Clinical Trials in Metastatic Colorectal Cancer: Combination IO Therapy

Transcript:

Kristen K. Ciombor, MD: I think in general, microsatellite-stable [MSS] metastatic colorectal cancer [mCRC] is such a challenge because the vast majority of our patients and everyone wants immunotherapy to work. So whether it’s with combinations or what. One recent example, Dr El-Khoueiry presented I think at ESMO [European Society for Medical Oncology Congress] last year and then we’re going to get an update tomorrow on the botensilimab study. Dr Hecht, tell us a little bit about what that looked at, and are you excited about the potential data?

Joel R. Hecht, MD: Actually, I am very excited about this. Unfortunately, I can’t get the LBA [late-breaking abstract] until tomorrow, but I’ve seen and I saw the data at SITC [Society for Immunotherapy of Cancer]. And actually, that was probably some of the most interesting data coming out of ESMO last year. And so we had talked about earlier that while there may be some, a little bit of smoke in patients who have MSS colon either with single-agent PD-1 or PD-L1 and CTLA-4s, but the response rate is very low and maybe something in the tail of the curve. So these drugs are a combination and they call it boten/bal [botensilimab, balstilimab] because I can’t pronounce… [LAUGHTER].

Kristen K. Ciombor, MD: I know. They’re getting harder and harder.

Joel R. Hecht, MD: No. This is what the company calls it, boten/bal, because they can’t pronounce it either. Basically, one of them is just I think a pretty run-of-the-mill PD-1 that everyone has. And most, even small companies are making their own so they don’t have to play with or don’t have to come hat-in-hand to a large company to say please give me your ‘X’ PD-1 or PD-L1. And it makes combinations much faster because you’re not going through committees and things like that. Now if you had asked me a year ago whether or not the other one is an engineer, has the engineering of the Fc [fragment crystallizable] domain of the CTLA-4. And the reason that I’d say if you asked me a year ago, we’ve looked actually over the last 10-15 years of a lot of engineered Fc domains that are supposed to make things more immunogenic. And they haven’t really worked. There are companies that have had whole pipelines of those. But this data, the proof is in the pudding. The received wisdom is that this somehow is better and it forms an immunologic synapse but the key thing at the end of the day, because often you work these out when you have something that works and then you go back in an iterative process, and say well, why exactly did this work?

Kristen K. Ciombor, MD: Why is it working?

Joel R. Hecht, MD: So instead of a pretty close to 0% at least, and I know there will be additional data, is that they looked at this in a number of different cancers. One thing that’s particularly interesting is that they’ve also seen responses in sarcomas, which has been in general both soft tissue and I think also bone. But definitely soft tissue, which is kind of an immuno-resistant disease as well, and a terrible disease and actually 100 different diseases all pretending to be 1 disease, even though colon cancer is getting segmented. A large group of them, and I went back to the SITC data that they had presented, and one of the things that we always worry about is that when you expect a 0% response rate like you would with a PD-1 and a CTLA-4 and you get 1, everyone gets excited because you expect none. And if you get a couple, you might get more excited. So at least at that time, they had 59 patients with CRC. And 13 of them had responses. So this is not 1 or 2 or hero or someone got messed up on their MSI testing or they really were poli. You know what I’m saying, is that you’re getting now numbers that are enough that I think that there’s really some there. And not only are you getting responses, but you’re getting durable responses as well. Not everyone of course, and the numbers are still small, and I know that larger trials are being planned. But I think this is actually extremely exciting. There are other ways that we’re trying to tweak. I think probably checkpoint inhibitors are necessary but not sufficient, at least PD-1, and we’ll talk about that. But this is as exciting as anything that I’ve seen in MSS colon recently.

Kristen K. Ciombor, MD: That’s great.

Joel R. Hecht, MD: [I am] curious what the others think.

Pashtoon M. Kasi, MD: While I think definitely the drug is unique, [CROSSTALK]. But I think the nonactive liver metastases or the lung only…

Joel R. Hecht, MD: That’s a good point.

Pashtoon M. Kasi, MD: It’s something that’s very intriguing that we’re seeing in IO [immunotherapy]/TKI [tyrosine kinase inhibitor] combinations. There’s a recent publication from just a couple of weeks ago where it’s not just the fact that liver metastases is a bad milieu. There’s simplistically speaking active communication going on from the sites in the liver with other sites. So I’m not discounting the fact that the drug is BOT [botensilimab]. The BOT [drug] is new, but also I think the observation of annotation of you could have a history of resected metastases or latent metastases or variant metastases. But the fact that their responses went from 24% to 42% in those who didn’t have liver metastases.

Joel R. Hecht, MD: I think that point about liver metastases is important, not just this but any IO. A number of groups, I think there was the Michigan group and I think UCSF, this immunologic siphon. I was on the other end of this having run oncolytic virus trials where we actually injected into the liver, and which I can tell you is not a great place necessarily to probably put your IO agent. But we did not know that at the time. I think you bring up a really good point about patient selection for these. Once again we’re segmenting people in a lot of different ways. We’re segmenting people by molecular findings such as MSI or HER2 or RAS. We segment people by things that are clinical like sidedness, which probably means a whole bunch of different things. And presumably, patients who have liver metastases as you pointed out, they’re probably actively immunosuppressive and they may be different in other ways that we don’t understand, the person who has liver metastases as opposed to the person who does not.

Pashtoon M. Kasi, MD: I think building on what Dr Ciombor was mentioning about the first-line MSI-high immunotherapy data, moving it just 1 step earlier in the neoadjuvant, we’re seeing responses…

Kristen K. Ciombor, MD: Incredible responses.

Pashtoon M. Kasi, MD: So I think it’s very fascinating how these subsets are just going beyond the genomic subsets and sidedness and location of metastases and the setting. So exciting times.

Transcript edited for clarity.