Abstract Background: HER2-low metastatic triple-negative breast cancer (mTNBC) is an aggressive disease with limited treatment options. Two antibody-drug conjugates (ADCs), sacituzumab-govitecan (SG) and trastuzumab-deruxtecan (T-DXd), have individually shown superior efficacy versus chemotherapy in advanced settings. Resistance to ADCs, however, frequently emerges due to heterogeneous expression of TROP2 and HER2, altered intracellular processing, and payload-specific mechanisms. As TROP2 and HER2 exhibit only partial overlap, sequential single-agent ADC use may leave tumor subclones insufficiently exposed to treatment. Alternating ADCs with distinct targets and chemically different topoisomerase-I inhibitor payloads may broaden tumor-cell coverage and help delay resistance. ALTER is the first randomized trial designed to evaluate whether an upfront alternating ADC strategy improves outcomes compared with standard SG monotherapy. The study also incorporates a comprehensive translational program, including serial biopsies, ctDNA monitoring, and PK/PD analyses to characterize determinants of response and resistance. Methods: ALTER (NCT07151586) is a multicenter, open-label, randomized Phase II trial conducted in France. A total of 260 adults with unresectable locally advanced or metastatic HER2-low TNBC (IHC 1+ or 2+/ISH−; estrogen and progesterone receptor expression 10%) and ECOG performance status ≤1 will be enrolled. Prior HER2- or TROP2-targeting ADCs are not allowed. Patients with treated and clinically stable brain metastases are eligible. Participants will be randomized 1: 1 to receive either a repeating alternating schedule consisting of two 21-day cycles of SG (10 mg/kg IV on days 1 and 8) followed by two 21-day cycles of T-DXd (5. 4 mg/kg IV on day 1), continued in this same alternating sequence until RECIST 1. 1-defined progression or unacceptable toxicity, or standard SG monotherapy. Randomization is stratified by number of metastatic sites (0-1 vs ≥2) and number of prior metastatic chemotherapy lines (0-1 vs ≥2). The primary endpoint is overall survival. Secondary endpoints include clinical benefit rate, objective response rate, progression-free survival, quality-adjusted progression-free survival, safety, and quality of life. Exploratory objectives include molecular profiling of baseline and progression tumor and liquid biopsies; ctDNA kinetics; PK/PD analyses. The sample size (248 evaluable patients, 207 events) provides 80% power to detect a hazards ratio of 0. 70 for overall survival with a one-sided alpha of 0. 05. Two interim analyses for futility will follow an O’Brien-Fleming boundary. Study initiation is planned for Dec 2025, with completion expected in Oct 2029. Citation Format: Alexandre de Nonneville, Jean-Marie Boher, Jean-Sébastien Frenel, Gerald Bagoe, Olivier Tredan, Marie-Ange Mouret-Reynier, Chayma Bousrih, Vincent Massard, Julien Grenier, Marie Robert, Florence Lerebours, Delphine Loriat, Florence Dalenc, Christelle Jouannaud, Stéphanie Becourt, Philippe Follana, Sylvain Ladoire, William Jacot, Bogdan-Valentin Popescu, Maxime Brunet, George Emile, Jerôme Lemmonier, Sylvie Mijonnet, Anthony Gonçalves, François Bertucci. ALTER: A randomized Phase II trial evaluating an upfront alternating regimen of sacituzumab-govitecan and trastuzumab-deruxtecan versus sacituzumab-govitecan alone in HER2-low metastatic triple-negative breast cancer (NCT07151586) abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr CT275.
Nonneville et al. (Fri,) studied this question.