ESMO 2026 | Krascendo 1: divarasib vs sotorasib/adagrasib in KRAS G12C-mutated NSCLC

This was a phase three randomized study presented at ESMO this last weekend. And it was studying KRAS-G12C mutated non-small cell lung cancers in patients who had previously received at least one prior line of therapy. The study design was really set up to be, you know, a typical open-label controlled study, meaning patients would know what their, and physicians would know what the patient is randomized to. But the choice of randomized standard of care therapy here is really the crux of the study. Up until now, all phase three studies for lung cancer had basically been randomized to docetaxel as the control arm. And as many of us know, docetaxel can be quite toxic and it’s just standard chemotherapy. But it’s pretty widely accepted as a standard of care now to offer either the first-generation Sotorasib or Adagrasib KRAS-G12C targeted therapies. And this study really asks the tough question of, we have a potentially best-in-class newer generation therapy, Adagrasib specifically, no, Divarasib, or more accurately, can this beat the current standard of care investigator’s choice? So in my opinion, this is really a well-set-up investigator’s study of choice because we don’t have to offer fairly toxic chemotherapy to patients as the only alternative. And the key endpoint here, the primary endpoint is progression-free survival, but also a very important secondary endpoint is overall survival in patients. And patients are also stratified by CNS metastasis and also what therapy, if randomized control, the investigators had to choose sotarasib or adagrasib beforehand. So that was actually a stratification factor, as well as keep one mutation status. And treatment occurred until patients either couldn’t tolerate therapy or progression occurred, and crossover was not allowed on this study. So looking at the actual endpoint, the question, is PFS better with divarasib? It is tremendously better. It’s 9.8 months versus 5.7 months for either so sotarasib divarasib or adagrasib. The hazard ratio here was 0.58. Very, very wide separation in the progression-free survival curves here. And it’s very readily apparent right off the bat. And if you look at the one-year mark, 44% of patients were still progression-free for divarasib, whereas for sotarasib or adagrasib, the progression-free survival rate was 24% at one year. And looking forward then at overall survival, the median overall survival for divarasib was 17.7 months, which is notably better than the control arm of 12 months with a hazard ratio of 0.56. Also a very apparent survival curve separation here with one year survival for divarasib at 67% overall versus 49% for the control arms. So those were the primary efficacy endpoints of note that were presented. In terms of safety, which I think is another really sometimes overlooked aspect of newer class of therapy, the safety here was really quite impressive as well. Because divarasib is a newer generation therapy, it has higher binding specificity to the switch to pocket of the KRAS of the KRAS molecule where the mutation occurs, has higher potency and higher affinity specificity in that pocket. And so you can have more direct on-target efficacy, but also less off-target toxicity. And this is translated into a lower rate of high-grade adverse events. There were some low-grade, slightly higher rate of low-grade nausea, vomiting, diarrhea, etc. But we found that we could mitigate a lot of these with prophylaxis and very standard management tactics. So if you look at the actual discontinuation rate of divarasib versus either sotarasib or adagrasib, it was notably lower for divarasib. So what we have here is a significantly improved efficacy profile with an improved safety and tolerability profile as well, which is really, I think, the gold standard for trying to move targeted therapy forward and trying to find a best in class. And I think this data suggests and lends itself to supporting that claim of, you know, I think at this point, divarasib will end up being the best-in-class therapy.

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