On December 21, 2022 Mirati Therapeutics, Inc. (NASDAQ: MRTX), reported that the FDA has granted BTD to adagrasib in combination with cetuximab in patients with KRASG12C-mutated, advanced CRC whose cancer has progressed following prior treatment with chemotherapy and an anti-VEGF therapy (Press release, Mirati, DEC 21, 2022, View Source [SID1234625512]). This designation is supported by results from the Phase 1b cohort of the KRYSTAL-1 trial.

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The FDA program grants BTD to expedite the development and regulatory review of drugs that have demonstrated preliminary clinical evidence of a substantial improvement over available therapy in the treatment of patients with serious diseases on at least one clinically significant endpoint.

In addition, today, the NEJM published findings from the ongoing multicohort KRYSTAL-1 Phase 1/2 study evaluating adagrasib as monotherapy or combined with cetuximab in patients with KRASG12C-mutated metastatic colorectal cancer. These data reported promising clinical activity and demonstrated a favorable tolerability profile with reversible adverse events.

Summary of Clinical Results

Of 28 evaluable patients, the combination of adagrasib and cetuximab demonstrated an objective response rate (ORR) of 46% (95% CI, 28 to 66); a median duration of response (DOR) of 7.6 months (95% CI, 5.7 to not estimable) and a median PFS of 6.9 months (95% CI, 5.4 to 8.1).
The safety profile of adagrasib was consistent with previously reported safety findings; and the safety of the combination of adagrasib and cetuximab did not result in synergistic adverse events. Grade 3 or 4 treatment related adverse events (TRAEs) occurred in 34% of patients who received adagrasib monotherapy and in 16% of patients who received adagrasib and cetuximab in combination. No grade 5 TRAEs were observed.
"Preclinical studies and early clinical data indicate that the combination of a KRAS inhibitor and an anti-EGFR antibody could be an effective strategy to mitigate EGFR reactivation," said Rona Yaeger, M.D., Associate Attending Physician at Memorial Sloan Kettering Cancer Center and study author. "These results provide a strong rationale for continued development of this combination regimen."

"KRASG12C-mutations occur in 3-4% of colorectal cancers and are associated with poor outcomes.1 Few effective treatment options exist for these patients," said Alan Sandler, M.D., Chief Medical Officer. "We are encouraged by this data, particularly adagrasib in combination with cetuximab. With the BTD status, we look forward to working together with the FDA to potentially bring this treatment option to late-line KRASG12C-mutant CRC patients through the accelerated approval pathway."

A Phase 3 trial evaluating adagrasib in combination with cetuximab in patients with KRASG12C-mutated colorectal cancer in the second line setting compared with standard chemotherapy (KRYSTAL-10; NCT04793958) is currently ongoing.

About KRAZATI (adagrasib)

In the U.S., KRAZATI was approved by the FDA for Accelerated Approval (Subpart H), which allows for the approval of drugs that treat serious conditions, and that fill an unmet medical need based on surrogate endpoints. KRAZATI was reviewed under the FDA Real-Time Oncology Review (RTOR) pilot program, which aims to explore a more efficient review process that ensures safe and effective treatments are made available to patients as early as possible. Mirati submitted a Marketing Authorization Application (MAA) in the EU in May 2022. In 2021, adagrasib achieved Breakthrough Therapy Designation in the U.S. as a potential treatment for patients with NSCLC harboring the KRASG12C mutation who have received at least one prior systemic therapy. For Prescribing Information, visit Mirati.com/KRAZATI_USPI

Adagrasib continues to be 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 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.

KRAZATI (adagrasib) U.S. Indication

KRAZATI is indicated for the treatment of adult patients with KRASG12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA-approved test, who have received at least one prior systemic therapy.

This indication is approved under accelerated approval based on objective response rate (ORR) and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of a clinical benefit in a confirmatory trial(s).