On June 6, 2022 Mirati Therapeutics, Inc. (NASDAQ: MRTX), a clinical-stage targeted oncology company, reported results of a prospective analysis from the Phase 1b cohort of the KRYSTAL-1 study evaluating intracranial (IC) responses of adagrasib in patients with KRASG12C-mutated non-small cell lung cancer (NSCLC) with active and untreated central nervous system (CNS) metastases (Press release, Mirati, JUN 6, 2022, View Source [SID1234615636]). This is the first clinical data demonstrating CNS-specific activity of a KRASG12C inhibitor in patients with NSCLC with active and untreated CNS metastases. Findings show that approximately one third of the patients had an IC response in patients with CNS metastases, consistent with what was observed systemically in this cohort.

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The data will be presented today as a late-breaking oral presentation in the session titled, "Clinical Science Symposium/Including the Excluded: Advancing Care for All Patients With Lung Cancer" at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting from 5:30 to 5:42 PM ET/4:30 to 4:42 PM CT (Abstract #LBA9009).

"We are proud to share the first clinical data demonstrating CNS-specific activity of a KRASG12C inhibitor in patients with NSCLC," said Charles Baum, M.D., Ph.D., president, founder and head of research and development, Mirati Therapeutics, Inc. "Central nervous system 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."

Results of Prospective Analysis

With a median follow up of 6.6 months (data cutoff date December 2021), 25 patients with active, untreated CNS metastases were enrolled in the study and treated with adagrasib 600 mg BID.

Of the radiographically evaluable patients (n=19), results showed an IC objective response rate of 32% (6/19) by modified response assessment in neuro-oncology-brain metastases (modified RANO-BM) by blinded independent central review.

In this analysis, three patients achieved a complete response and three patients achieved a partial response. The IC disease control rate was 84% (16/19, including 10 patients with stable disease). The median IC duration of response was not reached (95% confidence interval: 4.1 – not evaluable). Concordance of disease control between systemic and IC responses was 88% (14/16). For all patients enrolled, median overall survival was not reached.

Cerebrospinal fluid (CSF) samples were obtained from two patients for whom regression of CNS metastases was observed; adagrasib CSF/free plasma concentration ratios (Kp,uu: 0.47) were consistent with other agents with known CNS penetration and activity.

The safety profile of adagrasib in this study was consistent with the overall population with no new safety signals observed. Grade 1 and 2 treatment related adverse events (TRAEs) occurred in 60% of patients. Grade 3 TRAEs occurred in 36% of patients, and there were no Grade 4/5 TRAEs.
"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 five months, posing a serious clinical challenge," said Joshua K. Sabari, M.D., assistant professor of medicine, medical oncology at Perlmutter Cancer Center, NYU Langone Health. "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."

Mirati also presented results from the registration-enabling Phase 2 cohort of the KRYSTAL-1 study evaluating adagrasib in patients with pre-treated NSCLC harboring a KRASG12C mutation during the Lung Cancer–Non-Small Cell Metastatic session at ASCO (Free ASCO Whitepaper) on June 3, 2022.

Virtual Investor Event

Mirati Therapeutics will host an Investor Event on Monday, June 6, 2022, at 8:00 PM ET/ 7:00 PM CT.

Company executives will provide an overview of the adagrasib clinical data presented at the 2022 ASCO (Free ASCO Whitepaper) Annual Meeting and the Company’s broader lung cancer strategy, including in earlier lines of therapy.

Investors and the general public are invited to register and listen to a live webcast of the event through the "Investors and Media" section on Mirati.com. A replay of the event will be available shortly after the conclusion of the event.

Central Nervous System (CNS) Metastases in KRAS-Mutated Lung Cancer

The brain, along with the bone, adrenals, and liver are common sites of extra-thoracic metastases in NSCLC.[1]−3 CNS metastases occur in 27−42% of patients with KRASG12C-mutated NSCLC at diagnosis.1,4−6 Additionally, patients with CNS metastases and KRAS-mutated NSCLC may have poor outcomes, with median overall survival ranging of approximately five months. 7-9

About Adagrasib (MRTX849)

Adagrasib is an investigational, highly selective, and potent oral small-molecule inhibitor of KRASG12C that is optimized to sustain target inhibition, an attribute that could be important to treat KRASG12C-mutated cancers, as the KRASG12C protein regenerates every 24–48 hours. Adagrasib is being evaluated as monotherapy and in combination with other anti-cancer therapies in patients with advanced KRASG12C-mutated solid tumors, including NSCLC, colorectal cancer and pancreatic cancer. For more information visit Mirati.com/science.

Mirati has an Expanded Access Program (EAP) for investigational adagrasib for the treatment of eligible patients with KRASG12C-mutated cancers, regardless of tumor type, including patients with treated or untreated CNS metastases, in the U.S. Learn more about the EAP at Mirati.com/expanded-access-policy.