Checkpoint Inhibitor Effective in Subset of CRC Patients


Hi. I'm David Kerr, professor of cancer medicine at the University of Oxford. One of the recurring clinical problems that I have is that we don't have enough new drugs coming forward to treat colorectal cancer. It's a difficult nut to crack.

A very beautiful study has just been presented in the New England Journal of Medicine, by a very distinguished group led by Dr Luis Diaz [and Dr Bert Vogelstein] from Johns Hopkins University, that gives us some sense of promise that immune checkpoint inhibitors might be able to work in a subset of colorectal cancer patients.

We know that colorectal cancer has evolved a variety of different techniques to avoid immune surveillance: It downregulates MHC, it downregulates the various enzymes and proteins involved in antigen presentation, and its microenvironment is usually inimical to any sort of T-cell infiltrates. Therefore, it's a resistant, hard nut, as I've said.

This study had a very clear and simple hypothesis. Tumors that are mismatch-repair–deficient are likely to accumulate more somatic mutations and are therefore more likely to present a larger antigenic burden to the immune system. Mismatch-repair–deficient tumors should be more recognizable and more rejectable by the body's own immune set.

This is a rather nice study in which the authors recruited 41 colorectal cancer patients with and without mismatch-repair deficiency and a host of other tumor types that were mismatch-repair deficient. They treated the patients fortnightly with the anti–PD-1 immune checkpoint inhibitor pembrolizumab and got some fantastic results. The mismatch-repair–deficient tumors seemed to respond. Compared with colorectal cancer mismatch-repair–proficient tumors, they had improved progression-free survival, improved overall survival, and improved response rates. So the hypothesis seems to be intact.

Of course, because the study comes from Bert Vogelstein and the fantastic laboratory at Johns Hopkins, they went ahead to measure the number of mutations in different tumor types. They showed that in conventional sporadic colorectal cancer that is mismatch-repair proficient, the number of mutations, on average, was 70-75, compared with colorectal mismatch-repair–deficient tumors, in which the number of measured mutations was 1300-1500—an orders of magnitude difference that is showing up clinically in the potential for the immune checkpoint inhibitors to be effective in this subset of patients.

Now, if we look at advanced colorectal cancer, perhaps about 4%-5% would be expected to be mismatch-repair deficient. It's a small segment but one that is worth considering treating with these drugs. Of course, we require a large randomized trial to prove this, and this has been undertaken and is going ahead.

In the adjuvant setting, which is a particular interest of mine, probably 10%-15% of patients are mismatch-repair deficient. The problem with doing a trial in that setting, however, is that these tumors have a very good prognosis anyway. Therefore, the trial would have to be very large indeed, because the event rate would be small. Given the fact that baseline survival is so good, the absolute benefit or improvement that one might get from the immune checkpoint inhibitor, which has a bunch of side effects, might be more difficult to discern.

I think this is something that we should consider for advanced disease. We await with huge interest the results of a prospective randomized trial. It is a lovely piece of precision medicine for which a clear, simple hypothesis has generated some rather clear clinical results backed up by recent laboratory investigations.

I would love to hear what you think about it. Please post any of your comments online or contact me. What an interesting, clever study from a great group. Thanks for listening. Medscapers, ahoy.