Biomarker analyses from JAVELIN Renal 101: Avelumab + axitinib (A+Ax) versus sunitinib (S) in advanced renal cell carcinoma (aRCC).

Abstract

101 Background: The phase 3 JAVELIN Renal 101 trial in previously untreated patients (pts) with aRCC demonstrated a progression-free survival (PFS) benefit and higher objective response rate with A+Ax vs S (Motzer, ESMO 2018; LBA6_PR). Here, we report outcomes from biomarker analyses of baseline tumor samples. Methods: We correlated efficacy with the results of molecular analyses of tissue samples from all 886 pts enrolled in JAVELIN Renal 101. Nephrectomy or tumor samples were characterized by immunohistochemistry (CD8 and PD-L1), whole-exome sequencing (WES), and RNAseq. WES and RNAseq were used to examine somatic mutations and analyze relevant gene expression signatures (GES) in relation to clinical outcomes. GES analyses included published and de novo signatures: effector T cell (Teff), angiogenesis (angio),T cell-inflamed (Tinf), and a novel immune-related signature incorporating pathway indicators for T- and NK-cell activation and IFNγ signaling, among others. Results: PD-L1 expression (≥1% immune cells) was associated with the longest PFS in the A+Ax arm and the shortest in the S arm (HR, 0.63; 95% CI, 0.49, 0.81). Significant treatment arm–specific differences in PFS were observed relative to wildtype when mutations in genes such as CD1631L, PTEN, or DNMT1 were present. Tumor mutational burden did not distinguish pts with respect to PFS. High-angio GES was associated with significantly improved PFS in the S arm but did not differentiate PFS in the A+Ax arm. In the low-angio subset, A+Ax improved PFS vs S. Pts with high Teff and Tinf in the A+Ax arm had longer PFS vs the S arm. In the A+Ax arm, PFS was enhanced in patients with immune GES–positive tumors vs those in the negative group (HR, 0.63; 95% CI, 0.46, 0.86; 2-sided p = 0.004), as well as in an independent dataset (JAVELIN Renal 100; Choueiri, Lancet Oncol, 2018) (HR, 0.46; 95% CI, 0.20, 1.05; 2-sided p = 0.064). Updated efficacy, including overall survival, will be presented. Conclusions: These findings define molecular features that differentiate therapy-specific outcomes in first-line aRCC and may inform personalized therapy strategies for pts with aRCC. Funding: Pfizer and Merck KGaA. Clinical trial information: NCT02684006.

Immune Checkpoint Inhibition, the Key to Success in Renal Cell Carcinoma?

“…This finding was confirmed when this gene signature was prospectively tested in the 823 patients in the IMmotion 151 study [69]. Moreover, similar results from biomarker analyses of 886 tumor samples of the JAVELIN Renal 101 study (avelumab/axitinib vs. sunitinib) were recently presented by Choueiri et al [70]. It was demonstrated that high expression of the angiogenesis gene signature was associated with a longer PFS when treated with sunitinib and a low expression improved PFS in the avelumab/axitinib arm.…”

Mapping the Immune Landscape of Clear Cell Renal Cell Carcinoma by Single-Cell RNA-seq

“…However, in RCC, tumor-infiltrating lymphocyte (TIL) abundance is inversely correlated with survival (11)(12)(13). Biomarker analysis from recent clinical trials comparing PD-1 blockade versus anti-angiogenic inhibitors and combination therapies in treatment-naïve ccRCC patients also demonstrated the inverse relationship between T cell infiltration and clinical outcomes (14,15). Other abundant immune players in the ccRCC TME include monocytes, dendritic cells, and tumor-associated macrophages (16), which are now being harnessed for discovery of novel gene programs but remain far less studied than T cells.…”

Immuno‐oncology gene expression profiling of formalin‐fixed and paraffin‐embedded clear cell renal cell carcinoma: Performance comparison of theNanoString nCountertechnology with targetedRNAsequencing

“…A recent study showed that RNA‐based signatures interrogating angiogenesis and specific inflammatory conditions, such as upregulation of interferon‐gamma signaling, were associated with prolonged progression‐free survival under combinatorial therapy with sunitinib and atezolizumab 14 . Pointing in a similar direction, an exploratory analysis of the JAVELIN 101 trial suggested that focused gene expression profiling might identify patients who benefit the most from these novel combinatorial therapies 15 . Implementation of such biomarkers in a routine diagnostic setting requires the use of specific assays that are able to robustly interrogate formalin‐fixed and paraffin‐embedded (FFPE) clear cell renal cell carcinoma (ccRCC) samples but comparative studies analyzing technical aspects of different high throughput platforms are lacking.…”