Impact of ribociclib (RIB) dose modifications (mod) on overall survival (OS) in patients (pts) with HR+/HER2- advanced breast cancer (ABC) in MONALEESA(ML)-2.

person Lowell L. Hart Florida Cancer Specialists and Research Institute, Fort Myers, FL info_outline Lowell L. Hart, Aditya Bardia, Joseph Thaddeus Beck, Arlene Chan, Patrick Neven, Erika P. Hamilton, Joohyuk Sohn, Gabe S. Sonke, Thomas Bachelot, Laura Spring, Fabienne Le Gac, Huilin Hu, Ming Gao, Michelino De Laurentiis

Authors person Lowell L. Hart Florida Cancer Specialists and Research Institute, Fort Myers, FL info_outline Lowell L. Hart, Aditya Bardia, Joseph Thaddeus Beck, Arlene Chan, Patrick Neven, Erika P. Hamilton, Joohyuk Sohn, Gabe S. Sonke, Thomas Bachelot, Laura Spring, Fabienne Le Gac, Huilin Hu, Ming Gao, Michelino De Laurentiis Organizations Florida Cancer Specialists and Research Institute, Fort Myers, FL, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, Highlands Oncology Group, Springdale, AR, Breast Cancer Research Centre-WA, Perth & Curtin University, Perth, Australia, Universitaire Ziekenhuizen (UZ) - Leuven Cancer Institute, Leuven, Belgium, Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea, Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, Netherlands, Centre Léon Bérard, Lyon, France, Massachusetts General Hospital, Boston, MA, Clinical Development & Analytics Global Drug Development-Oncology, Basel, Switzerland, Novartis Pharmaceuticals Corp, East Hanover, NJ, Novartis Pharma AG, Basel, Switzerland, Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale"-Breast Oncology Unit, Naples, Italy Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Background: The phase 3 ML-2, -3, and -7 trials all demonstrated consistent and statistically significant OS benefit with RIB (starting dose: 600 mg/d 3 wk on/1 wk off) vs PBO in pts with HR+/HER2− ABC. RIB dose mod (reductions and/or interruptions) when needed did not impact OS benefit with RIB + endocrine therapy (ET) in previous analyses of ML-3/-7. Here we present data on the effect of RIB dose mod on OS in postmenopausal pts with HR+/HER2− ABC in ML-2. Methods: ML-2 (NCT01958021) enrolled postmenopausal pts randomized 1:1 to first-line RIB + letrozole (LET) or PBO + LET. Landmark (LM) analyses of OS were performed to evaluate the association between dose reductions (yes vs no) and OS. Multiple LM times were considered to determine the sensitivity of the findings. As an alternative to LM analysis, a Cox proportional hazards model with a time-varying covariate was performed. Two time-dependent variables, dose reduction (with/without mod from 600 mg starting dose) and relative dose intensity 2 (RDI2), were included in the respective model as covariates to explore the association with OS. To account for differences in time to first dose mod, RDI2 reflects the post–dose mod period. Median (m) OS was obtained using a modified Kaplan-Meier method. Results: At data cutoff (June 10, 2021; m follow-up, 49.35 [range, 0-86.7] mo), 209 of 334 pts (62.6%) had ≥ 1 RIB dose reduction and 125 of 334 (37.4%) had 0 RIB dose reduction. LM analyses by dose reduction are presented (Table). mOS was 66.0 (95% CI, 57.6-75.7) mo in pts with ≥ 1 RIB dose reduction vs 60.6 (95% CI, 42.5-79.2) mo in pts with no RIB dose reductions (HR, 0.87 [95% CI, 0.65-1.18]). RDI2 was classified according to tertile: low (< 64.27%), medium (64.27%-95.86%), and high (> 95.86%). In pts with low, medium, and high RDI2, mOS was 62.6 (95% CI, 50.0-80.7) mo, 63.9 (95% CI, 48.8-not reached [NR]) mo, and 65.3 (95% CI, 50.5-NR) mo, respectively (HR low vs high, 0.99 [95% CI, 0.69-1.42]; HR medium vs high, 0.97 [95% CI, 0.62-1.38]). Conclusions: In this exploratory analysis of ML-2, OS benefit was maintained in pts with HR+/HER2− ABC who required mod from the recommended starting dose of RIB (600 mg/d 3 wk on/1 wk off). No relationship was observed between OS and RIB dose reduction or RDI2; OS benefit with RIB was observed in all groups. Clinical trial information: NCT01958021. OS analysis for 3 LMT points. LMT, mo a Pts on treatment > LMT, n (%) Dose reduction prior to LMT Subgroup, n (%) No. of events 2-year post-LMT OS rate (95% CI) b Post-LMT HR (95% CI): Dose reduction Yes vs No 6 261 (78.1) Yes 120 (46.0) 63 0.86 (0.80-0.93) 1.19 (0.85-1.68) No 141 (54.0) 68 0.88 (0.83-0.94) 12 211 (63.2) Yes 117 (55.5) 53 0.89 (0.83-0.95) 1.20 (0.79-1.82) No 94 (44.5) 38 0.89 (0.83-0.96) 18 176 (52.7) Yes 101 (57.4) 37 0.90 (0.84-0.96) 0.94 (0.57-1.53) No 75 (42.6) 29 0.88 (0.80-0.96) LMT, landmark time. a Each LMT represents a distinct pt population treated on and after the LM. b OS rate 2 years after given LMT.