Introduction: Endocrine therapy (ET) is a standard first-line (1L) therapy for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) MBC, but treatment resistance eventually emerges. Dysregulation of cyclin-dependent kinases 4 and 6 (CDK4/6) is implicated in ET resistance; thus, combined ET and CDK4/6 inhibition is a rational approach to prolong disease control and delay cytotoxic therapy. We summarize available Phase 3 data of CDK4/6 inhibitors (CDK4/6i) + ET for the 1L treatment of HR+, HER2- MBC, and highlight ongoing studies.

Methods: PubMed was searched for: “advanced breast cancer” AND (“first” OR “initial” OR "previously untreated") AND (ribociclib OR palbociclib OR abemaciclib). Results were manually filtered for Phase 3 studies of 1L treatment. Abstracts at AACR, ASCO, ESMO, and SABCS from 2016-2017 were also considered; clinicaltrials.gov was searched for ongoing trials.

Results: PubMed yielded 42 results, with 5 relevant after filtering; key congresses resulted in 34 abstracts. Four randomized Phase 3 trials investigating 1L CDK4/6i + ET reported primary data and subgroup analyses. PALOMA-2 (palbociclib [PAL] + letrozole [LET]), MONALEESA-2 (ribociclib [RIB] + LET), and MONARCH-3 (abemaciclib [ABE] + nonsteroidal [NS] aromatase inhibitor [AI]) included postmenopausal women with HR+, HER2- MBC. Across the studies, median progression-free survival (PFS) with ET alone was 14.5-16.0 months, and was significantly prolonged with addition of a CDK4/6i: PAL 24.8 months (HR 0.58), RIB 25.3 months (HR 0.57), and ABE not reached (HR 0.54), all p<0.001. To date, no study has reported an overall survival advantage. PFS data from relevant subgroup analyses and comparison of study populations will be presented. Most common adverse events (>50% in any study) were neutropenia (PAL all-grade 80%/Grade 3 or 4 66%; RIB 74%/59%; ABE 41%/21%), diarrhea (PAL 26%/1%; RIB 35%/1%; ABE 81%/10%), nausea (PAL 35%/<1%; RIB 52%/2%; ABE 39%/1%), and infections (PAL not reported/4%; RIB 50%/4%; ABE 39%/5%). The MONALEESA-7 trial of RIB + tamoxifen/NSAI + goserelin, the only study in premenopausal women with ovarian suppression, met its PFS primary endpoint. Ongoing studies of CDK4/6i + 1L ET include: PAL + LET in postmenopausal Asian women (PALOMA-4), PAL + tamoxifen (NCT02668666) and RIB + LET (CompLEEment-1) in men and pre/postmenopausal women, PAL + AI followed by PAL + fulvestrant (vs continued PAL + AI) after emergence of ESR1 mutations (confer resistance to AIs) and before disease progression (PADA-1), and assessment of mechanisms of resistance to RIB + LET (NCT03050398).

Conclusion: Phase 3 trials support CDK4/6 inhibition + ET for the 1L treatment of women with HR+, HER2- MBC. Ongoing trials are evaluating the safety and efficacy of CDK4/6i with other ET, in more diverse populations, continuation of CDK4/6 inhibition after first progression, and mechanisms of resistance.

Citation Format: Kent F. Hoskins, Paul Richards, Kari Wisinski. First-line CDK4/6 inhibitor treatment for HR+, HER2-negative metastatic breast cancer (MBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1615.