The KRAS G12C inhibitor adagrasib may be effective at suppressing cancer growth not only within the lungs but also in brain metastases for patients with KRAS G12C–mutated non–small cell lung cancer (NSCLC), according to a new study published by Negrao et al in the Journal of Clinical Oncology.
Background
KRAS mutations occur in about 25% to 30% of NSCLC cases, with the KRAS G12C mutation accounting for around 13% of these instances. Whereas radiation therapy and surgery have historically been utilized to treat brain metastases, targeted therapies with central nervous system (CNS) penetration continue to demonstrate encouraging efficacy for the treatment of these metastases.
Adagrasib—which is designed to target the mutated KRAS protein and inhibit its ability to promote abnormal cancer cell growth—was recently approved by the U.S. Food and Drug Administration for the treatment of patients with advanced KRAS G12C–mutated NSCLC who have not responded to standard systemic therapy.
“Patients with brain metastases from KRAS [G12C-mutated] lung cancer face a poor prognosis,” explained lead study author Marcelo Negrao, MD, Assistant Professor of Thoracic/Head and Neck Medical Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center. “The data indicate adagrasib may offer patients a good chance of seeing responses in the brain without needing additional therapy, such as radiation,” he added.
Study Methods and Results
In the phase Ib KRYSTAL-1 trial, researchers assigned 25 patients with a median age of 66 years who had KRAS G12C–mutated NSCLC and untreated brain metastases—a majority of whom were female and identified as White—to receive 600 mg of oral adagrasib twice daily.
The researchers discovered that the patients who participated in the study demonstrated a systemic objective response rate of 30% with a median intracranial duration of response of 12.7 months. Further, the targeted therapy showed an intracranial disease control rate of 90%, and researchers observed a 42% objective response rate in shrinking tumors within the brain. The median intracranial progression-free survival was 5.4 months, whereas the median overall survival reached 11.4 months.
However, 37% of the patients experienced progression of brain metastases and two of them saw progression in the brain metastases alone.
The researchers also noted that adagrasib exhibited a manageable safety profile, with only a few CNS-specific side effects reported—including altered taste and dizziness, both consistent with previous reports from the KRYSTAL-1 trial.
Conclusions
"Adagrasib is the first KRAS G12C inhibitor to prospectively demonstrate intracranial activity in patients with KRAS G12C–mutated NSCLC and untreated brain metastases,” Dr. Negrao highlighted. “These findings support continued clinical development of adagrasib and of its combinations for patients with KRAS G12C–mutated NSCLC,” he concluded.
Disclosure: The research in this study was sponsored by Mirati Therapeutics. For full disclosures of the study authors, visit ascopubs.org.
