Tucatinib Enhances First-Line Maintenance Outcomes in HER2-Positive Metastatic Breast Cancer

Adding tucatinib (Tukysa; Array BioPharma) to trastuzumab (Herceptin; Genentech) and pertuzumab (Perjeta; Genentech) to first line maintenance therapy in patients with HER2-positive (HER2+) metastatic breast cancer led to clinically meaningful improvements in progression-free survival (PFS) and a manageable safety profile. The data from the phase 3 HerClimb-05 trial (NCT05132582)¹ were presented at the 2025 San Antonio Breast Cancer Symposium (SABCS) in San Antonio, Texas.

Trastuzumab plus pertuzumab remains the standard first-line approach for HER2+ metastatic breast cancer, delivered as induction with chemotherapy followed by antibody maintenance. Although this regimen provides durable disease control for many, most patients ultimately experience progression.²

HER2CLIMB-05 is a randomized, double-blind phase 3 trial evaluating whether adding tucatinib—an oral HER2-selective tyrosine kinase inhibitor—to trastuzumab and pertuzumab during maintenance can extend disease control after first-line induction therapy.^2,3

“Optimizing first-line maintenance therapy by targeting both HER2 intracellularly with tucatinib as well as extracellularly with the dual HER2 antibodies may enhance outcomes,” said Erika Hamilton, MD from the Sarah Cannon Research Institute in Nashville, TN.⁴

The HerClimb-05 Patient Population

The trial enrolled 654 female patients (median age: 54 years [range, 24-83]) with centrally confirmed HER2+ metastatic breast cancer who did not progress following first-line induction therapy with 4 to 8 cycles of a taxane combined with trastuzumab and pertuzumab. Eligibility criteria required an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 and no or asymptomatic brain metastases (BMs). Most patients had an ECOG PS of 0 (64.1%) and de novo metastatic disease (69.3%).²

Approximately half of the patient population was White (45.0%), 35.2% were Asian, 2.9% were Black/African American, and 19.3% were Hispanic/Latino(a)/Spanish origin.²

The trial assessed various patient subgroups differentiated by characteristics such as age, presence or evidence of BMs, and hormone-receptor (HR) status (n = 52.6%). The subgroup data presented at SABCS reported highlighted the efficacy and toxicity outcomes in HR-positive (HR+) and HR-negative (HR–) patients.²

Trial Methods

The investigators randomly assigned patients 1:1 to receive either 300 mg tucatinib (n = 326) or placebo (n = 328) twice daily, in combination with either trastuzumab (6 mg/kg intravenous [IV] or 600 mg subcutaneous [SC]) plus pertuzumab (420 mg/kg IV) or a SC fixed-dose combination of trastuzumab, pertuzumab, and hyaluronidase administered every 21 days. Patients with HR+ tumors could receive endocrine therapy.²

The trial’s primary end point is investigator-assessed PFS with key secondary end points including overall survival (OS), PFS by blinded independent central review, investigator-assessed central nervous system (CNS)-PFS, and safety.²

Trial Results

PFS outcomes were statistically significant and favored the addition of tucatinib compared with placebo to first-line maintenance therapy (hazard ratio [HR] = 0.641 [95% confidence interval (CI), 0.514-0.799]; 2-sided P < .0001). Patients in the tucatinib arm achieved a PFS of 24.9 months compared with 16.3 months in the placebo arm, representing an absolute improvement in median PFS of 8.6 months.^2,4

The PFS outcomes were also consistent across all prespecified patient subgroups and consistent with the overall population regardless of the presence or absence of BM or HR status. Tucatinib significantly outperformed placebo in both the HR+ and HR– subgroups, showing a PFS of 25.0 months and 24.9 months, respectively. Patients in the HR– subgroup saw a greater absolute benefit of 12.3 months compared with 6.9 months in the HR+ subgroup.^2,4

In the intention-to-treat population, the median CNS PFS had not been reached in either treatment arm at the data cutoff. In an exploratory subset of approximately 81 patients with baseline BMs, median CNS PFS was 4.3 months with trastuzumab and pertuzumab plus placebo versus 8.5 months with the addition of tucatinib—nearly a doubling of CNS PFS, though not statistically significant.^2,4

“Despite the fact that this [OS] analysis is immature, with only 20% of events occurring and only 51 deaths in the study,” explained Hamilton, “there was a trend towards improved [OS] with tucatinib.”⁴

Safety Outcomes

The most common all-grade treatment-emergent adverse events (TEAEs) in the tucatinib arm were diarrhea (72.7%), nausea (33.1%), elevated liver enzymes (28.2%), increased alanine aminotransferase (28.2%), and increased aspartate aminotransferase (25.8%). Instances of grade 3 or higher TEAEs occurred in 42% of patients.^2,4

Any grade hepatic TEAEs occurred in 43.6% of patients in the tucatinib arm, with a median time to onset of 40 days and median time to resolution of 40 days. Sixteen percent of patients had dose reductions due to hepatic TEAEs and 7.7% discontinued treatment.^2,4

Diarrhea was among the most frequently reported TEAEs with tucatinib. Any-grade diarrhea occurred in 72% of patients receiving tucatinib plus trastuzumab and pertuzumab. More severe grade 3 events had a median time to onset of approximately 49 days and typically resolved within a median of 8 days. Grade 3 or higher diarrhea occurred in 6.1% of patients. Dose modifications were uncommon: 6% required a dose reduction, and only 1.5% discontinued tucatinib because of diarrhea. ^2,4

The HerClimb-05 findings suggest that integrating tucatinib into first-line maintenance meaningfully extends disease control with a manageable safety profile, offering patients more durable benefit before needing additional chemotherapy.

“HER2Climb-05 has demonstrated that the addition of tucatinib to [trastuzumab and pertuzumab] represents an enhanced first-line maintenance therapy option for patients with [HER2+] metastatic breast cancer,” concluded Hamilton, “providing an opportunity not only to prolong time to disease progression, but also to provide longer time off cytotoxic chemotherapy in first-line maintenance.”⁴

REFERENCES

1. A study of tucatinib or placebo with trastuzumab and pertuzumab for metastatic HER2+ breast cancer (HER2CLIMB-05). Clinicaltrials.gov. Updated December 4, 2025. Accessed December 10, 2025. https://clinicaltrials.gov/study/NCT05132582

2. Hamilton E, Curigliano G, Martin M. 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. Presented at: SABCS 2025. December 9-12, 2025. San Antonio, TX. Abstract GS1-01

3. Gerlach A. Tucatinib in combination with trastuzumab demonstrates safety, efficacy in patients with HER2-mutated breast cancer. Pharmacy Times. January 25, 2025. Accessed December 10, 2025. https://www.pharmacytimes.com/view/tucatinib-in-combination-with-trastuzumab-demonstrates-safety-efficacy-in-patients-with-her2-mutated-breast-cancer

4. Glück S, Nanda R, Hamilton E, et al. General Session 1. Presented at: SABCS 2025. December 9-12, 2025. San Antonio, TX.