Tukysa Combo Boosts Frontline Maintenance in Advanced HER2+ Breast Cancer

Tukysa (tucatinib) combined with Herceptin (trastuzumab) and Perjeta (pertuzumab) extended progression-free survival as a frontline maintenance approach compared with placebo plus Herceptin and Perjeta in patients with HER2-positive metastatic breast cancer whose disease had not progressed after docetaxel with Herceptin and Perjeta, according to findings presented at the 2025 San Antonio Breast Cancer Symposium (SABCS).

Topline results from the phase 3 HER2CLIMB-05 trial were first announced in October 2025, indicating that the study met its primary end point. A preliminary look at the data, with median follow-up of approximately 23 months, showed that the median PFS was 24.9 months with tucatinib/HP (326 patients) versus 16.3 months with placebo/HP (328 patients).

The PFS benefit with tucatinib extended across all prespecified patient subgroups, including diagnosis (de novo or recurrent), hormone receptor (HR) status (negative or positive), brain metastases at baseline (yes or no), prior anti-HER2 therapy (yes or no), best response to THP induction (complete response/partial response or stable disease/non-CR/PR), disease type (visceral or nonvisceral), ECOG performance status (0 or 1), region (North America, Europe, Asia Pacific, or rest of the world), age (under 65 or aged 65 years and older), and race (White, Asian, or other).

“HER2CLIMB-05 has demonstrated that the addition of tucatinib to HP represents an enhanced frontline maintenance therapy option for patients with HER2-positive metastatic breast cancer, providing an opportunity to prolong time to disease progression and time off chemotherapy,” Dr. Erika Hamilton, lead study author and director of breast cancer research at Sarah Cannon Research Institute in Nashville, Tennessee, said during the meeting.

What were the key elements of the HER2CLIMB-05 trial?

First-line treatment for patients with HER2-positive metastatic breast cancer typically includes taxane-based chemotherapy with HP, followed by HP maintenance, but disease progression often prevents patients from reaching second-line therapy. Prior data from the pivotal HER2CLIMB trial showed that adding tucatinib to capecitabine and trastuzumab improved PFS and overall survival (OS) even in heavily pretreated populations, including patients with brain metastases. HER2CLIMB-05 evaluated whether incorporating tucatinib into first-line maintenance with HP could further improve outcomes by intensifying both extracellular and intracellular HER2 targeting.

HER2CLIMB-05 is a randomized, double-blind, placebo-controlled, international trial that enrolled patients with centrally confirmed HER2-positive metastatic breast cancer with no evidence of progression after 4 to 8 cycles of THP, no or asymptomatic brain metastases confirmed by contrast-enhanced MRI at screening, and an ECOG performance status of 0 or 1.

Patients were randomly assigned 1:1 to 300 mg of oral tucatinib twice daily (326 patients) or matched placebo (328 patients), both in combination with HP every 21 days with or without endocrine therapy. Trastuzumab was administered intravenously at 6 mg/kg or 600 mg subcutaneously and pertuzumab at 420 mg IV. The fixed-dose SC combination of 600 mg trastuzumab, 600 mg pertuzumab, and 20,000 units of hyaluronidase-zzxf (Phesgo) was also allowed.

Therapy continued until unacceptable toxicity, disease progression, consent withdrawal, or study closure. Crossover was prohibited.

The primary end point was investigator-assessed PFS per RECIST 1.1 criteria. Secondary end points included OS, PFS per blinded independent central review, central nervous system PFS, safety, health-related quality of life, and pharmacokinetics. Patients were stratified by diagnosis, hormone receptor status, and presence or history of brain metastases.

How did the regimen perform according to hormone receptor status and was an OS benefit seen?

With respect to PFS by hormone receptor status, greater benefit was seen in the hormone receptor–negative population, although benefit was also present in the hormone receptor–positive population. In the hormone receptor–negative cohort, median PFS was 24.9 months with tucatinib versus 12.6 months with placebo. In the hormone receptor–positive cohort, median PFS was 25.0 months with tucatinib versus 18.1 months with placebo. Assessment of OS showed a numerical trend for improvement with tucatinib.

What was the safety profile of the regimen?

“The tucatinib and HP combination showed a manageable safety profile, with diarrhea, nausea, and elevated liver enzymes, mostly low grade, being the most common side effects,” Hamilton reported. Treatment-emergent side effects occurred in 99.1% of patients receiving tucatinib and 96.6% of those receiving placebo. Grade 3 or greater side effects, serious side effects, and side effects leading to death occurred in 43.2%, 16.9%, and 0.3% of tucatinib patients, respectively, and in 24.4%, 8.0%, and 0.3% of placebo patients.

Side effects led to treatment discontinuation in 13.8% of tucatinib patients versus 4.6% of placebo patients. The most common side effects prompting discontinuation were hepatic events (7.7% tucatinib, 0% placebo) and diarrhea (1.5% tucatinib, 0.9% placebo). Dose modifications due to side effects were required in 55.8% of tucatinib patients and 34.6% of placebo patients.

References

1. “HER2CLIMB-05: A randomized, double-blind, phase 3 study of tucatinib versus placebo in combination with trastuzumab and pertuzumab as maintenance therapy for HER2+ metastatic breast cancer,” Dr. Erika Hamilton. Presented at: 2025 San Antonio Breast Cancer Symposium; December 9-12, 2025; San Antonio, TX. Abstract GS1-01.
2. “Tukysa combination significantly improves progression-free survival as first-line maintenance in HER2+ metastatic breast cancer in HER2CLIMB-05 trial,” Pfizer. News release; Oct. 14, 2025. Accessed December 10, 2025.

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