The phase III JAVELIN Renal 101 trial demonstrated prolonged progression-free survival (PFS) in patients (N = 886) with advanced renal cell carcinoma treated with first-line avelumab + axitinib (A+Ax) versus sunitinib. We report novel findings from integrated analyses of longitudinal blood samples and baseline tumor tissue. PFS was associated with elevated lymphocyte levels in the sunitinib arm and an abundance of innate immune subsets in the A+Ax arm. Treatment with A+Ax led to greater T-cell repertoire modulation and less change in T-cell numbers versus sunitinib. In the A+Ax arm, patients with tumors harboring mutations in ≥2 of 10 previously identified PFS-associated genes (double mutants) had distinct circulating and tumor-infiltrating immunologic profiles versus those with wild-type or single-mutant tumors, suggesting a role for non-T-cell-mediated and non-natural killer cell-mediated mechanisms in double-mutant tumors. We provide evidence for different immunomodulatory mechanisms based on treatment (A+Ax vs. sunitinib) and tumor molecular subtypes.
Our findings provide novel insights into the different immunomodulatory mechanisms governing responses in patients treated with avelumab (PD-L1 inhibitor) + axitinib or sunitinib (both VEGF inhibitors), highlighting the contribution of tumor biology to the complexity of the roles and interactions of infiltrating immune cells in response to these treatment regimens.
Cancer discovery. 2024 Feb 19 [Epub ahead of print]
Toni K Choueiri, Amber C Donahue, David A Braun, Brian I Rini, Thomas Powles, John B A G Haanen, James Larkin, Xinmeng Jasmine Mu, Jie Pu, Rosemary E Teresi, Alessandra di Pietro, Paul B Robbins, Robert J Motzer
The Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Pfizer, La Jolla, California., Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts., Hematology Oncology, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee., Department of Genitourinary Oncology, Barts Cancer Institute, Experimental Cancer Medicine Centre, Queen Mary University of London, St Bartholomew's Hospital, London, United Kingdom., Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands., Department of Medical Oncology, Royal Marsden NHS Foundation Trust, London, United Kingdom., Pfizer, New York, New York., Pfizer, Milan, Italy., Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.