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Translational RelevancePre-/perimenopausal patients with hormone-receptor positive (HR+)/human epithelial growth factor 2 negative (HER2-) advanced breast cancer (ABC) typically have a poorer prognosis and are under-represented in clinical trials. MONALEESA-7 is a phase 3 trial that studied ribociclib plus endocrine therapy (ET) versus placebo plus ET and dedicated specifically to peri-/premenopausal patients with HR+/HER2-ABC. The final protocol-specified overall survival (OS) analysis of MONALEESA-7 demonstrated a statistically significant OS benefit with ribociclib, however, outcomes can change over time, requiring prolonged observation to account for this disease's long natural history.An exploratory OS analysis of MONALEESA-7 with an extended follow-up (median, 53.5 months) was conducted revealing a median OS of 58.7 months in the ribociclib group versus 48.0 months in the placebo group (hazard ratio, 0.76; 95% CI, 0.61-0.96) with no new safety signals observed. These results show that ribociclib + ET continued to demonstrate OS benefit in pre-/perimenopausal patients long term.Research.

Background: MONALEESA-7 (NCT02278120), the first large randomized phase III clinical trial dedicated to investigating a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) plus ET vs ET + placebo (PBO) in pre- or perimenopausal patients with HR+/HER2− ABC, previously demonstrated a statistically significant improvement in OS with the addition of ribociclib (RIB) to ET vs PBO + ET (median, not reached vs 40.9 months; HR, 0.71 [95% CI, 0.54-0.95]; P = .00973; Im SA, et al. N Engl J Med. 2019). This concluded the protocol-defined final analysis of OS and the patients and investigators were unblinded to their treatment assignment allowing patients on the PBO arm to cross-over to RIB treatment. Longer follow-up allows for more events to further characterize the long-term survival benefits. Here we report an exploratory update of OS after a minimum of ~ four years of follow-up, an additional 20 months since the last report. Methods: Pre- or perimenopausal patients with HR+/HER2− ABC were randomized 1:1 to receive RIB or PBO plus goserelin with either a nonsteroidal aromatase inhibitor (NSAI; letrozole or anastrozole) or tamoxifen. RIB is approved in combination with an NSAI in pre- or perimenopausal patients. Patients who had received a prior CDK4/6i or ET in the advanced setting were excluded. Patients who received ET in the (neo)adjuvant setting or ≤ 1 prior line of chemotherapy for advanced disease were eligible to enroll. Updated OS were evaluated by Cox proportional hazards model and summarized using Kaplan-Meier methods. Additional post-progression endpoints such as progression-free survival 2 (PFS2), time to chemotherapy (CT) and CT-free survival were also evaluated and summarized. Results: The data cutoff for this updated OS analysis was 29 June 2020, and the median follow-up was 53.5 mo (min, 46.9 mo). These updated results with extended follow-up demonstrated an OS benefit with RIB + ET vs PBO + ET (median, 58.7 vs 48.0 mo; HR, 0.76 [95% CI, 0.61-0.96]). In patients receiving an NSAI, a similar OS benefit was observed with RIB + NSAI vs PBO + NSAI (median, 58.7 vs 47.7 mo; HR, 0.80 [95% CI, 0.62-1.04]). The survival benefit shown in subgroup analyses was consistent with the intent-to-treat (ITT) population. PFS2, time to chemotherapy (CT), and CT-free survival for the ITT and NSAI populations are in the Table. Among the patients who discontinued study treatment, 77.3% and 78.1% in the RIB + ET vs PBO + ET arms received a subsequent antineoplastic therapy, respectively, and 12.9% and 26.1% received a subsequent line of CDK4/6i. Additionally there were 