Treatment With Adagrasib Shows Intracranial Response in Patients With Lung Cancer, Untreated CNS Metastases


Approximately one-third of the individuals had an intracranial response among those with central nervous system metastases.

New results have been released from a prospective analysis in the phase 1b cohort of the KRYSTAL-1 study evaluating intracranial (IC) responses to adagrasib in individuals with KRASG12C-mutated non­­–small cell lung cancer (NSCLC) with active and untreated central nervous system (CNS) metastases.

The first clinical data showed CNS-specific activity of a KRASG12C inhibitor in individuals with NSCLC with active and untreated CNS metastases. Investigators said that among individuals with CNS metastases, about one-third had an IC response, consistent with what was observed systemically in the cohort.

The data was presented as a late-breaking oral presentation at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.

"[CNS] metastases disproportionately affect patients with NSCLC and should be carefully considered as part of the treatment approach.” Charles Baum, MD, PhD, president, founder and head of research and development at Mirati Therapeutics, said in a statement. “Adagrasib showed CNS penetration and intracranial responses in patients with active and untreated CNS metastases, demonstrating potential as a treatment option for this underserved patient population.”

In a median follow up of 6.6 months, 25 individuals with active, untreated CNS metastases were enrolled in the study and treated with adagrasib 600 mg twice daily.

Of those who were radiographically evaluable, the findings showed an IC objective response rate of about 32% by modified response assessment in neuro-oncology-brain metastases by a blinded independent central review.

In addition, 3 individuals achieved a complete response and 3 achieved a partial response. The IC disease control rate was about 84% and the median IC duration of response was not reached. The concordance of disease control between systemic and IC responses was 88%. For all individuals enrolled, the median overall survival was not reached.

Cerebrospinal fluid samples (CFS) were obtained from 2 individuals for whom regression of CNS metastases was observed. The adagrasib CFS and free plasma concentration ratios were consistent with other agents with known CNS penetration and activity.

"Central nervous system metastases occur in 27% to 42% of patients with KRASG12C-mutated NSCLC at diagnosis. These patients have a median overall survival of approximately 5 months, posing a serious clinical challenge," Joshua Sabari, MD, an assistant professor of medicine of medical oncology at Perlmutter Cancer Center at NYU Langone Health, said in a statement.

"With a median follow up of 6.6 months, these early and positive data show adagrasib demonstrated a meaningful overall intracranial response rate with early indications for overall survival. Adagrasib warrants further investigation on its potential to improve clinical outcomes for NSCLC patients harboring a KRASG12C-mutation who have active and untreated CNS metastases, including opportunities through Mirati's Expanded Access Program," Sabari said.

The safety profile was also consistent with the overall population with no new safety signals observed. About 60% of individuals experienced grade 1 and 2 treatment-related adverse events (TRAEs). Grade 3 TRAEs also occurred in 36% of individuals, and there were no TRAEs that were grades 4 or 5.

The company also presented results from the registration-enabling phase 2 cohort of the KRYSTAL-1 study evaluating the drug in individuals with pre-treated NSCLC harboring a KRASG12C mutation during the Lung Cancer–Non–Small Cell Metastatic session at ASCO on June 3, 2022.


New late-breaking data on investigational adagrasib show regression of central nervous system metastases in individuals with KRASG12C-mutated non­­–small cell lung cancer (NSCLC) with active, untreated CNS metastases. Mirati Therapeutics. News release. June 6, 2022. Accessed July 13, 2022.

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