Abstract 331P
Background
RIB + endocrine therapy (ET) had a significant OS benefit vs. placebo (PBO) in pts with HR+/HER2− ABC in the ML-3 (postmenopausal pts; HR, 0.71; P = .00973; Slamon et al. N Engl J Med. 2020) and ML-7 (premenopausal pts; HR, 0.72; P = .00455; Im et al. N Engl J Med. 2019) trials. Dose reductions to manage adverse events (AEs) were allowed; prior analysis showed no impact on progression-free survival with RIB dose reduction (Beck, et al. SABCS 2018). Here we present data on RIB dose reductions and evaluate the impact on OS in ML-3 and -7.
Methods
ML-3 randomized pts 2:1 to RIB or PBO (both + fulvestrant). ML-7 randomized pts 1:1 to RIB or PBO (both + ET); only pts treated with a nonsteroidal aromatase inhibitor were included in this analysis. Separate time-varying Cox regression models considering dose modifications over time were used to assess impact of dose reduction (from 600 mg) or relative dose intensity (RDI; accounts for reduction or interruption) on OS. Pooled ML-3/-7 data were analyzed to explore the relationship between pharmacokinetic RIB exposure (Ctrough) and OS.
Results
Pts by dose reduction and RDI are outlined in the table. In ML-3, HR for OS was 0.88 (95% CI, 0.64-1.21) in pts with ≥ 1 vs. 0 dose reduction, 0.98 (95% CI, 0.68-1.42) for low vs. high RDI, and 0.87 (95% CI, 0.60-1.27) for medium vs. high RDI. In ML-7, HR for OS was 0.79 (95% CI, 0.46-1.36) in pts with ≥ 1 vs. 0 dose reduction, 0.82 (95% CI, 0.44-1.52) for low vs. high RDI, and 0.88 (95% CI, 0.48-1.61) for medium vs. high RDI. Exposure-efficacy analysis suggested no clear impact of RIB exposure on OS relating to dose reductions of 400 and 200 mg. Table: 331P
| Dose reduction | RDI (%) | ||||
| ≥ 1 | None | Low1st tertile | Medium2nd tertile | High3rd tertile | |
| ML-3, n (%) | 197 (41) | 286 (59) | [<77.01]160 (33) | [77.01-97.66]163 (34) | [>97.66]160 (33) |
| ML-7, n (%) | 101 (41) | 145 (59) | [<73.43]81 (33) | [73.43-97.70]84 (34) | [>97.70]81 (33) |
Conclusions
RIB dose reduction does not compromise OS benefit as evidenced by the lack of relationship observed between OS and RIB dose reduction, RDI, or drug exposure. This suggests that pts starting on RIB at 600 mg who require a dose modification for AE management or other reasons do not attenuate the survival benefit.
Clinical trial identification
NCT02422615 (September 19, 2018); NCT02278120 (February 26, 2019).
Editorial acknowledgement
Medical writing support was provided by William Ho, PhD, at MediTech Media, Ltd, funded by Novartis Pharmaceuticals Corporation.
Legal entity responsible for the study
Novartis Pharmaceuticals Corporation.
Funding
Novartis Pharmaceuticals Corporation.
