Abstract OT2-04-02: CheckMate 7A8: A phase 2 trial of nivolumab + abemaciclib or palbociclib + anastrozole in postmenopausal women with ER+, HER2−primary breast cancer
Authors: Tolaney Sara , Jerusalem Guy , Salgado Roberto , Liu Xiaochun , Chen Tian , Zhang Hongxia , Roberts Mustimbo , Zardavas Dimitrios , Prat Aleix 
Published: March 2020

Abstract
Background: Programmed death-1 (PD-1) pathway inhibition has demonstrated clinical activity in breast cancer (BC), with modest response rate in advanced, heavily pretreated, hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2−) BC. Cyclin-dependent kinase 4/6 (CDK 4/6) inhibition coupled with estrogen receptor (ER) signaling blockade is an efficient treatment approach for patients with metastatic HR+/HER2− BC, evaluated in the primary setting. Preclinical data suggest potential synergistic activity of CDK 4/6 inhibition coupled with PD-1 blockade through modulation of the tumor microenvironment by the former modality. In a syngeneic mouse tumor model, improved efficacy and complete tumor regression were observed with abemaciclib priming the immune response in phased administration of abemaciclib + anti-programmed death ligand 1 (PD-L1) therapy. Preliminary clinical data demonstrated activity of pembrolizumab + abemaciclib in a phase 1b study of pretreated patients with metastatic HR+, HER2− BC.
Trial Design: CheckMate 7A8 is a randomized, noncomparative, multicenter, phase 2 study evaluating nivolumab + either abemaciclib or palbociclib + anastrozole in postmenopausal patients with ER+, HER2− primary BC. After determining safe doses for the nivolumab combination regimens in the safety run-in phase, patients will be randomized in a 4:4:3:4:4:3 ratio to 1 of 6 treatment arms (Table) stratified by PD-L1 expression (+ or −), node status (+ or −), and tumor size (&gt; 3 cm or ≤ 3 cm). Following treatment, all patients will undergo surgery and safety follow-up.
Eligible patients are postmenopausal women with newly diagnosed, untreated, histologically confirmed ER+, HER2− BC with primary tumor ≥ 2 cm; with measurable disease based on RECIST v1.1; suitable for neoadjuvant endocrine monotherapy and surgery; have an ECOG PS of 0 or 1; have tumor tissue available at baseline; and are willing to undergo on-treatment research biopsy and tissue collection at surgery. Women of childbearing potential or who are breastfeeding, have a history of ipsilateral invasive BC regardless of treatment or DCIS treated with radiotherapy, metastatic disease, inflammatory/inoperable, multicentric, or bilateral invasive BC, or those suitable for neoadjuvant chemotherapy are excluded.
Primary study endpoints are: i) number of patients with occurrence of dose-limiting toxicity (safety run-in phase), and ii) residual cancer burden (RCB) 0-I rate by central assessment at time of definitive surgery (randomized phase). Secondary endpoints include safety and tolerability, pathologic complete response, and objective response rate. Key exploratory endpoints include biomarkers indicative of pharmacodynamic changes in the tumor microenvironment, biomarkers predicting treatment sensitivity, changes in Ki67 levels, ER status and preoperative endocrine prognostic index score, and efficacy by PD-L1 status. Sample size was calculated assuming a 22% target RCB rate; 40 treated patients will provide 81% power at 10% 2-sided type I error to reject the null hypothesis that the true RCB rate is 8%, below which is not clinically meaningful. For primary and secondary endpoints, estimates of response rates and corresponding 95% confidence intervals will be generated for each arm using the Clopper-Pearson method.
No patients have yet been recruited. For information, please contact Xiaochun.Liu@bms.com.
Study arms during the safety run-in and randomized phasesSafety run-in phaseCohort 1 (n = 3–6)Nivolumab 480 mg Q4W IV + abemaciclib 150 mg BID PO + anastrozole 1 mg QD PO × 5 cyclesCohort 2 (n = 3–6)Nivolumab 480 mg Q4W IV + palbociclib 125 mg QD PO 3 weeks on 1 week off + anastrozole 1 mg QD PO × 5 cyclesRandomized phaseArm A (n = 40)Nivolumab 480 mg Q4W IV + abemaciclib 150 mg BID PO + anastrozole 1 mg QD PO × 5 cyclesArm B (n = 40)Abemaciclib 150 mg PO BID + anastrozole 1 mg QD PO × 1 cycle then nivolumab 480 mg Q4W IV + abemaciclib 150 mg BID PO + anastrozole 1 mg QD PO × 4 cyclesArm C (n = 30)Abemaciclib 150 mg BID PO + anastrozole 1 mg QD PO × 5 cyclesArm D (n = 40)Nivolumab 480 mg Q4W IV + palbociclib 125 mg QD PO 3 weeks on 1 week off + anastrozole 1 mg QD PO × 5 cyclesArm E (n = 40)Palbociclib 125 mg QD PO 3 weeks on 1 week off + anastrozole 1 mg QD PO × 1 cycle then nivolumab 480 mg Q4W IV + palbociclib 125 mg QD PO 3 weeks on 1 week off + anastrozole 1 mg QD PO × 4 cyclesArm F (n = 30)Palbociclib 125 mg QD PO 3 weeks on 1 week off + anastrozole 1 mg QD PO × 5 cyclesBID, twice daily; IV, intravenous; PO, by mouth; QD, once daily; Q4W, every 4 weeks.
Citation Format: Sara Tolaney, Guy Jerusalem, Roberto Salgado, Xiaochun Liu, Tian Chen, Hongxia Zhang, Mustimbo Roberts, Dimitrios Zardavas, Aleix Prat. CheckMate 7A8: A phase 2 trial of nivolumab + abemaciclib or palbociclib + anastrozole in postmenopausal women with ER+, HER2−primary breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-04-02.