On December 5, 2022 Mirati Therapeutics, Inc. (NASDAQ: MRTX), a clinical-stage oncology company reported preliminary results from the KRYSTAL-7 Phase 2 trial and KRYSTAL-1 Phase 1b cohort evaluating adagrasib (400mg twice daily) concurrently combined with pembrolizumab in patients for the treatment of first-line NSCLC harboring a KRASG12C mutation across all PD-L1 subgroups (Press release, Mirati, DEC 5, 2022, View Source [SID1234624807]). These data are the first to demonstrate the tolerability and feasibility of a concurrent combination regimen of a KRASG12C inhibitor and a PD-1/L1 checkpoint inhibitor.

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Summary of Clinical Results

The KRYSTAL-7 and KRYSTAL-1 trials represent the largest dataset evaluating a KRASG12C inhibitor in combination with a PD-1/L1 checkpoint inhibitor as a first-line treatment for patients with NSCLC harboring a KRASG12C mutation.
75 patients were enrolled and evaluable for safety with a median follow-up of 3.5 months (duration of treatment: 2 months). Treatment-related adverse events (TRAEs) were Grade 1-2 (39%), Grade 3 (40%) and Grade 4 (4%); there were no Grade 5 TRAEs observed. TRAEs led to discontinuation of both adagrasib and pembrolizumab in 2 patients and only pembrolizumab in 2 patients; there were no patients who discontinued only adagrasib due to a TRAE.
Increases in alanine transaminase (ALT)/ aspartate transaminase (AST) were consistent with either agent as a monotherapy with Grade 3 TRAEs being highest grade and total incidence of Grade 3 liver function test (LFT) increases of 9%. Median time from onset to an increase in ALT and AST was 26 and 37 days, respectively and only 1 patient experienced new onset treatment-related ALT/AST increase after 3 months.
Of patients who were clinically evaluable and received at least one on-study scan (n=53), adagrasib and pembrolizumab demonstrated promising preliminary clinical activity across all PD-L1 subgroups with an objective response rate (ORR) of 49%.
In a subset of response-evaluable patients enrolled at least 6 months prior to the data cutoff date, 6 of 26 clinical responses occurred at second on-study scan or later, and the ORR was 56%.
7 evaluable patients enrolled in the KRYSTAL-1 Phase 1b cohort (with a median follow-up of 19.3 months) reported an ORR of 57% and a disease control rate (DCR) of 100%. The four patients who responded maintained response for over nine months while two continued to receive treatment and remain in response beyond 18 months.
Safety in the KRYSTAL-1 Phase 1b cohort was consistent with what has been observed in KRSTYAL-7 and demonstrated a manageable safety profile with no Grade 4-5 TRAEs.
"Initial results across all cohorts suggest the concurrent combination of adagrasib and pembrolizumab may provide a chemotherapy-free option for treatment-naïve NSCLC with a manageable safety profile and encouraging clinical activity," said Pasi A. Jänne, MD, PhD, Dana Farber Cancer Institute. "Across all evaluated cohorts, liver-related TRAEs were predominantly low grade and occurred early in treatment, with limited new onset after 3 months."

"We look forward to progressing our clinical development in the first line setting with a goal of providing better options for patients with NSCLC harboring a KRASG12C mutation," said Chuck Baum, president, founder, and head of research and development, Mirati Therapeutics, Inc. "This data further underscores the potential of adagrasib as a well-tolerated treatment option for patients. Based on these data, we look forward to initiating a Phase 3 trial."

The data (Presentation #LBA4) will be presented in an oral presentation on Dec. 7 at 2:05 p.m.-2:15 p.m. CET / 8:05 a.m.-8:15 a.m. ET during the Proffered Paper session 1 at the European Society for Medical Oncology Immuno-Oncology (ESMO IO) Congress 2022.

Virtual Investor Event
Mirati Therapeutics will host an Investor Event on Wednesday, December 7, 2022, at 5:00 p.m. CET / 11:00 a.m. ET.

Company executives will provide an overview of the adagrasib and pembrolizumab combination data presented 2022 ESMO (Free ESMO Whitepaper) Immuno-Oncology Annual Congress.

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.

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. Studies of adagrasib have shown that the drug has a long half-life and extensive tissue distribution, and is well tolerated. In clinical trials, adagrasib also has shown, central nervous system penetrance and single-agent responses in non-small cell lung cancer (NSCLC), colorectal cancer, pancreatic cancer and other solid tumors with KRASG12C mutations. Adagrasib is being evaluated in several clinical trials in combination with other anti-cancer therapies in patients with advanced solid tumors. Registration-enabling studies are ongoing in NSCLC and colorectal cancer. For more information visit Mirati.com/science.