Abstract GS2-00: Correlative analysis of overall survival by intrinsic subtype across the MONALEESA-2, -3, and -7 studies of ribociclib + endocrine therapy in patients with HR+/HER2− advanced breast cancer
Authors: Carey Lisa , Solovieff Nadia , André Fabrice , O'Shaughnessy Joyce , Cameron David A , Janni Wolfgang , Sonke Gabe S , Yap Yoon-Sim , Yardley Denise A , Zarate Juan Pablo , Taran Tetiana , Su Faye , Lteif Agnes , Prat Aleix 
Published: March 2022

Background: The MONALEESA (ML)-2, -3, and -7 trials have shown a significant benefit in overall survival (OS) with ribociclib (RIB) + endocrine therapy (ET) over placebo (PBO) + ET in HR+/HER2− advanced breast cancer. HR+ breast cancer is a clinically and biologically heterogeneous disease, with identified intrinsic subtypes that vary in incidence, survival rate, and response to treatment. In a pooled analysis of the ML studies, patients with both luminal and HER2-enriched (HER2E) subtypes exhibited a consistent progression-free survival benefit with RIB + ET. The HER2E subtype (RIB, 14%; PBO, 11%), which is associated with ET resistance and poor outcomes, exhibited the greatest relative reduction in risk of progression or death (61%) with RIB + ET. Here, we report a pooled analysis of the ML-2, -3, and -7 trials, presenting OS by intrinsic subtype.. Methods: Tumor samples from patients enrolled in the ML-2, -3, and -7 trials underwent PAM50-based subtyping (blinded from clinical data), and the correlation between intrinsic subtype and OS was analyzed. Gene expression profiling of formalin-fixed, paraffin-embedded tumor samples was performed using a customized NanoString nCounter GX 800-gene panel. The prognostic and/or predictive relationship between PAM50-based subtypes and OS was evaluated using univariable and multivariable Cox proportional hazards models. Multivariable models were adjusted for known clinical prognostic factors, including age, prior chemotherapy, prior ET, ECOG performance status, visceral disease (presence of liver/lung metastases), bone-only metastases, histological grade, number of metastatic sites, tumor type, and de novo metastatic disease.. Results: From the pooled patient population (N = 2066), 997 tumor (71% primary) samples from the RIB (n = 585) and PBO (n = 412) arms of the ML trials (ML-2, n = 318; ML-3, n = 414; ML-7, n = 265) were profiled. Subtype distribution was consistent across treatment arms (Table). A similar benefit with RIB vs PBO was observed in the ITT (hazard ratio [HR], 0.76; 95% CI, 0.67-0.86) and biomarker (HR, 0.75; 95% CI, 0.63-0.89) populations. In both univariable and multivariable analyses, intrinsic subtype was prognostic for OS in both the RIB and PBO arms (P &lt; .0001 for both arms); patients with luminal A subtype had the best OS outcomes in both arms, whereas patients with basal-like subtype had the worst OS outcomes. Intrinsic subtype was also predictive of OS (subtype-treatment interaction: P = .016 [univariable], P = .007 [multivariable]) with a consistent OS benefit with RIB treatment in all subtypes except for basal-like (Table). Patients with HER2E (HR, 0.60; P = .018), luminal B (HR, 0.69; P = .023), and luminal A (HR, 0.75; P = .021) subtypes all derived benefit from RIB. In patients with the basal-like subtype (n = 30), the HR was 1.89 (P = .148); these results should be interpreted with caution due to the small sample size (3% in each arm) and exploratory nature of this analysis.Conclusions: This pooled analysis of the ML trials confirmed the prognostic and predictive value of intrinsic subtype (PAM50 based) for OS. The addition of RIB to ET resulted in consistent OS benefit across all subtypes except for basal-like. The. consistent survival benefit in the HER2E subtype, which is associated with endocrine resistance and a very poor prognosis compared with luminal disease, warrants further investigation.

SubtypeTreatment ArmDistribution, n (%)OS, median (95% CI), monthsHR (95% CI)P ValueaLuminal ARIB320 (55)68.0 (61.5-NR)0.75 (0.58-0.96).021PBO222 (54)54.6 (48.3-66.2)Luminal BRIB154 (26)58.8 (48.3-79.2)0.69 (0.50-0.95).023PBO124 (30)44.9 (35.5-52.6)HER2-enrichedRIB95 (16)40.3 (33.4-49.0)0.60 (0.40-0.92).018PBO52 (13)29.4 (23.9-42.0)Basal-likeRIB16 (3)19.4 (10.7-33.2)1.89 (0.80-4.47).148PBO14 (3)21.2 (12.8-NR)aP values are all two-sided. NR, not reached.

Citation Format: Lisa Carey, Nadia Solovieff, Fabrice André, Joyce O'Shaughnessy, David A Cameron, Wolfgang Janni, Gabe S Sonke, Yoon-Sim Yap, Denise A Yardley, Juan Pablo Zarate, Tetiana Taran, Faye Su, Agnes Lteif, Aleix Prat. Correlative analysis of overall survival by intrinsic subtype across the MONALEESA-2, -3, and -7 studies of ribociclib + endocrine therapy in patients with HR+/HER2− advanced breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS2-00.