FDA Approves Tucatinib Plus Trastuzumab for RAS Wild-Type, HER2+ mCRC


MOUNTAINEER study results have wowed the FDA, leading to an accelerated FDA approval of tucatinib plus trastuzumab as RAS wild-type, HER2-positive unresectable or metastatic colorectal cancer treatment.

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

The approval is based on findings from the phase 2 MOUNTAINEER study (NCT03043313) in which the combination achieved a confirmed objective response rate (cORR) of 38.1% (95% CI, 27.7%-49.3%), at a median follow-up of 20.7 months (interquartile range, 11.7-39.0). Complete responses were observed in 3.6% of patients, and partial responses were observed in 35%. Responses to tucatinib plus trastuzumab were durable with a median duration of response (DOR) of 12.4 months (95% CI, 8.5-20.5).

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

In the study, 117 patients received tucatinib at 300 mg doses twice per day in combination with intravenous trastuzumab at an 8 mg/kg loading dose followed by 6 mg/kg doses every 3 weeks after, in cohort A. Those in cohort B also received tucatinib plus trastuzumab, and in Cohort C, patients received tucatinib monotherapy.2

The primary end point of the study was cORR by RECIST version 1.1 criteria, in cohorts A and B. The secondary end points were DOR progression-free survival (PFS), overall survival (OS), and safety and tolerability of tucatinib plus trastuzumab.

Among the 177 patients enrolled, the median age of those treated with tucatinib plus trastuzumab was 55.0 years (range, 24-77). At baseline, liver metastases were observed in 64.3 of patients, and 70.2% had lung metastases. The median prior lines of systemic therapy received by patients in the study was 3.0 (range, 1-6).

Results for the secondary end points showed a median PFS of 8.2 months (95% CI, 4.2-10.3), and a median OS of 24.1 months (95% CI, 20.3-36.7), in the combination cohorts.

In terms of treatment-emergent adverse events (TRAEs), patients in the tucatinib and trastuzumab arm experience mainly grade 1 or 2 diarrhea (60.5%), grades 1 or 2 fatigue (41.9%), grade 1 or 2 nausea (34.9%), and grades 1 or 2 infusion-related reaction (20.9%). Grade 3 TRAEs in the combination arm included diarrhea (3.5%) and fatigue (2.3%). The most common grade 3 AE was hypertension (7.0%). AEs led to treatment discontinuation in 5.8% of all patients across all arms. There were no deaths caused by AEs.

“The accelerated approval of Tukysa for RAS wild-type, HER2-positive metastatic colorectal cancer expands Tukysa-based therapy to patients across two distinct types of cancer,” said Marjorie Green, MD, senior vice president and head of Late-Stage Development, Seagen, in the press release. “We believe the efficacy and safety profile of the Tukysa, and trastuzumab-based regimen further establishes its role as an important backbone of dual HER2 inhibition in the treatment of adult patients with certain HER2-expressing breast and colorectal cancers.”

The positive results from MOUNTAINEER led to the launch of the MOUNTAINEER-03 study (NCT05253651), which is evaluating tucatinib, trastuzumab and modified FOLFOX6 vs standard of care treatment for patients with frontline HER2-positive mCRC.

“If MOUNTAINEER-03 is positive, it will essentially open the doors for global approval for tucatinib and trastuzumab added to FOLFOX6 in HER2-positive colorectal cancer. That's the first element that would come from this study. Following this, we need to start understanding, not from the study but if this ends up being positive and approved, then we [have to] start looking at those patients with lower expression of HER2," Tanios S. Bekaii-Saab, MD, FACP, medical oncologist, medical director, Cancer Clinical Research Office, vice chair and section chief, Medical Oncology, Department of Internal Medicine, Mayo Clinic told Targeted Oncology™, in an interview.


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. Seagen, Inc. January 19, 2022Accessed. January 19, 2022.https://bwnews.pr/3QQkslQ

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. Press release. Seagen; July 2, 2022. Accessed January 19, 2023. https://bit.ly/3nMuXcs

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