On September 7, 2022 Mirati Therapeutics, Inc. (NASDAQ: MRTX), a clinical-stage targeted oncology company, reported results from KRYSTAL-1, a multicohort Phase 1/2 study, evaluating adagrasib with or without cetuximab in patients with advanced CRC harboring a KRASG12C mutation (Press release, Mirati, SEP 7, 2022, View Source [SID1234619206]).

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"These exciting results further our understanding of the well-tolerated profile with robust and sustained responses that adagrasib provides as a monotherapy and in combination with cetuximab to patients with KRASG12C-mutated advanced colorectal cancer," said Charles Baum, M.D., Ph.D., president, founder and head of research and development, Mirati Therapeutics, Inc. "We are pleased about the significant improvement these results demonstrate relative to the existing standard of care. We continue to explore the full potential of adagrasib in combination with cetuximab in late-line CRC in a potentially registration-enabling Phase 2 cohort of the KRYSTAL-1 study and in second line CRC in the ongoing Phase 3 KRYSTAL-10 study."

In this analysis, 44 patients received adagrasib monotherapy (600 mg twice daily) and 32 patients received the combination of adagrasib (600 mg twice daily) with full dose cetuximab, with a follow up of 20.1 months and 17.5 months, respectively.

Of the evaluable patients in the adagrasib monotherapy cohort (n=43), the investigator assessed confirmed objective response rate (ORR) was 19% (8/43) and the disease control rate (DCR) was 86% (37/43). The median duration of response was 4.3 months (95% CI, 2.3–8.3) and median progression-free survival (PFS) was 5.6 months (95% CI, 4.1–8.3).

Of the evaluable patients in the adagrasib plus cetuximab combination cohort (n=28), the investigator assessed confirmed ORR was 46% (13/28) and the DCR was 100% (28/28). The median DOR was 7.6 months (95% CI 5.7–NE) and median PFS was 6.9 months (95% CI, 5.4–8.1).

The prognosis for patients with CRC has historically been poor in later lines of therapy with response rates of approximately 1-2% and median PFS of approximately 2 months1,2,3 in patients with late-line CRC; patients with KRASG12C-mutated CRC tend to have even worse outcomes than the broader CRC patient population.

In the overall subset of patients with KRASG12C-mutated CRC evaluated in this study, adagrasib was found to be well-tolerated as a monotherapy and in combination with cetuximab. The majority of observed treatment-related adverse events (TRAEs) were grade 1–2 (59%); no grade 5 TRAEs were observed.

"These data illustrate the importance of durable KRAS inhibition in colorectal cancer and the added benefit that dual EGFR/KRAS blockade may provide for some patients in their regimen as evidenced by the more sustained responses from the adagrasib and cetuximab combination," commented Dr. Samuel J. Klempner of the Massachusetts General Cancer Center and study investigator. "Overall, it’s encouraging to see the emergence of KRAS inhibitors like adagrasib providing more targeted, efficacious, and safe treatment options for colorectal cancer and other solid tumors with KRAS mutations."

The data (Presentation #LBA24) will be presented in an oral presentation on Monday, September 12 at 4:15 am ET (10:15 am CET) during the Proffered Paper Session II at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2022.

In addition, at the ESMO (Free ESMO Whitepaper) Congress 2022, the Company shared a poster presentation detailing additional practice-informing data on adverse event patterns and management for investigational adagrasib in patients with KRASG12C-mutated non-small cell lung cancer (NSCLC). The presentation (Presentation #1133P) is available online via the ESMO (Free ESMO Whitepaper) website and will be available onsite in Poster Session 15, Hall 4 on September 12, 2022.

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 non-small lung cancer, 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.