The FDA has granted accelerated approval to tucatinib (Tukysa®, Seagen, Inc.) with trastuzumab for rat sarcoma (RAS) wild-type human epidermal growth factor receptor 2 (HER2)–positive unresectable or metastatic colorectal cancer (CRC) that has progressed following fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.
"Patients with chemotherapy-refractory HER2-positive metastatic colorectal cancer receive limited clinical benefit with currently available therapies," said John Strickler, MD, Associate Professor of Medicine at Duke University School of Medicine, and colleagues, in their report of the MOUNTAINEER trial (NCT03043313) on which approval was based. "With sustained responses and favorable tolerability in heavily pretreated patients, tucatinib in combination with trastuzumab has the potential to be a new treatment option for previously treated HER2-positive metastatic CRC."
Safety and efficacy were evaluated in the phase 2, multicenter, open-label trial in which 84 patients with a confirmed diagnoses of HER2-positive, RAS wild-type, unresectable, or metastatic CRC were enrolled. Patients had to have previous treatment with fluoropyrimidine, oxaliplatin, irinotecan, and an anti–vascular endothelial growth factor (VEGF) monoclonal antibody (mAb). Participating patients were given 300 mg of tucatinib, orally, twice daily, in combination with 8 mg/kg of trastuzumab intravenously on Day 1 of Cycle 1, and 6 mg/kg of trastuzumab on Day 1 of each subsequent cycle. Treatment continued until disease progression or unacceptable toxicity. Patients who received prior anti–HER2-targeting therapy were excluded.
At a median follow-up of 20.7 months, the primary end point measured was confirmed overall response rate as assessed by blinded independent central review via Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, with secondary end points including duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety and tolerability. The confirmed overall response rate was seen at 38.1%, and median duration of response was 12.4 months. The median PFS was 8.2 months, and the median OS was 24.1 months.
The most common adverse events in ≥20% of patients receiving tucatinib were diarrhea, fatigue, rash, nausea, abdominal pain, infusion-related reactions, and pyrexia. The most common laboratory abnormalities in ≥20% of patients were increased creatinine, increased glucose, increased alanine transaminase (ALT), decreased hemoglobin, increased aspartate aminotransferase (AST), increased bilirubin, increased alkaline phosphatase, decreased lymphocytes, decreased albumin, decreased leukocytes, and decreased sodium.
"In patients with chemotherapy-refractory HER2-positive metastatic CRC, tucatinib in combination with trastuzumab was well tolerated with clinically meaningful antitumor activity including durable responses and a median overall survival of 2 years," concluded Dr. Strickler and colleagues. "Tucatinib in combination with trastuzumab has the potential to become a new standard of care for patients with HER2-positive metastatic CRC."
The recommended dosage is 300 mg of tucatinib taken orally, twice daily, plus trastuzumab until disease progression or unacceptable toxicity.
For More Information
Strickler J, Cercek A, Siena S, et al (2022). LBA-2 primary analysis of MOUNTAINEER: A phase 2 study of tucatinib and trastuzumab for HER2-positive mCRC. Ann Oncol, 33(suppl_4): 375-376. DOI:10.1016/j.annonc.2022.04.440
Tuksya® (tucatinib) prescribing information (2023). Seagen. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/213411s004lbl.pdf
US Food and Drug Administration (2023). FDA grants accelerated approval to tucatinib with trastuzumab for colorectal cancer. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-tucatinib-trastuzumab-colorectal-cancer
Seagen (2022). Seagen announces results from pivotal MOUNTAINEER trial demonstrating clinically meaningful antitumor activity of Tuksya® (tucatinib) in combination with trastuzumab in previously treated HER2-positive metastatic colorectal cancer. Available at: https://investor.seagen.com/press-releases/news-details/2022/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/default.aspx
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