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 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
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