Abstract PD4-06: First-line ribociclib + letrozole in hormone receptor-positive, HER2-negative advanced breast cancer: Efficacy by baseline circulating tumor DNA alterations in MONALEESA-2

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.

Endocrine-Resistant Breast Cancer: Mechanisms and Treatment

“…The reason for these findings remains elusive but might be due to inadequate assays to reflect protein function as well as to tumor heterogeneity and the fact that most analyses have been done with archival tissue from primary tumors. Additionally, neither ESR1 mutations nor PI3CA mutations were found to be associated with efficacy of CDK4/6 treatment [83][84][85].…”

Circulating tumor DNA analysis in breast cancer: Is it ready for prime-time?

“…ET in HR+/HER2-MBC has been recently revolutionized by the introduction of the CDK4/6 inhibitors (i.e. palbociclib, ribociclib and abemaciclib), but a dedicated predictive biomarker is currently lacking [93][94][95][96].…”

Emerging data and future directions for CDK4/6 inhibitor treatment of patients with hormone receptor positive HER2‐non‐amplified metastatic breast cancer

“…In this study, ESR1 mutations (a mutation in gene coding for the ERα) were not predictive of long term PFS improvement. Similar correlative studies performed in the MONALEESA‐2 clinical trial demonstrated that the addition of ribociclib to letrozole resulted in an improved PFS irrespective of the status of baseline ctDNA biomarkers ( RTK or ZNF703/FGFR1 alterations) …”

“…ER‐positivity and HER2‐non‐amplification are currently the only biomarkers used to select breast cancer patients for treatment with CDK4/6 inhibitors. Further analysis from PALOMA and MONALEESA clinical trials showed response to CDK4/6 inhibitors were not linked to a range of biomarkers from baseline samples . However sequential plasma samples analyzed from the PALOMA‐3 trial did show a decrease in PIK3CA ctDNA after 2 weeks strongly predicted for prolonged PFS with palbociclib compared to placebo .…”

“…The resistance phenotype was abrogated with the FGFR tyrosine kinase inhibitor lucitanib. Furthermore, in the MONALEESA‐2 study, FGFR1 amplification in ctDNA was shown to correlate with early progression on ribociclib . The data suggest that FGFR signaling is a mechanism of resistance to endocrine therapies with or without CDK4/6 inhibitors, with overexpression of cyclin D1 induced by both FGFR signaling and ER transcription .…”