KRAS G12C mutations occur in approximately 14% of patients with non–small-cell lung cancer (NSCLC). These mutations are responsive to KRAS G12C inhibitors, including sotorasib, which is the first drug approved for the treatment of metastatic NSCLC harboring the KRAS G12C mutation. Patients with this tumor type have an approximately 40% lifetime incidence of brain metastases. However, effective treatment for central nervous system metastases is an unmet need in this patient population. Sotorasib has a response rate of 28% to 37% in patients with KRAS G12C NSCLC, with a median progression-free survival (PFS) of 5.6 to 6.8 months. Although brain metastases are common in patients with KRAS G12C NSCLC, published clinical trials of sotorasib have excluded these patients from participation.
Not much is known about the efficacy of sotorasib on the central nervous system. Lamberti and colleagues investigated this unmet need and recently released their results. They identified 899 patients who had received a diagnosis of metastatic NSCLC harboring the KRAS G12C mutation. Of these patients, 316 had brain metastases that occurred within 3 months of the initial diagnosis. Patients with KRAS G12C–mutated NSCLC without brain metastases had a 16.0-month overall survival, whereas those with brain metastases had a 13.2-month overall survival. No difference was seen in programmed cell death ligand 1 tumor proportion score or tumor mutational burden between the 2 patient groups.
The investigators identified 6 patients who developed active, untreated brain metastases before sotorasib was initiated. All 6 of these patients underwent magnetic resonance imaging (MRI) prior to starting treatment. One patient had disease progression and died 3 weeks after sotorasib initiation. The remaining 5 patients had ≥1 subsequent MRI while receiving sotorasib. One patient who had 5 nonmeasurable brain lesions at baseline MRI had resolution of 4 of these 5 lesions after sotorasib treatment. The remaining 4 patients had measurable disease, with 3 of the patients having a response to treatment. The median duration of response to sotorasib treatment was 4.1 months in these 3 patients, and the median PFS was 4.7 months. Of the 4 remaining patients, 1 was still receiving sotorasib treatment at study publication with an ongoing response of 7 months. A second patient had objective intracranial response along with systemic disease improvement, but the intracranial disease progressed while the systemic disease remained controlled. The third patient had an initial response both with brain lesions and systemically but had isolated intracranial progression with systemic response continuing. The final patient had both systemic and intracranial disease progression.
Source: Lamberti G, Aizer A, Ricciuti B, et al. Incidence of brain metastases and preliminary evidence of intracranial activity with sotorasib in patients with KRASG12C-mutant non–small-cell lung cancer. JCO Precis Oncol. 2023;7:e2200621.
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