Adagrasib Elicits Intracranial Response in NSCLC With KRAS G12C Mutations, Untreated CNS Metastases


Findings from the phase 1b cohort of the KRYSTAL-1 trial underscore the intracranial permeation of the KRAS G12C inhibitor adagrasib for patients with non–small cell lung cancer with untreated central nervous system metastases.

Marcelo V. Negrao, MD

Marcelo V. Negrao, MD

Findings from the phase 1b cohort of the KRYSTAL-1 trial (NCT03785249), underscore the intracranial permeation of the KRAS G12C inhibitor adagrasib (Krazati) for patients with non–small cell lung cancer (NSCLC) with untreated central nervous system (CNS) metastases. Data published in the Journal of Clinical Oncology show that 42% (95% CI, 20.3%-66.5%) of evaluable patients (n = 19) had an intracranial response using RECIST 1.1 criteria.1

“Patients with KRAS-mutated NSCLC and untreated CNS metastases have limited treatment options and poor clinical outcomes,” Marcelo V. Negrao, MD, and colleagues wrote in the study. Despite, radiation being the path for most patients with CNS metastases, penetrating the blood-brain barrier has been a goal of recent drug development. “This approach avoids adverse effects of radiation such as necrosis and cognitive impairment,” Negaro, of the Department of Thoracic-Head & Neck Med Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, added in the paper.

“The results presented here are the first prospective data for a KRAS G12C inhibitor in patients with NSCLC and untreated CNS metastases. Adagrasib 600 mg twice a day achieved promising [intracranial] clinical activity, a high concordance rate between [intracranial] and systemic activity (79%), and a low rate of CNS failure (37%). These results provide proof-of-concept for adagrasib’s ability to penetrate the CNS and provide CNS activity.”

Among the responses, 3 complete intracranial responses and 5 partial intracranial responses were reported, with an intracranial disease control rate (DCR) of 90%. The median time to response was 2.1 months.

Adagrasib received accelerated approval from FDA for the treatment of patients with KRAS G12C–mutated NSCLC who had previously undergone at least 1 previous line of systemic therapy on December 12, 2022.2

KRYSTAL-1 is an ongoing open-label, nonrandomized trial evaluating adagrasib, both as a monotherapy and as part of a combination, for the treatment of patients with advanced KRAS G12C–mutated solid tumors. The coprimary end points were safety, pharmacokinetics, and clinical activity measured by ORR. Secondary end points include establishing the maximum-tolerated dose and identifying dose-limiting toxicities.1

At baseline, the median patient age was 66 years (range, 47-89). Most patients were women (52%), White (84%), had an ECOG performance status of 1 (72%), were past smokers (68%), and had received a checkpoint inhibitor (80%) and/or a platinum-based agent (68%) as part of a prior regimen. In terms of prior lines of therapy, the median number was 1; patients received either 0 (16%), 1 (60%), 2 (12%), or at least 3 (12%) treatments.

Additional findings from the trial showed that, at a median follow-up of 13.7 months (95% CI, 8.5-not evaluable [NE]), the median intracranial progression-free survival (PFS) was 5.4 months (95% CI, 2.7-NE) and the median OS was 11.4 months (95% CI, 5.5-14.9). The median duration of response (DOR) was 12.7 months and treatment remained ongoing for over 10 months among 2 patients who were still responding.

All patients who experienced an intracranial response also underwent a dose modification during the study; 4 responders recorded their initial response at the second on-study scan. The systemic ORR was 30%, including a median DOR of 5.6 months and a median PFS of 5.3 months. Patients evaluable for intracranial activity by mRANO-BM criteria (n = 20) experienced a confirmed intracranial ORR of 35% and an intracranial DCR of 85%.

The label comes with warnings for gastrointestinal adverse effects (AEs), OTc prolongation, hepatotoxicity, and interstitial lung disease/pneumonitis.3 Significant clinical drug interactions are also noted and concomitant use with CYP34A and substrates are not advised.

In the safety population (N = 25), all patients experienced an any-grade treatment-related AE (TRAE); 40% of these were grade 3 in severity, 1 patient had grade 4 neutropenia, and no grade 5 events were reported. The most common any-grade TRAEs included nausea (88%), diarrhea (76%), vomiting (60%), increased alanine transaminase (40%), and increased aspartate transferase (40%). These respective events also occurred at grade 2 severity at rates of 32%, 8%, 8%, 12%, and 12%, and grade 3 severity at rates of 12%, 0%, 16%, 8%, and 4%.1

Dose reductions because of TRAEs were reported in 32% of patients, 56% experienced a dose interruption, and 2 patients discontinued treatment. Patients discontinued therapy because of grade 3 acute pancreatitis and grade 2 fatigue.

Any grade CNS-specific TRAEs consisted of dysgeusia (24%), dizziness (20%), ataxia (8%), aphasia (4%), confused state (4%), encephalopathy (4%), headache (4%), and insomnia (4%). There were no grade 4 or greater CNS-specific TRAEs; 3 patients had grade 3 dizziness and 1 experienced grade 3 encephalopathy.

Data from the phase 3 KRYSTAL-12 (NCT04685135) may be used to support full approval of the agent in this population.


  1. Negrao MV, Spira AI, Heist RS, et al. Intracranial efficacy of adagrasib in patients from the KRYSTAL-1 trial with KRASG12C–mutated non–small-cell lung cancer who have untreated CNS metastases. J Clin Oncol. Published online June 16, 2023. doi:10.1200/JCO.23.00046
  2. FDA grants accelerated approval to adagrasib for KRAS G12C-mutated NSCLC. FDA. December 12, 2022. Accessed July 11, 2023.
  3. Krazati. Prescribing information. Mirati Therapeutics Inc; 2022. Accessed July 11, 2023.
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