New Data on Adagrasib Show Regression of CNS Metastases in KRASG12C-mutated NSCLC


About one-third of participants in the phase 1b cohort of the KRYSTAL-1 study show an intracranial response, according to Mirati Therapeutics.

Mirati Therapeutics Inc announced results of a prospective analysis from the phase 1b cohort of the KRYSTAL-1 (NCT03785249) study evaluating intracranial (IC) responses of adagrasib in individuals with KRASG12C-mutated non­­–small cell lung cancer (NSCLC) with active and untreated central nervous system (CNS) metastases.

These are the first clinical data showing CNS-specific activity of a KRASG12C inhibitor in individuals with NSCLC with active and untreated CNS metastases.

Approximately one-third of the individuals had an IC response in individuals with CNS metastases, consistent with what was observed systemically in the cohort, according to investigators.

The data were 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. 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,” Charles Baum, MD, PhD, president, founder and head of research and development at Mirati Therapeutics, said in a statement.

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 a day.

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

Further, 3 individuals achieved a partial response, and 3 achieved a complete response. The IC disease control rate was approximately 84%. The median IC duration of response was no reached.

Additionally, the concordance of disease control between IC and systemic responses was 88%. For all individuals enrolled, the median overall survival was not reached.

The results also show that the cerebrospinal fluid samples (CFS) were obtained from 2 individuals for whom regression of CNS metastases was observed. The adagrasib CSF 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.

Furthermore, the safety profile was consistent with the overall population with no new safety signals observed. Approximately 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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