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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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In Cohort A, ribociclib was administered on Days 1\u201321 (28-day cycle) starting at 400\u2009mg, and spartalizumab at 400\u2009mg 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      33 patients enrolled (n=18, Cohort A; n=15, Cohort B). The RP2D of ribociclib in both cohorts was 600\u2009mg. Treatment-related adverse events in &gt;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\n                      <jats:sup>+<\/jats:sup>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2024-010430","type":"journal-article","created":{"date-parts":[[2025,2,26]],"date-time":"2025-02-26T01:30:39Z","timestamp":1740533439000},"page":"e010430","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":19,"title":["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"],"prefix":"10.1136","volume":"13","clinical-trial-number":[{"clinical-trial-number":"nct03294694","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Ana C","family":"Garrido-Castro","sequence":"first","affiliation":[{"name":"Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, Massachusetts, USA"},{"name":"Department of 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