Letrozole + ribociclib versus letrozole + placebo as neoadjuvant therapy for ER+ breast cancer (FELINE trial).

Abstract

505 Background: Ribociclib (R) + letrozole (L) is superior to L in metastatic breast cancer (BC). Preoperative endocrine prognostic index (PEPI) score 0 after neoadjuvant endocrine therapy (NET) is associated with low risk of relapse without chemotherapy in ER+ BC. On-therapy change in Ki-67 predicts adjuvant recurrence. FELINE is a biomarker-based multicenter randomized trial comparing changes in Ki-67 and PEPI between L+ Placebo (P) & L+R. Methods: Postmenopausal women with >2 cm or node+ ER+ HER2- BC were randomized 1:1:1 between L+P, L+R 400 mg continuous dose (Rc) and L+R 600 mg, 3 weeks on/1 week off - intermittent dose (Ri). Treatment was continued for six 28-day cycles. Core biopsies, blood samples were obtained at baseline, Day 14 cycle 1 (D14C1), and surgery. Clinical measurement, mammogram and US were obtained at baseline, surgery; MRI at baseline, week 8. Primary endpoint was rate of PEPI score 0 between L+P and L+R (i+c combined). Other endpoints were change in centrally performed Ki-67, complete cell cycle arrest (CCCA): Ki-67 <2.7%, clinical/imaging response, and difference in response & toxicity between the two R (Rc and Ri) arms. Results: From 2/2016 to 8/2018, 120 women were enrolled at 9 US centers. Thirty-eight were randomized to L+P and 82 to L+R groups (41 in Ri and Rc). Treatment groups were balanced at baseline. PEPI score of 0 was equal (25%) in L+P & L+R groups. CCCA at D14C1 was observed in 52% vs. 92% in L+P, L+R respectively (p < 0.0001). CCCA at surgery was observed in 63.3% vs. 71.4% in L+P, L+R respectively (p = NS). A significant increase in Ki-67 was observed between D14C1 and surgery in 66% vs. 33% in L+R, L+P respectively (p = 0.006). There was no difference in clinical, mammographic, US or MRI response between L+P and L+R. CCCA at D14C1 and surgery was similar in Ri & Rc arms. Grade >3 AEs were observed in 4 (10%) patients in L+P, 23 (56%) in L+Ri, 19 (46%) in L+Rc arms. Conclusions: Addition of R to L as NET did not result in more women with a PEPI score of 0. At D14C1 twice as many women on L+R had CCCA compared to L+P (92% vs 52%). However, significantly more women on L+R had increased proliferation between D14C1 and surgery , resulting in similar CCCA at surgery. Correlative studies are being performed to determine mechanisms of on-therapy acquired resistance to ribociclib. Continuous and intermittent doses of R have similar efficacy, toxicity. Clinical trial information: NCT02712723 . [Table: see text]

Inhibiting CDK4/6 in Breast Cancer with Palbociclib, Ribociclib, and Abemaciclib: Similarities and Differences

“…The addition of ribociclib to letrozole during six cycles in the neoadjuvant setting was explored in the FELINE trial. It showed a higher number of patients with a complete cell cycle arrest after 2 weeks of treatment in the ribociclib group compared with the placebo group, although at surgery no difference in proportion of patients with complete cell cycle arrest was found [65]. The NeoMonarch trial showed a reduction in Ki67 when abemaciclib was added to anastrazole compared with anastrazole monotherapy after 2 weeks of treatment [66].…”

Targeting Cell Cycle in Breast Cancer: CDK4/6 Inhibitors

“…Additionally, continuous and intermittent dose of ribociclib seem to have similar efficacy but different toxicity profiles. [105]. The adjuvant phase III trial NATALEE, aimed to delay acquired resistance to ET and to improve invasive disease-free survival (iDFS), compares the efficacy and the safety of ribociclib plus standard ET versus ET alone as adjuvant therapy for HR-positive, HER2-negative early BC and is still ongoing [106].…”

Neoadjuvant Endocrine Therapy in Breast Cancer Management: State of the Art

“…The phase II FELINE trial was designed to determine whether neoadjuvant therapy with ribociclib combined with letrozole for 24 weeks increases the proportion of patients with a PEPI score of 0 at surgery, compared with single agent letrozole. Preliminary results did not show any difference between the two treatment arms [ 89 ].…”