FDA Grants Breakthrough Therapy Designation to Adagrasib, Cetuximab Combination


The findings show promising clinical activity and a favorable tolerability profile in the treatment of KRASG12C-mutated advanced colorectal cancer.

The FDA has granted breakthrough therapy designation (BTD) to adagrasib (Krazati; Mirati Therapeutics) in combination with cetuximab in individuals with KRASG12C-mutated advanced colorectal cancer (CRC), which had progressed following treatment with chemotherapy and an anti-VEGF therapy.

The designation is supported by results from the phase 1b cohort of the KRYSTAL-1 (NCT03785249) trial.

“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,” Rona Yaeger, MD, associate attending physician at Memorial Sloan Kettering Cancer Center, said in a statement. “These results provide a strong rationale for continued development of this combination regimen.”

Additionally, the New England Journal of Medicine published findings from the ongoing KRYSTAL-1 phase 1/2 study, which evaluated adagrasib as a monotherapy or in combination with cetuximab.

The findings showed promising clinical activity and a favorable tolerability profile with reversible adverse events (AEs).

Of the 28 evaluable patients, the combination of adagrasib and cetuximab showed a median duration of response (DOR) of 7.6 months, and median progression-free survival rate of 6.9 months, and an objective response rate (ORR) of 46%.

The safety profile of adagrasib was consistent with previously reported safety findings. Additionally, the safety of the combination did not result in synergistic AEs.

Grade 3 or 4 treatment-related adverse events (TRAEs) occurred in 34% of individuals who received the monotherapy and in 16% who received the combination.

There were no reported grade 5 TRAEs.

KRASG12C-mutations occur in 3 [to] 4% of colorectal cancers and are associated with poor outcomes. Few effective treatment options exist for these patients.” Alan Sandler, MD, chief medical officer at Mirati Therapeutics, said in the statement.

“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,” Sandler said.

A phase 3 KRYSTAL-10 (NCT04793958) trial, evaluating adagrasib in combination with cetuximab in individuals with KRASG12C-mutant CRC in the second line compared with standard chemotherapy, is ongoing.

The FDA grants BTD to expedite the development of regulatory review of drugs that have preliminary clinical evidence of a substantial improvement over available therapies in the treatment of individuals with serious diseases.

Adagrasib is indicated for the treatment of individuals with KRASG12C-mutant locally advanced or metastatic non–small cell lung cancer (NSCLC), determined by an FDA-approved test, and who have received at least 1 prior systemic therapy.

This indication is approved based on data supporting DOR and ORR of adagrasib.

Adagrasib will continue to be evaluated as a monotherapy and in combination with other anti-cancer therapies in individuals with KRASG12C-mutant solid tumors, including CRC, NSCLC, , and pancreatic cancer.


Mirati announces adagrasib (Krazati) receives breakthrough therapy designation from FDA for patients with advanced, KRAS-mutated colorectal cancer and NEJM publishes phase 1b/2 data from adagrasib with or without cetuximab in colorectal cancer. Mirati Therapeutics. News release. December 21, 2022. Accessed January 5, 2023. https://ir.mirati.com/press-releases/press-release-details/2022/Mirati-announces-Adagrasib-KRAZATI-Receives-Breakthrough-Therapy-Designation-from-FDA-for-Patients-with-Advanced-KRAS-Mutated-Colorectal-Cancer-and-NEJM-Publishes-Phase-1b2-Data-from-Adagrasib-With-or-Without-Cetuximab-in-Colorectal-Cancer/default.aspx

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