Mirati Therapeutics presented the first clinical data demonstrating CNS-specific activity of a KRASG12C inhibitor in patients with NSCLC with active and untreated CNS metastases.
Mirati Therapeutics presented promising results from the KRYSTAL-1 trial of intracranial (IC) responses to its KRAS inhibitor adagrasib in patients with KRASG12C-mutated non-small cell lung cancer (NSCLC) with active and untreated central nervous system (CNS) metastases.
Although it’s an early study, the data from the Phase Ib cohort looks good. But the key question: is it good enough to beat Amgen’s Lumakras, (sotorasib) which already has conditional approval?
The data Mirati presented at the American Society of Clinical Oncology (ASCO) Annual Meeting indicated that about one-third of patients had intracranial (IC) responses in patients with CNS metastases. There was a median follow-up of 6.6 months, with 25 patients with active, untreated CNS metastases. They received adagrasib 600 mg twice a day. Of the 19 patients who could be evaluated radiographically, there was an IC objective response rate of 32%.
“Central nervous system metastases occur in 27% to 42% of patients with KRASG12C-mutated NSCLC at diagnosis,” Dr. Joshua K. Sabari, M.D., assistant professor of medicine, medical oncology at Perlmutter Cancer Center, NYU Langone Health said. “These patients have a median overall survival of approximately five months, posing a serious clinical challenge. With a median follow-up of 6.6 months, these early and positive data show adagrasib demonstrated a meaningful overall intracranial response rate with early indications for overall survival.”
Adagrasib appears to be marginally better than Lumakras. But Lumakras’ big advantage is that it’s already approved and on the market. Mirati’s target action date with the U.S. Food and Drug Administration for adagrasib is December 14.
This appears to be one reason Mirati stock has been in the doldrums recently. Other reasons include a new chief executive officer, David Meek, in September 2021, who brought in his own people.
Another reason is that Mirati was hoping to get a priority review with a six-month review period as well as accelerated approval. The FDA, however, dug in its heels and gave the company the standard 10-month review period. Amgen is likely to release its confirmatory data on Lumakras around the same time.
And finally, although adagrasib appears to be a fairly safe drug, its safety profile is not as good as Amgen’s, with a greater risk of sudden cardiac death, which occurred in 14% of patients treated with adagrasib but was not observed with Lumakras.
Both drugs appear to be highly similar for NSCLC. Analysts, however, give adagrasib an edge for other cancers, including colorectal cancer, pancreatic and gastrointestinal tumors. However, these aren’t head-to-head studies, and the comparisons across different studies should be taken with a grain of salt.
Analysts with Stifel, however, noted that Mirati’s most recent readout “more or less confirms the similarity of full dose Lumakras and adagrasib monotherapy.”
Dr. Charles Baum, M.D., Ph.D., president, founder and head of research and development for Mirati, said, “We are proud to share the first clinical data demonstrating CNS-specific activity of a KRASG12C inhibitor in patients with NSCLC. Central nervous system metastases disproportionately affect patients with NSCLC and should be carefully considered as part of the treatment approach. Adagrasib showed CNS penetration and intracranial responses in patients with active and untreated CNS metastases, demonstrating potential as a treatment option for this underserved patient population.”
