Abstract P5-15-06: Impact of post-progression therapy on overall survival (OS) in the IMELDA randomized phase III trial evaluating the addition of capecitabine (CAP) to maintenance bevacizumab (BEV) for HER2-negative metastatic breast cancer (mBC)
Authors: Mustacchi G , Bines J , Alba E , Cortes P , Doval D , de Ducla S , Button P , Gligorov J 
Published: March 2017

Abstract
BACKGROUND The open-label randomized phase III IMELDA trial demonstrated that adding CAP to maintenance BEV until disease progression after initial BEV + docetaxel (DOC) provides statistically significant and clinically meaningful improvements in both progression-free survival (PFS [primary endpoint]; hazard ratio [HR] 0.38, 95% CI 0.27–0.55; log-rank p&lt;0.001; median 4.3 vs 11.9 months with BEV vs BEV + CAP, respectively) and OS (HR 0.43, 95% CI 0.26–0.69; median 23.7 vs 39.0 months, respectively) [Gligorov, Lancet Oncol 2014]. The type and extent of post-progression therapy were not collected prospectively; to address questions from the oncology community and provide further insight into the observed OS benefit with CAP, we collected these data retrospectively in the post-IMELDA study.
METHODS In IMELDA, patients (pts) with HER2-negative measurable mBC and no prior chemotherapy for mBC received 3-6 cycles of BEV + DOC. Pts with a response or stable disease were randomized to BEV alone or BEV + CAP (BEV 15 mg/kg d1 q3w; CAP 1000 mg/m2 bid d1-14 q3w) until disease progression, unacceptable toxicity, or consent withdrawal. OS from randomization was a secondary endpoint. In post-IMELDA, data until study closure were collected retrospectively from available records of pts randomized in IMELDA. Ethics, consent, and feasibility reasons prevented some sites participating in post-IMELDA.
RESULTS Post-IMELDA data were available from 118 (64%) of the 185 randomized pts. Of these, all but 8 had received further systemic anticancer therapy and 92 of 118 (78%) had received chemotherapy. Post-progression treatment exposure and efficacy are shown below. In Cox regression models stratified by further anticancer therapy after stopping study therapy, HRs were 0.30 (95% CI 0.19–0.48) for PFS and 0.50 (95% CI 0.30–0.82) for OS. Sensitivity analyses using two extremes of imputation (assuming all pts with missing follow-up data did vs did not receive further anticancer therapy) supported OS findings.
ParameterBEV (n=59)BEV + CAP (n=59)Any further systemic anticancer therapy, n (%)56 (95)54 (92)Chemotherapy 49 (83)43 (73) CAP34 (58)7 (12) Non-CAP-containing43 (73)41 (69)Targeted therapy/immunotherapy 12 (20)3 (5) BEV8 (14)1 (2)Endocrine therapy 24 (41)31 (53)Other 11 (19)10 (17)Median PFS, months (95% CI)4.3 (2.7–7.4)15.0 (9.9–19.3)Subgroup with further anticancer therapy 4.3 (3.5–7.4)14.1 (9.9–19.3)Median OS, months (95% CI)22.3 (12.1–29.8)36.5 (27.6–NE)Subgroup with further anticancer therapy 22.9 (16.5–31.7)36.5 (24.0–NE)NE=not estimable
CONCLUSIONS Post-IMELDA is limited by retrospective collection of data from only two-thirds of randomized pts and only until the date of study closure (thus potentially underestimating crossover to CAP). Nevertheless, these analyses suggest that the OS benefit from adding CAP to maintenance BEV in the IMELDA trial was robust despite extensive post-progression therapy in both treatment arms and crossover to CAP in more than half of pts randomized to maintenance BEV alone. Ongoing and future mBC trials should include prospective collection of information on subsequent therapy.
Citation Format: Mustacchi G, Bines J, Alba E, Cortes P, Doval D, de Ducla S, Button P, Gligorov J. Impact of post-progression therapy on overall survival (OS) in the IMELDA randomized phase III trial evaluating the addition of capecitabine (CAP) to maintenance bevacizumab (BEV) for HER2-negative metastatic breast cancer (mBC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-15-06.