NEW YORK – Bristol Myers Squibb's KRAS inhibitor Krazati (adagrasib) has been shown in a Phase III trial to be an effective treatment for patients with previously treated KRAS G12C-mutant non-small cell lung that has spread to the brain.
KRYSTAL-12, data from which were reported on Saturday at the European Society for Medical Oncology Congress in Barcelona, Spain, randomized 114 KRAS-mutant advanced NSCLC patients with stable, previously treated brain metastases to receive either Krazati or docetaxel.
BMS subsidiary Mirati Therapeutics previously reported Krazati's efficacy in NSCLC patients with stable untreated brain metastases from the Phase I/II KRYSTAL-1 trial in 2022 and 2023. Based on the 2022 readout from KRYSTAL-1, the National Comprehensive Cancer Network (NCCN) added Krazati to its guidelines as a treatment for KRAS G12C-mutant NSCLC patients with central nervous system (CNS) metastases. Krazati was approved in the US in 2022 and in Europe in 2024 for the treatment of KRAS G12C-mutant advanced non-small cell lung cancer.
The latest readout from KRYSTAL-12 at ESMO focused on patients whose brain metastases were stable after treatment and are subsequently receiving Krazati in the trial. In the study, Krazati led to better systemic outcomes overall for KRAS-mutant NSCLC patients with baseline brain metastases than docetaxel, Fabrice Barlesi, general director at Gustave Roussy and professor at Paris-Saclay University, said in a presentation of the data.
KRYSTAL-12 enrolled advanced NSCLC with metastasis to various organs. In the brain metastases cohort, the median progression-free survival among 78 patients who received Krazati was 4.4 months compared to 2.9 months among the 36 patients who received docetaxel. In the cohort without brain metastases, the median progression-free survival was 5.9 months on Krazati and 3.9 months on docetaxel.
The systemic response rate on Krazati for patients with brain metastases was 26.9 percent compared to 2.8 percent on docetaxel. Patients responded for a median of 7.4 months on Krazati versus 5.4 months on docetaxel in the brain metastases group. The median intracranial time to progression in patients who received Krazati was 18.6 months and not evaluable in the patients who received docetaxel due to a small number of events. However, Barlesi noted that the median intracranial time to progression favored Krazati.
"These results clearly reinforce adagrasib as an efficacious treatment option for patients, including those with baseline brain metastases, with previously treated KRAS G12C-mutated non-small cell lung cancer," Barlesi said.
Brain metastases are a common occurrence in NSCLC patients, occurring in up to 25 percent of newly diagnosed patients. In patients with KRAS G12C-mutant disease, the rate of brain metastases is estimated to be even higher, at around 42 percent. Therefore, whether KRAS G12C inhibitors under development for lung cancer can also treat brain metastases is a key question that many drugmakers are exploring. There is data on the CNS activity of Amgen's Lumakras (sotorasib), Innovent Biologics' fulzerasib, InventisBio's garsorasib, and Jacobio Pharma's glecirasib.
While cross-trial comparisons aren't ideal, during a discussion of the KRYSTAL-12 data at the meeting, Sai-Hong Ignatius Ou, a clinical professor at the University of California, Irvine, reflected on some of the evidence generated on these other drugs.
In the CodeBreaK-200 trial evaluating Lumakras, for example, KRAS G12C-mutant NSCLC patients with previously treated CNS metastases demonstrated a median progression-free survival of 6.1 months and time-to-CNS recurrence of 9.6 months. In KRYSTAL-12, median progression-free survival in the Krazati arm was 5.9 months and median time-to-intracranial progression was 18.6 months.
Based on the available data on the two commercially available KRAS G12C inhibitors in the US, Krazati and Lumakras, Ou said there is still "insufficient evidence to say one is better than the other [for treating brain metastases]."
Ou also noted that most of the data on the activity of KRAS G12C inhibitors in NSCLC patients with brain metastases has been generated in small cohorts of patients who have had prior treatment. The only data reported for Krazati's activity in untreated brain metastases was in 19 patients, and there have been small case studies exploring Lumakras' activity in untreated brain metastases. This makes it "harder to tell whether you have a clean intracranial overall response rate [on the KRAS inhibitors]," he said, because patients may still be benefiting from prior treatment. "Both [Krazati and Lumakras] have likely CNS activity, but the [analyses] are incomplete at this point," Ou said.