Doublet vs Singlet Immunotherapy for Patients With Metastatic MSI-High Colorectal Cancer

At Great Debates and Updates in Gastrointestinal Malignancies in New York, New York, Michael Overman, MD, MD Anderson Cancer Center, Houston, Texas, discussed advantages associated with use of doublet immunotherapy among patients with MSI-high colorectal cancer. 

Transcript: 

Hello, I'm Michael Overman, MD Anderson Cancer Center GI medical oncologist, and I'm here at the 2024 New York Great Debates. We had a discussion today related to immune therapy for MSI-high colorectal cancer. The debate was really whether there is a role for doublet versus single immune therapy. I was representing the pro argument, we should be using doublet immune therapy for metastatic, MSI-high colorectal cancer. 

In particular, that doublet question is really related to the 2 drugs, nivolumab and ipilimumab, which we have data for from the CheckMate 142 study and the CheckMate-8HW study, which we recently saw at GI ASCO and we'll also have an update from that at this upcoming ASCO meeting. 

In my role of discussing this, I'm going to say 2 kind of key points here, one is that our goal for MSI-high metastatic colorectal cancer has really evolved and our goal really should be cure. We have great activity with monotherapy and doublet therapy and what really matters is durability of the progression-free survival curve. At 2 years, 3 years, 4 years, or 5 years, which curve is actually having a higher plateau– that's where I would say the data from the randomized 8HW, which again was nivolumab, ipilimumab vs chemotherapy, is higher than what you see when you look at the comparative cross-draw comparison study of the KEYNOTE-177, looking at pembrolizumab versus chemotherapy. That higher flattening of the curve on progression-free survivalI do think reflects what we'll see long-term and really an improved cure fraction. We have seen that consistently with CheckMate-142 where the consistency of the curves stay high, flatten, and persist and CheckMate-142 now has 5-year progression-free survival data, really saying that we've kind of hit that durability mark where I think it's fair to say we are curing patients, and I'm gonna make the argument that when we do therapy to cure patients, we do a lot, that's really our highest kind of bar that we like to shoot for and I think in that context of increasing a cure fraction, that really makes the argument for us using doublet immune therapy up front with nivolumab and ipilimumab. 

The second point in regards to this argument is really from the toxicity perspective. The concern over doublet therapy is really increased toxicity, but when we look at the dosing that we've seen with 1mg/kg every 6 weeks, we see a lot better tolerability that was seen in the front-line cohort of CheckMate-142. We've also seen that use in other studies such as in lung cancer randomized clinical trials, and really when we do that, we actually do see a much more tolerable toxicity profile. I think it really suggests the combination of nivolumab and ipilimumab when we use the ipilimumab every 6 weeks really appears to be a much better tolerated approach and one that makes this concern of our toxicity I think a lot less warranted and dramatic, and really suggests that with that efficacy benefit I mentioned first, I think we have a combination that is appropriate with manageable toxicity, leading to an increased cure fraction is worth our initial upfront approach.

Source: 

Overman M. Debate: Should single agent or doublet immune checkpoint inhibition be the new standard of care in metastatic MSI-H colon cancer? For doublet or against doublet. Presented at Great Debates and Updates in Gastrointestinal Malignancies. May 17-18, 2024. New York, NY.