The addition of the selective HER2 inhibitor tucatinib to trastuzumab and pertuzumab as first-line maintenance therapy significantly prolonged investigator-assessed progression-free survival in patients with HER2-positive metastatic breast cancer, according to findings presented at the 2025 San Antonio Breast Cancer Symposium (SABCS) and simultaneously published in the Journal of Clinical Oncology.^1,2

Results from the randomized, double-blind, phase III HER2CLIMB-05 study establish this triplet regimen as an enhanced maintenance option following induction chemotherapy, offering substantial clinical benefit, authors of the study emphasized.

The study met its primary endpoint of progression-free survival across all prespecified patient subgroups, regardless of baseline brain metastases or hormone receptor status. This efficacy was achieved with a manageable safety profile consistent with known toxicities of the individual agents.

“The HER2CLIMB-05 trial demonstrates that the addition of tucatinib to trastuzumab and pertuzumab as first-line maintenance therapy provides a statistically significant and clinically meaningful progression-free survival benefit in patients with HER2-positive metastatic breast cancer,” said Erika P. Hamilton, MD, FASCO, Chief Development Officer and Director of Breast Cancer Research at Sarah Cannon Research Institute, in Nashville. “This enhanced first-line maintenance therapy offers an opportunity to prolong time to disease progression and potentially provide a longer time off cytotoxic chemotherapy.”

Erika P. Hamilton, MD, FASCO

As Dr. Hamilton explained, the current standard of care for first-line treatment of HER2-positive metastatic breast cancer typically involves induction chemotherapy (often a taxane) combined with dual HER2-targeted antibodies, trastuzumab and pertuzumab. This is subsequently followed by antibody maintenance therapy with trastuzumab and pertuzumab with or without endocrine therapy.

Although this regimen has been associated with sustained disease control, said Dr. Hamilton, most patients eventually experience disease progression, and a significant proportion may not go on to receive second-line therapies.

The original HER2CLIMB registration trial previously demonstrated that adding tucatinib to capecitabine and trastuzumab significantly prolonged both progression-free survival and overall survival in heavily pretreated patients with HER2-positive metastatic breast cancer, including those with brain metastases. This established the rationale for investigating tucatinib earlier in the treatment paradigm to further enhance initial maintenance therapy.

HER2CLIMB-05 Study Design

The HER2CLIMB-05 study was a randomized, double-blind, phase III clinical trial that enrolled patients with centrally confirmed HER2-positive metastatic breast cancer who had no evidence of disease progression after completing four to eight cycles of first-line taxane-based induction chemotherapy combined with trastuzumab and pertuzumab.

Eligible patients had an ECOG performance status of 0 or 1 and allowed for no or asymptomatic brain metastases. Contrast-enhanced brain MRI was performed at screening and regular intervals throughout the study. Patients were randomly assigned 1:1 to receive either tucatinib (300 mg orally twice-daily) or placebo, in combination with trastuzumab (6 mg/kg intravenously or 600 mg subcutaneously) plus pertuzumab (420 mg/kg intravenously) or a subcutaneous fixed-dose combination of trastuzumab, pertuzumab, and hyaluronidase, all administered once every 21 days. Endocrine therapy was permitted for patients with hormone receptor-positive tumors.

The primary endpoint was investigator-assessed progression-free survival per RECIST 1.1. Key secondary endpoints included overall survival, progression-free survival by blinded independent central review, investigator-assessed central nervous system-progression-free survival, and safety.

Between March 2022 and July 2024, 654 patients were randomized (326 to the tucatinib arm; 328 to the placebo arm). The patient characteristics were well balanced between the arms. All enrolled patients were female, with a median age of 54 years (range, 24 to 83 years).

At the time of data cutoff (September 5, 2025), with a median follow-up of 23 months for progression-free survival, 54% of patients in the tucatinib arm and 40.5% in the placebo arm remained on study treatment.

Significant and Clinically Meaningful Improvement in Progression-Free Survival

As Dr. Hamilton reported, the primary endpoint of investigator-assessed progression-free survival was statistically significantly lengthened with the addition of tucatinib. Median progression-free survival was 24.9 months with tucatinib plus trastuzumab and pertuzumab, compared to 16.3 months with trastuzumab and pertuzumab alone, representing an absolute magnitude of benefit of 8.6 months (hazard ratio [HR] = 0.641; two-sided P < .0001).

