Expert Discusses Durable Results With Nivolumab/Ipilimumab in mCRC, Future of Immunotherapy

In the first report of the full cohort of 119 patients in the CheckMate-142 study, positive results were demonstrated with nivolumab (Opdivo) alone or in combination with ipilimumab (Yervoy) in patients with previously treated microsatellite instability-high (MSI-H) or DNA mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC).

The overall response rate (ORR) with the combination was 55%, with 31% achieving stable disease. The disease control rate (DCR) was 80%. Patients treated with nivolumab alone had a 31% ORR and a 69% DCR at 13 months of follow-up.

Patients treated with the combination had a median time to response of 2.8 months and the responses were durable. The median duration of response was not reached and 94% of responders had ongoing responses at data cutoff.

The durable results found in this subgroup of patients is just the beginning of immunotherapy for patients with mCRC, says Thierry André, MD, who presented these findings during the 2018 Gastrointestinal Cancers Symposium earlier this year.

In an interview withTargeted Oncology, André, medical director, Gastroenterology Oncology Unit, Hôpital Saint Antoine, Paris, France, discussed the findings from this trial and where the future of immunotherapy is heading in CRC.

TARGETED ONCOLOGY: Can you start by giving an overview of the Checkmate-142 study?

André:The study is a multi-cohort phase II international study. It has 2 cohorts of patients, the first cohort was given monotherapy with nivolumab treatments of 3 mg/kg every 15 days, and a second cohort was given nivolumab of 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks of a full cycle, followed by nivolumab 3mg/kg every 15 days. This was for patients with MSI-H or dMMR mCRC. The majority of the 119 patients received more than 2 lines of chemotherapy. We present the data from the 21-month follow-up. It demonstrates the responses continue for a long time, and it is very good news for the patients.

TARGETED ONCOLOGY: What were the results with the combination?

André:In this population, the ORR rate, which was the primary [endpoint] of the trial, was 55%. We have 80% of patients with disease control at 12 weeks. The results are really amazing. It's a low toxicity profile, with a little increase compared to monotherapy, but approximately 30% are grades 3/4. Fifteen percent of patients stopped treatment due to toxicity.

The conclusion is that this is a new combination for the patients in this very small population. This is a non-randomized trial where the ORR and disease control seems better compared to monotherapy. The number of patients with progressive disease is only 12% in this study, which is very low for this population. In conclusion, this proves that in a very small patient population — MSI-H is only 4% of mCRC – immuno-oncology provides long control of the disease, we have nivolumab, pembrolizumab, and now the combination of nivolumab with ipilimumab.

TARGETED ONCOLOGY: With the positive findings from this, are there any challenges you think we will need to overcome with this combination moving forward?

André:We don't have randomized data, and that is the problem. It's really the beginning of the story for immuno-oncology in mCRC. It's really up to try and move on and find more patients — 4% is not enough. We have to try a larger population and a number of mutations to try to increase the number of patients to treat with immunotherapy.

TARGETED ONCOLOGY: Do you think the positive results indicate that this may have potential to be standard of care for this population?

André:The problem is it’s a non-randomized trial, so it's difficult to have approval by the FDA in the US. Nivolumab and pembrolizumab are approved right now for this population. In Europe, it's a little more complicated because without a randomized trial, we are awaiting the evaluation by the EMEA, which is more complicated than in the US.

The problem is, in my opinion, it is really an ethics problem to avoid this therapyfor this patient population. But at this time, for example, in France, it's not possible to offer this drug outside of clinical trial and it's really a problem. It's a very expensive drug, pembrolizumab and nivolumab, and if you add ipilimumab, it's more expensive. It’s not possible to give to the patient without reimbursement. It's really a problem for the next month or next year. I don't know what the solution for that is because for nivolumab and ipilimumab in this population, it's only phase II data. In my opinion, at some time we will need a phase III trial. It will be necessary.

TARGETED ONCOLOGY: What do you hope community oncologists take away from your presentation?

André: