FDA Approves Tucatinib Plus Trastuzumab for RAS Wild-type, HER2+ Metastatic Colorectal Cancer


On January 19, 2023, the U.S. Food and Drug Administration granted accelerated approval to Tucatinib plus Trastuzumab for adult patients with RAS wild-type metastatic colon cancer with HER2-positive status as detected at a Clinical Laboratory Improvement Act (CLIA)-certified or International Organization for Standardization (ISO)-accredited laboratory.


Study ID number: NCT03043313


Approval was based on MOUNTAINEER Study, a Phase II, Open-Label Study that included 117 patients with RAS wild-type, HER2-positive unresectable metastatic colon cancer confirmed using an FDA-approved or Conformité Européene (CE)-marked HER2 ICH test. These patients had received and failed standard therapy. The study was originally designed to include one cohort of patients who would receive Tucatinib at a twice-daily dose of 300 mg in combination with Trastuzumab at a dose of 8 mg/kg on day 1 of the first 21-day cycle, followed by 6 mg/kg in ensuing cycles until any adverse effects were observed. Later, 70 additional patients were assigned in a 4:3 ratio to receive either dual therapy or single-agent Tucatinib therapy.


Efficacy was established based on the overall response rate among both cohorts. As secondary endpoints, the 12-week overall response rate, duration of response, progression-free survival, overall survival, safety, and tolerability were observed.


The study showed that patients treated with dual therapy (n = 84) achieved an overall response rate (ORR) of 38% (95% CI, 28%-49%). Of those who responded to the regimen, 3.6% (n = 3) achieved a complete response and 35% (n = 29) had a partial response. The median duration of response (DOR) was 12.4 months (95% CI, 8.5-20.5). The median progression-free survival was 8.2 months (95% CI, 4.2-10.3), and the median overall survival (OS) was 24.1 months (95% CI, 20.3-36.7).


Among 84 patients who received Tucatinib and Trastuzumab combination therapy, three patients showed complete response while 29 showed partial response. The duration of therapy was about 12 months, and half of the patients on the therapy were still alive 24 months after initiation of the treatment.


The most common side effects experienced by at least 20% of patients administered Tucatinib plus Trastuzumab were diarrhea, fatigue, rash, nausea, abdominal pain, infusion-related reactions, and pyrexia. However, 22% of the patients were noted to have severe adverse effects that included intestinal obstruction (7%), urinary tract infection (3.5%), pneumonia (2.3%), abdominal pain (2.3%), and rectal perforation (2.3%).


The recommended dose of Tucatinib and Trastuzumab combination therapy in RAS Wild-type, HER2+ Metastatic Colorectal Cancer which has failed standard therapy, is the twice-daily dose of 300 mg of Tucatinib in combination with Trastuzumab at a dose of 8 mg/kg on day 1 of the first 21-day cycle, followed by 6 mg/kg until unacceptable toxicity or serious adverse effect.


“This adds to the armamentarium of HER-2 targeted agents in advanced CRC. Previously trastuzumab + pertuzumab (Mypathway), trastuzumab + lapatinib (HERACLES), and more recently trastuzumab deruxtecan (DESTINY CRC-01) have established utility and are endorsed by NCCN guidelines for use in refractory settings with HER-2 overexpression and wildtype RAS-RAF status. However, it is worth noting that none of these regimens have received FDA approval. In that context, the approval of trastuzumab + tucatinib is an important landmark for this cohort of patients with colorectal cancer” said Babar Bashir, MD, assistant professor of medical oncology and pharmacology, Sidney Kimmel College Medical College at Jefferson, PA.



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