2L KRAS Inhibitors for Patients With KRAS G12C–Mutated NSCLC

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Joshua K. Sabari, MD: That being said, most of our patients, even if you're PD-L1 expression high, greater than 50, only a third of our patients are alive at 5 years. If you're PD-L1 low or negative, your response rate goes from 50, 60% to in the 20 to 30% range, and the durability is not ideal. Most of our patients, are progressing into the second-line regimen. And what are you using currently, Martin, in your standard of care second-line patient population who is KRAS G12C?

Martin Dietrich, MD, PhD: Well, we've seen some data in the second-line setting building on CodeBreaK 100 to the side-by-side comparison of sotorasib and Taxotere in a randomized controlled prospective setting. And there was a little bit of disappointment that the overall survival there didn't change much. I do have to remind myself that when we initially checked the chemotherapy followed by EGFR inhibitors, versus EGFR inhibitors followed by chemotherapy, that we didn't see an overall survival either. We must make assumptions about how, in concepts, how to prioritize them. I do think that a KRAS inhibitor here is much easier to take for the patients. I know that there were comparisons about the number of Grade 3, 4 toxicities, and that they seemed kind of balanced, but not every Grade 3 toxicity is equally experienced by the patients. At my observation for sotorasib vs Taxotere, is very clearly favoring the targeted therapy, the mobility, the mode of administration, and the flavor of adverse effects are very different. I wasn't discouraged by this overall survival outcome. We think this should be the standard of care; we lose patients between different lines, and I think that we want to give the best possible experience of patients. This is a very patient-centric world we live in now and to making sure that we are providing the best quality of life upfront, I believe is the mantra of KRAS inhibitors. CodeBreaK 200 did not discourage me from using the KRAS inhibitor standard of care in this well-defined subset up and progression on immunotherapy. In fact, I embraced it as an opportunity, as a starting point and maybe thinking about how to move these agents into an earlier line setting. I think this is where they find their role, where they can replace chemotherapy and basically deliver the cytostatic response that we want to see for immunotherapy to have enough time, basically, on effect to basically exert its maximum potency.

Joshua K. Sabari, MD: Martin I couldn't agree more. Sotorasib, a KRAS G12C inhibitor, we saw in the CodeBreaK 100 response rate's about 37%, and then in the 2 year updated survival analysis, 32.5% of patients alive at 2 years. For me, that was far better than what I was seeing with docetaxel in my clinical practice. One major complaint with all of the G12C inhibitors as they are now the PFS, or progression free survival, is quite low at about 5.6 or so monseir in this setting. And I agree with you, the CodeBreaK 200, that was a randomized Phase 3 trial, mostly XUS comparing sotorasib versus docetaxel, remember docetaxel is a standard of care agent in the second-line with about a 10% response rate overall. Sotorasib clearly better than docetaxel, but when you look at the data, I agree, Martin, I was somewhat disappointed. It wasn't powered for overall survival, and it didn't meet overall survival. There was a PFS benefit of about a month or so, and when you looked at the response rate to sotorasib, it dropped below 30%, it was 28% or so. Again, it's still our standard of care now in this second-line setting, but I think we need more, and we could do better for our patients. The one nice thing about sotorasib is the toxicity is not significant, it's a pretty well-tolerated medicine, I like to keep docetaxel in my back pocket. Now, what about adagrasib, Martin? Adagrasib is another KRAS G12C inhibitor. It blocks that cysteine residue, it prevents signaling through the kinase's pathway here and prevents sort of, keeps it in the GDB-bound state to prevent signaling. We saw data from the KRYSTAL-1 study. What were your thoughts on the KRYSTAL-1, that's the Phase 1 and then Phase 2 expansion of this agent? Very interesting clinical trial and I do think another great addition to our armamentarium expected to be approved here hopefully in the next couple of weeks, with adagrasib targeting KRAS G12C in a similar manner like we see of course with sotorasib, with a covalent binding of the cysteine residue. It's a little bit of a different, I want to say different experience, we had a twice daily targeting here with 600 milligrams twice daily. And we've seen data that was very comparable for sotorasib and adagrasib in the setting; we've seen very robust response rates for second-line setting, roughly 40% in those 2 trials. But what we didn't see before, and this is a novelty, was the inter-cranial responses that were not only not very visible, but also durable in many cases. We had a response rate in the brain of over 30%, 31%, and in many of these responses, maintained durability. We have had a meaningful amount of progress, plus the duration of response complemented by a stable disease population that was larger, even, than the response population. If somebody has systemic involvement of the brain that does not require radiation from an upfront perspective of symptoms, it's going to be very well-served with a close follow up and initiation of targeted therapy. 80% disease control rate for this setting, we did see treatment related to adverse events that were high but again, many of those toxicities to have a toxicity in a level of, I want to say, elevation that are not experienced by the patients, but mainly managed by the providers. We have a very easy way of those adjustment there. This is going to come in a 200 milligram kind of increments of treatments, so for us a very easy, on-the-go adjustments for treatments. I am very hopeful that we're going to be seeing opportunities here, and I believe there's work on the formulation of the medication as well that will address some of the GI toxicities that have been seen in the clinical trial. I do have to say as an oncologist, I don't think there's an adverse effect that we are more capable of treating than GI toxicities, that is nausea, diarrhea, or cramping. I think we are quite equipped to do that, so hopefully seeing an approval here soon. I don't know what your impressions are, but I'm excited about seeing this coming to market as well.

The KRYSTAL-1 data, I agree, 43% response rate in this patient population. Progression free survival about 6.8 months, relatively like what we saw with sotorasib, but there's 2 major differentiators for me. One is that the dosing of adagrasib is dosed dependent the PK, meaning that at 600 milligrams twice a day, you're truly inhibiting RAS signaling; with sotorasib at 960, it's controversial whether that is the correct dose or not. You mentioned the toxicity, and I think that's also a major differentiator. Adagrasib has more GI toxicity, about two-fold more than sotorasib. We are working on a different formulation of the pill in an effort to minimize, I don't think its drug related per say, but maybe formulation-related. The biggest differentiator for me, and our group was able to report on this, is really the activity in the brain. We looked at patients with active and untreated CNS metastases and, as you mentioned, response rate about 32%. We don't have data yet for sotorasib intra-cranially in the brain, we looked at data for patients who had treated CNS metastases in the sotorasib cohort, and the response rate was about 15%. One of the realty exciting things about adagrasib is in 2 patients who were enrolled on that study, we did lumbar punctures, and we were able to measure the level of the drug adagrasib in the CSF at very high rates. I think, and particularly in a patient with CNS metastases, I would select utilization of adagrasib over sotorasib, but clearly there's some issue with formulation, with toxicity that need to be worked out. And a lot of my patients who were treated on the study were dose-reduced to 400 milligrams BID.

Transcript edited for clarity.