Abstract P3-14-03: A phase 1b study of the CDK4/6 inhibitor ribociclib in combination with the PD-1 inhibitor spartalizumab in patients with hormone receptor-positive metastatic breast cancer (HR+ MBC) and metastatic ovarian cancer (MOC)
Authors: Herold Christina I , Trippa Lorenzo , Li Tianyu , Do Khanh , Bardia Aditya , Anderson Leilani , Montazeri Kamaneh , Pittenger Jessica , Andrews Chelsea , Mittendorf Elizabeth A , Goel Shom , Winer Eric P , Shapiro Geoffrey I , Tolaney Sara M 
Published: March 2020

Abstract
Background: Immune checkpoint inhibitors (ICI), such as those targeting the PD-1/PD-L1 axis, have shown modest activity as monotherapy in both HR+ MBC and MOC. Strategies to improve ICI for these diseases are under investigation. In mouse models, CDK4/6 inhibitors boost anti-tumor immunity in part by increasing the infiltration and activation of cytotoxic T lymphocytes, and by suppressing regulatory T lymphocyte function, providing rationale for combining CDK4/6 inhibition and ICI.
Methods: We conducted an open-label phase 1b dose escalation study with the primary objectives of determining the safety, tolerability, maximum-tolerated dose (MTD) and recommended phase 2 dose (RP2D) of ribociclib and spartalizumab in patients with HR+ MBC and MOC. Ribociclib was administered on days 1-21 and spartalizumab on day 1 of a 28-day cycle. The study used a 3 + 3 dose escalation design with dose-limiting toxicities (DLTs) formally defined during the first cycle. For the dose escalation there were no restrictions on prior chemotherapy or CDK4/6 inhibitor use but prior PD-1/PD-L1 inhibitor use was not allowed. Once the MTD/RP2D was determined, we conducted a safety run-in for the combination of ribociclib and spartalizumab with fulvestrant in patients with HR+ MBC.
Results: During dose escalation, 9 patients with HR+ MBC and 1 patient with MOC were enrolled. Three patients each were enrolled to dose levels 1 and 2 (ribociclib 400 mg and 600 mg PO QD for 21/28 days, respectively, and spartalizumab 400 mg IV q28 days) and no DLTs were observed. Four additional patients were enrolled to dose level 2; one was deemed unevaluable due to drug compliance issues and was replaced. Among the 3 evaluable patients, 1 experienced a DLT of grade 3 atrial fibrillation and flutter, which were possibly related to both ribociclib and spartalizumab. Based on this experience, the MTD/RP2D was declared to be ribociclib 600mg PO QD for 21/28 days in combination with spartalizumab 400mg IV q28 days. For the safety run-in, evaluating the addition of fulvestrant to the combination of ribociclib and spartalizumab, 6 patients with HR+ MBC were enrolled and no additional DLTs were observed. Among all patients with MBC (n=15), the median number of prior hormonal therapies was 2 (range 0-4); 10 patients (67%) had previously received fulvestrant, and all patients had previously received a CDK4/6 inhibitor. For the entire group (n=16), 10 patients (63%) had received 4 or more prior lines of chemotherapy for metastatic disease. The most common grade 3 and 4 toxicities regardless of treatment attribution were neutropenia (n = 8, 50%), increased aspartate aminotransferase (n = 4, 25%), increased alanine aminotransferase (n = 4, 25%). Median follow-up for all patients was 3.5 months (95% CI: 2.8 - 5.1). Among the 16 patients treated, 1 breast cancer patient had a PR (ORR=6.25%, 95% CI: 0-30%) and 1 breast cancer patient had SD for &gt; 24 weeks (6.25%, 95% CI 0-30%); CBR = 12.5% (95% CI: 1.6-38.3%): both of these patients received ribociclib and spartalizumab with fulvestrant. The median PFS for all patients was 3.1 months (95% CI: 1.9 - NR), and the median OS was 6.0 months (95% CI: 6.0 - NR).
Conclusion: In this phase 1b study, the combination of ribociclib and spartalizumab was well tolerated with toxicity consistent with that expected from each agent alone and no new toxicities were observed. The RP2D for the combination is ribociclib 600mg PO QD for 21/28 days and spartalizumab 400mg IV q28 days with or without fulvestrant. Clinical benefit was achieved in 2 breast cancer patients who had previously received a CDK4/6 inhibitor combined with hormonal therapy. Dose expansion cohorts are currently enrolling for patients with HR+ MBC and MOC.
Citation Format: Christina I Herold, Lorenzo Trippa, Tianyu Li, Khanh Do, Aditya Bardia, Leilani Anderson, Kamaneh Montazeri, Jessica Pittenger, Chelsea Andrews, Elizabeth A Mittendorf, Shom Goel, Eric P Winer, Geoffrey I Shapiro, Sara M Tolaney. A phase 1b study of the CDK4/6 inhibitor ribociclib in combination with the PD-1 inhibitor spartalizumab in patients with hormone receptor-positive metastatic breast cancer (HR+ MBC) and metastatic ovarian cancer (MOC) [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 P3-14-03.