FDA Approves Tucatinib Maintenance Regimen in HER2+ Metastatic Breast Cancer

The FDA has approved tucatinib (Tukysa), an oral, selective HER2 tyrosine kinase inhibitor, in combination with trastuzumab (Herceptin) and pertuzumab (Perjeta) for the maintenance treatment of adults with unresectable locally advanced or metastatic HER2-positive breast cancer following induction treatment.¹

The approval is supported by the phase 3 HER2CLIMB-05 trial (NCT05132582), in which the addition of tucatinib extended median progression-free survival (PFS) by 8.6 months vs placebo (HR, 0.64; 95% CI, 0.51-0.80; P < .0001).

Study Design

HER2CLIMB-05 was a randomized, double-blind, placebo-controlled trial that enrolled 654 adult patients with HER2-positive, unresectable locally advanced or metastatic breast cancer, with or without brain metastases.¹ Eligible patients had no evidence of disease progression by investigator assessment after induction treatment with 4 to 8 cycles of trastuzumab, pertuzumab, and a taxane. Enrollment ran from March 2022 to July 2024, with 326 patients randomly assigned to tucatinib and 328 to placebo.²

Patients received tucatinib 300 mg or placebo orally twice daily alongside intravenous trastuzumab and pertuzumab, or alongside the subcutaneous fixed-dose combination of trastuzumab, pertuzumab, and hyaluronidase.¹ Patients with hormone receptor–positive disease could continue endocrine therapy, and treatment continued until disease progression or unacceptable toxicity.¹

The primary end point was investigator-assessed PFS per RECIST v1.1, with overall survival (OS) as an additional efficacy end point.

Efficacy Results

Median 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.¹ OS data were not mature at the time of the PFS analysis.¹

Results were presented at the 2025 San Antonio Breast Cancer Symposium and published in the Journal of Clinical Oncology.² The investigators reported that the PFS benefit was observed regardless of the presence or absence of brain metastases or hormone receptor status.

“Patients with hormone receptor-positive disease were permitted, though not required, to receive endocrine therapy, based on shared decision-making between the patient and physician at the local institutional level,” explained Erika Hamilton, MD, director of Breast Cancer and Gynecologic Cancer Research at Sarah Cannon Research Institute, in an interview with Targeted Oncology^TM. “Only about 45% of these patients received endocrine therapy, while the majority, 55%, did not. Patients who did not receive endocrine therapy had PFS that was about 15 months shorter than those who did, underscoring the importance of endocrine therapy in this population. Regardless of endocrine therapy use, tucatinib lengthened PFS compared with placebo.”

Safety Profile

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

In the published analysis, the most common treatment-emergent adverse events (TEAEs) in the tucatinib arm were diarrhea (72.7%; grade 3 or higher, 6.1%), nausea (33.1%; 0.9%), elevated alanine aminotransferase (28.2%; 13.5%), and elevated aspartate aminotransferase (25.8%; 7.1%).² A total of 13.5% of patients in the tucatinib arm discontinued tucatinib because of TEAEs. The authors concluded that no new safety signals were identified.

Dosing

The recommended tucatinib dose is 300 mg orally twice daily in combination with trastuzumab and pertuzumab until disease progression or unacceptable toxicity.¹ The FDA directs clinicians to the prescribing information for trastuzumab and pertuzumab for their dosing and administration.¹ The agency used the Assessment Aid, a voluntary submission from the applicant intended to facilitate its review.

Regulatory History and Treatment Landscape

Tucatinib first received FDA approval on April 17, 2020, in combination with trastuzumab and capecitabine for adults with advanced unresectable or metastatic HER2-positive breast cancer, including those with brain metastases, who had received 1 or more prior anti-HER2–based regimens in the metastatic setting.³ That approval was based on the HER2CLIMB trial (NCT02614794), which enrolled 612 patients. On January 19, 2023, the agency granted accelerated approval to tucatinib with trastuzumab for RAS wild-type, HER2-positive unresectable or metastatic colorectal cancer that had progressed after fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.⁴

The latest approval arrives after the FDA approved fam-trastuzumab deruxtecan-nxki (Enhertu) with pertuzumab on December 15, 2025, as first-line treatment for unresectable or metastatic HER2-positive breast cancer, based on the open-label DESTINY-Breast09 trial (NCT04784715), which enrolled 1157 patients.⁵

Watch Dr Hamilton discuss updated data from the HER2CLIMB-05 trial presented at the 2026 ASCO Annual Meeting.

REFERENCES

1. FDA approves tucatinib with trastuzumab and pertuzumab for the maintenance treatment of HER2-positive breast cancer. News release. FDA. October 7, 2026. Accessed October 7, 2026. https://tinyurl.com/3h8r3epe

2. Hamilton E, Curigliano G, Dieras V, 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. Published online December 10, 2025. doi:10.1200/JCO-25-02600

3. FDA approves tucatinib for patients with HER2-positive metastatic breast cancer. News release. FDA. April 17, 2020. Accessed October 7, 2026. https://tinyurl.com/yxxsf4p8

4. Shah M, Wedam S, Cheng J, et al. FDA Approval Summary: Tucatinib for the Treatment of Patients with Advanced or Metastatic HER2-positive Breast Cancer. Clin Cancer Res. 2021 Mar 1;27(5):1220-1226. doi: 10.1158/1078-0432.CCR-20-2701.

5. FDA approves fam-trastuzumab deruxtecan-nxki with pertuzumab for unresectable or metastatic HER2-positive breast cancer. News release. FDA. December 15, 2025. Accessed October 7, 2026. https://tinyurl.com/4cha3jh6