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
-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.
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.
OncLive: Can you tell us about the recent study of nivolumab and ipilimumab in CRC?
: 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.
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.
What role do you envision immunotherapy having in this disease?
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.