NEW YORK – Results from a larger analysis within the KRYSTAL-1 trial of Mirati Therapeutics' Krazati (adagrasib) confirmed earlier readouts of its benefits in patients with KRAS-mutant advanced non-small cell lung cancer and suggested certain co-mutations may influence the drug's efficacy.
Researchers presented two-year follow-up data from 132 evaluable patients in the Phase I/II trial at the International Association for the Study of Lung Cancer World Conference on Lung Cancer (WCLC) on Sunday. The results show that Krazati has "durable clinical benefit," said Shirish Gadgeel, division head for hematology and oncology at Henry Ford Cancer Institute who presented the trial results at the meeting.
As of the Jan. 1, 2023, data cutoff, around a third of Krazati-treated patients were alive at two years and more than half were alive for a year. The median overall survival was 14.1 months, and the median progression-free survival was 6.9 months.
Gadgeel also highlighted that the median duration of response is now nearly four months longer at 12.4 months, compared to the 8.5 months researchers had reported in an earlier KRYSTAL-1 readout. The increase in duration of response was "striking," he noted, since median overall survival only increased slightly compared to the earlier readout by about two months. "[An increase in] overall survival means that patients went on to get other treatments," Gadgeel said.
In patients with baseline central nervous system (CNS) metastases, Krazati continued to show benefit. Among 26 patients with CNS metastases, the median overall survival was 14.7 months and median progression-free survival was 6.9 months. Based on this data, the National Comprehensive Cancer Network earlier this year added Krazati to its guidelines as a treatment for KRAS G12C-mutant advance NSCLC patients with CNS metastases.
The rate of treatment-related adverse events among those on the drug for more than a year was low — 67 percent versus 97 percent for the whole cohort — providing investigators another signal of Krazati's long-term benefit. "Among patients who received the drug for one year or longer, the rate of treatment-related adverse events was somewhat less than the overall population, raising the possibility that there is no cumulative toxicity observed with long-term use of this drug," Gadgeel said.
He noted that the two-year survival rate for patients who needed dose modifications due to adverse events was similar to the overall population, 32 percent, suggesting that these modifications did not affect efficacy. Furthermore, none of the patients who began Krazati within 30 days of immunotherapy treatment experienced grade 3 or higher liver toxicity, which signaled to Gadgeel that Krazati can be safely given after immunotherapy.
"The data presented at WCLC continues to demonstrate that adagrasib offers a differentiated option for people living with KRAS G12C-mutated NSCLC and reinforces the ability of adagrasib to positively impact patients as a potential best-in-class KRAS G12C inhibitor," Mirati Chief Medical Officer Alan Sandler said over email. "This differentiation is demonstrated through the clinical activity in the CNS and the ability to sequence [treatment with] adagrasib immediately after immunotherapy."
The updated analysis also provided a preliminary snapshot of how co-mutations in KEAP1, CDKN2A, STK11, and TP53 may impact patients' outcomes on Krazati. Compared to the 14.1-month median overall survival in the entire study population, median overall survival was lower among 25 patients with KEAP1 and 44 patients with STK11 co-mutations, at 5.7 months and 9.2 months, respectively.
Those with CDKN2A co-mutations lived for a median of 13 months, closer to the experience of the overall study population, while those with TP53 co-mutations fared better with a median overall survival of 18.7 months.
"There does appear to be a suggestion that, in patients with KEAP1-mutated tumors, the outcomes are inferior," Gadgeel said, cautioning that the data are insufficient to definitively conclude KRAS G12C inhibitors are less effective in this subset. "What our data shows, and the numbers are very small, is that there is efficacy seen in all these subsets. We'll need [to evaluate] more [patients] to truly understand if co-mutation influences the efficacy of these [KRAS G12C] inhibitors."
While these updated results from KRYSTAL-1 contribute to the body of evidence on the drug's efficacy, Mirati is awaiting results from the confirmatory Phase III KRYSTAL-12 trial evaluating Krazati versus chemo in previously treated patients with KRAS G12C-mutated NSCLC. Sandler confirmed that the company plans to submit the KRYSTAL-12 data once it's available to the US Food and Drug Administration with the goal of converting Krazati's accelerated approval into a full approval.
Meanwhile, Mirati faced a setback over the summer when the European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP) advised against approving Krazati as a treatment for KRAS G12C-mutated advanced NSCLC. Sandler said the company in August submitted a formal request asking CHMP to reexamine its recommendation to the European Commission.