frontline angiogenesis, a strategy works. I think we’re just going to have to go back to the drawing board, and perhaps we can find better agents or this is more of a second-, third-line drug, but it was clearly disappointing to all of us.

Transcript Edited for Clarity