Expert Sheds Light on Promising Immunotherapy Combo Data in mCRC

Michael J. Overman, MD

In patients with high microsatellite instability (MSI-H) colorectal cancer (CRC), the immunotherapy combination of nivolumab (Opdivo) and ipilimumab (Yervoy) showed encouraging activity, according to interim phase II results of the CheckMate-142 study.¹

The findings, which were presented during the 2016 ASCO Annual Meeting, show that at a follow-up of ≥12 weeks, the investigator-assessed objective response rate was 25.5% (95% CI, 15.4-38.1) in patients who received single-agent nivolumab and 33.3% (95% CI, 18.6-50.9) in those who received the combination. The progression-free survival (PFS) rates at 6 months were 45.9% (95% CI, 29.8-60.7) and 66.6% (95% CI, 45.5-81.1), respectively.

In the open-label, international, non-comparative trial, 70 MSI-H patients received 3 mg/kg of nivolumab every 2 weeks and 30 patients received 4 doses of nivolumab (3 mg/kg) combined with ipilimumab (1 mg/kg) followed by nivolumab (3 mg/kg) every 2 weeks until progression or unacceptable toxicity. Among microsatellite stable patients, 1 cohort of 10 patients received nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg and the other cohort of 10 patients received nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg.

Among MSI-H patients who received single-agent nivolumab, the rates of stage I/II, III, and IV disease were 21.4%, 34.3%, and 42.9%, respectively. The rates of KRAS/BRAF wild-type, BRAF-positive, and KRAS-positive patients were 37.1%, 15.7%, and 32.9%, respectively. Mutation status was unknown for 14.3% of patients.

Additionally, all patients had prior treatment, with 12.9% receiving 1 previous regimen and 30% and 55.7% receiving 2 and ≥3 previous regimens, respectively. Prior radiotherapy had been received by 37.1% of patients.

OncLive: Can you tell us about the recent study of nivolumab and ipilimumab in CRC?

In an interview with OncLive, lead study author Michael J. Overman, MD, associate professor, Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses the CheckMate-142 study and what potential immunotherapy could have on the treatment paradigm of CRC.Overman: We presented the abstract from the CheckMate-142 study, which looked at nivolumab and ipilimumab in MSI-H CRC. This is a subset that has shown previously immune responsiveness and, at the 2016 ASCO Annual Meeting, we demonstrated our interim results with 70 patients treated with nivolumab, and 30 patients treated with nivolumab and ipilimumab.

These results in particular demonstrate, as previously shown, marked activity with checkpoint therapy in this particular type of colon cancer. We have a PFS that is around 6 months with single-agent nivolumab, and the more impressive findings related to our data is the durability of our responses and the stable disease.

Our PFS at 12 months with single-agent nivolumab is approximately 45%, demonstrating that patients who are on therapy for greater than 12 weeks, at that point, really stay on therapy for the remainder. We see very few late progression events. In an overall sense, we do see both partial response and stable disease in about 30% for each, but those seem to be durable and in both cases.

In regards to the combination therapy, again, that's a smaller cohort that started later in this study design, so the follow-up is a shorter time period for the combination. At least preliminarily, in regards to tumor reduction, 80% of cases have demonstrated a reduction in size. If you look at the monotherapy arm of ipilumimab, you have approximately 55% with tumor reduction, so it does appear that there's potentially more benefit from combination therapy. However, I would like to stress that monotherapy is fairly dramatic in regards to the activity that we're seeing, and the durability of those kind of responses and stable disease.

What role do you envision immunotherapy having in this disease?

Within this study, there was a MSS cohort that was used to determine the dose for the combination arm. That was the purpose of having this very small, 20-patient MSS cohort. Based on that cohort, the safety data demonstrated that we move forward with combination arm of nivolumab of 3 mg/k and ipilumimab at 1 mg/kg. Within that 20 patient cohort, we had 1 response and, in general, the PFS was fairly short at about 2 months.I think it's really exciting. There's been pembrolizumab data, and the nivolumab findings kind of support the information that was seen in that data set. Our data set is a little larger in sample size at this point, so I think we robustly confirm the activity of PD-1 targeting. Both assets really show a dramatic level of activity. We're seeing some of the highest response stable-disease rates that we've seen in many different types of solid tumors with immune checkpoint therapy.

Are there any next steps for this?

This subset is going to be defined as an immune therapy subset, meaning they will be treated with immune therapy. Going forward, I think we're going to see these immune checkpoints being moved into earlier lines of therapy. There's already studies that are investigating that. The question that's really open now and is of great interest is, "Do they really just replace chemotherapy in the MSI-H population?" I think there are some early data in the refractory base that shows that that could really be the case, but how that works out or if there is a combination approach that's best is what will play out in the future.This study is still ongoing. It was a two-stage design with monotherapy and combination therapy, and so the second stage of the combination therapy is still open and still enrolling. Clearly, we need more follow-up from the combination arms, because those were started later based on the design, so the follow-up is much shorter. The first future step would be to do further follow-up on this data.

We will have biomarker-based analyses that we will be presenting soon, so clearly the question of how the other biomarkers play out will be things we'll talk about going forward to see if we can further narrow down the population that has such a high benefit.

Overman MJ, Kopetz S, McDermott RS, et al. Nivolumab ± ipilimumab in treatment (tx) of patients (pts) with metastatic colorectal cancer (mCRC) with and without high microsatellite instability (MSI-H): CheckMate-142 interim results. J Clin Oncol. 34, 2016 (suppl; abstr 3501).