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

Author(s): Veronique Dieras, MD¹; Giuseppe Curigliano, MD, PhD^2,3; Miguel Martin, MD, PhD⁴; Florence Lerebours, MD, PhD⁵; Junji Tsurutani, MD, PhD⁶; Marie-France Savard, MD⁷; Katarzyna J. Jerzak, MD, MSc, FRCPC⁸; Xichun Hu, MD, PhD⁹; Luciana Carla Martins de Aquino Pimentel, MD¹⁰; Ciara C. O’Sullivan, MB BCh BAO¹¹; Eriko Tokunaga, MD¹²; Alicia Okines, MD, MBChB, FRCP^13,14; Chiun-Sheng Huang, MD, PhD, MPH¹⁵; William Jacot, MD, PhD¹⁶; Joohyuk Sohn, MD¹⁷; Eduardo Cronemberger Silva, MD, MSc¹⁸; Volkmar Mueller, MD¹⁹; Shan Yang, PhD²⁰; Giovanna Granata, PhD²¹; Qi Shen, MD, PhD²²; Libero Santarpia, MD, PhD²³; Erika Hamilton, MD²⁴; on behalf of the HER2CLIMB-05 Investigators;

Source: DOI: 10.1200/JCO-25-02600

Dr. Maen Hussein's Thoughts

Progression-free survival (PFS) was statistically significantly improved with addition of tucatinib versus placebo 24.9 v 16.3 months regardless of the presence/absence of BM or hormone receptor status.

PURPOSE

The HER2CLIMB-05 study (ClinicalTrials.gov identifier: NCT05132582) is investigating the efficacy and safety of adding tucatinib to trastuzumab and pertuzumab as first-line (1L) maintenance therapy in patients with human epidermal growth factor receptor 2–positive (HER2+) metastatic breast cancer (MBC).

METHODS

Patients with centrally confirmed HER2+ MBC without evidence of progression post induction therapy and no or asymptomatic brain metastases (BM) were enrolled. Patients were randomly assigned 1:1 to tucatinib (300 mg) or placebo twice a day combined with trastuzumab/pertuzumab. The primary end point is investigator-assessed progression-free survival (PFS); secondary end points include overall survival (OS), PFS per blinded independent central review, CNS-PFS, and safety.

RESULTS

Between March 2022 and July 2024, 654 patients were randomly assigned to tucatinib (n = 326) and placebo (n = 328) arms. All patients were female (median age, 54 years), 69.3% had de novo MBC, 52.6% were hormone receptor–positive, and 12.4% had presence/history of baseline BM. In this primary analysis, PFS was statistically significantly improved with addition of tucatinib versus placebo (hazard ratio, 0.641 [95% CI, 0.514 to 0.799]; P < .0001; median PFS: 24.9 v 16.3 months); a PFS benefit was seen regardless of the presence/absence of BM or hormone receptor status. OS data remain immature. The most common treatment-emergent adverse events (TEAEs) in the tucatinib arm were diarrhea (72.7%), nausea (33.1%), and elevated liver enzymes (ALT: 28.2%; AST: 25.8%), of which 6.1%, 0.9%, 13.5%, and 7.1%, respectively, were grade ≥3. In the tucatinib arm, 13.5% discontinued tucatinib because of TEAEs.

CONCLUSION

Tucatinib addition to trastuzumab and pertuzumab demonstrated improvement in PFS with no new safety signals identified and may be an option for 1L maintenance therapy in patients with HER2+ MBC.

Author Affiliations

¹Medical Oncology Department, Centre Eugène Marquis, Rennes, France; ²European Institute of Oncology, IRCCS, Milano, Italy; ³Department of Oncology and Hemato-Oncology, University of Milano, Milano, Italy; ⁴Medical Oncology Service, Hospital General Universitario Gregorio Marañon, Universidad Complutense, CIBERONC, GEICAM, Madrid, Spain; ⁵Institut Curie, Saint-Cloud, Paris, France; ⁶The Innovative Center of Translational Research and Clinical Science for Cancer Therapy, Showa Medical University Hospital, Tokyo, Japan; ⁷Department of Medicine, The Ottawa Hospital Cancer Centre, Ottawa, ON, Canada; ⁸Department of Medicine, Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, ON, Canada; ⁹Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; ¹⁰Medical Oncology, Liga Norte-Rio Grandense Contra o Cancer, Natal, Brazil; ¹¹Department of Medical Oncology, Mayo Clinic, Rochester, MN; ¹²Department of Breast Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan; ¹³Medical Oncology, The Royal Marsden NHS Foundation Trust, London, United Kingdom; ¹⁴Institute of Cancer Research, London, United Kingdom; ¹⁵Breast Care Center, National Taiwan University Hospital, Taipei, Taiwan; ¹⁶Département d'Oncologie Médicale, Institut Regional du Cancer de Montpellier, Montpellier University, INSERM U1194, Montpellier, France; ¹⁷Division of Medical Oncology, Yonsei Cancer Center, Yonsei University Health System, Seoul, Republic of Korea; ¹⁸Medical Oncology, Centro Regional Integrado de Oncologia (CRIO), Fortaleza, Brazil; ¹⁹Department of Gynecology and University Breast Center, Universitaetsklinikum Hamburg-Eppendorf, Hamburg, Germany; ²⁰Biostatistics, Pfizer Inc, Bothell, WA; ²¹Oncology Late Stage Development, Pfizer AG, Zug, Switzerland; ²²Oncology, Research and Development, Pfizer Inc, Collegeville, PA; ²³Oncology, Research and Development, Pfizer AG, Zug, Switzerland; ²⁴Medical Oncology, Sarah Cannon Research Institute, Nashville, TN

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