Tucatinib and Trastuzumab Combination Gains FDA Approval for RAS Wild-Type HER2+ mCRC

The FDA has granted accelerated approval to tucatinib and trastuzumab for RAS wild-type, HER2-positive metastatic colorectal cancer. The prescribing information includes warnings for diarrhea and hepatotoxicity.

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

Data from the phase 2 MOUNTAINEER trial (NCT03043313) supported the decision. Among the 84 patients treated with the combination, the overall response rate was 38.1% (95% CI, 28%-49%) per blinded independent central review. Most responders had partial responses (35%) and 3 patients had a complete response. The median duration of response (DOR) was 12.4 months (95% CI, 8.5-20.5). Eighty-one percent of responders had a DOR lasting at least 6 months and 34% had a DOR of at least 12 months.1,2

The recommended dose of tucatinib for patients with mCRC is 300 mg orally twice daily with or without food. Of note, for patients with severe hepatic impairment, the recommended dosage is 200 mg orally twice daily.2 Patients can take their tablets with or without a meal, and should take them about 12 hours apart at the same time every day.

“Historically, patients with HER2-positive mCRC who have progressed following frontline therapy have had poor outcomes,” John Strickler, MD, associate professor of medicine at Duke University Medical Center in Durham, North Carolina stated in a news release.1 “The FDA approval of a chemotherapy-free combination regimen that specifically targets HER2 is great news for these patients.” At the time of enrollment on MOUNTAINEER patients had a median age of 55 years (range, 24-77). Sixty-four percent of patients had liver metastases and 70% had lung metastases.1,2

In terms of safety, the label includes warnings for diarrhea, which may lead to severe dehydration, and hepatotoxicity. Among patients in MOUNTAINEER, 64% experienced diarrhea with most cases being grade 1 (50%). Ten percent of diarrhea events were grade 2 and 3.5% were grade 3. Dose interruption due to diarrhea was reported among 3.5% of patients and 2.3% of patients discontinued treatment due to the event.

For patients who experienced hepatotoxicity, 6% of patients had an increase of bilirubin increase greater than 3 × upper limit of normal (ULN), 6% had elevation in aspartate transaminase greater than 5 × ULN, and 4.7% had an alanine transaminase increase greater than 5 × ULN. Dose reductions were documented in 3.5% of patients and discontinuation was documented in 2.3% of patients due to hepatotoxicity.

Serious AEs, which occurred among 22% of patients, included intestinal obstruction (7%), urinary tract infection (3.5%), pneumonia (2.3%), abdominal pain (2.3%), and rectal perforation (2.3%).1 The most common AEs observed in MOUNTAINEER included diarrhea, fatigue, rash, nausea, abdominal pain, infusion-related reactions, and pyrexia.

Prescribing information also highlights drug-drug interactions that may arise for patients receiving tucatinib. It is advised to avoid concomitant use of tucatinib with strong or moderate CYP2C8 or CYP3A inhibitors due to their effect on tucatinib. It has been noted that tucatinib increases plasma concentrations of the CYP3A substrate and providers are advised to avoid concomitant use of tucatinib with CYP3A substrates.2 Additionally, the agent may increase plasma concentrations of the P-gp substrate and increase associated toxicities. Reductions in P-gp substrate doses are advised if administering tucatinib.2

Providers should teach patients to report any signs of diarrhea or liver problems to their health care team. Liver function should be tested every 3 weeks throughout treatment with tucatinib, and patients should report any signs of itching, yellowing of the skin or eyes, dark or brown urine, abdominal pain, fatigue suppressed appetite, or an increase of bruising, as these may be indicative of hepatotoxicity.

“The accelerated approval of [tucatinib] for RAS wild-type, HER2-positive mCRC expands tucatinib-based therapy to patients across 2 distinct types of cancer,” Marjorie Green, MD, senior vice president and head of late-stage development at Seagen stated in a news release.1 “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.”


  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, 2023. Accessed January 19, 2023. bit.ly/3wbKV45
  2. Tukysa. Prescribing information. Seagen Inc; 2023. Accessed January 19, 2023. bit.ly/3WpAPXY