Non–Small Cell Lung Cancer: Selecting 1L Therapy for Patients With KRAS G12C Mutations


Key opinion leaders identify the first-line treatment armamentarium for patients with KRAS G12C–mutated non–small cell lung cancer.


Joshua K. Sabari, MD: Let's dive into KRAS G12C here. We said it's quite common, 12% of my patient population. Curious, Martin, out in Florida are you seeing it at similar rates?

Martin Dietrich, MD, PhD: Yes. It's not that different. We do have a very strong smoking population, so KRAS is by far the most common driver that we're seeing.

Joshua K. Sabari, MD:In that patient population, in the frontline setting, what is your standard of care regimen for a patient with a KRAS G12C mutation with let's say, non-small-cell lung cancer, adenocarcinoma, and let's say their PD-L1 expression is 25%? Let's start there.

Martin Dietrich, MD, PhD: I do have 2 columns, one is the molecular one, the second one is the clinical presentation. If the patient comes in and is not symptomatic and needs a fast response with chemotherapy, I will look at the molecular markers. And in my definition, what we define as PD-L1 high has been moving up, up, up, closer to 100%. We are seeing, obviously, a patient here with a low PD-L1 level, particularly difficult to treat subset. And with a lower expectation of a PD1 response. My approach here would be the combination of a chemotherapy plus and anti-PD1 in the first-line setting. Again, obviously, if a patient had clinical factors that are important as well, I would obviously be even stronger weighing on chemotherapy. The number of regimens that we have now available, and it's a little bit of dealer's choice, none of them are compared head-to-head, but I would think that would be an approach that is reasonable and covers most scenarios for the patient's care. Question is, what to do in a second-line setting and how to move a patient going forward. And we've seen some data there in the second-line setting, and I made it my practice in second-line setting to screen every patient for a clinical trial. I don't think that we had a strongly established second-line standard of care post-chemo-IO. We mainly relied on extrapolated data from docetaxel in the second-line setting. I was looking for options that may be more appealing, if they're not particularly more efficacious, at least more tolerable and looking for targeted therapy options. As you mentioned, there's absolutely no time to look for these mutations, if I have a second-line patient that is KRAS G12C mutant, obviously, this would be my preference, not only because it is an efficacious therapy, but also because they are in, in the patient experience of adverse effects, they are much more favorable than the chemotherapy counterparts that we're having.

Joshua K. Sabari, MD: This is a tough patient population PD-L1 low or even the negative, the 0, what do we think about those patients? And I agree, with more and more data now points to using chemotherapy and immunotherapy combinations. I'll go even a little deeper, more on a patient who has a STK11 and a KEAP1, those are co-alterations that may predict poor response to immunotherapy. Are you adding a CTLA4 inhibitor in this patient population who's KRAS G12C in the frontline setting, or are you still doing the potentially carbo pembrolizumab?

Martin Dietrich, MD, PhD: I've been very interested in the data from CTLA4 targeted therapies in the last couple of years I’ve probably been using it more than most. Especially in the population that you mentioned where we have an unfavorable PD1 constellation, where we have basically no limited targeted of PD1, PD-L1 activity. I do think that they have great value. We have three positive Phase 3 trials across two separate agents that have been approved, some recently, some over the last two years. I do think that CTLA4s carry their weight, they're not putting the world upside down like CAR T cells, but I do think that they incrementally improve benefit and durability. I want to say, a cost-benefit ratio with regards to adverse effects, but I've started to embrace auto-immune adverse effects as a necessary evil for long-term outcomes, and oftentimes long-term outcomes that are treatment free. My impression has always been that we need deeper responses than when we go into chemotherapy. We're probably covering the immunotherapy insensitive disease compartment. I don't think of these 2 mechanisms as synergistic, in fact I would have to make the claim, and I tell this to my patients, the long-term outcomes are truly dependent only on the strength of their immunotherapy response. I do use the CTLA4s for PD-L1 negatives very frequently, and I don't know if there's a safe cut-off where I can say the CTLA4 doesn't have any value, but for those genomic set ups that you outlined with multiple resistance mutations that are negative prognostic predictors here in the setting, low PD-L1, absolutely I do think that we either have to think of a clinical trial or an intensification of the therapies that we have. I wish we had segued into the CTLA4 and lung cancer differently. We've had it in other disease spaces, in melanoma, in renal cell, where the CTLA4s have been embraced very differently, but I do think that we stumbled into CTLA4 which I think hindered the uptake of those agents, unfortunately. And I think is still a hindrance for the way we use it.

Joshua K. Sabari, MD: Ipilimumab, nivolumab and chemotherapy, the CheckMate 9LA FDA approved, and again, no prospective data in these subsets of patients who are STK11 KEAP1 co-altered, but yes, it's a regimen that I've been using in that patient population. They're generally PD-L1 low or negative, and just about 2 weeks ago, the approval of POSEIDON regimen, which is durvalumab, tremelimumab, and chemotherapy; also a very interesting subset analysis in this patient population.

Transcript edited for clarity.

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