Recent FDA-Approvals: KRAS G12C-Mutated NSCLC

Benjamin Levy, MD: Let’s move on to 1 of the most exciting stories in lung cancer over the past few months, which is the KRAS G12C story. We’ve got multiple drugs that have been evaluated and an FDA approval with sotorasib as of June 2021. Alex, we had some data from the CodeBreaK 100 trial, and we also have data from adagrasib. Do you want to talk briefly at a high level about the data we saw at ASCO [American Society of Clinical Oncology Annual Meeting] for sotorasib? I know you’ve been involved in some of the data generation for adagrasib as well.

Alex Spira, MD, PhD, FACP: I can start the conversation by saying you have a drug that targets something we could never target before. If you stop the conversation right there, we have enough going forward. But the sotorasib data just came out published in the New England Journal of Medicine with updates as well. This is a second-line study, so patients had to have been treated before with chemotherapy and multiple lines of therapy. Response rate 37%, median duration of response 11 months, 80% disease control rate. It’s a very well-tolerated drug: some grade 3 events, some hepatotoxicity, some diarrhea, some GI [gastrointestinal] adverse effects. We saw a little update on this across different subgroups. The typical ones we looked at were KEAP1, STK11, TP53, prior PD-L1 therapy, lines of therapy, and it works across the board. Very impressive data. This is a first-in-class drug. It’s something that we could never target before. Phenomenal result. None of this was a surprise. We’ve seen this before as part of the phase 1 study. This was the update for it [at World Conference on Lung Cancer], published concurrently in the New England Journal. This was an ASCO update. The funny thing about the question is how is it going to move forward in first line. What do people think about that? We can discuss that in the discussion section.

We haven’t seen an update for adagrasib, which is a similar drug. I’d use the analogy that it’s probably 6 to 12 months behind, with very similar concept: 600 mg [orally twice a day]. Pasi Jänne published some of this at World Lung last year. Those updated data had slightly higher response rates, in the low 40% range; slightly higher toxicity rates; a little more diarrhea; a little more GI adverse effects. But it’s also a very active drug. Phase 2 has accrued, with an ongoing randomized phase 3 vs docetaxel. Amgen’s drug had their randomized phase 3 versus docetaxel already completed. We’ll expect those updates as well. I have 2 targeted therapies against G12C. The fundamental question is, are other ones being developed? Where’s the next generation, and what do you combine it with moving to front line? 

Benjamin Levy, MD: That’s my segue. Melissa, you’re involved in a phase 1 program. Where do we go with these drugs? Are they single agent? Are they combination? If so, what do we use it with? Is it first line? Is it reserved for second line? How do we move forward for these KRAS G12C inhibitors?

Melissa Johnson, MD: It’s a good question. I have a few thoughts. We participated in the phase 1 in Denver of sotorasib and then in Nashville with adagrasib. And we’ve seen responses not just in lung cancer but also in colon cancer and ovarian cancer, that other solid tumors with KRAS G12C mutations will respond. But they haven’t done as well as the lung cancer cohort of patients. This underscores the fact that not all tumors work the same. But there’s more work to be done. For example, what could we combine? In colorectal cancer, the G12C plus cetuximab is an interesting combination. There’s a lot of talk about combining direct KRAS G12C inhibitors with SHIP inhibitors, SOS inhibitors, other proteins in that same MAP kinase pathway, ERK inhibitors even. The question will be whether 2 hits increases the toxicity 2-fold, which is what we found when we tried to target MEK and ERK, for example, in many different tumor types.

The other question in lung cancer is, couldn’t we move it into the frontline space? Especially for patients with KRAS mutations and concurrent STK11 mutations, which may predict less response to immunotherapy in particular. Is there a pathway to receive this KRAS G12C inhibitor alone with immunotherapy, with chemotherapy in the front line? The duration of response is the key end point that we’re watching because you have to be able to dose this drug and dose it for a long time. The sotorasib data reported a duration of response of around 11, 12 months, which is in line with a good response to chemoimmunotherapy. PFS [progression-free survival] for PD-L1 low patients is still 5 or 6 months. There’s a path to the front line. It’s a tricky space because so many people are being treated with chemoimmunotherapy.

Benjamin Levy, MD: I’d be curious to see, as we move these drugs up front, whether response rates will increase. Given that there’s potentially less tumor heterogeneity in the treatment-naїve setting, and perhaps as you move along subsequent lines, there are more and more challenges treating.

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