No abstract

Background: The addition of first-line ribociclib (RIB; cyclin-dependent kinase 4/6 inhibitor) to letrozole (LET) significantly improved progression-free survival (PFS) compared with placebo (PBO) + LET in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC) in the Phase III MONALEESA-2 study. Identifying biomarkers that predict response to treatment remains a key challenge in pts with HR+ ABC. Here we analyze results from MONALEESA-2 by molecular alterations detected in circulating tumor DNA (ctDNA) at baseline, including PIK3CA mutations and other alterations considered to be important in HR+ ABC. Methods: Postmenopausal women (N=668) with HR+, HER2– ABC who had not received any prior therapy for ABC were randomized 1:1 to RIB (600 mg/day; 3-weeks-on/1-week-off) + LET (2.5 mg/day; continuous) or PBO + LET. The primary endpoint was PFS. Biomarker analysis of the ctDNA mutation profile was an exploratory endpoint. Plasma samples for ctDNA analysis were collected at baseline and end of treatment. ctDNA was analyzed using next-generation sequencing with a targeted panel of ˜550 genes. Results: Baseline ctDNA was successfully sequenced in 494 pts (RIB + LET: n=212; PBO + LET: n=215); 67 (14%) of 494 pts were removed from the analysis due to limited tumor DNA in circulation. 427 (86%) pts had ≥1 alteration, including 1,573 mutations, 513 short insertions/deletions, 166 amplifications, and 8 translocations. Alterations (frequency) were commonly observed in the following genes: PIK3CA (33%), TP53 (12%), ZNF703/FGFR1 (5%), and ESR1 (4%), and in genes involved in receptor tyrosine kinase (RTK) signaling (12%). RIB + LET treatment benefit was consistent in pts with wild-type (WT) and altered PIK3CA, and in pts with WT and altered TP53 (Table). RIB + LET improved PFS regardless of RTK or ZNF703/FGFR1 alterations. However, there was a weak trend for increased benefit in pts with WT vs altered RTK genes and in pts with WT vs altered ZNF703/FGFR1 genes. These results should be interpreted with caution due to the small number of pts with these alterations. There were too few ESR1 alterations for firm conclusions to be drawn.  Events, n/NMedian PFS, months Gene(s)RIB + LETPBO + LETRIB + LETPBO + LETHazard ratio (95% confidence interval)PIK3CAWT54/14393/14229.614.70.44 (0.31–0.62)Altered40/6955/7319.212.70.53 (0.35–0.81)TP53WT72/180129/19427.614.70.44 (0.33–0.59)Altered22/3219/2110.25.50.43 (0.23–0.83)ZNF703/FGFR1WT88/202139/20524.814.60.47 (0.36–0.62)Altered6/109/1010.611.40.73 (0.23–2.29)RTKWT81/189128/18724.814.40.46 (0.35–0.61)Altered13/2320/2821.311.40.72 (0.34–1.53) Conclusions: Consistent RIB + LET treatment benefit was observed compared with PBO + LET, irrespective of the status of baseline ctDNA biomarkers. Citation Format: Hortobagyi GN, Stemmer S, Campone M, Sonke GS, Arteaga CL, Paluch-Shimon S, Petrakova K, Villanueva C, Nusch A, Grischke E-M, Chan A, Jakobsen E, Marschner N, Hart LL, Alba E, Ohnstand HO, Blau S, Yardley DA, Solovieff N, Su F, Germa C, Yap Y-S. First-line ribociclib + letrozole in hormone receptor-positive, HER2-negative advanced breast cancer: Efficacy by baseline circulating tumor DNA alterations in MONALEESA-2 [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD4-06.