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The addition of tucatinib (Tukysa) to maintenance therapy with trastuzumab (Herceptin) and pertuzumab (Perjeta) displayed a statistically significant improvement in progression-free survival (PFS) vs placebo as a first-line treatment for patients with HER2-positive metastatic breast cancer, according to a news release from the drug’s developer, Pfizer Inc.¹

The investigational agent was assessed in combination with trastuzumab and pertuzumab across the aforementioned patient population in the phase 3 HER2CLIMB-05 trial (NCT05132582). The trial met its primary end point of PFS per investigator assessment, and the tucatinib-based regimen was well-tolerated, with the safety profile consistent with the established profiles of each individual agent.

“[HER2-positive] breast cancer is a particularly challenging subtype, with many patients experiencing disease progression despite effective treatments in the first-line setting,” Erika Hamilton, MD, principal investigator of HER2CLIMB-05 and director of Breast Cancer Research at the Sarah Cannon Research Institute (SCRI), stated in the news release on the study findings.¹ “The [phase 3] HER2CLIMB-05 results demonstrate that the addition of [tucatinib] 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.”

The double-blind phase 3 trial enrolled patients with HER2-positive metastatic breast cancer following taxane-based induction therapy. Those who completed induction therapy with trastuzumab, pertuzumab, and a taxane with no evidence of disease progression were randomly assigned 1:1 to receive tucatinib (n = 326) or placebo (n = 328) plus trastuzumab and pertuzumab as maintenance.

Patients in both arms received trastuzumab at 6 mg/kg intravenously or 600 mg subcutaneously plus pertuzumab at 420 mg intravenously every 21 days as maintenance therapy.² Those in the investigational arm received tucatinib at 300 mg orally twice daily every 21 days, with those in the control arm receiving matching placebo.

The primary end point of the trial was investigator-assessed PFS. Secondary end points included overall survival, PFS per blinded independent central review, central nervous system PFS, health-related quality of life, and adverse effects (AEs).²

Warnings and precautions of treatment with tucatinib include severe diarrhea, dehydration, hypotension, acute kidney injury, and death. Additionally, patients may be at risk of hepatotoxicity, including alanine aminotransferase increases, aspartate aminotransferase increases, and bilirubin increases. Furthermore, tucatinib may cause embryo-fetal toxicities among patients who are pregnant or of reproductive potential.

In the phase 3 HER2CLIMB trial (NCT02614794), serious AEs were reported in 26% of the tucatinib arm, the most common of which included diarrhea (4%), vomiting (2.5%), nausea (2%), abdominal pain (2%), and seizure (2%). The most common fatal AEs included sudden death, sepsis, dehydration, and cardiogenic shock.

Dose reductions related to AEs occurred in 21% of patients, the most common of which were hepatotoxicity (8%) and diarrhea (6%).

Currently, tucatinib is approved for the treatment of patients with HER2-positive metastatic breast cancer in the third-line setting in the US as well as more than 50 countries. Additionally, it is approved by the FDA when used in combination with trastuzumab and capecitabine in adult patients with advanced unresectable or metastatic HER2-positive disease who received at least 1 prior HER2-based treatment in the metastatic setting in April 2020.³

“The positive results from HER2CLIMB-05, combined with [tucatinib’s] known safety profile in later-line settings, underscore its potential to play a meaningful role in front-line maintenance, where it may benefit a broader population of patients with [HER2-positive] disease,” Johanna Bendell, MD, chief development officer of Oncology at Pfizer, expressed in the news release.¹ “We are grateful to the patients and investigators who contributed to this important research.”

References

1. TUKYSA combination significantly improves progression-free survival as first-line maintenance in HER2+ metastatic breast cancer in HER2CLIMB-05 trial. News release. Pfizer Inc. October 14, 2025. Accessed October 14, 2025. https://tinyurl.com/3xc5xb5d
2. 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 14, 2025. https://tinyurl.com/3w2d454n
3. FDA approves tucatinib for patients with HER2-positive metastatic breast cancer. News release. FDA. April 17, 2020. Accessed October 14, 2025. https://tinyurl.com/ppzb6mnx