Supplementary Figure S1 shows forest plots of PFS according to numbers of circulating cell populations in the overall trial population (both arms combined) at baseline. Supplementary Figure S2 shows forest plots of PFS with A+Ax or sunitinib according to cytokine, chemokine, or protein concentrations in peripheral blood at baseline and during treatment (cycle 2 day 1). Supplementary Figure S3 shows PFS according to metrics describing TCR repertoire change from baseline to cycle 2 day 1 with A+Ax vs sunitinib. Supplementary Figure S4 shows PFS according to updated mutation subgroup definitions and treatment group. Supplementary Figure S5 shows normalized numbers of total T cells in pretreatment tumors according to molecular subgroup. Supplementary Figure S6 shows peripheral T-cell receptor quantitation and clonality metrics at baseline and cycle 2 day 1 by mutation subgroup.
ARTICLE ABSTRACT
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.This article is featured in Selected Articles from This Issue, p. 384
