Second-line tucatinib plus trastuzumab combo gets accelerated approval in metastatic disease

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 who have progressed following treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, Seagen announcedopens in a new tab or window.

This is the first FDA-approved treatment for HER2-positive metastatic colorectal cancer, the company noted.

Approval was based on results from the phase II MOUNTAINEER trialopens in a new tab or window, showing a 38% overall response rate (95% CI 28-49) with the combination per blinded independent central review. Complete responses were observed in 3.6% of patients and partial responses were seen in 35%. The median duration of response was 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 lead investigator John Strickler, MD, of Duke University Medical Center in Durham, North Carolina, in a press release. “The FDA approval of a chemotherapy-free combination regimen that specifically targets HER2 is great news for these patients.”

The multicenter, open-label, randomized, phase II MOUNTAINEER trial evaluated 84 patients with RAS wild-type, HER2-positive unresectable or metastatic colorectal cancer following previous treatment with standard-of-care therapies. They had not received prior anti-HER2 therapy.

At study entry, 64% and 70% of these patients had liver or lung metastases, respectively.

Patients received tucatinib 300 mg twice daily orally in combination with trastuzumab intravenously (8 mg/kg loading dose, then 6 mg/kg every 3 weeks thereafter) until disease progression or unacceptable toxicity.

The prescribing information for tucatinib includes warnings and precautions for diarrhea, hepatotoxicity, and embryo-fetal toxicity, some of which may be severe or fatal.

The most common adverse reactions (≥20%) in patients treated with the combination were diarrhea, fatigue, rash, nausea, abdominal pain, infusion-related reactions, and pyrexia. Serious adverse reactions occurred in 22% of patients, with intestinal obstruction (7%), urinary tract infection (3.5%), and pneumonia, abdominal pain, and rectal perforation (2.3% each) being the most common.

Adverse reactions leading to permanent discontinuation of tucatinib occurred in 6% of patients.