FDA Approves Tucatinib Plus Trastuzumab/Pertuzumab as First-Line Maintenance in Advanced HER2+ Breast Cancer

The FDA has approved tucatinib (Tukysa) in combination with trastuzumab (Herceptin) and pertuzumab (Perjeta) for the maintenance treatment of adult patients with unresectable locally advanced or metastatic HER2-positive breast cancer following induction treatment.^1,2

The regulatory decision was supported by data from the phase 3 HER2CLIMB-05 trial (NCT05132582), which showed that treatment with tucatinib plus trastuzumab and pertuzumab led to a 35.9% reduction in the risk of disease progression or death compared with placebo plus trastuzumab and pertuzumab following induction treatment (HR, 0.64; 95% CI, 0.51-0.80; 2-sided P < .0001).² The median investigator-assessed progression-free survival (PFS) was 24.9 months (95% CI, 21.3-not reached) in the tucatinib arm vs 16.3 months (95% CI, 12.6-18.7) in the placebo arm.

Overall survival data were immature at the time of the PFS analysis.¹

“Since its first approval in 2020, [tucatinib] has become an important treatment for patients with second-line HER2-positive metastatic breast cancer. Today's FDA approval marks the next chapter for [tucatinib], bringing it into the frontline maintenance setting and offering patients a chemotherapy-free option that can help delay disease progression after initial treatment,” Aamir Malik, executive vice president and chief U.S. commercial officer at Pfizer, stated in a news release.² “This approval reflects Pfizer’s commitment to advancing therapies across the breast cancer treatment journey and delivering meaningful new options for people living with metastatic breast cancer.”

In April 2020, the FDA approved tucatinib in combination with trastuzumab and capecitabine for the treatment of patients with unresectable locally advanced or metastatic HER2-positive breast cancer, including patients with brain metastases, following at least 1 prior anti-HER2-based regimen in the metastatic setting.³

How was the HER2CLIMB-05 trial conducted?

The randomized, double-blind, placebo-controlled phase 3 study enrolled patients at least 18 years of age with centrally confirmed, unresectable locally advanced or metastatic HER2-positive breast cancer.⁴ For patients with recurrent disease, a treatment-free interval of at least 6 months from any trastuzumab and pertuzumab received in the early breast cancer setting to diagnosis of advanced HER2-positive disease was required. Patients could not have evidence of disease progression following 4 to 8 cycles of trastuzumab, pertuzumab, and a taxane, although patients who received less than 6 cycles of a taxane were eligible if they discontinued the chemotherapy due to toxicity.

Patients were randomly assigned 1:1 to receive tucatinib at 300 mg or placebo twice daily, both in combination with trastuzumab at 6 mg/kg (600 mg subcutaneously) and pertuzumab at 420 mg intravenously once every 3 weeks. Notably, trastuzumab (600 mg) and pertuzumab (600 mg) could both be given subcutaneously when combined with hyaluronidase at 20,000 units.

PFS per RECIST 1.1 criteria and investigator assessment served as the primary end point. Secondary end points included OS, blinded independent central review–assessed PFS, and central nervous system PFS.

What safety data have been reported for the tucatinib-based combination?

The prescribing information for tucatinib includes a boxed warning for hepatotoxicity, along with warnings and precautions for diarrhea, embryo-fetal toxicity, and increased serum creatinine without affecting renal function.¹

Data reported from HER2CLIMB-05 showed that grade 3 or higher treatment-emergent adverse effects (TEAEs) were reported in 42.3% of patients in the tucatinib arm (n = 326) vs 24.4% of patients in the control arm (n = 324).⁴ The most common grade 3 or higher TEAEs included elevated alanine aminotransferase levels (13.5% vs 0.6% for the tucatinib arm vs placebo arm, respectively), elevated aspartate aminotransferase levels (7.1% vs 0.6%), and diarrhea (6.1% vs 4.0%). TEAEs leading to any study treatment discontinuation were reported in 13.8% of patients in the tucatinib arm compared with 4.6% of patients in the control arm.

References

1. FDA approves tucatinib with trastuzumab and pertuzumab for the maintenance treatment of HER2-positive breast cancer. FDA. October 7, 2026. Accessed October 7, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tucatinib-trastuzumab-and-pertuzumab-maintenance-treatment-her2-positive-breast-cancer
2. Pfizer’s Tukysa regimen receives FDA approval as front-line maintenance treatment for HER2+ metastatic breast cancer. News release. Pfizer. October 7, 2026. Accessed October 7, 2026. https://www.pfizer.com/news/press-release/press-release-detail/pfizers-tukysa-regimen-receives-fda-approval-front-line
3. FDA approves tucatinib for HER2+ breast cancer. OncLive. April 17, 2020. Accessed October 7, 2026. https://www.onclive.com/view/fda-approves-tucatinib-for-her2-breast-cancer
4. Dieras V, Curigliano G, Martin M, et al. HER2CLIMB-05: a phase III study of tucatinib versus placebo in combination with trastuzumab and pertuzumab as first-line maintenance therapy for HER2+ metastatic breast cancer. J Clin Oncol. 2026;44(17):1597-1607. doi:10.1200/JCO-25-02600