Tumor Mutational Burden in CRC

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Transcript: Johanna C. Bendell, MD: Okay, so now since you brought up lung cancer, everybody is very excited right now about tumor mutational burden [TMB]. Is that better? Does that trump PD-L1 [programmed death-ligand 1] status? We know in colon cancer, PD-L1 is out the window. It doesn’t matter if you’re PD-L1 high or low in the MSI [microsatellite instability]-high population, you still get benefit. So what do we think about tumor mutational burden? We can test it now in our sprinkles as well as NGS [next-generation sequencing].

Heinz-Josef Lenz, MD, FACP: It is now, yes.

Johanna C. Bendell, MD: Would we ever consider thinking about—now realizing there’s no clinical trial to say one way or the other—would you think about treating somebody based on the tumor mutational burden status with an immunotherapy for colon cancer?

Zev A. Wainberg, MD: I wouldn’t do it off of a trial. I mean, first of all, the large majority of colon cancer patients who are MSS [microsatellite stable] do not have a high tumor mutational burden. Some of these are coming back as intermediate, which are suggestive of maybe some tumor mutational burden. But, at this point in time, I don’t think there’s sufficient data to treat with a checkpoint inhibitor in someone, just based on tumor mutational burden. Because there’s a lot more to this story obviously than just is their tumor mutational burden high, low, or medium. And the specific characteristics of those within each patient are still very much unknown.

Johanna C. Bendell, MD: So now let’s sober us [up]. Oh, you would, Heinz?

Heinz-Josef Lenz, MD, FACP: Yes. We know in many examples, anal cancer is not MSI-high, high tumor mutation load—responds very well. [Poor] mutation will not have MSI, one who has had tumor mutation load—they respond. And when you do tumor mutation load with MSI, it predicts better sensitivity to immunotherapy than MSI.

Johanna C. Bendell, MD: Yeah, and that’s the question. These cohorts are definitely being addressed right now in trial patients.

Heinz-Josef Lenz, MD, FACP: So I think we will see more [benefits] from immunotherapy than [with] MSI alone. It will be TMB coming in. The question is here, the cutoff, 6, 8, 10, 12, 100 [tumor mutation load] or whatever. But I had a patient—I was freaking out—with no MSI, germline completely negative, tumor mutation load of 1200; 1200. A French scientist, OK? And he says, “I don’t understand.” What did we do? Whole genome sequencing ... explained it, and for the first time, I understood. So that’s the reason I see this [as] incredible. I didn’t know how to explain it. High tumor mutation load and not MSI, and all germline variations covered. So what I’m saying, we will learn more and more as we go along.

Johanna C. Bendell, MD: So let’s sober us up just a little bit. For microsatellite stable patients, Dirk, you’re presenting some sad data but very relevant data here at ESMO [European Society for Medical Oncology]. Tell us a little bit about it.

Dirk Arnold, MD, PhD: Oh yeah, the combinations again and the hope that we may somehow sensitize tumors [that] are likely to respond [with] checkpoint inhibitors, which has been done before. Only in this setting we use immunotherapy in the MSS patient when no response is needed, say in a maintenance setting after patients already underwent responses and after they had antigen release. I think it’s [an] ideal situation in the microenvironment, but also here the checkpoint inhibition fails to improve the duration of maintenance treatment or to ensure that the maintenance treatment failed. So, therefore, this is not the solution, I can say.

Johanna C. Bendell, MD: So MSS remains the white whale that we continue to search for how to treat these patients better, find out if we can make immunotherapy work.

Dirk Arnold, MD, PhD: Yeah, or we have to say, we have to stimulate the immune system by way more and beat, what should I say, oncolytic viruses, or whatever. [These] could be interesting copartners for these drugs. But we’ll see in the future.

Johanna C. Bendell, MD: Definitely. Well, this discussion has been great. Before we conclude, I’d like [to] ask each of our panelists to remark with some closing thoughts regarding what we have just covered. Dr Arnold, back to you. What are your final closing thoughts? What’s the hope?

Dirk Arnold, MD, PhD: The hope is clear that with better knowledge of patients and patients’ biological characteristics, we can clearly dive in deeper into the right decision making and getting more drugs to this field. We have to really, you mentioned, sober up. We have now been receiving rather disappointing data during the last 2, 3 years. Not much happened. Yeah, small steps, but hopefully [we’ll get] better characterization. And I think we made big progress here. Also thanks to Heinz’s group and the work [that] has been done from your group. With better molecular characterization, I think that’s the precondition and let’s embark from here.

Johanna C. Bendell, MD: Dr Lenz?

Heinz-Josef Lenz, MD, FACP: We’re living in the middle of the molecular revolution, I couldn’t agree more. And we see the first evidence. We know that BRAF-[mutation] potentially moves into first-line. That’s ongoing. MSI, the data suggest, it may have a role in first-line. So patients [that] were considered poor are now in first-line treated with targeted novel treatments. I think that we need more sprinkles in our lives. And I think with the evolving technology, we will [achieve] much more, not only [identifying] new targets, characterizing these patients better, but also protecting them [from] toxicity, like DPD [dihydropyrimidine dehydrogenase], an old target, but we will integrate that into our practices. And I’m sure patients will live longer and better.

Johanna C. Bendell, MD: Dr Wainberg?

Zev A. Wainberg, MD: So also I share the enthusiasm that I think the future is bright. I think the advent of new technologies—which are becoming cheaper and cheaper, and more community oncologists will have access to these—will change the way we think about this disease. It might take some time, but whether it’s serial liquid biopsying patients to see how tumors evolve over a period of time and adjusting the treatments, or just fine-tuning a little bit more, whether immuno-phenotype of a patient or a specific molecular target may be of relevance, we’ll find out more in the next few years than we have in the last few years, I suspect. So we remain optimistic.

Johanna C. Bendell, MD: I love it. Well, thank you all for your contributions to this discussion. On behalf of our panel, we thank you for joining us, and we hope you found this OncLive Peer Exchange® discussion to be insightful and informative.

Transcript Edited for Clarity