The U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation (BTD) for adagrasib (Krazati™; Mirati Therapeutics) in combination with cetuximab (Erbitux®; Eli Lilly and Company) in patients with KRASG12C-mutated advanced colorectal cancer (CRC) whose cancer has progressed following prior treatment with chemotherapy and an anti-VEGF therapy.
The breakthrough designation is supported by results from the Phase 1b cohort of the KRYSTAL-1 trial. Findings from this ongoing, multicohort study, designed to evaluate adagrasib as monotherapy or combined with cetuximab in patients with KRASG12C-mutated metastatic colorectal cancer showed promising clinical activity and demonstrated a favorable tolerability profile with reversible adverse events.
The FDA program grants Breakthrough Therapy Designation 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.
Summary of Clinical Data
- 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,” Yaeger added.
“KRASG12C-mutations occur in 3-4% of colorectal cancers and are associated with poor outcomes. 
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,” Sandler added.
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.
Phase 1/2 Study of MRTX849 in Patients With Cancer Having a KRASG12C-Mutation KRYSTAL-1 – NCT03785249
Phase 3 Study of MRTX849 With Cetuximab vs Chemotherapy in Patients With Advanced Colorectal Cancer With KRAS G12C Mutation (KRYSTAL-10) – NCT04793958
Highlights of Prescribing Information
Cetuximab (Erbitux®; Eli Lilly and Company)[Prescribing Information]
 Yaeger R, Weiss J, Pelster MS, Spira AI, Barve M, Ou SI, Leal TA, Bekaii-Saab TS, Paweletz CP, Heavey GA, Christensen JG, Velastegui K, Kheoh T, Der-Torossian H, Klempner SJ. Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated KRAS G12C. N Engl J Med. 2022 Dec 21. doi: 10.1056/NEJMoa2212419. Epub ahead of print. PMID: 36546659.
 Fakih M, Tu H, et al. Real-World Study of Characteristics and Treatment Outcomes Among Patients with KRAS p.G12C-Mutated or Other KRAS Mutated Metastatic Colorectal Cancer. The Oncologist. 2022;27(8):663-674
Featured image: Dictionary definition of Colorectal cancer. Photo courtesy: © 2016 – 2022 Fotolia/Adobe. Used with permission.