Tucatinib and Trastuzumab for HER2-Positive, Metastatic Colorectal Cancer

Prior phase 2 trials have demonstrated consistent activity with various combinations of HER2-targeted agents in patients with HER2-positive, metastatic colorectal cancer (mCRC).

Now, investigators in the U.S. and Europe have conducted an industry-sponsored, randomized, open-label, phase 2 trial (MOUTAINEER) to evaluate dual HER2-targeted therapy with tucatinib and trastuzumab in patients with chemotherapy-refractory, HER2-positive, RAS wild-type mCRC who had received no prior HER2-directed therapy. Among 116 participants, 86 received tucatinib plus trastuzumab, and 30 received tucatinib alone. Of patients who received combination therapy, 85% had left-sided primaries, 78% had received 2 or more lines of prior therapy, and 40% had received 3 or more lines of prior therapy. HER2 amplification was identified by next-generation sequencing in 61% of patients, by an immunohistochemistry (IHC) test score of 3+ in 40%, and by an IHC test score of 2+ and fluorescence in-situ hybridization (FISH) amplification in 32%.

In patients receiving tucatinib and trastuzumab, the centrally determined response rate (the primary endpoint) was 38.1%, the median duration of response was 12.4 months, progression-free survival (PFS) was 8.2 months, and overall survival (OS) was 24.1 months. Among patients receiving combination therapy who had centrally confirmed HER2 status, the response rate was numerically higher in those with IHC 3+ tumors (46.7%) than in those with IHC 2+/FISH+ tumors (20.0%). Patients receiving tucatinib alone had a response rate of only 3.3% and were allowed to cross over to combination therapy. Toxicity for combination therapy included grade 3 hypertension in 7% of patients and grade 3 diarrhea in 3%.