Overall survival, quality of life and magnitude of clinical benefit of breast cancer drugs over the last 25 years.
Authors: Tapia J. Carlos , Bujosa Rodríguez Aida , Molto Consolacion , Templeton Arnoud J. , Shepshelovich Daniel , Goldvaser Hadar , Gich Saladich Ignasi J. , Barnadas Agusti , Amir Eitan , Tibau Ariadna 
Published: June 2021

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Background: The American Society of Clinical Oncology Cancer Research Committee (ASCO-CRC), the ASCO Value Framework Net Health Benefit score version 2 (ASCO-VF), and the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale version 1.1 (ESMO-MCBS) are validated tools quantifying the clinical benefit for cancer drugs. Here, we assess the overall survival (OS), quality of life (QoL) and magnitude of clinical benefit of trials supporting breast cancer drug approval by the US Food and Drug Administration (FDA) in the last 25 years. Methods: We searched Drugs@FDA website for all breast cancer drug approvals from January 1, 1995 to December 30, 2020. Drug labels and reports of registration trials were reviewed. We collected data on trial characteristics, efficacy, toxicity and QoL. When more than one study supported a single indication, we preferred efficacy-oriented endpoints (typically OS) to QoL. We excluded trials supporting accelerated-approval indications if these were converted to regular approval during the study period. We scored clinical benefit using the ASCO-CRC in palliative setting, and ASCO-VF and ESMO-MCBS in both curative and palliative setting. Substantial clinical benefit was defined as: OS gains ≥2.5 months and progression-free survival gains ≥ 3 months for ASCO-CRC criteria; ASCO-VF scores ≥ 45 and grade of A or B for trials of curative intent and 4 or 5 for those of non-curative intent using ESMO-MCBS. Trends over time were assessed using Chi-squared test for trend. Results: We identified 51 trials supporting the approval of 32 individual drugs for 51 indications; 12 (24%) were in the curative setting and 39 (76%) in the palliative setting. At the time of approval, 8 (16%) trials reported significant improvement in OS. QoL was reported in 22 trials (43%). Among these, 8 (36%) showed improvement in QoL. For curative intent, we applied ASCO-VF and ESMO-MCBS score to 11 (92%) trials, finding clinical benefit in 10 (91%) and 2 (18%) trials, respectively. In the palliative setting, we used ASCO-CRC, ASCO-VF and ESMO-MCBS scores to rate 32 (82%), 33 (85%) and 38 (97%) trials. Substantial clinical benefit was observed in 20 (63%), 12 (36%) and 7 (19%) trials, respectively. Over time, there has been a decrease in the number of trials supporting approval based on OS (1996-2003 50% vs 2004-12 38% vs 2013-20 13%, P trend = 0.033). There were no statistically significant changes over time in QoL, ASCO-CRC, ASCO-VF and ESMO-MCBS scores. Conclusions: For palliative intent, most trials supporting FDA approval of breast cancer drugs do not meet the ASCO-VF or ESMO-MCBS criteria for substantial clinical benefit. There is substantial inter-framework variability in the assessment of clinical benefit in the curative setting. Over time, there has been a substantial shift towards use of surrogate endpoints as the basis for approval without a clear improvement in substantial clinical benefit.