Tucatinib plus trastuzumab represents a valuable, novel option for HER2-positive, RAS wild-type, unresectable or metastatic colorectal cancer that is chemotherapy refractory, according to the authors of the phase 2 MOUNTAINEER trial.
Treatment with tucatinib (Tukysa) plus trastuzumab (Herceptin) demonstrated clinically meaningful and enduring clinical activity as well as tolerability in patients with chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer (CRC), according to published findings from the phase 2 MOUNTAIINER trial (NCT03043313).1
Among patients in cohorts A—which received 300 mg of tucatinib and an 8 mg/kg initial loading dose of trastuzumab followed by 6 mg/kg every 21 days—and cohort B—which received tucatinib and trastuzumab following random assignment via an interactive web response system and stratification—the confirmed objective response rate (ORR) per blinded independent central review (BICR) was 38.1% (95% CI, 27.7%-49.3%), including complete responses (CRs) in 4% and partial responses (PRs) in 35%. The confirmed ORR by investigator assessment was 42.9% (95% CI, 32.1%-54.1%), including CRs in 2% and PRs in 41%.
Based on a post hoc subgroup analysis, the ORR by BICR was 36.4% (95% CI, 22.4%-52.2%) in those who received previous anti-EGFR treatment and 40.0% (95% CI, 24.9%-56.7%) for those who did not. With respect to HER2 status based on immunohistochemistry (IHC), the ORRs by BICR were 46.7% for patients with IHC 3+ tumors, 20.0% for those with IHC 2+ and in-situ hybridization-positive tumors, and 10.0% for those with HER2-negative tumors.
In the tucatinib monotherapy cohort, the ORR per BICR was 3.3%, with 1 patient experiencing a PR.
“These promising anti-tumor activity and safety outcomes have resulted in tucatinib plus trastuzumab being the first treatment option approved by the FDA and recommended by established guidelines for patients with chemotherapy-refractory, HER2-positive, RAS wild-type metastatic [CRC],” the study authors wrote.
Investigators of the global, open-label, phase 2 MOUNTAINEER study assessed tucatinib plus trastuzumab in the treatment of patients across 34 sites in Belgium, France, Italy, Spain, and the United States. Investigators then expanded the study and randomly assigned patients 4:3 to cohort A, cohort B, or cohort C—which received tucatinib monotherapy.
The primary end point was the confirmed ORR per BICR for patients who received tucatinib plus trastuzumab in cohorts A and B. Secondary end points included duration of response (DOR), progression-free survival (PFS), and overall survival (OS).
Patients aged 18 years and older who received prior treatment for chemotherapy-refractory, HER2-positive, RAS wild-type, unresectable or metastatic CRC were eligible for enrollment on the study. Additional eligibility criteria included having radiographically measurable disease per RECIST v1.1 criteria and an ECOG performance status of 0 to 2.
The study included 45 patients in cohort A, 41 in cohort B, and 30 in cohort C who received at least 1 dose of study treatment. The median patient age in the full analysis set was 56.0 years (interquartile range [IQR], 47-64). Additionally, 58% of patients were male, 77% were White, and 5% were Black or African American.
Among patients receiving tucatinib plus trastuzumab and those receiving tucatinib alone, respectively, most had an ECOG performance status of 0 (60% vs 57%), a primary tumor in the left colon and rectum (85% vs 90%), stage IV disease (60% vs 63%), and received 2 prior lines of systemic therapy in metastatic or current settings (38% vs 53%).
Among patients who received tucatinib plus trastuzumab, the median time to confirmed response was 2.1 months (IQR, 2.0-3.6), and the median DOR was 12.4 months (IQR, 8.3-25.5) per BICR and 15.4 months (95% CI, 6.2-not estimable [NE]) per investigator assessment. Additionally, the median PFS was 8.2 months (95% CI, 4.2-10.3) per BICR and 7.0 months (95% CI, 4.3-9.7) per investigator assessment. The median OS was 24.1 months (95% CI, 20.3-36.7).
The median OS for those who received tucatinib monotherapy followed by tucatinib plus trastuzumab was 21.1 months (95% CI, 18.6-NE).
The most frequent treatment-emergent adverse effects (TEAEs) among patients who received at least 1 dose of tucatinib plus trastuzumab included diarrhea (64%), fatigue (44%), nausea (35%), and infusion-related reactions (21%). The most frequent grade 3 or higher AE was hypertension (7%). Additionally, 3 patients experienced serious AEs related to tucatinib, including 1 instance each of acute kidney injury, colitis, and fatigue.
Among patients who received tucatinib monotherapy, the most frequent any-grade TEAEs included diarrhea (33%), abdominal pain (20%), and fatigue (20%). The most common grade 3 or higher AEs included increased alanine aminotransferase (7%) and aspartate aminotransferase (7%). Investigators reported no deaths due to AEs, and all deaths occurred due to disease progression.
In January 2023, the FDA granted accelerated approval to tucatinib plus trastuzumab in the aforementioned patient population based on supporting data from the MOUNTAINEER trial.2