FDA Grants Accelerated Approval to Tucatinib Combination for Patients with HER2-Positive Metastatic Colorectal Cancer

The FDA has granted accelerated approval to tucatinib (Tukysa; Seagen Inc) in combination with trastuzumab for adult patients with RAS wild-type, human epidermal growth factor receptor 2 (HER2)-positive unresectable or metastatic colorectal cancer that has progressed following fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy. This is the first FDA-approved treatment for HER2-positive metastatic colorectal cancer.

“[It] is great news for these patients,” said lead investigator John Strickler, MD, associate professor of medicine, Duke University Medical Center, in a press release, since “historically, patients with HER2-positive metastatic colorectal cancer who have progressed following frontline therapy have had poor outcomes.”

The approval was based on tumor response rate and durability of response from the phase 2 MOUNTAINEER clinical trial. Continued approval for the indication may be contingent on verification and description of clinical benefit in confirmatory trials.

MOUNTAINEER was an open-label, multicenter clinical trial that evaluated tucatinib with trastuzumab for HER2-positive, RAS wild-type, unresectable or metastatic colorectal cancer in patients already treated with frontline therapies. Patients initially received tucatinib as an oral 300 mg pill twice per day with an intravenous 8 mg/kg loading dose of trastuzumab. Tucatinib was then taken with 6 mg/kg of trastuzumab for the next 3 weeks.

The primary outcome measures of the trial were overall response rate (ORR) and duration of response (DOR) according to version 1.1 of RECIST (Response Evaluation Criteria in Solid Tumors).

The results showed a 38% ORR in the tucatinib/trastuzumab cohort. Among tucatinib patients, 35% achieved partial response, and DOR was 12.4 months. A randomized phase 3 clinical trial is currently underway, which will compare the combination of tucatinib, trastuzumab, and mFOLFOX6 with standard of care.

The most common adverse events (AEs) were diarrhea, fatigue, rash, nausea, abdominal pain, infusion-related reactions, and pyrexia. Serious AEs such as intestinal obstruction, urinary tract infection, pneumonia, abdominal pain, and rectal perforation occurred in 22% of patients.

Tucatinib is available in 50 mg and 150 mg tablets. It is an oral tyrosine kinase inhibitor that, in vitro, prevents HER2 and HER3 phosphorylation, and has anti-tumor activity on HER2-expressing cells to inhibit proliferation. When taken with the anti-HER2 antibody trastuzumab, the individual anti-tumor activities are compounded in vitro and in vivo, according to the study authors.

In 2023, nearly 153,000 people are expected to be diagnosed with colorectal cancer, with 22% of patients diagnosed at an advanced stage. It is the number 3 cause of cancer-related deaths in the United States, and it is expected to affect even more younger adults.

Fortunately, biomarker testing is making it possible for patients with RAS wild-type, HER2-positive colorectal cancer to receive targeted treatments, according to Michael Sapienza, CEO, Colorectal Cancer Alliance, in the press release.

“We believe the efficacy and safety profile of the tucatinib 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,” said Marjorie Green, MD, senior vice president and head of late-stage development, Seagen, in the press release.

Reference

Seagen Inc. 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 on January 19, 2023. https://investor.seagen.com/press-releases/news-details/2023/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/default.aspx