June 2024: The Food and Drug Administration has given accelerated approval to adagrasib (Krazati; Mirati Therapeutics, Inc.) in combination with cetuximab for adults who have KRAS G12C-mutated locally advanced or metastatic colorectal cancer (CRC), as confirmed by an FDA-approved test, and who have previously undergone treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.
The evaluation of efficacy was conducted in KRYSTAL-1, which is a trial including multiple centers and a single-arm expansion cohort. Patients who were considered suitable had to have locally advanced or metastatic colorectal cancer (CRC) with a specific KRAS G12C mutation. They must have received prior treatment with the chemotherapeutic drugs fluoropyrimidine, oxaliplatin, and irinotecan, as well as a VEGF inhibitor, if they satisfied the criteria.
Patients received adagrasib at a dosage of 600 mg twice a day, along with cetuximab given either every two weeks at a rate of 500 mg/m2 or weekly with an initial dose of 400 mg/m2 followed by 250 mg/m2. Regular evaluations of the tumor were conducted at 6-week intervals. Discontinuation of adagrasib necessitated discontinuation of cetuximab, however, patients were allowed to continue adagrasib if cetuximab was withdrawn.
The confirmed overall response rate (ORR) and the duration of response (DOR) were the two main ways to measure how well the treatment worked. They underwent a neutral, independent central review and were based on the RECIST v1.1 criteria.
Among the 94 patients who participated in the study, the overall response rate (ORR) was 34%, with a 95% confidence interval (CI) ranging from 25% to 45%. All of the responses seen were partial responses. The median duration of response (DOR) was 5.8 months, with a 95% CI ranging from 4.2 to 7.6 months. 31% of the patients who responded had a duration of response (DOR) of 6 months or more.
The predominant side effects (≥20%) included rash, nausea, diarrhea, vomiting, fatigue, musculoskeletal discomfort, hepatotoxicity, headache, dry skin, stomach pain, decreased appetite, edema, anemia, cough, disorientation, constipation, and peripheral neuropathy.
The suggested dosage for adagrasib is 600 mg administered orally twice a day until there is evidence of disease progression or the presence of adverse effects that are deemed intolerable. Consult the Cetuximab prescribing information for more details regarding the recommended dosage of Cetuximab.
