Nivolumab plus ipilimumab improves on chemo in previously untreated MSI-H/dMMR mCRC

Dr Thierry André - Sorbonne Université, Paris, France

My study is about the therapy of metastatic colorectal cancer with MSI or dMMR status. It’s 5% of metastatic colorectal cancer, it’s Lynch Syndrome or sporadic MSI, and it is a very particular category of patients with carcinoma heterogenesis, very particular, and with the fact that MSI and dMMR status is a predictive factor of immune checkpoint inhibitor.

What was the study design?

The study design is a phase III. It’s a phase III with two endpoints and three arms. The arms are nivolumab plus ipilimumab, nivolumab alone, and chemo plus cetuximab or bevacizumab. The first primary endpoint presented at ASCO this year was a comparison in first line between nivolumab plus ipilimumab versus chemotherapy. The second endpoint, not presented at this time because it’s not mature, is a comparison between nivolumab and nivolumab plus ipilimumab in all lines.

What were the results?

The results are the fact that the study met its primary endpoint, demonstrating statistically and clinically meaningful improvement in PFS by nivolumab plus ipilimumab versus chemo. The hazard ratio was at 0.21, it’s not frequent in oncology, with a median PFS not reached with nivolumab/ipilimumab and at 5.9 months for chemo. There was a very early separation of PFS curves starting at approximately 3 months and the PFS at 2 years was 72% for nivolumab/ipilimumab and 14% for chemo.

The primary analysis was done on centrally confirmed MSI/dMMR, it’s not the intent to treat population but it was the endpoint, the primary endpoint. For the intent to treat population the hazard ratio is at 0.32. One of the reasons of this analysis is the fact that 10% of the patients, 10.5%, was misdiagnosed and was MSS and pMMR, the reason the primary objective was on the centrally confirmed MSI and dMMR.

How can these results impact the treatment of colorectal cancer?

In the past, and it was recent, but pembrolizumab is the standard of care in first line dMMR/MSI metastatic colorectal cancer. The combination of nivolumab plus ipilimumab is now a new option with better results. It’s not a comparison but the hazard ratio of the study comparing pembrolizumab versus chemotherapy plus or minus targeted therapy was 0.6. There we are 0.21 with nivolumab/ipilimumab and it’s clearly a new first-line option in first line at this time. It’s difficult to tell it is the only option – we have two options and we have now to determine. Probably some patients need only monotherapy but at this time we don’t know and it’s clear that the combination of nivolumab plus ipilimumab had better results compared to pembrolizumab in this category of patients.

Is there anything else you would like to add?

I will add the fact that the therapy had some toxicity. It’s clear that nivolumab plus ipilimumab gives 23% of grade 3/4 toxicity and chemo plus or minus bevacizumab or cetuximab gives more toxicity – 48%. But there were two treatment-related immune-mediated deaths in the nivolumab plus ipilimumab arm and it is the safety analysis in this trial.

I have also to add the fact that when we did the prespecified PFS analysis by baseline characteristics, all subgroups benefited from the combination versus chemo, including liver metastasis, lung metastasis, RAS status and also peritoneal carcinomatosis.