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

The FDA granted breakthrough therapy designation (BTD) to adagrasib (Krazatitm) in combination with cetuximab (Erbitux) for the treatment of patients with KRAS G12C-mutated advanced colorectal cancer (CRC) whose cancer has progressed following prior treatment with chemotherapy and an anti-VEGF therapy.

The BTD is intended to accelerate the development and regulatory review of drugs that have shown preliminary clinical evidence that have potential to improve upon standard treatment.

"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, MD, associate attending physician at Memorial Sloan Kettering Cancer Center, and study author, in a press release. "These results provide a strong rationale for continued development of this combination regimen."

In the case of the BTD for adagrasib plus cetuximab for the treatment of KRAS G12C-mutated advanced CRC whose cancer has progressed following prior treatment with chemotherapy and an anti-VEGF therapy, evidence came from the phase 1/2 KRYSTAL-1 study (NCT03785249).

According to results published in the New England Journal of Medicine, adagrasib administered with or without cetuximab demonstrated antitumor activity in the heavily pretreated study population. Out of 28 evaluable patients, the objective response rate (ORR) was 46% (95% CI, 28-66) with a median 7.6-month duration of response (95% CI, 5.7 to not estimable). Moreover, the median progression-free survival observed with adagrasib was 6.9 months (95% CI, 5.4-8.1).

Adagrasib’s safety profile in KRYSTAL-1 was consistent with previous findings. No synergistic adverse events (AEs) were shown with adagrasib/cetuximab. Grade 3 or 4 treatment-related adverse events (TRAEs) were observed in 34% of patients who received adagrasib alone and 16% of patients who received adagrasib plus cetuximab. There were no grade 5 TRAEs.

The KRYSTAL-1 study is an ongoing multiple expansion cohort trial in which up to 740 patients with advanced solid tumors will be treated with adagrasib orally once or twice daily at a 600 mg dose, or adagrasib in combination with cetuximab at an initial loading dose of 400 mg per square meter of body-surface area, followed by a dose of 250 mg per square meter given intravenously once every week or every 2 weeks.

ORR is being investigated as the primary end point of the study in addition the secondary end points of safety/tolerability and pharmacokinetics.

Patients with histologically confirmed, unresectable/metastatic disease, and adequate organ function who were not eligible for or decline on standard therapy are begin recruited for the study. Those with a history of intestinal disease or major gastric surgery, inability to swallow oral medications, or another active cancer are excluded from the study.

"KRAS G12C-mutations occur in 3% to 4% of colorectal cancers and are associated with poor outcomes.1 Few effective treatment options exist for these patients," said Alan Sandler, MD, chief medical officer, in the press release. "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 KRAS G12C-mutant CRC patients through the accelerated approval pathway."

_REFERENCES:

_{1. 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.}

_{2. Yaeger R, Weiss J, Pelster MS, et al. Adagrasib with or without cetuximab in colorectal cancer with mutated KRAS G12C. N Engl J Med. Published December 21, 2022. doi: 10.1056/NEJMoa2212419}

_{3. Phase 1/2 study of MRTX849 in patients with cancer having a KRAS G12C mutation KRYSTAL-1. Clinicaltrials.gov. Updated February 22, 2022. Accessed December 22, 2022.}