Phase I study of ribociclib (CDK4/6 inhibitor) with spartalizumab (PD-1 inhibitor) with and without fulvestrant in metastatic hormone receptor-positive breast cancer or advanced ovarian cancer

Garrido-Castro, AC; Graham, N; Ali, LR; Herold, C; Desrosiers, J; Do, K; Parsons, H; Li, T; Goel, S; DiLullo, M; Wrabel, E; Williams, AJ; Liu, JF; Mittendorf, EA; Dougan, SK; Tayob, N; Shapiro, GI; Tolaney, SM

Author(s): Garrido-Castro, AC; Graham, N; Ali, LR; Herold, C; Desrosiers, J; Do, K; Parsons, H; Li, T; Goel, S; DiLullo, M; Wrabel, E; Williams, AJ; Liu, JF; Mittendorf, EA; Dougan, SK; Tayob, N; Shapiro, GI; Tolaney, SM;
Details: Publication Year 2025-02-25,Volume 13,Issue #2,Page e010430
Journal Title: Journal for Immunotherapy of Cancer
Publication Type: Research article
Abstract: BACKGROUND: Preclinical evidence suggests that cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors enhance antitumor immunity. We conducted a phase I trial of ribociclib (CDK4/6 inhibitor) plus spartalizumab (PD-1 inhibitor) in patients with hormone receptor (HR)-positive/HER2-negative metastatic breast cancer (MBC) or advanced ovarian cancer (AOC). The combination was also evaluated with fulvestrant in MBC. METHODS: In Cohort A, ribociclib was administered on Days 1-21 (28-day cycle) starting at 400 mg, and spartalizumab at 400 mg on Day 1. Dose escalation was followed by expansion in AOC. Fulvestrant was added (Cohort B) with a safety run-in followed by expansion in MBC. Primary objectives were to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D), and safety and tolerability of the combinations. RESULTS: 33 patients enrolled (n=18, Cohort A; n=15, Cohort B). The RP2D of ribociclib in both cohorts was 600 mg. Treatment-related adverse events in >20% of patients in either cohort were neutropenia, fatigue, anemia, thrombocytopenia, hypertransaminasemia, maculopapular rash, fatigue, and nausea. Hypertransaminasemia occurred in 66.7% (AST) and 46.7% (ALT) of patients in Cohort B, including 46.7% and 40.0%, respectively, of grade 3 or 4 events. Two confirmed partial responses were observed (13.3%) in Cohort B, in patients with low baseline serum thymidine kinase activity, coupled with an increase on-treatment. Peripheral blood flow cytometry across patients demonstrated on-target drug binding with increases in PD-1 occupancy and activated CD8(+) T cells during treatment, irrespective of response. PD-L1-positivity, tumor-infiltrating lymphocytes, or tumor mutational burden did not correlate with progression-free survival (PFS). Several copy-number variations detected with next-generation sequencing correlated with PFS. CONCLUSIONS: Ribociclib with spartalizumab and fulvestrant showed limited efficacy and elevated hepatotoxicity, precluding further development. Correlative analyses revealed treatment-induced immunological effects, and genomic alterations associated with PFS.
Publisher: BMJ
Keywords: Humans; Female; *Purines/therapeutic use/pharmacology/administration & dosage; *Breast Neoplasms/drug therapy/pathology; Middle Aged; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse; effects/pharmacology; *Ovarian Neoplasms/drug therapy; Aged; *Aminopyridines/therapeutic use/administration & dosage/pharmacology; Adult; *Fulvestrant/therapeutic use/administration & dosage; *Antibodies, Monoclonal, Humanized/therapeutic use/administration &; dosage/adverse effects/pharmacology; Receptors, Estrogen/metabolism; Aged, 80 and over; Neoplasm Metastasis; Breast Cancer; Immunotherapy; Ovarian Cancer
Department(s): Medical Oncology
Publisher's Version: https://doi.org/10.1136/jitc-2024-010430
Open Access at Publisher's Site: https://doi.org/10.1136/jitc-2024-010430
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-03-18 06:23:42

Last Modified: 2025-03-18 06:24:11