15 patients in the PBO arm that crossed over to the RIB arm following unblinding and prior to disease progression. Conclusions: With an extended follow-up of more than 4 years, RIB + ET continued to demonstrate a clinically relevant OS benefit compared with ET alone in pre- or perimenopausal patients with a median OS ~5 years with RIB +ET in HR+/HER2− ABC. A similar benefit with RIB was observed for PFS2, time to CT, and CT-free survival. ITTNSAI cohortRIB + ETn=335PBO + ETn=337RIB + NSAIn=248PBO + NSAIn=247PFS2Events, n (%)177 (52.8)221 (65.6)131 (52.8)159 (64.4)Median, mo44.231.043.630.4HR (95% CI)0.68 (0.56-0.83)0.69 (0.55-0.87)Time to first CTEvents, n (%)144 (43.0)173 (51.3)107 (43.1)129 (52.2)Median, mo50.936.850.936.0ITT HR(95% CI)0.69 (0.56-0.87)0.66 (0.51-0.85)CT-free survivalEvents, n (%)190 (56.7)236 (70.0)139 (56.0)169 (68.4)Median, mo42.426.442.525.9HR (95% CI)0.67 (0.55-0.81)0.64 (0.51-0.81) Citation Format: Debu Tripathy, Seock-Ah Im, Marco Colleoni, Fabio Franke, Aditya Bardia, Nadia Harbeck, Sara Hurvitz, Louis Chow, Joohyuk Sohn, Keun Seok Lee, Saul Campos-Gomez, Rafael Villanueva Vazquez, Kyung Hae Jung, K Govind Babu, Paul Wheatley-Price, Michelino De Laurentiis, Young-Hyuck Im, Sherko Kümmel, Nagi El-Saghir, Mei-Ching Liu, Sharonjeet Kaur, Claudia Gasch, Craig Wang, Yongyu Wang, Arunava Chakravartty, Yen-Shen Lu. Updated overall survival (OS) results from the phase III MONALEESA-7 trial of pre- or perimenopausal patients with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2−) advanced breast cancer (ABC) treated with endocrine therapy (ET) ± ribociclib [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD2-04.

PURPOSE This analysis evaluated the genomic landscape of premenopausal patients with hormone receptor–positive and human epidermal growth factor receptor 2–negative advanced breast cancer and the association of genetic alterations with response to ribociclib in the phase III MONALEESA-7 trial. METHODS Premenopausal patients were randomly assigned 1:1 to receive endocrine therapy plus ribociclib or placebo. Plasma collected at baseline was sequenced using targeted next-generation sequencing for approximately 600 relevant cancer genes. The association of circulating tumor DNA alterations with progression-free survival (PFS) was evaluated to identify biomarkers of response and resistance to ribociclib. RESULTS Baseline circulating tumor DNA was sequenced in 565 patients; 489 had evidence of ≥ 1 alteration. The most frequent alterations included PIK3CA (28%), TP53 (19%), CCND1 (10%), MYC (8%), GATA3 (8%), receptor tyrosine kinases (17%), and the Chr8p11.23 locus (12%). A treatment benefit of ribociclib was seen with wild-type (hazard ratio [HR] 0.45 [95% CI, 0.33 to 0.62]) and altered (HR 0.57 [95% CI, 0.36 to 0.9]) PIK3CA. Overall, patients with altered CCND1 had shorter PFS regardless of treatment, suggesting CCND1 as a potential prognostic biomarker. Benefit with ribociclib was seen in patients with altered (HR 0.21 [95% CI, 0.08 to 0.54]) or wild-type (HR 0.52 [95% CI, 0.39 to 0.68]) CCND1, but greater benefit was observed with altered, suggesting predictive potential of CCND1. Alterations in TP53, MYC, Chr8p11.23 locus, and receptor tyrosine kinases were associated with worse PFS, but ribociclib benefit was independent of alteration status. CONCLUSION In this study—to our knowledge, the first large study of premenopausal patients with hormone receptor–positive and human epidermal growth factor receptor 2–negative advanced breast cancer—multiple genomic alterations were associated with poor outcome. A PFS benefit of ribociclib was observed regardless of gene alteration status, although in this exploratory analysis, a magnitude of benefits varied by alteration.