CheckMate142: Checkpoint combination therapy in first-line colorectal cancer

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Published: 26 Oct 2018
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Dr Heinz-Josef J. Lenz - Keck School of Medicine of USC, Los Angeles, USA

Dr Lenz speaks with ecancer at ESMO 2018 in Munich about the CheckMate 142 trial of nivolumab with ipilimumab as first-line therapy in DNA mismatch repair deficient (dMMR) and microsatellite instability-high (MSI-high) metastatic colorectal cancer (mCRC).

He outlines previous research into differing doses of the combination, and reports the improved disease control rate, response rate and tolerability of this trials 6 week schedule.

The use of checkpoint combination therapy in early colon cancer as neo-adjuvant therapy is also discussed by Dr Myriam Chalabi.

I reported today the data on CheckMate142 which is a multi-cohort phase II study. Previously the data on the refractory colorectal cancer patients with MSI high tumours were reported in the JCO showing significant activity with nivolumab and ipilimumab in the refractory patient population. The response rate in that group was 55% for the combination and 31% for the immunotherapy. The median progression free survival and overall survival have not been reached. The toxicity was treatment related grade 3 and grade 4 about 16% for the monotherapy and 32% for the combination treatment. The twelve month progression free rate was 77% and overall survival at twelve months was 83%.

Today I’ve reported for the first time the first line treatment with a combination of nivolumab at 3mg/kg and ipilimumab at 1mg/kg. This is in six week intervals which is in contrast to the three week interval in the refractory patient population. The refractory efficacy data led to an accelerated FDA approval for nivolumab alone or in combination with ipilimumab for patients with metastatic MSI high tumours who were treated previously with fluoropyrimidines oxaliplatin and irinotecan.
In the first line cohort we enrolled 45 patients, 50% were male, median age 66. We collected data on PD-L1 expression, KRAS mutation, BRAF mutation status as well as the presence of Lynch syndrome. The efficacy data were very impressive with an overall response rate of 60%, 7% with a complete response. The disease control rate which indicates at least stable disease beyond twelve weeks was 84%.

Now the response was independent of PD-L1 expression, independent of KRAS or BRAF mutational status as well as independent of the Lynch syndrome presence or not. In addition to the significant efficacy we saw significant lower toxicity because of the increased interval used for the ipilimumab. Only 16% had grade 3/4 treatment related adverse events which is basically the same as nivolumab as monotherapy. Only 7% discontinued treatment because of treatment related adverse events which is the same as for nivolumab monotherapy. So this data indicate a highly effective treatment option in first line for patients with MSI high metastatic colorectal cancer.

The big question is are these data sufficient for potential registration with the FDA? I’m sure that the BMS team will start discussion with the FDA what would be needed. I think we are all waiting for the KEYNOTE study which used pembrolizumab in first line for the same patient population if they are consistent with it. I think it’s very important maybe to mention that MSI high tumours have a very poor prognosis so PFS rates are around only 7 months and the overall survival only 20 months. In this trial the median has not been achieved, the twelve month rate is 77% for PFS and 84% for overall survival, so these data look very promising for a sustained long-term survival benefit for these patients who are usually poorly prognostic.