12 TIP HARMONIA SOLTI-2101/ AFT-58: A Head-to-Head Phase III Study Comparing Ribociclib (RIB) and Palbociclib (PAL) in Patients (pts) With Hormone Receptor– Positive/HER2-Negative/HER2- Enriched (HR+/HER2−/HER2-E) Advanced Breast Cancer (ABC)

Background

RIB and PAL are CDK4/6 inhibitors with efficacy and tolerability in pts with HR+/HER2− ABC when administered in combination with endocrine therapy (ET). RNA-based intrinsic subtyping has strong prognostic and predictive value in advanced HR+/HER2− tumors treated with ET. Nonluminal subtypes, such as HER2-E and basal-like, are relatively endocrine-resistant and have a poorer prognosis than luminal. Tumors can switch subtypes over time to more aggressive and less endocrine-responsive biology, which may also be reversed by effective treatment. A pooled retrospective analysis of MONALEESA 2/3/7 trials showed that HER2-E tumors had surprising benefits from RIB treatment, while basal-like tumors did not. Pre/clinical data suggest that RIB may outperform PAL in HER2-E. HARMONIA seeks to identify the best therapeutic option between RIB and PAL for pts with HR+/ HER2−/HER2-E ABC and aims to test whether RIB changes tumor biology thus enabling better response to ET and improving the disease course. In addition, it explores the value of earlier treatment with chemotherapy in pts with basal-like tumors.

Materials and Methods

This is an international, multicenter, randomized, open-label, phase 3 study, using prospective pre-selection based on tumor biology in pts with HR+ (ER <100%)/HER2– ABC, with HER2-E tumors (main cohort, 456 pts) and with basal-like tumors (exploratory cohort ~60 pts). Pts with HER2-E tumors will be randomized 1:1 to RIB+ET (letrozole or fulvestrant) or PAL+ET. In the basal-like cohort, pts will be treated with paclitaxel. Primary end point (EP): progression-free survival (PFS) per RECIST v1.1 by investigator-assessment. Secondary EP: overall survival, PFS2, clinical benefit rate, duration and time to response, quality of life, and exploratory EP, including subtype switching between primary and metastatic tumors, and after-trial treatment. Primary EP final analysis will be performed after 310 PFS events are observed (~80% power using one-sided 5% α).

Status

HARMONIA will recruit in Spain (40 sites), Portugal (5), and the US (35) within SOLTI & AFT network.

AFFILIATIONS:

Lisa Carey,^1,2 Tomas Pascual,^1,2 Daniel Stover,³ Astrid Thuerigen,⁴ Charles Perou,⁵ Eva Ciruelos,^1,6 Ana Casas,¹ Patty Spears,⁷ Estelle Roux,⁴ Faye Su,⁸ Hullin Hu,⁸ Yen-Shen Lu,⁹ Sara M. Tolaney,¹⁰ Ann Partridge,¹⁰ Guillermo Villacampa,¹¹ Juan Manuel Ferrero-Cafiero,¹ Aleix Prat^1,2

¹SOLTI Cancer Research Group, Barcelona Spain.

²Medical Oncology Department, Hospital Clinic de Barcelona, Translational Genomics and Targeted Therapies in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.

³Medical Oncology Department, Stefanie Spielman Comprehensive Breast Center, Columbus, OH.

⁴Novartis Pharma AG, Basel, Switzerland.

⁵Perou Lab, UNC – Lineberger Comprehensive Cancer Center, Chapel Hill, NC.

⁶Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain.

⁷Lineberger Comprehensive Cancer Center, UNC - Lineberger Cancer Center, Chapel Hill, NC.

⁸Novartis Pharmaceuticals Corp., East Hanover, NJ.

⁹Department of Oncology, NTUH – National Taiwan University Hospital, Taipei City, Taiwan. 10Medical Oncology, Dana Farber Cancer Institute, Boston, MA.

¹¹Statistics Department, Vall d’Hebron Institute of Oncology (VHIO)-Cellex Center, Barcelona, Spain.

¹²Alliance Breast Committee/UNC – Lineberger Comprehensive Cancer Center, Chapel Hill, NC.