Table 3.

FDA Benefit:Risk Analysis

Dimension	Evidence and uncertainties	Conclusions and reasons
Analysis of condition	•HER2 overexpression or amplification is rare in CRC, and can be seen in up to an estimated 5% of patients with RAS WT tumors. •  The prognostic role of HER2 in CRC is unclear. •  Relapsed or refractory advanced or metastatic CRC is a serious condition, with estimated median survival after treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based ± monoclonal antibodies regimens of 6–7 months	Refractory colorectal cancer is a serious and life-threatening disease
Current treatment options	•For the non-biomarker driven population, treatment after disease progression/relapse is limited to regorafenib and tipiracil/trifluridine; both drugs were approved based on improvement in overall survival- ORR was less than 2%. •  No available treatment approved for HER2+ patients.	Current treatment options for patients with RAS wild-type, HER2+ refractory colorectal cancer are limited and provide a limited benefit; patients with this disease have an unmet medical need.
Benefit	•The ORR benefit in 84 patients with RAS WT HER2+ advanced or metastatic CRC who received treatment with tucatinib in combination with trastuzumab in the MOUNTAINEER trial was 38% (95% CI 28, 49) •  The median DoR was 12.4 months (95% CI 8.5, 20.5) •  32 patients had confirmed responses; 81% had a response duration ≥6 months.	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. An ongoing randomized study comparing standard of care chemotherapy in combination with tucatinib and trastuzumab for the first line treatment of patients with RAS WT HER2+ metastatic CRC is ongoing.
Risk and risk management	•Among the 86 patients with RAS WT, HER2+ refractory unresectable or metastatic colorectal cancer treated with tucatinib and trastuzumab in Cohorts A and B of MOUNTAINEER, the most common adverse reactions and laboratory abnormalities (incidence ≥ 20%) were diarrhea, increased creatinine increased glucose, increased ALT, decreased hemoglobin, fatigue, increased AST, rash, nausea, increased bilirubin, increased alkaline phosphatase, decrease lymphocytes, decreased albumin, decreased leukocytes, and fever	The observed safety profile is acceptable when assessed in the context of the treatment of a life-threatening disease. Information in the Warnings and Precautions and Dosage and Administration sections of product labeling address these toxicities adequately.

Source: FDA analysis