Novel Therapy for NSCLC With KRAS G12C Mutation


Expert perspectives on the management of KRAS G12C–mutant non–small cell lung cancer in the context of novel targeted agents.


Benjamin Levy, MD: Let’s move on to an undruggable mutation, or at least historically it has been undruggable: KRAS G12C. Alex, you’ve been front and center on this. You presented the data with adagrasib and simultaneously released your paper in the New England Journal of Medicine. Congratulations. Before adagrasib it was sotorasib. Do you want to walk us through those [sotorasib] data briefly and then the adagrasib data?

Alexander Spira, MD: Sotorasib came out about a year ago with multiple presentations. It was presented at ASCO [American Society of Clinical Oncology Annual Meeting], and it’s a game changer, right? Response rates are in the 30%-to-40% range, and it’s very efficacious and well tolerated by all. It’s interesting because at that time there was criticism because response rates were not what we were expecting. Taking a step back, I’m old enough to—I don’t know if I’m the oldest 1 here.

Benjamin Levy, MD: You are.

Alexander Spira, MD: Thanks, Dr Levy. I participated in at least 5 KRAS trials, all of which were stone-cold negative. We had an undruggable target and we made it druggable. It’s not perfect, but what a phenomenal thing for our patients. It’s a real number. You talk about exon 20, you talk about ALK, and you talk about single digits—it’s 14% of our patients, so that’s a huge deal. Adagrasib is about a year behind sotorasib. The response rate is 43%. There’s a little concern raised because there’s a little more toxicity there. A lot of patients got their dose reduced, but the discontinuation rate is the same. We have the beginning of some CNS [central nervous system] data. There were some more presented by Joshua Sabari at ASCO. Both are very good drugs. At the end of the day, they’re both similar. The discussion yesterday did what you’re not supposed to do: put cross-trial comparisons side by side. We’re hard-pressed to notice a difference in the end. We might have some CNS data on adagrasib soon. We don’t have it on sotorasib, but it’s an exciting time.

Benjamin Levy, MD: Who would have thought?

Alexander Spira, MD: Who would have thought, right?

Benjamin Levy, MD: For sotorasib, it’s so exciting to see those data last year and see a median overall survival of 12 months at the second or third line. That’s not first line. Remember, for most patients with KRAS-mutant lung cancer, the median survival at the time of diagnosis was 12 months. To see this time at the start and at the receipt of this drug, which was second or third line, is pretty incredible.

Alexander Spira, MD: Adagrasib, the median number of lines of therapy was 2 but a quarter of patients got 3 or more. I mean just think about that. I mean that’s insane so the game changes for everybody. Now it’s going to be how do we move it to the front line or whatever and there’s going to be a whole pile of literature in other cancers too. I briefly mentioned it but maybe it’ll be one of those tumor agnostic things, which, it’s a lung cancer discussion but how cool is that?

Benjamin Levy, MD: KRAS mutation is a genotype that immunotherapy works quite well in, unlike EGFR and ALK. Is it going to be TKI [tyrosine kinase inhibitor] with immunotherapy for these patients? Are you still thinking it’s going to be chemotherapy–I/O [immuno-oncology] or I/O first for the high PD-L1s?

Alexander Spira, MD: Great question. How is this going to evolve, and how are they going to do the studies? There are ongoing studies with both combining immunotherapy. There are clear data that adagrasib is being combined now. With the CRYSTAL-7 study ongoing, I keep getting left with frontline therapy with I/O. It may expand later, but there’s going to be a lot of questions. Do you need to give it with I/O? What’s the PD-L cutoff that you use? There are a lot of questions, but that’s going to be the future. Let’s face it, we want it in the front line. No. 1, it’s efficacy is probably better tolerated than chemotherapy. But as oncologists, there’s nothing more ingratiating than identifying a target and treating the target. Patients love it, and we love it. It makes a lot more sense.

Jonathan Wesley Riess, MD: I was going to say that, as opposed to EGFR, ALK, and so forth, KRAS G12C patients can do quite well on immunotherapy for a long time. How to best bring it up front? A lot of what will evolve to is level of PD-L1 expression, which we already use, and also the role of comutations. There are some data for STK11, KEAP1, ARID1A, and others that may influence outcomes to both immunotherapy and—although they’re very small numbers—perhaps KRAS G12C direct inhibitor. Once again, it’s going to get more complicated in sorting out the first line. Maybe not all KRAS G12C are created equal in terms of whether immunotherapy may be the best first-line treatment vs sotorasib or adagrasib.

Alexander Spira, MD: It’s a great question. The challenge is that now you start to do these subgroups. Break it down to at least 2, maybe 3 cohorts of PD-L testing, and then break down to STK1, KEAP11, and God forbid you need to have that testing back before you stratify the patients. You start getting smaller numbers, and then you get results that look overlapping.

Benjamin Levy, MD: Great discussion. I’m sure we’ll have more in the next 6 months to discuss with these newer drugs coming out and combination strategies.

Transcript edited for clarity.

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