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

Oncology Nursing NewsJune 2023
Volume 17
Issue 3

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 given accelerated approval to tucatinib (Tukysa) plus trastuzumab (Herceptin) for patients with RAS wild-type, HER2-positive metastatic colorectal cancer (mCRC). To be eligible, patients must have disease that has progressed after chemotherapy with fluoropyrimidine, oxaliplatin, and irinotecan.1

Data from the phase 2 MOUNTAINEER trial (NCT03043313) supported the decision. Overall response rate per blinded independent central review was 38.1% (95% CI, 28%-49%) among the 84 patients treated with the combination. Most responders had partial responses (35%), and 3 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 of at least 6 months, and 34% had a DOR of at least 12 months.1,2

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

“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 company news release.1 “The FDA approval of a chemotherapy-free combination regimen that specifically targets HER2 is great news for these patients.” Patient median age at time of enrollment in MOUNTAINEER was 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 hepatotoxicity and diarrhea, which may lead to severe dehydration. Among study patients, 64% experienced diarrhea. Fifty percent of cases were grade 1, 10% were grade 2, and 3.5% were grade 3. Dose interruption due to this adverse reaction was reported among 3.5% of patients and discontinuation, among 2.3%.2

Of those who experienced hepatotoxicity, 6% had an increase of bilirubin greater than 3 times the upper limit of normal (ULN), 6% had aspartate transaminase elevation greater than 5 times ULN, and 4.7% had a rise in alanine transaminase greater than 5 times ULN. Dose reductions due to hepatotoxicity were documented in 3.5% of patients and discontinuation, in 2.3%.2

Serious adverse events (AEs), which occurred in 22% 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 AEs were diarrhea, fatigue, rash, nausea, abdominal pain, infusion-related reactions, and pyrexia.1

Prescribing information also highlights drug-drug interactions and recommends avoidance of concomitant use of tucatinib and strong or moderate CYP2C8 or CYP3A. It has been noted that tucatinib increases plasma concentrations of the CYP3A substrate, and providers are advised to avoid concurrent use of tucatinib and CYP3A substrates. The agent may also increase plasma concentrations of the P-gp substrate and its associated toxicities. Reductions in P-gp substrate doses are suggested when 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 during 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, and increased bruising, as these may indicate hepatotoxicity.2

“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,” Marjorie Green, MD, Seagen senior vice president and head of Late-Stage Development, said in the 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 April 12, 2023. bit.ly/3wbKV45
  2. Tukysa. Prescribing information. Seagen Inc; 2023. April 12, 2023. bit.ly/3WpAPXY
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