Abstract OT-37-01: Ribociclib-endocrine therapy (ET) combination versus chemotherapy as 1st line treatment in patients (pts) with visceral metastatic breast cancer (BC). A multicenter, randomized phase III trial: SAKK 21/18
Authors: Schwitter Michael , Zaman Khalil , Jerusalem Guy , Cazzaniga Marina , Greil Richard , Ursula Ursula Strub , Mueller Andreas , Nussbaum Catrina Uhlmann , Auteri Agnès , Rothgiesser Karin , Dietrich Daniel , Ruhstaller Thomas 
Published: February 2021

Abstract
Background: Pts with hormone receptor (HR)-positive/HER2-negative BC and visceral metastases have a worse outcome. Despite international guidelines recommending first line ET, many oncologists prefer to treat these pts primarily with chemotherapy, expecting a faster response. Combination of CDK4/6 inhibitors with ET was shown to be superior to ET alone, in terms of progression free survival (PFS), overall survival (OS), response rate and time to response, while maintaining QoL. The value of an initial period of chemotherapy followed by ET maintenance+/-CDK4/6i versus upfront ET+CDK4/6i is unknown, particularly in a population with visceral disease and mainly luminal B tumors, usually less endocrine sensitive.Trial design:As cancer response and QoL are the main parameters leading the decision of the oncologists, a composite endpoint “QoL-adjusted early disease control” (QoL-eDC) was developed to assess tumor response (progression-free at 12 weeks) and QoL (no deterioration according to FACT-B). The pts are randomized to: arm A, endocrine therapy (aromatase inhibitor or fulvestrant) with ribociclib; arm B, mono-chemotherapy at the choice of the physician for at least 12 weeks - thereafter, a switch to a maintenance ET+/-ribociclib is allowed.Baseline measurements and procedures: ECG, blood count, liver and renal functions, tumor assessment and QoL form (FACT-B, BPI-SF single item “worst pain”). Tumor and QoL assessments are repeated at baseline, on week 6, 12, then every 12 weeks, and at the end of trial treatment. Translational research: Plasma is collected for ctDNA at baseline, week 12, 24, then every 6 months, and at progression. Fresh tissue is collected at baseline and at progression, when feasible. Eligibility: Postmenopausal women presenting hormone receptor positive(ER ≥ 10%) and HER2-negative BC with measurable visceral disease, according to RECIST v1.1. Exclusion criteria include visceral crisis, previous systemic treatment for metastatic disease, prior adjuvant CDK4/6i, symptomatic and uncontrolled brain metastases, or significant organ dysfunction. Specific aims: Primary endpoint is QoL-eDC. Secondary endpoints are DC at 12 weeks, objective response rate (ORR), time to OR, PFS, time to treatment failure, OS at 3 years, overall change in QoL until 24 months or PD, time to QoL deterioration/improvement, time to pain improvement, and adverse events.Statistical methods:Group sequential two proportions non-inferiority design. Hypotheses for QoL-eDC during the first 12 weeks. H0: difference arm B – arm A is ≥ 12.5% and H1: difference arm B – arm A is &lt; 12.5%. With a significance level of 0.05, a power of 0.8 and one interim analysis a sample size of 190 pts in each arm (total sample size increased to 400 pts for potential excluded pts). Interim analysis: after 95 evaluable pts for the primary endpoint in each arm.Testing: one-sided group-sequential z-test with pooled variance according to the statistical design; categorical variables summarized using frequencies and percentages; modelling binary outcomes by logistic regression; time-to-event medians estimated by Kaplan-Meier method (95% CI); treatment effect on time-to-event endpoints assessed using Cox proportional hazard models with stratification factors as strata.Present accrual and target accrual: Recruitment started Q2, 2019. Recruitment on July 07, 2020: 20/400.22 centers are open for inclusion in Switzerland and 1/8 in Belgium. Study activation process is ongoing in Belgium (8 centers), Italy (15 centers) and Austria (5 centers).Contact: Karin Rothgiesser, SAKK Coordinating Center, Switzerland. karin.rothgiesser@sakk.ch ClinicalTrials.gov Identifier: NCT03905343
Citation Format: Michael Schwitter, Khalil Zaman, Guy Jerusalem, Marina Cazzaniga, Richard Greil, Ursula Strub Ursula, Andreas Mueller, Catrina Uhlmann Nussbaum, Agnès Auteri, Karin Rothgiesser, Daniel Dietrich, Thomas Ruhstaller. Ribociclib-endocrine therapy (ET) combination versus chemotherapy as 1st line treatment in patients (pts) with visceral metastatic breast cancer (BC). A multicenter, randomized phase III trial: SAKK 21/18 [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 OT-37-01.