Key Takeaways
- Tucatinib addition to trastuzumab and pertuzumab improved progression-free survival in HER2-positive metastatic breast cancer patients in the HER2CLIMB-05 trial.
- The trial demonstrated tucatinib’s potential to reduce disease progression or death risk with a tolerable safety profile.
- HER2CLIMB-05 included patients without disease progression on initial therapy and excluded those with specific CNS conditions.
- Results suggest tucatinib’s role in a chemotherapy-free maintenance approach for a broader HER2-positive patient population.
The addition of tucatinib (Tukysa) to trastuzumab (Herceptin) and pertuzumab (Perjeta) led to a statistically significant and clinically meaningful improvement in progression-free survival (PFS) vs placebo plus trastuzumab and pertuzumab as maintenance therapy in patients with HER2-positive metastatic breast cancer who did not experience disease progression on frontline therapy with trastuzumab, pertuzumab, and a taxane, meeting the primary end point of the phase 3 HER2CLIMB-05 trial (NCT05132582).1
Treatment in the experimental arm was reported to be tolerable, with a safety profile that generally mirrored those of the monotherapies. Results from the trial will be shared at an upcoming medical congress and discussed with regulatory agencies.
“HER2-positive breast cancer is a particularly challenging subtype, with many patients experiencing disease progression despite effective treatments in the first-line setting,” Erika Hamilton, MD, FASCO, principal investigator of HER2CLIMB-05 and director of breast cancer and gynecologic cancer research at Sarah Cannon Research Institute in Nashville, Tennessee said in a news release. “The HER2CLIMB-05 results demonstrate that the addition of [tucatinib] to first-line maintenance therapy may further lower the risk of disease progression or death, with a treatment that has a well-established safety profile.”
What Was the Design of the HER2CLIMB-05 Trial?
HER2CLIMB-05 is a randomized, double-blind, placebo-controlled, pivotal phase 3 trial evaluating the additive effect of combining tucatinib with trastuzumab and pertuzumab vs placebo plus trastuzumab and pertuzumab alone as first-line maintenance therapy in patients with HER2-positive metastatic breast cancer.2
To be eligible for enrollment patients must have centrally confirmed, unresectable locally advanced or metastatic HER2-positive breast carcinoma per 2018 ASCO CAP guidelines. Only those with no evidence of disease progression on frontline treatment with trastuzumab, pertuzumab, and a taxane were eligible for the study. With respect to central nervous system (CNS) inclusion criteria, patients could have no evidence of brain metastasis, untreated brain metastases that are asymptomatic and not progressive, or previously treated brain metastases that are asymptomatic and not progressive.
Patients who received any HER2-directed or EGFR TKI or those unable to undergo a contrast brain MRI were excluded from enrollment. In addition to symptomatic and progressive brain metastases, patients who are receiving ongoing corticosteroid treatment at a total daily dose exceeding 2 mg of dexamethasone or an equivalent, have an untreated brain lesion that may endanger the patient, have known or suspected leptomeningeal disease, or have poorly controlled seizures or other chronic neurologic symptoms were prohibited from enrollment.
Per the trial design patients who completed between 4 and 8 cycles of induction therapy with trastuzumab, pertuzumab, and a taxane were randomly assigned to the experimental (n = 326) or placebo (n = 328) arm in 21-day cycles. Tucatinib is administered orally at a dose of 300 mg twice daily. Trastuzumab and pertuzumab are given intravenously (IV) at a dose of 6 mg/kg or 600 mg subcutaneously, and 420 mg once every cycle, respectively. Alternatively, trastuzumab and pertuzumab can be given at a fixed dose of 600 mg of trastuzumab, 600 mg of pertuzumab, and 20,000 units of hyaluronidase subcutaneously.
Notably, patients with hormone receptor–positive disease may receive endocrine therapy per local guidance.
The primary end point is investigator-assessed PFS. Secondary end points include overall survival, PFS by blinded independent central review, CNS-PFS, time to deterioration of health-related quality of life, safety, and pharmacokinetic assessments.
What Did Pfizer Share Regarding the Significance of the Study Results?
“Pfizer aims to help shape the future of frontline treatment for HER2-positive metastatic breast cancer, where we see significant opportunity for a chemotherapy-free maintenance approach,” Johanna Bendell, MD, chief development officer of Oncology at Pfizer, added in the news release.1 “The positive results from HER2CLIMB-05, combined with [tucatinib’s] known safety profile in later-line settings, underscore its potential to play a meaningful role in frontline maintenance, where it may benefit a broader population of patients with HER2-positive disease. We are grateful to the patients and investigators who contributed to this important research.”
References
- Tukysa combination significantly improves progression-free survival as first-line maintenance in HER2+ metastatic breast cancer in HER2CLIMB-05 trial. News release. Pfizer. October 14, 2025. Accessed October 14, 2025. https://www.pfizer.com/news/press-release/press-release-detail/tukysa-combination-significantly-improves-progression-free
- Hamilton EP, O’Sullivan CCM, Martin M, et al. Phase 3 study of tucatinib or placebo in combination with trastuzumab and pertuzumab as maintenance therapy for HER2+ metastatic breast cancer (HER2CLIMB-05, trial in progress). J Clin Oncol. 2022;40(suppl 16):TPS1108. doi:10.1200/JCO.2022.40.16_suppl.TPS1108