Adagrasib Demonstrates CNS Penetration and Intracranial Activity in Patients with KRAS G12C-Mutated NSCLC with Brain Metastases

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The Kirsten rat sarcoma viral oncogene (K-ras) is found in 20% to 30% of non–small-cell lung cancer (NSCLC) patients, and the KRAS G12C mutation is the most prevalent, found in 15% of NSCLC patients.1 When glycine is substituted by cysteine as it occurs with the G12C mutation, this leaves KRAS in an active state.2 This results in an accumulation of active GTP-bound KRAS proteins, which in turn causes an increased proliferation and survival of cancer cells.1,2

In patients with KRAS G12C ̶ mutated NSCLC, central nervous system (CNS) metastases occur in 27% to 42% of patients and confer a poor prognosis. Adagrasib is a small-molecule investigational oral drug that inhibits KRAS G12C.2 It selectively and irreversibly binds and locks KRAS G12C into its inactive form. Adagrasib has a long half-life and has demonstrated dose-dependent CNS penetration along with intracranial tumor regression for CNS metastases in preclinical models.2

The multicohort phase 1/2 KRYSTAL-1 study evaluated adagrasib in patients with advanced KRAS G12C-harboring solid tumors as monotherapy or in combination with other therapeutic agents. The results of the phase 1b cohort of patients with NSCLC with KRAS G12C mutations and active untreated CNS metastases treated with 600 mg adagrasib have been reported. The study objectives were to evaluate objective response rate (ORR), duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Of the 25 patients enrolled in the study, 2 patients had regression of CNS metastases and had cerebrospinal fluid samples taken. In these patients, adagrasib exhibited CNS penetration and antitumor activity.

The study enrolled patients with NSCLC with a median age of 66 years. The median follow-up was 6 months. All patients had an Eastern Cooperative Oncology Group performance status of 0/1, 52% were women, and the median lines of prior systemic therapy was 1. Intracranial ORR was 31.6%, intracranial DCR was 84.2%, and the median intracranial PFS was 4.2 months. The median intracranial DOR was not reached. Systemic ORR was 35.0%, DCR was 80.0%, median DOR was 9.6 months, and median PFS was 5.6 months. Treatment-related adverse events (TRAEs) of any grade occurred in 96% of patients, 36% experienced grade 3 TRAEs, and none reported grade 4 or 5 TRAEs. Adagrasib was well tolerated by the patients in this study.

Source: Sabari J, Spira A, Heist SR, et al. Activity of adagrasib (MRTX849) in patients with KRAS G12C-mutated NSCLC and active, untreated CNS metastases in the KRYSTAL-1 trial. J Clin Oncol. 2022; 40(17):suppl, LBA9009-LBA9009.

References

  1. Cui W, Franchini F, Alexander M, et al. Real world outcomes in KRAS G12C mutation positive non-small cell lung cancer. Lung Cancer. 2020;146:310-317.
  2. Ou SI, Jänne PA, Leal TA, et al. First-in-Human Phase I/IB Dose-Finding Study of Adagrasib (MRTX849) in Patients With Advanced KRASG12C Solid Tumors (KRYSTAL-1). J Clin Oncol. 2022;40(23):2530-2538.

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