FDA Grants Breakthrough Therapy Designation to Adagrasib/Cetuximab for KRAS G12C+ CRC


The FDA granted breakthrough therapy designation to adagrasib plus cetuximab for patients with KRAS G12C–mutated advanced colorectal cancer based on findings from the phase 1b cohort of the KRYSTAL-1 trial.

Adagrasib (Krazati) in combination with cetuximab (Erbitux) has been granted breakthrough therapy designation by the FDA for the treatment of patients with KRAS G12C–mutated advanced colorectal cancer (CRC) that has progressed after previous treatment with chemotherapy and anti-VEGF agents, according to a press release from Mirati Therapeutics.

The designation was supported by data from the phase 1b cohort of the KRYSTAL-1 trial (NCT03785249), in which investigators assessed adagrasib on its own and in combination with cetuximab in metastatic CRC harboring KRAS G12C mutations. Of 28 evaluable patients, adagrasib plus cetuximab yielded an objective response rate (ORR) of 46% (95% CI, 28%-66%), a median duration of response of 7.6 months (95% CI, 5.7-not estimable), and a median progression-free survival (PFS) of 6.9 months (95% CI, 5.4-8.1).

Additionally, adagrasib produced a safety profile that was consistent with findings reported in previous studies for the agent. The adagrasib and cetuximab combination regimen did not yield any synergistic adverse effects (AEs). Among patients receiving adagrasib monotherapy and those receiving adagrasib in combination with cetuximab, 34% and 16% of patients, respectively, experienced grade 3 or 4 treatment-related AEs (TRAEs). Investigators reported no grade 5 TRAEs.

“We are encouraged by this data, particularly adagrasib in combination with cetuximab,” Alan Sandler, MD, chief medical officer at Mirati, said in the press release. “With the [breakthrough therapy designation] status, we look forward to working together with the FDA to potentially bring this treatment option to [patients with] late-line KRAS G12C-mutant [CRC] through the accelerated approval pathway.”

In the phase 1b portion of the ongoing phase 1/2 KRYSTAL-1 trial, patients received adagrasib orally once or twice a day with or without cetuximab administered as an intravenous infusion once a week or once every 2 weeks.

The primary end points of the KRYSTAL-1 trial included the safety and pharmacokinetics of adagrasib as well as ORR. Key secondary end points included the maximum tolerated dose and the safety and tolerability of adagrasib in combination with selected therapeutic agents.

Patients 18 years and older with a histologically confirmed diagnosis of a solid tumor malignancy harboring a KRAS G12C mutation were eligible to enroll on the study. Additional inclusion criteria included having unresectable or metastatic disease and adequate organ function. Patients with a history of intestinal disease, prior major gastric surgery, an inability to swallow oral medications, or other active cancer were unable to enroll on the trial.

“[Results from the KRYSTAL-1 trial] provide a strong rationale for continued development of [the adagrasib and cetuximab] combination regimen,” study author Rona Yaeger, MD, an associate attending physician at Memorial Sloan Kettering Cancer Center, concluded.

Adagrasib in combination with cetuximab is also being assessed as second-line treatment in patients with KRAS G12C-mutated CRC compared with chemotherapy in the ongoing phase 3 KRYSTAL-10 trial (NCT04793958). Primary end points of the KRYSTAL-10 trial included overall survival and PFS.


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. News release. Mirati Therapeutics, Inc. December 21, 2022. Accessed December 22, 2022. bit.ly/3PLkdYK

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