The progression-free survival benefit was consistent across all prespecified patient subgroups, whether considering de novo or recurrent disease, hormone receptor-positive or negative status, presence or absence of brain metastases at baseline, or age (less than 65 vs 65 or older).

Hormone receptor-negative disease: The benefit for patients with hormone receptor–negative disease was particularly pronounced, increasing from 12.6 months to 24.9 months (absolute magnitude of benefit of 12.3 months; HR = 0.554; P = .002).

Hormone receptor-positive disease: In patients with hormone receptor-positive breast cancer, progression-free survival improved from 18.1 months to 25.0 months (absolute magnitude of benefit of 6.9 months; HR = 0.725; P = .039).

Progression-free survival by blinded independent central review was consistent with the primary endpoint, showing a statistically longer progression-free survival and a slightly greater magnitude of benefit (12.9 months improvement) with the addition of tucatinib in the hormone receptor-negative group.

At the time of follow-up, overall survival data were immature, with 20% of events (51 deaths) having occurred on the study. Despite this, said Dr. Hamilton, there was a positive trend toward improved overall survival with tucatinib (HR = 0.539; two-sided P = .032).

Regarding central nervous system (CNS) progression-free survival, the median was not reached in either arm in the intention-to-treat population. However, an exploratory analysis in patients who entered the study with baseline brain metastases (approximately 81 patients) showed an almost doubling of CNS progression-free survival from 4.3 months to 8.5 months.

Manageable Safety Profile

Finally, Dr. Hamilton reported that the safety profile of tucatinib in combination with trastuzumab and pertuzumab was manageable and consistent with expected toxicities for this regimen, with no new safety signals identified.

Grade 3 or higher treatment-emergent adverse events occurred in 42% of patients receiving tucatinib. Discontinuation of tucatinib due to treatment-emergent adverse events occurred in 13.5% of patients, with the majority (7.7%) due to hepatic events. Diarrhea, while common overall in both arms (72.7% any grade with tucatinib vs 51% with trastuzumab and pertuzumab alone), led to discontinuation infrequently (1.5% with tucatinib vs 0.9% with trastuzumab and pertuzumab alone).

Elevated liver enzymes (ALT and AST increase) were the most common grade 3 or higher treatment-emergent adverse events with tucatinib (13.5% and 7.1%, respectively), but these were generally asymptomatic, transient, and reversible with dose modifications, said Dr. Hamilton. 

Disclosure: Dr. Hamilton has served as a consultant or advisor for Pfizer, Genentech/Roche, Lilly, Daiichi Sankyo, Mersana, AstraZeneca, Novartis, Stemline Therapeutics, Accutar Biotechnology, Entos, Gilead Sciences, Jazz Pharmaceuticals, Medical Pharma Services, Zentalis, Jefferies, Tempus, Arvinas, Circle Pharma, Janssen, Johnson and Johnson, BeiGene, Halda Therapeutics, Incyclix Bio, IQvia, Pyxis, Samsung Bioepis, and Shorla Pharma; has received research funding from AstraZeneca, Hutchison MediPharma, OncoMed, MedImmune, Stem CentRx, Genentech/Roche, Curis, Verastem, Zymeworks, Syndax, Lycera, Rgenix, Novartis, Mersana, Millennium, TapImmune Inc, Lilly, Pfizer, Tesaro, Boehringer Ingelheim, H3 Biomedicine, Radius Health, Acerta Pharma, MacroGenics, AbbVie, Immunomedics, Fujifilm, eFFECTOR Therapeutics, Merus, Nucana, Regeneron, Leap Therapeutics, Taiho Pharmaceutical, EMD Serono, Daiichi Sankyo, ArQule, Syros Pharmaceuticals, Clovis Oncology, CytomX Therapeutics, InventisBio, Deciphera, Sermonix Pharmaceuticals, Sutro Biopharma, Zenith Epigenetics, Arvinas, Harpoon, Black Diamond Therapeutics, Orinove, Molecular Templates, Seagen, Compugen, G1 Therapeutics, Karyopharm Therapeutics, Dana Farber Cancer Hospital, Shattuck Labs, PharmaMar, Olema Pharmaceuticals, Immunogen, Plexxikon, Amgen, Akeso Biopharma, ADC Therapeutics, AtlasMedx, Aravive, Ellipses Pharma, Incyte, MabSpace Biosciences, ORIC Pharmaceuticals, Pieris Pharmaceuticals, Pionyr, Repertoire Immune Medicines, Treadwell Therapeutics, Jacobio, Accutar Biotech, Artios, Bliss Biopharmaceutical, Cascadian Therapeutics, Dantari, Duality Biologics, Elucida Oncology, Infinity Pharmaceuticals, Relay Therapeutics, Tolmar, Torque, BeiGene, Context Therapeutics, K-Group Beta, Kind Pharmaceuticals, Loxo, Oncothyreon, Orum Therapeutics, Prelude Therapeutics, ProfoundBio, Cullinan Oncology, Bristol Myers Squibb, Eisai, Fochon Pharmaceuticals, Gilead Sciences, Inspirna, Myriad Genetics, Silverback Therapeutics, and Stemline Therapeutics.

