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

FDA

The FDA has granted a breakthrough therapy designation to adagrasib (Krazati) plus cetuximab (Erbitux) in patients with KRAS G12C–mutated, advanced colorectal cancer (CRC) whose cancer has progressed following prior treatment with chemotherapy and an anti-VEGF therapy.¹

The designation was supported by data from the CRC cohort of the phase 1b KRYSTAL-1 trial (NCT03785249). Data showed that among 28 evaluable patients, the combination of adagrasib and cetuximab elicited an objective response rate (ORR) of 46% (95% CI, 28%-66%), a median duration of response (DOR) 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).²

“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 and KRYSTAL-1 study author, stated in a press release. “These results provide a strong rationale for continued development of this combination regimen.”

On December 12, 2022, the FDA granted accelerated approval to adagrasib monotherapy for the treatment of adult patients with KRAS G12C–mutated locally advanced or metastatic non–small cell lung cancer (NSCLC), as determined by an FDA-approved test, who have received at least 1 prior systemic therapy.³ The approval was based on previously reported data for patients with NSCLC in the KRYSTAL-1 trial.

The open-label, nonrandomized KRYSTAL-1 trial also evaluated adagrasib monotherapy and adagrasib in combination with cetuximab in patients at least 18 years of age with a histologically confirmed diagnosis of advanced, unresectable, or metastatic CRC with a KRAS G12C mutation who had no available treatment with curative intent and no available standard-of-care treatment. Patients were required to have an ECOG performance status of 0 or 1 and measurable disease per RECIST v1.1.

Key exclusion criteria included active central nervous system metastases, carcinomatous meningitis, and receipt of systemic or radiation therapy within 2 weeks before the planned initiation of adagrasib.

Enrolled patients received oral adagrasib at 600 mg twice daily with or without intravenous cetuximab once per week at an initial loading dose of 400 mg/m². That was followed by a dose of 250 mg/m² cetuximab once per week or every 2 weeks at 500 mg/m².

In the monotherapy group, the primary end point was ORR. Key secondary end points for this group included DOR, PFS, overall survival (OS), 1-year OS, and safety. In the combination group, safety served as the primary end point, and secondary end points consisted of the same efficacy outcomes as the monotherapy group.

Among all patients enrolled in the combination group (n = 32), the median age was 60 years (range, 41-74), 53% of patients were female, and 81% were White. Additionally, 56% of patients had an ECOG performance status of 1. The median number of prior lines of therapy was 3 (range, 1-8), and 31% of patients received at least 4 prior lines of therapy.

Prior therapies included fluoropyrimidine (100%), oxaliplatin (100%), irinotecan (88%), fluoropyrimidine-oxaliplatin-irinotecan (88%), anti-VEGF (88%), regorafenib (Stivarga), trifluridine/tipiracil (Lonsurf), or both (19%), and PD-1 or PD-L1 inhibitor (12%).

Metastatic target lesions included liver (59%), lung (50%), lymph nodes (28%), and other (28%). One patient had EGFR amplification, 69% of patients had a TP53 mutation, and 12% had a PIK3CA mutation.

The combination of adagrasib and cetuximab did not result in synergistic adverse effects (AEs). Grade 3 or 4 treatment-related AEs (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.

Adagrasib plus cetuximab is undergoing further evaluation in patients with KRAS G12C–mutated CRC in the second-line setting compared with standard chemotherapy in the ongoing phase 3 KRYSTAL-10 trial (NCT04793958).

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. December 21, 2022. Accessed December 22, 2022. https://bit.ly/3PJkMT7
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 online December 21, 2022. doi:10.1056/NEJMoa2212419
3. FDA grants accelerated approval to adagrasib for KRAS G12C-mutated NSCLC. News release. FDA. December 12, 2022. Accessed December 22, 2022. https://bit.ly/3WdCKPs