On January 19, 2023, the FDA granted accelerated approval to tucatinib in combination with trastuzumab for the treatment of patients with unresectable or metastatic RAS wild-type, HER2-positive colorectal cancer who have received prior treatment with fluoropyrimidine, oxaliplatin, and irinotecan. Approval was based on the pooled analysis of patients receiving tucatinib in combination with trastuzumab in MOUNTAINEER (NCT03043313), an open-label, multicenter trial. The primary endpoint was overall response rate (ORR) by RECIST 1.1 as per blinded central review committee (BIRC) assessment. The main secondary endpoint was duration of response (DOR) per BIRC assessment. Eighty-four eligible patients received the combination tucatinib and trastuzumab. With a median follow-up of 16 months, the ORR was 38% [95% confidence interval (CI): 28–49] and median DOR was 12.4 months (95% CI: 8.5–20.5); 81% of responders had a response lasting more than 6 months. The most common adverse reactions observed in at least 20% of patients receiving tucatinib in combination with trastuzumab were diarrhea, fatigue, rash, nausea, abdominal pain, infusion-related reactions, and fever. FDA concluded that the magnitude of ORR and durable responses observed in patients treated with tucatinib in combination with trastuzumab in the MOUNTAINEER trial are clinically meaningful, particularly in the context of a disease with estimated survival of 6–7 months with available therapy. This is the first approval for the subset of patients with HER2-positive colorectal cancer. This article summarizes the FDA's thought process and review of the data supporting this accelerated approval.

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