References

1. Hamilton E, et al: A randomized, double-blind, phase III study of tucatinib vs placebo in combination with trastuzumab and pertuzumab as maintenance therapy for HER2+ MBC. SABCS 2025. Abstract GS1-01. Presented December 10, 2025.

2. Dieras V, et al: A phase III study of tucatinib vs 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. 

EXPERT POINT OF VIEW

Invited discussant Ciara O’Sullivan, MB, BCh, BAO, Associate Professor of Oncology at the Mayo Clinic in Rochester, Minnesota, underscored the rapidly evolving landscape of HER2-positive metastatic breast cancer while emphasizing the critical need for personalized treatment strategies.

“Despite significant advancements in HER2-positive metastatic breast cancer treatment, including dual HER2 blockade, patients still face substantial morbidity and mortality, particularly from brain metastases,” said Dr. O’Sullivan. “The advent of highly potent agents like fam-trastuzumab deruxtecan-nxki (T-DXd) from DESTINY-Breast09 are the ‘new standard,’ improving progression-free survival by 14 months compared to previous standards.”

Ciara O’Sullivan, MB, BCh, BAO

According to Dr. O’Sullivan, this context sets the stage for maintenance trials like HER2CLIMB-05 and PATINA, which aimed to further optimize outcomes after induction therapy.

“The HER2CLIMB-05 trial demonstrated a statistically significant progression-free survival advantage of 8.6 months with tucatinib added to trastuzumab and pertuzumab maintenance, achieving a 36% reduction in the risk of disease progression or death,” said Dr. O’Sullivan. “This benefit was observed across all patient subtypes, with a particularly notable 12.3-month improvement in progression-free survival for patients with hormone receptor–negative disease.”

“A numeric improvement in central nervous system progression-free survival was also observed in patients with baseline brain metastases,” she added.

With respect to positioning HER2CLIMB-05’s findings alongside other first-line options, Dr. O’Sullivan acknowledged that T-DXd plus pertuzumab upfront is “clearly a highly effective regimen,” offering large progression-free survival improvements, potentially more complete responses, and possibly preventing or treating brain metastases. However, she also highlighted the risk of interstitial lung disease and chemotherapy-like side effects, which may not be suitable for all patients.

“For those who do well with initial taxane, trastuzumab, and pertuzumab induction, subsequent maintenance with trastuzumab and pertuzumab, with or without targeted agents like tucatinib, remains a ‘reasonable’ approach, being mindful of additional toxicities and costs,” said Dr. O’Sullivan, who stressed the difficulty of accurately comparing across first-line trials.

“There are two new options (tucatinib for both hormone receptor-negative and hormone receptor-positive disease, and palbociclib for hormone receptor-positive disease) to add to trastuzumab and pertuzumab maintenance,” Dr. O’Sullivan continued. “For hormone receptor-positive disease, it’s critically important to add endocrine therapy to trastuzumab and pertuzumab maintenance.”

Ultimately, said Dr. O’Sullivan, treatment decisions are becoming more nuanced, requiring careful consideration of clinical-pathologic factors, patient comorbidities, and preferences. She advocated for personalizing upfront regimens, defining treatment duration, and determining the need for escalation or de-escalation, even safe discontinuation for exceptional responders.

“As always, our priorities must be patient longevity and quality of life as well as minimizing toxicity and personalizing treatments,” Dr. O’Sullivan concluded.

Disclosure: Dr. O’Sullivan reported personal financial relationships with OncLive, Medscape, AstraZeneca, Pfizer, and Daiichi Sankyo.

Reference

1. O’Sullivan CC. Evolving landscape of HER2+ breast cancer. 2025 San Antonio Breast Cancer Symposium. Abstract GS1-01, Discussion. Presented December 10, 2025.