ASCO GI 2023 | DisTinGuish: DKN-01 with tislelizumab and chemotherapy in GC/GEJC
Whilst findings from the CheckMate649 (NCT02872116) and KEYNOTE-590 (NCT03189719) trials demonstrated the utility of chemotherapy and checkpoint inhibition in gastric or gastroesophageal junction cancer (GC/GEJC), a significant number of patients will not benefit. Samuel Klempner, MD, Massachusetts General Hospital, Boston, MA, describes the rationale and trial design of the Phase II DisTinGuish (NCT04363801) trial of DKN-01 with tislelizumab and chemotherapy in patients with unresectable, locally advanced or metastatic GC/GEJC. DKN-01 targets DKK1, which is hoped to enhance the efficacy of immune checkpoint inhibitors. This interview took place at the American Society of Clinical Oncology (ASCO) 2023 Gastrointestinal Cancers (GI) Symposium in San Francisco, CA.
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Transcript (edited for clarity)
The DisTinGuish trial falls largely under an umbrella of continuing to try to develop biomarkers and biomarker directed therapies in gastric and gastroesophageal adenocarcinomas. So as you well know, recently the standard has evolved to primarily 5FU and platinum with or without a checkpoint inhibitor, PD-1. And this is based on Checkmate 649 and Keynote 590 and Orient 16, et cetera...
The DisTinGuish trial falls largely under an umbrella of continuing to try to develop biomarkers and biomarker directed therapies in gastric and gastroesophageal adenocarcinomas. So as you well know, recently the standard has evolved to primarily 5FU and platinum with or without a checkpoint inhibitor, PD-1. And this is based on Checkmate 649 and Keynote 590 and Orient 16, et cetera. However, there’s still a very large portion of patients who are not getting a lot of benefit from the addition of checkpoint inhibitors. We don’t entirely understand the mechanisms of resistance to checkpoint inhibitors in gastric and esophageal cancers, but certainly the tumor microenvironment plays a large role and DKK1, which is a secreted factor, can drive an immune suppressive microenvironment suggesting that PD-1 is less likely to work in a DKK1 high tumor. It also sets up a rationale whereby if you could neutralize the DKK1 from the environment, you might be able to remodel the microenvironment and make it more favorable to checkpoint inhibitor response.
That was the idea behind combining DKNO1, which is a neutralizing antibody against DKK1 with a checkpoint inhibitor and standard of care chemotherapy that was considered part A. And then there is part B and C, which are looking at later line populations. And so part A is where most of the effort has been committed to looking at this in the frontline population because that’s where checkpoint inhibitors are currently being used. And so the rationale for the distinguished trial was really to build upon 5FU Oxaliplatin and PD1 and try to give an agent that could continue to remodel the microenvironment and increase the proportion of patients who are going to benefit from immunotherapy.