Latest Immunotherapy Research in Treating Colorectal Cancer

Michael Overman, MD

As part of our coverage of the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting held June 3–7 in Chicago, we are speaking with Michael J. Overman, MD, a medical oncologist who specializes in the treatment of gastrointestinal cancers at the University of Texas MD Anderson Cancer Center in Houston. Dr. Overman presented interim results from the phase II CheckMate 142 trial of nivolumab plus or minus ipilimumab in patients with metastatic colorectal cancer (abstract 3501).

 - Interviewed by Anna Azvolinsky 

Cancer Network: This trial tested either the anti–programmed death 1 (PD-1) monoclonal antibody nivolumab as a monotherapy or in combination with another immune checkpoint antibody, ipilimumab, in a subpopulation of colorectal cancer patients. Could you give us a brief overview of what makes this patient population unique?

Dr. Overman: We looked at microsatellite instability [MSI]-high patients, also termed deficient mismatch repair, and that is a subset that has been evaluated in early colorectal cancer, in part, because a subset of patients with MSI-high will have an inherited condition termed Lynch. But, basically, MSI-high is a marker for deficient mismatch repair and so when you have a deficiency in this repair you end up with many mutations, so these are hypermutated tumors and, based on the hypothesis within this study and other data in other tumor types, tumors with many mutations tend to be more immunogenic. This is likely related to increased tumor-specific neoantigens that are expressed. That was the premise of this study and why we focused on this small population. The one key thing to note is that MSI-high in early-stage disease is about 15% of patients, but among metastatic patients, it is really 4% of metastatic colorectal cancers. This is really a small subset of the metastatic colorectal cancer space.

Cancer Network: Could you tell us what the efficacy and safety interim results were?

Dr. Overman: This is a small subpopulation, so the data, I think, are really dramatic and robust, suggesting that this subpopulation is an extremely immune-responsive group. That is the fundamental excitement from our data here. We looked at a population of 70 patients, so a large cohort, treated with single-agent nivolumab, and that is the therapy for which we have had data on for the longest amount of time, the most robust data to speak to right now. In those 70 patients that got nivolumab, 3 mg/kg every 2 weeks, what we saw was that the confirmed partial response rate was 25% and the stable disease rate was 30%-basically a clinical benefit of about 55%. But the most interesting and exciting data are that both the stable disease and the responses were extremely durable. The progression-free survival [PFS] at 6 months was 46%, at 12 months was also 46%, so there is a flattening of the curve, and that occurs at a pretty high level. We saw extremely few progressions occurring after 12 weeks on study.

Besides that cohort, we looked at the combination cohort in MSI-high colorectal cancer of nivolumab and ipilimumab. Now, for the combination study it was 30 patients and a much shorter follow-up, so it’s a little hard to express the PFS benefit. The curve tends to be a bit higher and there is a higher flattening of the PFS curve, but what you can say is that the response we see is about 30% and stable disease is about 50%, so the clinical benefit rate at an early point appears to be higher. Whether that will be as durable is the question that will require further follow-up. But, clearly, the nivolumab data in conjunction with prior data with pembrolizumab in the same population really cements this concept that immune checkpoint therapy with PD-1 in MSI-high colorectal cancer is a fantastically active option. There are many clinical trials in this space and testing for MSI-high in metastatic patients, and a clinical trial with a checkpoint inhibitor is something that should be considered because of the tremendous benefit that patients are seeing.

Cancer Network: Could you go over some of the safety results that are notable?

Dr. Overman: The single-agent therapy was fairly well tolerated. There was a 3% discontinuation rate with single-agent nivolumab. The grade 3/4 all-comer toxicity rate was around 13% and in general was fairly well manageable. The combination, as expected, did have increased toxicity. The combination dosing we explored was nivolumab at 3 mg/kg and ipilimumab at 1 mg/kg given for 4 doses, and then as single-agent nivolumab after that. The discontinuation rate was 13% related to toxicity, and the overall grade 3/4 toxicity rate was around 26%. So, there was higher toxicity with the combination and hence some early preliminary sense that maybe it was more efficacious, but again this was not a comparison-based study, so I think further follow-up might support that. Clearly, that is the question with the combination. Is that increased toxicity going to be appropriate in the context of increased efficacy? We really don’t have the answer but, again, with further follow-up we hope to get clarity on that. However, as I said, the single agent was clearly well tolerated as in other solid tumor trials, and no new unique toxicities related to colorectal cancers occurred.

Cancer Network: When could we expect the full results from this clinical trial?

Dr. Overman: At present, we are still enrolling combination therapy patients, and that will continue for a short amount of time. After that, we want further follow-up with the combination, but I think we have planned a data analysis that will happen later on this year and, following that, a publication will come out. My expectation is that the publication will come out at the end of this year or early next year.

Cancer Network: Are there other colorectal cancer clinical trials testing immunotherapy regimens that you could highlight?

Dr. Overman: The real key question is, I talked about 4% of patients with MSI-high colorectal cancer, but what about the 96% of patients with microsatellite-stable metastatic colorectal cancer? Clearly that is a large group in which we want to do better with immunotherapy and we haven’t seen immune therapy activity occur in that group. At this ASCO meeting, there was a presentation from Johanna Bendell that looked at the combination of atezolizumab plus cobimetinib, a MEK inhibitor that is designed to increase T-cell tracking, and that combination, in a very early phase I clinical trial with 23 colorectal cancer patients, saw a 17% response rate. So, there is at least a signal with an immune-based approach in combination with this MEK inhibitor that could indicate that microsatellite-stable colorectal cancer patients could have some benefit from immune therapy. That combination of atezolizumab and cobimetinib is going to go forward into a large phase III study investigating its activity in refractory microsatellite-stable colorectal cancer, in the late summer to the fall.

Cancer Network: Thank you so much for joining us today, Dr. Overman.

Dr. Overman: You’re welcome, and thank you.