Instructor of Medicine Harvard Medical School Dana-Farber Cancer Institute Needham, MA, United States
Background: There is a need to develop new therapeutic combinations and targets for the treatment of advanced ccRCC. The cell cycle pathway is dysregulated in a significant proportion of ccRCC and pre-clinical studies have suggested that CDK4/6 inhibitors (i) have single-agent activity in ccRCC as well as synergism with IO. We hypothesize that this triplet will have efficacy and demonstrate additive activity compared to the approved doublet.
Methods: NCT05176288 is a multi-center single-arm phase 2 trial. The primary objective is to evaluate the ORR per RECIST 1.1 of axi+avelumab+palbociclib in untreated advanced ccRCC. Secondary objectives: evaluate safety, the rate of CR and deep PR (≥80% reduction in target lesions) and determine PFS and OS. Exploratory objectives: immunologic and biologic correlates of response, resistance and survival with the triplet. Optional research biopsies will be performed as well as bulk whole-exome sequencing (seq) and single-cell RNA-seq to evaluate changes in gene signatures and immune cell populations during therapy. Alterations in candidate genes (cyclin D, CKD4 and CDK6) will be correlated with response to therapy. Blood will be collected to evaluate serum thymidine kinase 1 (sTK1) levels, a functional biomarker of cell cycle activity. Key eligibility criteria: untreated advanced ccRCC (sarcomatoid histology allowed), measurable disease per RECIST 1.1, adequate organ/marrow function, ECOG ≤2. Exclusions: prior systemic therapy, untreated brain metastases, active autoimmune disease or a history of interstitial lung disease. Patients who have received adjuvant or neoadjuvant immunotherapy are eligible provided >12 months have elapsed. All IMDC risk groups are permitted. The planned sample size of 25 patients will provide 85% power to detect an improvement in ORR from 50% (seen with axitinib/avelumab) to 75% with the triplet under the exact binomial test at a one-sided alpha of 0.05. This would provide a clinically meaningful signal to merit further study of this triplet.
