Efficacy and correlative analyses of avelumab plus axitinib versus sunitinib in sarcomatoid renal cell carcinoma: post hoc analysis of a randomized clinical trial.

BACKGROUND: Among patients with advanced renal cell carcinoma (RCC), those with sarcomatoid histology (sRCC) have the poorest prognosis. This analysis assessed the efficacy of avelumab plus axitinib versus sunitinib in patients with treatment-naive advanced sRCC. METHODS: The randomized, open-label, multicenter, phase III JAVELIN Renal 101 trial (NCT02684006) enrolled patients with treatment-naive advanced RCC. Patients were randomized 1 : 1 to receive either avelumab plus axitinib or sunitinib following standard doses and schedules. Assessments in this post hoc analysis of patients with sRCC included efficacy (including progression-free survival) and biomarker analyses. RESULTS: A total of 108 patients had sarcomatoid histology and were included in this post hoc analysis; 47 patients in the avelumab plus axitinib arm and 61 in the sunitinib arm. Patients in the avelumab plus axitinib arm had improved progression-free survival [stratified hazard ratio, 0.57 (95% confidence interval, 0.325-1.003)] and a higher objective response rate (46.8% versus 21.3%; complete response in 4.3% versus 0%) versus those in the sunitinib arm. Correlative gene expression analyses of patients with sRCC showed enrichment of gene pathway scores for cancer-associated fibroblasts and regulatory T cells, CD274 and CD8A expression, and tumors with The Cancer Genome Atlas m3 classification. CONCLUSIONS: In this subgroup analysis of JAVELIN Renal 101, patients with sRCC in the avelumab plus axitinib arm had improved efficacy outcomes versus those in the sunitinib arm. Correlative analyses provide insight into this subtype of RCC and suggest that avelumab plus axitinib may increase the chance of overcoming the aggressive features of sRCC.

Tec kinase signaling in T cells is regulated by phosphatidylinositol 3-kinase and the Tec pleckstrin homology domain.

Tec, the prototypical member of the Tec family of tyrosine kinases, is abundantly expressed in T cells and other hemopoietic cell types. Although the functions of Itk and Txk have recently been investigated, little is known about the role of Tec in T cells. Using antisense oligonucleotide treatment to deplete Tec protein from primary T cells, we demonstrate that Tec plays a role in TCR signaling leading to IL-2 gene induction. Interestingly, Tec kinases are the only known family of tyrosine kinases containing a pleckstrin homology (PH) domain. Using several PH domain mutants overexpressed in Jurkat T cells, we show that the Tec PH domain is required for Tec-mediated IL-2 gene induction and TCR-mediated Tec tyrosine phosphorylation. Furthermore, we show that Tec colocalizes with the TCR after TCR cross-linking, and that both the Tec PH and Src homology (SH) 2 domains play a role in this association. Wortmannin, a phosphatidylinositol 3-kinase inhibitor, abolishes Tec-mediated IL-2 gene induction and Tec tyrosine phosphorylation, and partially suppresses Tec colocalization with the activated TCR. Thus, our data implicate the Tec kinase PH domain and phosphatidylinositol 3-kinase in Tec signaling downstream of the TCR.