ASCO 2022 | KRYSTAL-1: activity of adagrasib in KRASG12m NSCLC with untreated CNS metastases

The KRYSTAL-1 study is a large registrational phase I/II study for patients with non-small cell lung cancer, as well as other cancers with KRASG12C mutant non-small cell lung cancer. My colleague, Dr. Alex Spira is going to be presenting data on the efficacy of adagrasib, formerly known as MRTX849, which is a KRASG12C-specific inhibitor in patients with non-small cell lung cancer who have progressed on prior lines of therapy.

There is already an FDA-approved KRASG12C inhibitor here with sotorasib, formerly known as AMG 510. Response rate there was 37.1%, median progression-free survival about 6.8 months and median overall survival 12.5 months. But that showed the proof of concept that we can drug KRASG12C, which has been undruggable for many years.

Adagrasib is a novel KRASG12C inhibitor. It has 24-hour half-life so long half-life, PK-dependent dosing, and interestingly, very good CNS penetration. Dr. Alex Spira, my colleague, will show that the response rate in our study was 43% median progression-free survival of 6.5 months, as well as a median overall survival of 12.6 months.

What’s interesting is if you look at the patients who had one scan or more evaluable, response rate went up to 50%. So quite an interesting dataset. We also saw that in patients who had treated brain metastasis, the response rate was 33% by a blinded independent committee review.

The presentation that I’m giving is on the data for active untreated brain metastasis. We had a cohort of 25 patients. This is on the same study, the KRYSTAL-1 cohort 1B, where we looked at patients who had active untreated brain metastasis and we looked at the efficacy of adagrasib by the KRASG12C inhibitor.

What we found was that the response rate was quite high, 32% so equivalent to what we saw in the treated brain metastasis patient population, median progression-free survival in the four to five month range, and we did not reach yet median overall survival.

The reason why this is so important is we know that patients who have brain metastasis tend to have very poor prognosis. Median overall survival for patients with KRASG12C mutant lung cancer it’s about five months who have active untreated brain metastasis so the data’s quite exciting for this patient population.

We also looked at specific intracranial dose of the drug or CSF concentrations and there’s a concept called KPUU, where similar agents in the EGFR and ALK population have KPUUs that range from 0.4 to 0.9. Drugs such as osimertinib in the EGFFR space, alectinib and lorlatinib in the ALK prearranged space and these are drugs that have phenomenal CNS intracranial activity.

We looked at two patients doing lumbar punctures in the CSF to identify the KPUU of adagrasib and it was 4.7 so equally as good as some of these other inhibitors that are approved. So really excited about this data potentially opportunity to help patients in the future.