Tucatinib Maintenance Improves PFS Across Key Subgroups in HER2+ MBC

Adding tucatinib (Tukysa) to first-line maintenance therapy with HP (trastuzumab [Herceptin] and pertuzumab [Perjeta]) produced clinically meaningful improvements in progression-free survival (PFS) and other end points in patients with HER2-positive metastatic breast cancer regardless of key characteristics, according to subgroup analyses from the phase 3 HER2CLIMB-05 trial (NCT05132582) presented at the 2026 ASCO Annual Meeting.¹

Tucatinib led to improved PFS, confirmed objective response rate (cORR), and duration of response (DOR) regardless of hormone receptor (HR) status, presence or absence of brain metastases (BM), or whether metastatic disease was de novo or recurrent. Safety profiles remained consistent across all subgroups, with no meaningful differences compared with the overall trial population.

“Results were consistent with the overall population and support the addition of tucatinib to HP as a potential new maintenance therapy across patients with HER2-positive metastatic disease,” said Erika P. Hamilton, MD, of the Sarah Cannon Research Institute in Nashville, Tennessee, in her presentation of the updated results.

Primary Findings in the Overall Population

The trial randomly assigned patients to receive tucatinib or placebo along with HP as first-line maintenance, with additional endocrine therapy (ET) allowed in eligible patients with HR-positive disease.

In the previously reported primary analysis of HER2CLIMB-05 conducted at a median follow-up of approximately 23 months, the addition of tucatinib to HP extended median PFS by nearly 9 months compared with placebo plus HP (24.9 months vs 16.3 months; hazard ratio, 0.641; 95% CI, 0.514-0.799; P <.0001).² There was also a reported cORR of 22.6% with tucatinib vs 15.2% with placebo among evaluable patients, and median DOR of 20.9 months vs 16.9 months, respectively.

Efficacy by Hormone Receptor Status

Among the 47.4% of patients with HR-negative disease, the addition of tucatinib nearly doubled median PFS compared with HP alone (24.9 months vs 12.6 months; hazard ratio, 0.554; 95% CI, 0.403-0.761; P = .0002). The cORR improved from 17.9% to 25.2%, and median DOR was not reached in the tucatinib arm vs 14.5 months with placebo plus HP.

In the HR-positive subgroup (52.6% of patients), tucatinib also demonstrated benefit, extending median PFS from 18.1 months to 25.0 months (hazard ratio, 0.725; 95% CI, 0.535-0.983; P = .0003)).¹ The cORR increased from 12.9% to 20.1%, and DOR improved from 18.7 to 20.9 months.

A further analysis of HR-positive patients by concomitant ET use highlighted a striking difference in outcomes based on whether patients received ET. Among the 45.1% of HR-positive patients who did receive concurrent ET, median PFS in the tucatinib arm reached 27.2 months, compared with 12.6 months among HR-positive patients in the tucatinib arm who did not use ET. Hamilton noted that this finding underscores the importance of incorporating ET in patients with dual HR-positive and HER2-positive disease.

Efficacy by Brain Metastasis Status

Only 12.4% of patients enrolled in HER2CLIMB-05 had baseline brain metastases, reflecting the trial's entry criteria requiring no or asymptomatic brain metastases confirmed by contrast-enhanced MRI. In this smaller subgroup, tucatinib more than doubled median PFS compared with placebo plus HP (8.5 months vs 4.2 months; hazard ratio, 0.640; 95% CI, 0.373-1.097; P = .1058), with cORR improving from 8.3% to 15.0%.

For the 87.6% of patients without baseline BM, the benefit was even more pronounced in absolute terms: median PFS extended from 18.1 months to 27.2 months with the addition of tucatinib, and cORR improved from 10.1% to 23.8%.

Efficacy by De Novo vs Recurrent Disease

Nearly 70% of enrolled patients presented with de novo metastatic disease. In this group, tucatinib added to HP extended median PFS from 16.8 months to 28.9 months (hazard ratio, 0.621; 95% CI, 0.475-0.813; P = .0006). Among the 30.7% of patients with recurrent metastatic disease, median PFS improved from 12.7 months to 21.3 months (hazard ratio, 0.671; 95% CI, 0.457-0.986; P = .0410). Hamilton noted that patients with brain metastases at baseline were more likely to have recurrent rather than de novo metastatic disease.

Safety Profile

The safety analysis demonstrated no meaningful differences in treatment-emergent adverse events (TEAEs) across any of the subgroups examined, including HR status, ET use, presence of brain metastases, and disease onset, compared with the overall population. Any-grade TEAEs occurred in nearly all patients receiving tucatinib across subgroups, mirroring the overall rate. Grade 3 or higher TEAEs occurred in 42% with tucatinib vs 24% with placebo overall with comparable differences in outcomes in the examined subgroups.

“We also looked at serious [TEAEs] across the subgroups…, as well as discontinuation of tucatinib or placebo due to [TEAEs]…, and again compared them to the overall population…, and did not see any significant differences,” Hamilton said.

Context and Implications

The standard first-line treatment approach for HER2-positive metastatic breast cancer has consisted of induction chemotherapy with a taxane combined with trastuzumab and pertuzumab, followed by HP maintenance therapy. Despite this treatment strategy, the majority of patients experience disease progression within 2 years. The rationale for HER2CLIMB-05 was to augment dual extracellular HER2 blockade with tucatinib, potentially improving outcomes while sparing patients additional cytotoxic therapy in the first-line maintenance setting.

“These results were consistent with the overall population and support the addition of tucatinib to HP as a potential new maintenance therapy across patients with HER2-positive metastatic disease,” Hamilton concluded.

REFERENCES

1. Hamilton EP, Curigliano G, Martin M, et al. Efficacy and safety of tucatinib (TUC) vs placebo (PBO) combined with trastuzumab and pertuzumab (HP) as maintenance therapy for HER2+ metastatic breast cancer by stratified subgroups. J Clin Oncol. 2026;44(suppl 16):1005. doi: 10.1200/JCO.2026.44.16_suppl.1005

2. 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. Published online December 10, 2025. doi:10.1200/JCO-25-02600