Historical Perspective on Treatment of Gastric and GEJ Cancers 

Daniel Catenacci, MD: Hi there, I’m Dan Catenacci, a GI [gastrointestinal] medical oncologist at the University of Chicago in Illinois, and today we have Sam Klempner joining us from Massachusetts General Hospital in Boston. Welcome, Sam.

Sam Klempner, MD: Thanks, Dan. Thanks for having me.

Daniel Catenacci, MD: We’re going to be talking about advanced gastric and GE [gastroesophageal] junction cancers. Sam, talk to me about the background of the disease, the survival trends over the years, standards of care, up until the more recent immunotherapy [I-O] revolution, and then we can go from that point.

Sam Klempner, MD: Sure, a big topic, so I’ll focus this on the metastatic patients where most of the changes have happened most recently. But if we take a step back and think about 2000 and 2005, maybe the last really big trial like REAL-2 where we saw almost a 1000-patient trial looking at a frontline population, we saw that the survival with chemotherapy was under a year, somewhere in the 10-, 11-month range for an unselected gastric and esophageal adenocarcinoma population. Then over the years as our understanding of the disease has improved, our outcomes have improved. Both because of improved supportive care, but more importantly, as we understand certain biomarkers, HER2, PD-L1, MSI [microsatellite instability], etc, that we’ll discuss. Outcomes in some of these subsets have certainly improved, and then fast forward to now where we look at say a chemotherapy plus I-O trial. We see that chemotherapy alone continues to perform about the same, around an 11-month survival, but the addition of immunotherapy agents may push the survival to over a year now, particularly in some biomarker-enriched groups that I’m sure we’ll be discussing.

Daniel Catenacci, MD: You mentioned the immunotherapy studies, and we’re going to be getting to each of them. But what’s the mechanistic role that we can come up with in terms of combining chemotherapy with these immune checkpoint inhibitors? Then another wave of combinations is chemotherapy plus trastuzumab plus immunotherapy for HER2-positive tumors. What’s the mechanistic rationale of that?

Sam Klempner, MD: I’ll talk a little bit about chemotherapy plus checkpoint inhibition, and then I’ll let you take on the antibody, PD-1 combinations, like trastuzumab and pembro [pembrolizumab]. But we know, largely from other tumors, that chemotherapy has some effects on the tumor microenvironment, and they may include increased antigen presentation from cytotoxic kill of chemotherapy. They may include downregulation of certain immunosuppressive populations like T regs [regulatory T cells] and tumor-associated macrophages. Chemotherapy may modulate the microenvironment to a perhaps more proinflammatory, or at least set the soil for immunotherapy. Then when you combine an agent that may reinvigorate an exhausted T-cell population like a checkpoint inhibitor, particularly the anti–PD-1 antibodies, the hypothesis is that there’s not only some additive effects but potential synergy between the 2 mechanisms of chemotherapy, TME [tumor microenvironment] modulation, coupled to reinvigorating an antitumor T-cell response. And I’ll be honest, the mechanistic details there are not really well worked out in gastric and esophageal, and it’s an area where there’s a concerted effort that is needed to better understand it, but that is the working hypothesis. I’ll ask you to discuss a little about the targeted antibody plus PD-1 in chemotherapy rationale.

Daniel Catenacci, MD: Building on what you just discussed in terms of the synergy that we see with chemotherapy and PD-1 inhibitors and all the reasons you discussed, in the subgroup of HER2+ cancers where, of course, the standard of care is chemotherapy plus trastuzumab antibody. The intuitive approach would be to add to that, but there is mechanistic rationale as well, in the sense that as you point out that the PD-1 inhibitors are eliciting the T-cell response through the adaptive immune arm of the immune system. But we’ve known for some time that antibodies like trastuzumab, which work through a number of different mechanisms of action, one being that it’s inhibiting the HER2 signaling pathway, but it also enhances an ADCC [antibody-dependent cellular cytotoxicity] in immune response through the innate immune system by recruiting natural killer cells, macrophages, etc, through the Fc [fragment crystallizable] domain of the antibody. The concept of leveraging both arms of the immune system in a synergistic sort of fashion has been shown preclinically and has also been shown in other tumor types now, and even in early phase 2 studies in the first- and second-line setting of this disease, and that’s going to come up when we get to the first-line study, one of which has already read out at least in part, with KEYNOTE-811.

TRANSCRIPT EDITED FOR CLARITY