ASCO 2019: Biomarker Analyses from JAVELIN Renal 101: Avelumab + Axitinib Versus Sunitinib in Advanced Renal Cell Carcinoma

Chicago, IL ( The JAVELIN Renal 101 trial testing avelumab plus axitinib versus sunitinib as first-line therapy for advanced renal cell carcinoma was published earlier this year in the New England Journal of Medicine.1 This trial randomly assigned patients 1:1 to receive avelumab (10 mg/kg) IV every 2 weeks plus axitinib (5 mg) orally twice daily or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The two independent primary endpoints were progression-free survival (PFS) and overall survival (OS) among patients with PD-L1-positive tumors. A key secondary endpoint was progression-free survival in the overall population.

There were 886 patients assigned to receive avelumab plus axitinib (n = 442) or sunitinib (n = 444). Among the 560 patients with PD-L1-positive tumors (63.2%), the median PFS was 13.8 months with avelumab plus axitinib, compared with 7.2 months with sunitinib (HR 0.61, 95% CI 0.47-0.79). In the overall population, the median PFS was 13.8 months with avelumab plus axitinib, compared with 8.4 months for sunitinib (HR 0.69, 95% CI 0.56-0.84). At a median follow-up for OS of 11.6 months and 10.7 months in the two groups, 37 patients and 44 patients had died, respectively. At the ASCO 2019 annual meeting, Toni Choueiri, MD, presented results of the biomarker analysis performed on patients participating in JAVELIN Renal 101.

This study consisted of four biomarker analyses:
  • PD-L1 expression (n=804)
  • CD8 expression (n=795)
  • A novel 26-gene JAVELIN gene signature (n=720)
  • Mutations and polymorphisms (n=733)
PFS according to PD-L1 immunohistochemistry showed no difference in the avelumab plus axitinib arm (HR 0.89, 95%CI 0.652-1.220), however in the sunitinib arm, patients that were PD-L1+ had worse PFS (HR 1.57, 95%CI 1.156-2.142).


PFS according to CD8+ cells showed no difference for patients in the sunitinib arm (HR 1.42, 95%CI 0.955-2.115), however, patients with greater than the median value had a PFS benefit in the avelumab plus axitinib arm (HR 0.59, 95%CI 0.361-0.967).


The investigators then described how they developed their 26-gene JAVELIN Renal 101 signature. Whole transcriptome data from 720 baseline tumor samples were filtered for informative genes. Next, individuals blinded to the outcome assessed co-expression to identify 306 genes. High expression of a 306-gene signature was associated with better PFS in the avelumab plus axitinib arm but not in the sunitinib arm. Further filtering of the co-expressed 306 genes based on the immune-related functionality and most significant association with PFS in the avelumab plus axitinib arm identified the 26-gene subset. PFS according to the signature showed that high expression in the avelumab plus axitinib arm lead to a PFS benefit (HR 0.60, 95%CI 0.439-0.834), but no difference in the sunitinib arm (HR 0.89, 95%CI 0.670-1.172).

Dr. Choueiri notes that this 26-gene signature was also validated in the phase 1b JAVELIN 100 cohort, finding that high expression was also associated with a PFS benefit (HR 0.36, 95%CI 0.157-0.805). Specific genes that were associated with PFS benefit in the avelumab plus axitinib arm included CCL5, CD3E, and CD8A.

PFS according to mutations and polymorphisms found that several genes were associated with PFS benefit in the avelumab plus axitinib arm: CD163L1 (HR 0.20, 95%CI 0.05-0.80), DNMT1 (HR 0.34, 95%CI 0.17-0.91), IL-16 (HR 0.54, 95%CI 0.35-0.85), and MC1R (HR 0.25, 95%CI 0.03-0.79).

Dr. Choueiri summarized his talk with several remarks:
  • PD-L1 expression did not distinguish PFS benefit in the avelumab plus axitinib arm, however, in the sunitinib arm patients with PD-L1+ tumors showed reduced PFS
  • Patients whose tumors contained a greater number of CD8+ cells had extended PFS in the avelumab plus axitinib arm and reduced PFS in the sunitinib arm
  • The novel JAVELIN Renal 101 signature comprised immune-related genes most significantly associated with PFS in the avelumab plus axitinib arm and was verified in an independent data set (JAVELIN Renal 100)
  • Significant treatment arm-specific differences in PFS were observed relative to the wild type when mutations in genes such as CD163L1, DNMT1 or PTEN were present
He concluded that these findings define molecular features that differentiate therapy-specific outcomes with IO + TKI in first-line advanced RCC and may inform personalized therapy strategies for patients with advanced RCC. Examination of blood-based biomarkers in serial samples, as well as further investigation of the relevance and significance of these findings, is ongoing.

Presented by: Toni K. Choueiri, MD, Medical Oncology, Dana-Farber Cancer Institute, Boston, MA

Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md at the 2019 ASCO Annual Meeting #ASCO19, May 31- June 4, 2019, Chicago, IL USA

  1. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med 2019;380(12):1103-1115.