Opinion
Video
Adagrasib for Patients with KRAS G12C–Mutant NSCLC
Author(s):
Joshua K. Sabari, MD, discusses adagrasib as a treatment of patients with NSCLC with KRAS G12C mutations, and provides insight on treating patients who have progressed on prior KRAS G12C inhibitors.
Transcript:
Martin Dietrich, MD, PhD: Dr Sabari, you were one of the main investigators on KRYSTAL-1 and have an enormous wealth of experience with the drug. Could you give us an update on adagrasib, the second KRAS inhibitor [and its effect on] brain metastases? And could you also give your clinical perspective on hepatotoxicity in conjunction with immunotherapy?
Joshua K. Sabari, MD: Sure. As Dr Brahmer mentioned, [this is] our first go-round at these therapies for our patients with KRAS G12C. And I’m a glass full kind of guy, but as you mentioned, we’re moving a needle where there was no needle before. Similar to the data we saw with sotorasib, with adagrasib, a similar G12C inhibitor, it’s a GTPA small molecule, we saw response rates of about 43% median progression-free survival, 6.5 months, so clearly not a home run for our patients. We know that resistance is quite common, and it’s not only point mutations in RAS, but really bypass track alterations. Median overall survival on this phase 1/1b expansion, essentially equivalent to a phase 2, was about 12 or 12½ months. So, we need to do more for our patients.
One unique thing about adagrasib is the toxicity. I think the GI [gastrointestinal] toxicity is 2-fold higher than what we see for sotorasib. Things like nausea and upset stomach need to be managed appropriately in this patient population. Some of the unique things about adagrasib [are] that it is dose dependent, it’s PK, whereas with sotorasib we saw…responses all over the curve and the map at low doses, like 240 mg equivalent to 360 or 960. With adagrasib, the 600 mg [twice a day] I think does have a dose dependency. We also see very nice intracranial activity, and we just recently published with Marcelo V. Negrao[, MD,] at [The University of Texas] MD Anderson [Cancer Center] a small set of about 19 patients enrolled prospectively with active untreated CNS metastases, and we showed about a 42% response rate and median progression-free survival in this group over 5 months, which doesn’t seem like a lot but is clearly a lot in patients who have brain metastasis, where on average, median overall survival in this population is only 4 to 5 months. I’ve had patients who have been on therapy for 2-plus years with durable long-term responses. I think we need more data. We also need better combinations.
You mentioned one of the important combinations of potentially moving this to the frontline setting is the addition of a PD-1 or PD-L1 inhibitor. We have looked at adagrasib in combination with a PD-1 inhibitor, and the data [are] OK. Response rate was 49%. It’s immature, so we don’t really have great PFS or durability data, but I think the 1 golden ray of sunshine here is that the amount of grade 3 or clinically significant liver toxicity is not high, it’s less than 10%. So it does appear that adagrasib is safe to combine with a PD-1 inhibitor, unlike sotorasib, which was a lot more difficult in the studies that Dr Sepulveda described.
Martin Dietrich, MD, PhD: Yes, and you mentioned the GI toxicity. I think there were 2 pitfalls in the study. One is the capsule formulation that has been switched to tablets, and the option of nonfasting intake. I think those are 2 concepts that made it a lot easier after approval to give the drug with GI toxicity. We see response rates as more intrinsic resistance. I think that’s clear. When you have a patient [who] has responded initially to a KRAS G12C inhibitor and then progresses, what is your management approach?
Joshua K. Sabari, MD: This is difficult. I’m often obtaining plasma NGS [next-generation sequencing] as we mentioned earlier, liquid biopsy, as well as a tissue biopsy, because I’m thinking about next strategy. We have multiple clinical trials available for patients who’ve had prior KRAS G12C inhibitors. But remember, these are patients who’ve already had chemotherapy and immunotherapy in the frontline setting. So what we’re really thinking about standard of care here are taxane-based agents. One of the clinical trials that I’m most excited about is a pan-RAS(ON) inhibitor. It inhibits both RAS mutant as well as RAS wild type. It’s an interesting concept, and we’re starting to see early responses in patients. There’s also a G12C-specific RAS(ON) inhibitor. As Dr Brahmer mentioned, these are the early days here. Go back to when we were talking about first-generation EGFR TKI [tyrosine kinase inhibitor]—that’s where we are. We’re first-generation KRAS small molecules. The future is bright and hopeful, but we need to think about better mechanistic action of these agents and better combination strategies that are well tolerated for our patients.
Martin Dietrich, MD, PhD: Yes, I was surprised that the pan-RAS inhibitors seem to be tolerable. Kind of a surprising insight.
Joshua K. Sabari, MD: We do see rash at about 100%, but it’s mostly grade 1 and grade 2. And again, these are the early days. As we learn about these agents, we’re going to hopefully be able to better mitigate some of these adverse effects.
Transcript is AI-generated and edited for clarity and readability.
