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
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 br...
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BMJ Publishing Group
2025-02-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/13/2/e010430.full |
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| author | Sara M Tolaney Tianyu Li Elizabeth A Mittendorf Geoffrey I Shapiro Stephanie K Dougan Nabihah Tayob Joyce F Liu Khanh Do Heather Parsons Molly DiLullo Eileen Wrabel Lestat R Ali Ana C Garrido-Castro Noah Graham Christina Herold Jennifer Desrosiers Shom Goel Amy J Williams |
| author_facet | Sara M Tolaney Tianyu Li Elizabeth A Mittendorf Geoffrey I Shapiro Stephanie K Dougan Nabihah Tayob Joyce F Liu Khanh Do Heather Parsons Molly DiLullo Eileen Wrabel Lestat R Ali Ana C Garrido-Castro Noah Graham Christina Herold Jennifer Desrosiers Shom Goel Amy J Williams |
| author_sort | Sara M Tolaney |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-7bd0ffce46c74c5f81c3f53db1c6caa5 |
| institution | DOAJ |
| issn | 2051-1426 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-7bd0ffce46c74c5f81c3f53db1c6caa52025-08-20T03:11:25ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-02-0113210.1136/jitc-2024-010430Phase 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 cancerSara M Tolaney0Tianyu Li1Elizabeth A Mittendorf2Geoffrey I Shapiro3Stephanie K Dougan4Nabihah Tayob5Joyce F Liu6Khanh Do7Heather Parsons8Molly DiLullo9Eileen Wrabel10Lestat R Ali11Ana C Garrido-Castro12Noah Graham13Christina Herold14Jennifer Desrosiers15Shom Goel16Amy J Williams17Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USADepartment of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts, USABreast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, Massachusetts, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USADepartment of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, USAHarvard Medical School, Boston, Massachusetts, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USAHarvard Medical School, Boston, Massachusetts, USABreast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, Massachusetts, USABreast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, Massachusetts, USAHarvard Medical School, Boston, Massachusetts, USABreast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, Massachusetts, USADepartment of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts, USABreast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, Massachusetts, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USABreast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, Massachusetts, USABiovica International AB, Uppsala, Uppsala County, SwedenBackground 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.https://jitc.bmj.com/content/13/2/e010430.full |
| spellingShingle | Sara M Tolaney Tianyu Li Elizabeth A Mittendorf Geoffrey I Shapiro Stephanie K Dougan Nabihah Tayob Joyce F Liu Khanh Do Heather Parsons Molly DiLullo Eileen Wrabel Lestat R Ali Ana C Garrido-Castro Noah Graham Christina Herold Jennifer Desrosiers Shom Goel Amy J Williams 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 Journal for ImmunoTherapy of Cancer |
| 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| url | https://jitc.bmj.com/content/13/2/e010430.full |
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