Tucatinib Shows Improvement in PFS in Patients with HER2+ Metastatic Breast Cancer

Data from a phase 3 trial (NCT05132582)¹ revealed positive topline results of first-line combination therapy with the tyrosine kinase inhibitor (TKI) tucatinib (Tukysa) in patients with human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (mBC).

The trial, HER2CLIMB-05, is evaluating tucatinib vs placebo, both in combination with first-line standard-of-care maintenance therapy (trastuzumab [Herceptin] and pertuzumab [Perjeta]) following chemotherapy-based induction. The primary endpoint of the trial was met, demonstrating a statistically significant improvement in progression-free survival (PFS) among patients.² 

Results from the HER2CLIMB-05 trial will be presented at a future medical congress.

The phase 3 trial is a randomized, double-blind, placebo-controlled trial with the purpose of evaluating the efficacy and safety of tucatinib compared with placebo in combination with trastuzumab and pertuzumab for patients with HER2+ MBC. The trial had a total enrollment of 654 patients and was conducted across 295 locations internationally.²

Patients who completed induction therapy of trastuzumab, pertuzumab, and a taxane with no evidence of progression were randomized to receive tucatinib (n = 326), or placebo in combination with trastuzumab and pertuzumab (n = 328).² 

What Were the Adverse Events?

Serious adverse events (AEs) occurred in 26% of patients who received tucatinib. AEs experienced included diarrhea (4%), vomiting (2.5%), nausea (2%), abdominal pain (2%), and seizure (2%). Fatal AEs occurred in 2% of patients who received tucatinib, including sudden death, sepsis, dehydration, and cardiogenic shock. AEs that lead to dose reduction in the tucatinib group occurred in 21% of patients. The most common AEs experienced by patients included diarrhea, palmar-plantar erythrodysesthesia, nausea, hepatotoxicity, vomiting, stomatitis, decreased appetite, anemia, and rash.² 

Grade ≥3 laboratory abnormalities were reported in ≥5% of patients who received tucatinib. Abnormalities included decreased phosphate, increased alanine aminotransferase (ALT), decreased potassium, and increased aspartate aminotransferase (AST).²

What Were Patient Criteria?

Eligibility criteria among patients included having centrally confirmed HER2+ breast carcinoma; having unresectable locally advanced or metastatic disease; having received 4 to 8 cycles of prestudy induction therapy including trastuzumab, pertuzumab, and taxane as first-line treatment prior to enrollment; having known hormone receptor status; and having an ECOG performance status of 0 or 1.¹ 

Exclusion criteria among patients included receiving prior treatment with any TKI targeting HER2 and/or epidermal growth factor receptor (EGFR) including pyrotinib (Irene), lapatinib (Tykerb), tucatinib, neratinib (Nerlynx), and afatinib (Gilotrif), and being unable to undergo contrast-enhanced MRIs of the brain.¹ 

What Was the Treatment Plan?

Treatment for patients receiving tucatinib included 300mg orally of the drug, twice daily, 6mg/kg of trastuzumab intravenously every 21 days, 420mgof pertuzumab intravenously every 21 days, and a combination of600mg each of trastuzumab and pertuzumab, with 20,000 units hyaluronidase given by subcutaneous injection every 21 days.¹

Patients in the placebo group received 6mg/kg of trastuzumab intravenously every 21 days, 420mg of pertuzumab intravenously every 21 days, a combination of 600mg each of trastuzumab and pertuzumab, with 20,000 units hyaluronidase given by subcutaneous injection every 21 days, and placebo given orally twice daily.¹

“HER2+ breast cancer is a particularly challenging subtype, with many patients experiencing disease progression despite effective treatments in the first-line setting,” concluded Erika Hamilton, MD, the principal investigator of HER2CLIMB-05 and director of breast cancer research at the Sarah Cannon Research Institute (SCRI), in a press release.²“The HER2CLIMB-05 results demonstrate that the addition of TUKYSA to first-line maintenance therapy may further lower the risk of disease progression or death, with a treatment that has a well-established safety profile.”

REFERENCES:

1. A Study of Tucatinib or Placebo With Trastuzumab and Pertuzumab for Metastatic HER2+ Breast Cancer (HER2CLIMB-05). ClinicalTrials.gov. Updated October 14, 2025. Accessed October 15, 2025. https://clinicaltrials.gov/study/NCT05132582 

2. TUKYSA Combination Significantly Improves Progression-Free Survival as First-Line Maintenance in HER2+ Metastatic Breast Cancer in HER2CLIMB-05 Trial. News Release. Pfizer. October 14, 2025. Accessed October 15, 2025. https://tinyurl.com/29kd9erp