Disclosure
M. De Laurentiis: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Advisory Board/Consultancy; Speaker's Bureau: Pfizer; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Advisory Board/Consultancy; Speaker's Bureau: Novartis; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Advisory Board/Consultancy; Speaker's Bureau: Roche; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Advisory Board/Consultancy; Speaker's Bureau: Celgene; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Advisory Board/Consultancy; Speaker's Bureau: AstraZeneca; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Advisory Board/Consultancy; Speaker's Bureau: Eisai; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Advisory Board/Consultancy; Speaker's Bureau: Eli Lilly; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Advisory Board/Consultancy; Speaker's Bureau: Amgen; Honoraria (self), Advisory/Consultancy, Advisory Board/Consultancy: MSD; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Advisory Board/Consultancy; Speaker's Bureau: Pierre Fabre. L. Hart: Honoraria (self), Speaker Bureau/Expert testimony, Research grant/Funding (institution), Research Grant; Speaker's Bureau: Novartis. A. Bardia: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses, Research Grant; Advisory Board/Consultancy; Travel Support: Genentech; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses, Research Grant; Advisory Board/Consultancy; Travel Support: Novartis; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses, Research Grant; Advisory Board/Consultancy; Travel Support: Pfizer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses, Research Grant; Advisory Board/Consultancy; Travel Support: Merck; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses, Research Grant; Advisory Board/Consultancy; Travel Support: Sanofi; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses, Research Grant; Advisory Board/Consultancy; Travel Support: Radius Health; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses, Research Grant; Advisory Board/Consultancy; Travel Support: Immunomedics; Research grant/Funding (institution), Research Grant: Mersana; Research grant/Funding (institution), Research Grant: Innocrin; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Research Grant; Advisory Board/Consultancy: Biothernostics, Inc.; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses, Advisory Board/Consultancy; Travel Support: Spectrum Pharma; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses, Advisory Board/Consultancy; Travel Support: Taiho; Honoraria (self), Advisory/Consultancy, Advisory Board/Consultancy: Daiichi Sankyo; Honoraria (self), Advisory/Consultancy, Advisory Board/Consultancy: Puma. S-A. Im: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Research Grant; Advisory Board/Consultancy: AstraZeneca; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses, Advisory Board/Consultancy; Travel Support: Novartis; Honoraria (self), Advisory/Consultancy, Advisory Board/Consultancy: Hanmi; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Research Grant; Advisory Board/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Research Grant; Advisory Board/Consultancy: Eisai; Honoraria (self), Advisory/Consultancy, Advisory Board/Consultancy: Amgen; Honoraria (self), Advisory/Consultancy, Advisory Board/Consultancy: MediPacto; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Research Grant; Advisory Board/Consultancy: Roche; Honoraria (self), Advisory/Consultancy, Advisory Board/Consultancy: Eli Lilly; Research grant/Funding (institution), Research Grant: Daewoong. J. Sohn: Research grant/Funding (institution), Research Grant: MSD; Research grant/Funding (institution), Research Grant: Roche; Research grant/Funding (institution), Research Grant: Novartis; Research grant/Funding (institution), Research Grant: AstraZeneca; Research grant/Funding (institution), Research Grant: Eli Lilly; Research grant/Funding (institution), Research Grant: Pfizer; Research grant/Funding (institution), Research Grant: Bayer; Research grant/Funding (institution), Research Grant: Glaxo-Smith Kline; Research grant/Funding (institution), Research Grant: Contessa; Research grant/Funding (institution), Research Grant: Daiichi Sankyo. M. Martin: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Advisory Board/Consultancy; Speaker's Bureau: Eli Lilly; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Advisory Board/Consultancy; Speaker's Bureau: Pfizer; Honoraria (self), Advisory/Consultancy, Advisory Board/Consultancy: AstraZeneca; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Research Grant; Advisory Board/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Research Grant; Advisory Board/Consultancy: Roche-Genentech; Honoraria (self), Advisory/Consultancy, Advisory Board/Consultancy: GlaxoSmithKline; Honoraria (self), Advisory/Consultancy, Advisory Board/Consultancy: Pharmamar; Honoraria (self), Advisory/Consultancy, Advisory Board/Consultancy: Taiho Oncology. Y. Ji: Shareholder/Stockholder/Stock options, Full/Part-time employment, Employment and Stock Ownership: Novartis. S. Yang: Shareholder/Stockholder/Stock options, Full/Part-time employment, Employment and Stock Ownership: Novartis. H. Hu: Shareholder/Stockholder/Stock options, Full/Part-time employment, Employment and Stock Ownership: Novartis. A. Lteif: Shareholder/Stockholder/Stock options, Full/Part-time employment, Employment and Stock Ownership: Novartis. D. Tripathy: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Research Grant; Advisory Board/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy, Advisory Board/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy, Advisory Board/Consultancy: Genomic Health; Honoraria (self), Advisory/Consultancy, Advisory Board/Consultancy: GlaxoSmithKline; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Research Grant; Advisory Board/Consultancy: Polyphor; Advisory/Consultancy, Advisory Board/Consultancy (unpaid): Puma Biotechnology; Honoraria (self), Speaker Bureau/Expert testimony, Speaker's Bureau: AstraZeneca; Honoraria (self), Advisory/Consultancy, Advisory Board/Consultancy: OncoPep; Honoraria (self), Advisory/Consultancy, Advisory Board/Consultancy: Sellas Life Sciences Group. All other authors have declared no conflicts of interest.