A review of phase III clinical trials of CDK4/6 inhibitor combination therapy in premenopausal women.

Abstract

141 Background: Clinical guidelines for the treatment of hormone receptor–positive (HR+), HER2− advanced breast cancer (ABC) are similar regardless of menopausal status, except for the role of ovarian suppression. However, breast cancers in premenopausal women frequently have an aggressive phenotype and a distinct underlying disease biology unaffected by ovarian suppression. Methods: We compared published trial designs, baseline characteristics, and efficacy and safety results of Phase 3 trials of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors including premenopausal women with HR+, HER2− ABC. Results: The MONALEESA-7 trial (NCT02278120) investigated ribociclib (or placebo) with a nonsteroidal aromatase inhibitor or tamoxifen + goserelin ovarian suppression in premenopausal women with ≤1 line of prior chemotherapy for ABC (N = 672); 40% had de novo metastases. Median progression-free survival (PFS) was 23.8 vs 13.0 months with ribociclib (n = 335) vs placebo (n = 337). In the PALOMA-3 trial (NCT01942135), 108 of 521 patients were premenopausal and treated with palbociclib (n = 72) or placebo (n = 36) + fulvestrant + goserelin; 75% had prior endocrine therapy (ET) or chemotherapy for ABC. Median PFS in the palbociclib vs placebo group was 9.5 vs 5.6 months. Adverse events common to both ribociclib and palbociclib ( > 30%) were neutropenia, leukopenia, and nausea. The MONARCH 2 trial (NCT02107703) evaluated abemaciclib (or placebo) with fulvestrant in 669 women with no prior chemotherapy for ABC (38% had 1 line of ET for ABC). In the premenopausal subset (abemaciclib, n = 72; placebo, n = 42; all with ovarian suppression), abemaciclib prolonged PFS (hazard ratio, 0.415 [95% confidence interval, 0.246–0.698]). Conclusions: While trial and patient characteristics differed substantially, safety and efficacy established in the MONALEESA-7 trial of premenopausal women and premenopausal subsets of the PALOMA-3 and MONARCH 2 trials support the activity and use of CDK4/6 inhibitor combination therapy in these patients. The treatment benefit observed in these trials was consistent with that in Phase 3 trials of postmenopausal women with HR+, HER2− ABC treated with CDK4/6 inhibitor combination therapy.