As reported in The Lancet Oncology by John H. Strickler, MD, and colleagues, the phase II MOUNTAINEER trial has shown the activity of the combination of tucatinib plus trastuzumab in patients with HER2-positive, chemotherapy-refractory, RAS wild-type, unresectable or metastatic colorectal cancer.
The study supported the January 2023 accelerated approval of tucatinib in combination with trastuzumab based on response rate and duration of response in patients with RAS wild-type, HER2-positive, unresectable or metastatic colorectal cancer that has progressed following fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.
John H. Strickler, MD
In the open-label study, a total of 114 evaluable patients (full analysis set) were enrolled from sites in Belgium, France, Italy, Spain, and the United States into three cohorts between August 2017 and September 2021. Patients initially received tucatinib at 300 mg twice daily plus trastuzumab at a loading dose of 8 mg/kg followed by 6 mg/kg every 21 days (cohort A, n = 45) until disease progression. Subsequently, patients were randomly assigned 4:3 to receive tucatinib plus trastuzumab (cohort B, n = 39) or tucatinib monotherapy (cohort C, n = 30). The primary endpoint was confirmed objective response rate on blinded independent central review in cohorts A and B combined.
Among the 84 patients in cohorts A and B, objective response was observed in 32 (38.1%, 95% confidence interval [CI] = 27.7%–49.3%), with complete response seen in 3 (4%). An additional 28 patients (33%) had stable disease, yielding a disease control rate of 71%. Median response duration was 12.4 months (interquartile range = 8.3–25.5 months). The objective response rate with tucatinib monotherapy in cohort C was 3.3% (95% CI = 0.1%–17.2%).
In cohorts A and B, median progression-free survival on blinded independent central review was 8.2 months (95% CI = 4.2–10.3 months); rates at 6 and 12 months were 59.0% and 34.2%. At data cutoff, 65 (77%) of the 84 patients were off of treatment; of these, 38 (58%) received subsequent systemic anticancer therapy, including HER2-directed therapy in 18 (28%). Median overall survival was 24.1 months (95% CI = 20.3–36.7 months); rates at 12 and 24 months were 72.7% and 51.3%.
In the safety population, the most common adverse events of any grade among 45 patients in cohort A and 41 in cohort B were diarrhea (64%), fatigue (44%), and nausea (35%). Grade 3 or 4 adverse events occurred in 38% of patients, the most common being hypertension (7%) and urinary tract infection (5%). Tucatinib-related serious adverse events occurred in three patients (3%; consisting of acute kidney injury, colitis, and fatigue, respectively).
Among 30 patients receiving tucatinib monotherapy in cohort C, the most common adverse events of any grade were diarrhea (33%), abdominal pain (20%), and fatigue (20%). Grade 3 or 4 adverse events occurred in 27% of patients (all grade 3), the most common being increased alanine aminotransferase and aspartate aminotransferase (7% each). A serious tucatinib-related adverse event occurred in one patient.
Among all patients, no deaths were attributable to adverse events.
The investigators concluded, “Tucatinib plus trastuzumab had clinically meaningful antitumor activity and favorable tolerability. This treatment is the first U.S. Food and Drug Administrationapproved anti-HER2 regimen for metastatic colorectal cancer and is an important new treatment option for chemotherapy-refractory HER2-positive metastatic colorectal cancer.”
Tanios S. Bekaii-Saab, MD, of Mayo Clinic Arizona, Phoenix, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by Seagen and Merck & Co. For full disclosures of the study authors, visit thelancet.com.
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