FDA Approves Tucatinib Plus Trastuzumab for RAS Wild-type, HER2+ Metastatic Colorectal Cancer

FDA

The FDA has granted accelerated approval to tucatinib (Tukysa) in combination with trastuzumab (Herceptin) for adult patients with RAS wild-type, HER2-positive unresectable or metastatic colorectal cancer (CRC) that has progressed after treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.¹

The approval is supported by data from the phase 2 MOUNTAINEER trial (NCT03043313), which showed that patients treated with the doublet (n = 84) achieved an overall response rate (ORR) of 38% (95% CI, 28%-49%) per blinded independent central review (BICR). Of those who responded to the regimen, 3.6% (n = 3) achieved a complete response and 35% (n = 29) had a partial response. The median duration of response (DOR) by BICR was 12.4 months (95% CI, 8.5-20.5).

The median progression-free survival was 8.2 months (95% CI, 4.2-10.3), and the median overall survival (OS) was 24.1 months (95% CI, 20.3-36.7).²

“Historically, patients with HER2-positive metastatic CRC who have progressed following frontline therapy have had poor outcomes,” John Strickler, MD, lead study investigator and an associate professor of medicine at Duke University Medical Center, stated in a press release. “The FDA approval of a chemotherapy-free combination regimen that specifically targets HER2 is great news for these patients.”

The open-label, multicenter MOUNTAINEER trial enrolled patients with HER2-positive, RAS wild-type, unresectable or metastatic CRC following previous standard-of-care (SOC) therapies. Patients were not permitted to have received prior anti-HER2 therapy.

MOUNTAINEER was originally designed to include 1 cohort of patients who would receive tucatinib at a twice-daily dose of 300 mg in combination with trastuzumab at a dose of 8 mg/kg on day 1 of the first 21-day cycle, followed by 6 mg/kg in ensuing cycles. The protocol was amended to enroll an additional 70 patients who were randomly assigned 4:3 to receive the doublet or single-agent tucatinib.

ORR in both investigative cohorts by BICR and RECIST v1.1 criteria served as the trial’s primary end point. Secondary end points consisted of 12-week ORR, DOR, PFS, and OS in the investigative cohorts, as well as safety, dose modifications, and laboratory data.³

Additional data presented during the 2022 ESMO World Congress on Gastrointestinal Cancer demonstrated that at 12 weeks, patients in the tucatinib monotherapy cohort (n = 30) experienced an ORR of 3.3% (95% CI, 0.1%-17.2%). The disease control rate was 80%. Notably, patients who did not respond at 12 weeks or who experienced disease progression were permitted to cross over to receive the doublet.²

Regarding safety, serious adverse effects (SAEs) were reported in 22% of patients. The most common SAEs reported in at least 2% of patients included intestinal obstruction (7%), urinary tract infection (3.5%), pneumonia (2.3%), abdominal pain (2.3%), and rectal perforation (2.3%).

The most common any-grade AEs experienced by at least 20% of patients administered tucatinib plus trastuzumab were diarrhea, fatigue, rash, nausea, abdominal pain, infusion-related reactions and pyrexia.

AEs led to discontinuation of tucatinib in 6% of patients. The most common AE to lead to discontinuation was increased alanine aminotransferase (2.3%).

The ongoing, global, randomized phase 3 MOUNTAINEER-03 trial (NCT05253651) is evaluating tucatinib in combination with trastuzumab and mFOLFOX6 (leucovorin calcium, fluorouracil, and oxaliplatin) vs SOC as first-line treatment for patients with HER2-positive metastatic CRC. This study is intended to serve as a confirmatory trial and could potentially support future global regulatory submissions.

References

1. Seagen announces FDA accelerated approval of Tukysa (tucatinib) in combination with trastuzumab for people with previously treated RAS wild-type, HER2-positive metastatic colorectal cancer. News release. January 19, 2023. Accessed January 19, 2023. http://bit.ly/3IWR7o9
2. Seagen announces results from pivotal MOUNTAINEER trial demonstrating clinically meaningful antitumor activity of Tukysa (tucatinib) in combination with trastuzumab in previously treated HER2-positive metastatic colorectal cancer. News release. Seagen Inc. July 2, 2022. Accessed January 19, 2023. https://bwnews.pr/3yC4xQH
3. Tucatinib plus trastuzumab in patients with HER2+ colorectal cancer. ClinicalTrials.gov. Updated June 8, 2022. Accessed January 19, 2023. https://clinicaltrials.gov/ct2/show/NCT03043313