LBA16 Dalpiciclib plus letrozole or anastrozole as first-line treatment for HR+/HER2- advanced breast cancer (DAWNA-2): A phase III trial

Abstract

Dalpiciclib (dalp), a novel CDK4/6 inhibitor, with fulvestrant improved PFS in patients (pts) with HR+/HER2- advanced breast cancer (ABC) progressing after endocrine therapy (ET) in the phase 3, DAWNA-1 trial (Nature Medicine 2021). Here we assessed dalp with ET in the 1st-line setting. DAWNA-2 was a randomized, multicenter, double-blind, phase 3 trial done in 42 centers in China. Pts with untreated HR+/HER2- locally recurrent or metastatic BC, and any menopausal status were randomized 2:1 to receive dalp (150 mg, po, qd, d1-21, q4w) or placebo + letrozole (2.5 mg, po, qd) or anastrozole (1 mg, po, qd). The primary endpoint was PFS per investigator (INV). A prespecified interim analysis was done after 186 (70.5% of total expected) PFS events occurred (Jun 1, 2022), and the corresponding superiority boundary was 1-sided P <0.0076. 456 pts were randomized to dalp + letrozole/anastrozole (N=303) or placebo+ letrozole/anastrozole (N=153). With a median follow-up of 21.7 and 21.4 mo respectively, PFS per INV was significantly improved in the dalp group vs the placebo group (median, 30.6 mo [95% CI 30.6-NR] vs 18.2 mo [16.5-22.5]; HR 0.51 [95% CI 0.38-0.69], 1-sided P <0.0001). PFS benefit with dalp was evident regardless of menopausal status (Table 1). ORR and DoR per INV also favored the dalp group (Table 1). The most frequent grade ≥3 AEs in the dalp group was neutropenia (85.8% [grade 3/4, 64.6%/21.2%] vs 0 in the placebo group) and leukopenia (66.6% [grade 3/4, 65.9%/0.7%] vs 0). SAEs occurred in 11.9% in the dalp group and 6.5% in the placebo group; 4.0% and 2.0% discontinued any treatment due to AEs respectively.Table: LBA16Efficacy summaryDalp group (N=303)Placebo group (N=153)PFSOverall populationMedian (95% CI), mo30.6 (30.6-NR)18.2 (16.5-22.5)HR (95% CI)∗, P†0.51 (0.38-0.69), P <0.0001Pre/peri-menopausal womenMedian (95% CI), moNR (27.7-NR)16.6 (12.9-27.7)HR (95% CI)‡0.53 (0.33-0.85)Postmenopausal womenMedian (95% CI), mo30.6 (24.9-NR)19.4 (16.6-24.6)HR (95% CI)‡0.52 (0.36-0.75)ORR, % (95% CI)57.4 (51.6-63.1)47.7 (39.6-55.9)Median DoR (95% CI), moNR (26.9-NR)15.0 (12.9-20.3)∗ StratifiedCox proportional hazards model.† 1-sided stratified Log-rank test. ‡ Unstratified Cox proportional hazards model. NR=not reached. Open table in a new tab ∗ StratifiedCox proportional hazards model.† 1-sided stratified Log-rank test. ‡ Unstratified Cox proportional hazards model. NR=not reached. Adding dalp to letrozole/anastrozole significantly prolonged PFS in HR+/HER2- ABC, with manageable toxicities. Dalp is the 4th CDK4/6 inhibitor showing survival benefit with letrozole or anastrozole in untreated HR+/HER2- ABC, or with fulvestrant in pretreated HR+/HER2- ABC, in addition to palbociclib, ribociclib and abemaciclib.