Evaluating the benefit-risk balance of second-line therapies for HR+/HER2- metastatic breast cancer: A comparative analysis using ASCO VF and ESMO MCBS frameworks.

Abstract

e13100 Background: The treatment landscape for HR+/HER2- metastatic breast cancer (mBC) is evolving at an unprecedented pace, necessitating a comprehensive evaluation of both clinical efficacy and toxicity profile to guide evidence-based decision-making. Established tools, such as the American Society of Clinical Oncology Value Framework (ASCO VF) v2.0 and the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO MCBS) v1.1, have been developed to support clinicians in interpreting clinical trial data by balancing the potential clinical efficacy with toxicity. In this analysis, these frameworks were employed to evaluate the risk-benefit profiles of therapeutic strategies in second line (2L) treatment for HR+/HER2- mBC. Methods: Thirteen phase II-III clinical trials, which contributed to the approval of agents used in clinical practice as 2L therapies for HR+/HER2- mBC were included in the analysis (DESTINY-Breast04, MAINTAIN, EMERALD, CAPItello-291, TROPiCS-02, PADA-1, DESTINY-Breast06, OlympiAD, EMBRACA, METEORA-II, TROPION-Breast01, SOLAR-1, and BOLERO-2). Key clinical benefit endpoints (e.g., PFS, OS), treatment-related adverse events (TRAE; CTCAE grade [G]1-4), and bonus points (e.g., tail of the survival curve, symptom palliation and/or treatment-free intervals and/or quality of life) were retrieved for each study. ASCO Net Health Benefit (NHB) and ESMO MCBS scores were independently calculated. Results: DESTINY-Breast04, TROPION-Breast01, and DESTINY-Breast06 achieved the highest ASCO VF NHB scores (58, 50, and 46, respectively). In contrast, METEORA-II (32), PADA-1 (30), MAINTAIN (20), and SOLAR-1 (15) reported the lowest ASCO VF NHB scores. Notably, EMERALD and CAPItello-291 yielded moderate NHB scores (32 and 30) in the PIK3CA/AKT/PTEN-mutated and ESR1-mutated subgroups, respectively. In terms of toxicity, BOLERO-2 (CTCAE ≥G3 TRAE rates 41% vs 22% in the control arm) and DESTINY-Breast06 (≥G3 53% vs 44%; ILD incidence 11% vs 0.2%) recorded the worst score (-10). According to the ESMO MCBS, DESTINY-Breast04, TROPION-Breast01, EMBRACA, and OlympiAD achieved the highest scores (Grade 4), while DESTINY-Breast06 (Grade 2) and SOLAR-1 (Grade 2) recorded the lowest ratings. Moreover, EMERALD and CAPItello-291 were graded 3 and 4 in the ESR1- and PIK3CA/AKT/PTEN-mutated subgroups, respectively. Conclusions: DESTINY-Breast04 and TROPION-Breast01 demonstrated the most favorable balance of efficacy, toxicity, and quality of life improvements according to both ASCO VF NHB and ESMO MCBS. In contrast, DESTINY-Breast06 received a Grade 2 MCBS due to its unfavorable toxicity profile. EMERALD and CAPItello-291 showed moderate benefit in biomarker-defined subgroups. Moderate concordance between ASCO and ESMO frameworks reflects differences in parameter weighting across the two scales.