Imbalance in treatment discontinuation without progression between experimental and control arms among randomized trials in advanced breast cancer.

Faris Tamimi Division of Medical Oncology & Hematology, Department of Medicine, Princess Margaret Cancer Centre and University of Toronto, Toronto, ON, Canada info_outline Faris Tamimi, Abhenil Mittal, Consolacion Molto, Diego Malon Gimenez, Michelle B. Nadler, Eitan Amir

Authors Faris Tamimi Division of Medical Oncology & Hematology, Department of Medicine, Princess Margaret Cancer Centre and University of Toronto, Toronto, ON, Canada info_outline Faris Tamimi, Abhenil Mittal, Consolacion Molto, Diego Malon Gimenez, Michelle B. Nadler, Eitan Amir Organizations Division of Medical Oncology & Hematology, Department of Medicine, Princess Margaret Cancer Centre and University of Toronto, Toronto, ON, Canada Abstract Disclosures Research Funding No funding received None. Background: In Randomized Controlled Trials (RCT), treatment discontinuation (TD) can result in censoring. Imbalanced frequency of TD between arms could impact interpretation of results. Here, we quantify TD between the experimental and control arms among RCT supporting registration of drugs for advanced breast cancer. Methods: We identified RCT supporting US Food and Drug Administration's approval of drugs for advanced breast cancer between 2013 and 2023. We extracted data for the number of participants with TD for reasons other than disease progression (PD), death, or completion of treatment. Odds ratio (OR) for TD comparing experimental to control arms were determined for each trial. To assess progression-free survival (PFS) translation into an overall survival (OS) benefit, we calculated hazard ratio (HR) for PFS/OS. Then we assessed whether there was quantitative association between the OR for TD and the ratio of HR for PFS/OS. Quantitative significance was defined according to the criteria of Burnand. Results: Analysis included 22 RCT comprising 13853 participants and supporting approval for 18 distinct drugs. TD was reported in 2212 (16.0%) participants. Among these participants, the leading causes of TD were withdrawal of consent (27.8%), site termination (20.7%), adverse events (17.2%), and loss of follow-up (10.9%). There was a statistically significant imbalance in the experimental arm in 4 RCT (18%) (Table), which was observed for everolimus, ribociclib (with fulvestrant), alpelisib, and neratinib. The OR for TD showed quantitative, but not statistically significant negative association with the ratio of the HR for PFS/OS (Beta -0.393; p=0.18). Conclusions: TD without PD, death, or completion of treatment occurs in a substantial proportion of participants of several RCT supporting approval of drugs for advanced breast cancer. all the statistically significant imbalanced TD in the RCT were in experimental arms. Quantitative association between imbalanced TD and the ratio of HR for PFS/OS suggests imbalanced TD may impact ability to translate improvements in PFS to OS. Results of RCT with imbalance in TD should be interpreted cautiously. OR for TD comparing experimental to control arms. RCT OR [95% CI] OlympiAD 0.66 [0.24, 1.79] ALTERNATIVE 0.72 [0.29, 1.77] EMBRACA 0.73 [0.47, 1.13] EMBRACE 0.74 [0.54, 1.02] CONFIRM 0.76 [0.53,1.07] SOPHIA 0.89 [0.54, 1.48] CLEOPATRA 0.90 [0.59, 1.37] MONARCH 3 0.90 [0.48, 1.72] MONARCH 2 0.90 [0.53, 1.54] MONALEESA-7 0.92 [0.57, 1.49] PALOMA-3 1.10 [0.53, 2.30] EMILIA 1.27 [0.98, 1.65] DESTINY-Breast03 1.33 [0.86, 2.06] PALOMA-2 1.34 [0.90, 1.99] ASCENT 1.43 [0.95, 2.16] NALA 1.45 [1.02, 2.07] * MONALEESA-2 1.55 [0.98, 2.47] HER2CLIMB 1.60 [0.58, 4.43] KEYNOTE-355 1.77 [0.70, 4.43] SOLAR-1 1.93 [1.19, 3.12] * MONALEESA-3 1.94 [1.19, 3.13] * BOLERO-2 4.04 [2.33, 7.00] * * Significant p-value.