Abstract PS4-11-12: Impact of the ESMO-MCBS v2.0 on Benefit-Risk Assessment of Emerging Therapies in Early Breast Cancer: A Comparison with the ASCO Value Framework

Abstract Background: Balancing the clinical benefit and tolerability of adjuvant systemic therapies in patients with early breast cancer (eBC) remains challenging. Frameworks 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 v2.0) have been developed to help clinicians interpret trial results by weighing potential clinical benefit and toxicity. The European Society for Medical Oncology has recently revised ESMO-MCBS to version 2.0, which refines benefit thresholds and introduces explicit annotations for acute (AT) and persistent (PT) toxicity. This analysis applied these frameworks to evaluate the benefit-risk profiles of therapeutic strategies for high-risk eBC. Methods: Twelve phase II-III trials (KATHERINE, APHINITY, ExteNET, PEONY, NOAH, NeoSphere, KEYNOTE-522, OlympiA, CREATE-X, monarchE, NATALEE, and GIM2) were evaluated using ESMO-MCBS v2.0 and the ASCO Value Framework. Data were extracted from the latest available publications. Key endpoints included invasive disease-free survival (iDFS), overall survival (OS), pathological complete response (pCR), treatment-related adverse events (TRAEs), and quality of life (QoL). According to ESMO MBCS v2.0, standardized AT annotations for ≥30% G≥3 AEs, or ≥10% premature treatment discontinuation or hospitalization, and PT annotations for ≥20% persistent grade ≥3 toxicity, were retrieved. Concordance between ESMO MCBS and ASCO net health benefit (NHB) scores was assessed using Cohen’s Kappa coefficient. Results: The trials KATHERINE, NOAH, PEONY, KEYNOTE-522, CREATE-X, OlympiA, monarchE, and NATALEE achieved the highest ESMO-MCBS scores (Grade A) owing to improvements in iDFS and quality of life. In contrast, NeoSphere, APHINITY, and ExteNET were rated Grade C due to more modest absolute benefit. Notably, KATHERINE, KEYNOTE-522, OlympiA, CREATE-X, ExteNET, NATALEE, NOAH, and PEONY were annotated for acute toxicity (AT) under ESMO-MCBS v2.0, reflecting substantial rates of severe adverse events or treatment discontinuation. Among ASCO net health benefit (NHB) scores, NOAH (74), OlympiA (72), and CREATE-X (52) recorded the highest values, whereas NATALEE (12), ExteNET (5), and APHINITY (1) had the lowest scores. The APHINITY trial also showed the lowest toxicity score (-20), primarily due to the incidence of grade 3-4 diarrhoea (9.8% with pertuzumab vs. 3.7% with placebo). Overall, concordance between ESMO-MCBS v2.0 and ASCO VF was limited (Cohen’s Kappa -0.143; percentage agreement 33.3%). Conclusions: The revised ESMO-MCBS v2.0 provides a more rigorous assessment of clinical benefit by refining thresholds for absolute gains and systematically evaluating acute and persistent toxicities. NOAH and OlympiA achieved the most favourable benefit-risk balance across both tools. APHINITY and NATALEE recorded the lowest ASCO VF NHB scores, whereas APHINITY, NeoSphere and ExteNET were graded C under the ESMO-MCBS. These results emphasise differences in methodology and support the combined application of both frameworks to guide evidence-based choices in early breast cancer care. Citation Format: A. Longobardi, V. Molinaro, V. Cantile, R. Buonaiuto, A. Caltavituro, G. Crimaldi, M. Giuliano, G. Arpino, C. De Angelis. Impact of the ESMO-MCBS v2.0 on Benefit-Risk Assessment of Emerging Therapies in Early Breast Cancer: A Comparison with the ASCO Value Framework [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-11-12.