KRAS-Mutant NSCLC: Current Systemic Treatment Options


Benjamin P. Levy, MD: David, you talked a lot about the importance of subtyping KRAS mutations, and KRAS G12C certainly is a mutation that we are now considering to be actionable with some of these new therapies. Before we talk about the newer therapies that are coming down the pike and have been reported on, we’ve also learned a great deal about KRAS biology in general in terms of outcomes, as well as coalterations with KRAS that may impact how these patients do with particular therapies. What’s the historical view on the prognosis of patients with KRAS-mutated lung cancer?

David R. Gandara, MD: It’s been very mixed, and many papers contradict one another. My estimation on why is that they either didn’t have enough numbers or they failed to account for all the different KRAS mutations, which are so biologically different from 1 to the other. I can remember seeing these papers. I would talk about KRAS, and someone from the audience would say, “Well, I read this review article on so-and-so, and they said it didn’t make any difference.” Sometimes papers would say it’s prognostic but not predictive of outcome. That being said, for many years and even in preclinical data such as those from coclinical trials, it has been shown that an association—for example, G12C with STK11—makes that a very difficult target to drug with a MEK inhibitor. But if you had a chemotherapeutic like docetaxel, you actually get some response. That led to the trial that you talked about, which failed in phase 3. Even now, we have quite good data that say trametinib, for example, has a response rate of 10%, and if you add docetaxel to that, it’s 25%. But the duration of the responses is short, and there’s a fair amount of toxicity associated with those therapies.

Yes, we have had therapies in the past. Now we should move on to what we do now. What we do now in almost every patient with non–small cell lung cancer is checkpoint immunotherapy.

Benjamin P. Levy, MD: Let’s talk about that and get to the meat of the issue. We’re both doing next-generation sequencing on our patients. I assume for patients outside a clinical trial who are KRAS positive, depending on their PD-L1 status, you may offer single-agent pembrolizumab if their PD-L1 is greater than 50% or triplet therapy with carboplatin-pemetrexed-pembrolizumab. With less than 50% PD-L1 expression, you would offer triplet therapy with carboplatin-pemetrexed-pembrolizumab. Is that your practice? We can talk about how these coalterations may change things for you, but is that what you’re generally doing?

David R. Gandara, MD: Yes, and I think there are data to support the fact that patients—at least with a KRAS mutation—do better on checkpoint immunotherapy than those without.

Benjamin P. Levy, MD: Yes.

David R. Gandara, MD: The problem has been how do you disassociate that from their smoking history? As I said, G12C is highly associated with tobacco carcinogenesis. But some recent analyses, which I’m sure you’ve seen. For instance, the KEYNOTE trials with monotherapy showed that patients who had the greatest benefit in survival with checkpoint immunotherapy, almost independent of PD-L1 or tumor mutational burden, were those who had a KRAS mutation in their cancer. They did the best, particularly with G12C. They did the very best. Interestingly, a preliminary analysis of the same checkpoint inhibitor, pembrolizumab, given together with chemotherapy was less clear. I think that’s because chemotherapy is agnostic to some of these biomarkers. It’s an emerging field, but it’s quite interesting.

Benjamin P. Levy, MD: There are very interesting data emerging, and we’re still wrestling with this. I agree, when immunotherapy quickly arose as cemented in the second and then first line, we thought KRAS may be 1 of these predictive biomarkers for better outcome.

Transcript edited for clarity.

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