Clinical Trials Show Efficacy of Adagrasib in Patients with NSCLC and Brain Metastases

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KRAS G12C mutation is found in 14% of patients with non–small-cell lung cancer (NSCLC) with adenocarcinoma and 0.5% to 4% of patients with squamous carcinoma. Central nervous system (CNS) metastases are found in 27% to 42% of patients with KRAS G12C NSCLC at diagnosis, which conveys a poor patient prognosis. Adagrasib is an oral small molecule that inhibits KRAS G12C by binding and locking it into an inactive form, thereby blocking KRAS signaling and exerting an antitumor effect.

An article published by Tian and colleagues discussed the findings of various clinical trials of adagrasib, focusing on its ability to penetrate the CNS. The KRYSTAL-1 clinical trial investigated the use of 600 mg of adagrasib twice daily in 116 patients with unresectable or metastatic KRAS G12C NSCLC previously treated with ≥1 platinum-based chemotherapy and immune checkpoint therapy. Treatment-related adverse events were found in 97.4% of patients, with gastrointestinal-related events being the most common. Despite this high rate of adverse events, treatment discontinuation was low—6.9%. This treatment regimen demonstrated good efficacy with acceptable safety and can offer a novel treatment for patients with KRAS G12C–mutated NSCLC.

Sotorasib was the first FDA-approved KRAS G12C inhibitor for patients with KRAS G12C NSCLC. When comparing adagrasib data with sotorasib data, Tian and colleagues found an objective response rate (ORR) of 42.9% for adagrasib, whereas sotorasib had an ORR of 37.1%. The median overall survival (OS) for sotorasib was 12.5 months with a progression-free survival (PFS) of 6.8 months. For adagrasib, the median OS was 12.6 months, and PFS was 6.5 months.

In KRYSTAL-1, CNS metastases were found in 42 patients receiving adagrasib at baseline, with a median intracranial PFS of 5.4 months. Radiographic evaluation was performed for 33 patients, and investigators found an intracranial confirmed ORR of 33.3% and a median duration of intracranial response of 11.2 months. A previous study found that sotorasib resulted in a 13% intracranial response in 16 patients with KRAS G12C NSCLC with CNS metastases.

At the 2022 American Society of Clinical Oncology Annual Meeting, the results of a phase 1b cohort of patients with NSCLC and active, untreated CNS metastases receiving adagrasib demonstrated an intracranial ORR of 32% with an intracranial disease control rate of 84%. A 2022 meta-analysis found that anti–PD-L1 therapy with or without chemotherapy resulted in a more prolonged survival than chemotherapy alone for KRAS-driven NSCLC. Despite these findings, a preclinical study found that combining a KRAS G12C inhibitor with immune checkpoint inhibitors was not successful universally, suggesting that not all patients will benefit from this treatment regimen, necessitating the further study of patient selection for successful therapy.

Source: Tian H, Yang Z, He J. Adagrasib: a landmark in the KRASG12C-mutated NSCLC. MedComm (2020). 2022;3(4):e190.

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