DR HECHT: Never has standard of care changed so rapidly and so profoundly on such a few number of patients. That being said, we all have seen that when we’ve given checkpoint inhibitors to patients who have MSI. We are seeing that, so it’s not just an outlier.

So, back to the data, as we slice and dice colon cancer, there are different ways to get to colon cancer. So, as I said, about 10% of patients have microsatellite instability, so what they have is abnormalities in their DNA mismatch repair proteins, either by epigenetically or whether by mutation.

Some tumors have a lot of mutations, like melanoma. Some pediatric tumors actually have very few. Colon cancer is to the right of the curve in the high part, though it varies, because some have a really high or, with the TCGA, they call those hypermutated. And they all have hundreds to thousands of mutations. And the idea is that these mutations then become targets that the immune system can recognize.

Now the problem is, obviously these people are dying of metastatic colon cancer, so the immune system is not recognizing it enough. So the combination of checkpoint inhibitors has been something that people had thought about and looked at. And I have to give the Hopkins group — and we were actually supposed to be part of that — really a lot of credit in not just getting the checkpoint inhibitor, which is pembrolizumab, but also doing really wonderful correlative science with that and with the number of mutations and the tumor-associated antigens. There was a huge amount of work that was done on that.

DR LOVE: And are the PD-1 levels actually elevated in patients with MSI high?

DR HECHT: I don’t think it’s actually quite as much that. You bring up another really good point, which is that biomarkers for one disease may not be the same biomarkers for another disease. We were talking, actually, about the gastric cancer trials. They saw benefit in both patients who were MSI with anti-PD-1 antibodies as well as patients who were MSS.

DR LOVE: And you couldn’t even really tell the difference that much. I was surprised because a quarter of gastric is MSI high.

DR HECHT: I think percentage-wise, though, they do better.

DR LOVE: Maybe higher.

DR HECHT: They’re better, yes. But they saw both, which was really important, because if only they’d seen benefit in MSI, that’s not telling something new. In colon cancer, however, there are a few scattered reports, but basically it they don’t work as a single agent.

So, back to the MSI, we see not just impressive response rates, with the response rate and clinical benefit rate that’s really higher than any other solid malignancy, higher than melanoma, higher than lung, but also these are like the good responses in melanoma and lung. These are durable responses. And so that is really in a very short period of time. It hasn’t been that long, and it’s really changed the way that we treat people.

There are actually trials looking in first line. Because the response rates are equivalent to chemotherapy and the idea that you get prolonged benefit, if you can’t get a patient on a trial, we can get it.

DR LOVE: Could I just clarify, though, which is the line of therapy that ideally you’d like to use? I know maybe it might differ in the patient who’s symptomatic and needs a response. I’m not sure about that. But in general right now, based on the data, first of all, what are the current numbers? Because we’ve seen some that have come out. I’m not sure if they’re dropping down a little bit.

DR HECHT: Well, there are differences depending on nivolumab versus pembrolizumab, though the numbers are small. Some of them are using PD-L1. I think it’s not quite as good, but the numbers are pretty high. They still probably are better tolerated than chemotherapy.

DR LOVE: Well, that’s for sure.

DR HECHT: Though, as you pointed out, checkpoint inhibitors are not bevacizumab. You see rare but severe toxicity that patients do need to have dose reductions sometimes.

DR LOVE: Can you clarify with them: Would you use checkpoint inhibitor first line in somebody who you know is MSI high?

DR HECHT: I would very much consider it. It’s a long discussion with the patient. And, as I said, there are trials actually right now looking at that front line. And, actually, there’s a talk that I give, and I use Clint Eastwood. “Are you feeling lucky, punk?” That’s saying they’re going against pretty standard therapy that helps. About 80% of patients are helped by first-line therapy nowadays. Only helped for so long, but they’re helped.

I think it would be a reasonable thing to do. And I have no problem with putting patients on that study. And off study, with a discussion, because we can often get these drugs.

Metastatic wild-type nonsquamous non-small cell lung cancer (NSCLC)

Metastatic colorectal cancer (mCRC)

Metastatic epithelial ovarian cancer (OC)