Video

Emerging Agents and Biomarkers in Gastric and GEJ Cancers 

Daniel Catenacci, MD, and Sam Klempner, MD, conclude their discussion by examining emerging agents and biomarkers for the management of advanced gastric and esophagogastric junction cancers.

Sam Klempner, MD: Let’s move on to the new biomarkers, which I know is an area that we’re both quite interested in. I don’t know, maybe you want to give a high-level overview of agents that you’re excited about.

Daniel Catenacci, MD: I’ll start with 2 of the more prominent ones. The first 1 that came to the storyline was claudin. You know the claudin story based on the randomized phase 2 FAST study, which used albeit now an obsolete chemo regimen with epirubicin, cisplatin or platinum, and 5-FU [5-fluorouracil]. We should point out that that should never be used ever in any situation, the magic regimen. But regardless, that was the backbone back then and it was with or without a drug that was a claudin antibody in patients that were selected for claudin expression, which was defined as having expression levels in 40% of tumor cells or more. In that analysis it showed a survival benefit, that phase 2 randomized placebo-controlled study. In that higher cutoff of 70% of cells seem to be where all the benefit was from. After the drug changed hands and was bought by Astellas [Pharma] it led to the 2 prospective phase 3 studies which are ongoing global randomized phase 3 placebo-controlled studies called SPOTLIGHT and GLOW. They’re both accruing and both near accrue to about 75%, so that could change the landscape significantly because it’s about 35% of patients that are estimated to express that protein. The other 1 is the FGFR2 [fibroblast growth factor receptor 2] storyline, which is a targeted therapy monoclonal antibody called bemarituzumab. It was studied in late line as a monotherapy, showed efficacy as a monotherapy in FGFR2-amplified tumors with a response rate that was almost 20%, and that led to it being fast-tracked to [a] phase 3 study in the first-line setting with FOLFOX [folinic acid, fluorouracil, and oxaliplatin], placebo-controlled global study. Then, during the conduct of the study, it was actually downsized to phase 2 for some logistical reasons, and the company changed hands to Amgen recently from the previous company. The important thing at that study was the selection criteria for FGFR2-positive tumors, which was defined as immunohistochemistry positive or ctDNA [circulating tumor DNA] positive for amplification. Amplified tumors were a smaller subset of the group. About 20% of the accrued patients were amplified and the remainders were overexpressed but not amplified. That was a positive survival benefit and response rate and PFS [progression-free survival], and that is now going onto [a] phase 3 design study through Amgen and should hopefully change the standard of care there. Those are the 2 that I would point out. Are there any other emerging agents and biomarkers that are on your radar other than those 2?

Sam Klempner, MD: Yes, there are. It’s integrating the overlap of biomarkers and is going to be a relevant topic. We don’t have data yet but there’s going to be some overlap, let’s say, claudin and that may impact our choices and certainly the control arms of some of these trials. We know that EGFR and MET are seen somewhere in the 5% to 7% amplification range across our patient population in adenocarcinomas. It’s lessons in drug development for all of us in terms of how to identify and select these patients because there’s been some larger negative phase 3 trials for both of these targets. In my own opinion, they weren’t necessarily negative because the biology is not real and there’s not a target, it’s just we didn’t have the most appropriate understanding of how to identify these patients. It speaks to the biology. There’s some co-amplification where an EGFR-amplified HER2 co-amplified patient is probably not going to derive significant benefit from EGFR alone, so maybe the REAL33 or EXPAND trial. Which overall negative trials would have benefited from some little bit greater selection criteria? Similar story for MET. Those are valid targets. We need to understand our diffuse-type patients better. This is a disease that has seemingly lesser benefits from IO [immunotherapy] agents as well as chemotherapy. This is where some CDH1 [cadherin 1] biology, and we’ve wondered whether claudin may be slightly more prominent in that patient population, but really understanding that that subset is going to be a place to look for new targets. To build on FOLFOX and nivolumab [Opdivo], we need to understand what our drugs are really doing. Should we be targeting additional tumor microenvironmental features to try to further reduce the T-reg, or reprogramming the macrophage subset to further build and boost the activity of IO approaches in the frontline? I would say mainly EGFR and MET to build on FGFR and claudin, and then some novel diffuse agents and better TME [tumor microenvironment] understanding.

Daniel Catenacci, MD: I totally agree with you. As we were alluding to earlier, this is why I and others, and you, are making a point that we want to see where drugs are working and where they’re not working because they may have a better choice. There are a number of biomarkers here now that we’re looking at and if you’re negative for one but positive for another one, the better option for that particular patient is the one that they’re positive for. You pointed out, sometimes there’s overlap and there’ll be more than one choice, and at least for now, until we evidence of combining these things, which is another promising approach. It’s like combining all the different biomarkers we just talked about there, targeted therapies together. Until we have safety and efficacy about that, we’re going to have to choose one or the other and you’re going to have to prioritize it for the patient, which one they’re going to get. You asked about ctDNA, that’s one way to give a sense of which one of the biomarkers is a higher priority. For example, you mentioned EGFR and HER2, sometimes they do co-occur and sometimes it’s like rip-roaring EGFR 100 copies compared to HER2’s 8. We know that the level of copy number is important and should dictate ultimately what their target should be and vice versa if it was the other way around. That’s one thing we’ve done prospectively in PANGEA, which seemed to have some good outcomes. That line of thinking should continue, especially now that patients are fortunate that there are a number of biomarkers we can look for and now we have to prioritize them. That’s great. Any other thoughts about novel approaches, clinical trials, new agents coming around the market?

Sam Klempner, MD: The message of trials just because we have a new standard doesn’t mean we should be satisfied. In the best population, the improvement in CheckMate 649 was 3 months. It took 1500 patients to show that in the optimally selected patients and so there’s still a lot of work to be done. I hope that the approval of IO, as well as the [KEYNOTE]-811 regimen doesn’t stifle the ability to develop better things.

Daniel Catenacci, MD: Very well said. It’s a promising time for gastroesophageal cancer. There’s a lot of movement, a lot of new agents that have shown some incremental benefit in some cases. Really remarkable benefit, like MSI [microsatellite instability]-high tumors with immunotherapy. And more promise going forward with combinations of these therapies, new therapies coming along. The future is bright and I thank Sam for this great discussion, and thank you all for listening. 

TRANSCRIPT EDITED FOR CLARITY

Related Videos
Pamela L. Kunz, MD, associate professor, internal medicine (medical oncology), Yale School of Medicine; director, Center for Gastrointestinal (GI) Cancers, chief, GI Medical Oncology, Smilow Cancer Hospital, Yale Cancer Center
Suneel Kamath, MD
Suneel Kamath, MD
Jennifer R. Eads, MD, physician lead, GI Cancer Research, director, National Clinical Trials Network, Abramson Cancer Center, University of Pennsylvania, associate professor, clinical medicine (hematology-oncology), Penn Medicine, Perelman Center for Advanced Medicine
Olivia Aranha, MD, PhD
Michael Iglesia, MD, PhD
Petros Grivas, MD, PhD; and Chandler Park, MD, MSc, FACP
Arndt Vogel, MD
Daniel M. Halperin, MD, associate professor, Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center
Haeseong Park, MD, MPH