ASCO 2021: Integrating Peripheral Biomarker Analyses From JAVELIN Renal 101: Avelumab + Axitinib vs Sunitinib in Advanced Renal Cell Carcinoma

(UroToday.com) There have been transformational changes in first-line therapy for patients with advanced renal cell carcinoma (RCC) in the past three years. Foremost among these is the move from monotherapy to combination approaches. While CheckMate 214 first brought combination therapy with dual checkpoint inhibition to the forefront, subsequent studies have examined combinations of immune checkpoint inhibitors and tyrosine-kinase inhibitors in the first-line setting. One such study was the phase 3 JAVELIN Renal 101 trial (NCT02684006), which demonstrated improvements in progression-free survival and increased objective response rates for patients treated with avelumab and axitinib compared to sunitinib. In the Kidney and Bladder Poster session at the American Society of Clinical Oncology (ASCO) 2021 Annual Meeting, Dr. Choueiri presented a secondary analysis of this trial aimed at identifying blood-based biomarkers with differential responses to treatment.

To briefly summarize as JAVELIN Renal 101 has previously been presented and published, this trial accrued patients with advanced renal cell carcinoma and randomized them in a 1:1 fashion to avelumab and axitinib or sunitinib. In addition to clinical outcomes, blood samples were taken for biomarker analysis. The authors assessed both pre-treatment and on-treatment blood samples among 886 patients enrolled on the trial. They correlated biomarkers from these samples with clinical outcomes and molecular profiling data from corresponding tumor samples. The biomarkers examined include blood counts of unique populations, T-cell receptor sequencing, circulating cytokines, and serum proteomics by mass spectrometry MALDI-TOF.

The authors derived a novel, proprietary proteomic signature which was prognostic, independent of treatment approach.

Examining baseline characteristics, the authors found that patients with higher pre-treatment monocyte counts at baseline were associated with shorter PFS among patients randomized to avelumab and axitinib. There were many T-cell-related metrics, including the percent of productively rearranged peripheral T cells, that were associated with longer progression-free survival among those patients who received sunitinib which did not demonstrate associations among patients who received avelumab and axitinib. While higher pre-treatment neutrophil counts were associated with shorter PFS in both arms, neutrophil-to-lymphocyte ratio (NLR) was only associated with PFS for those treated with sunitinib.

The authors then assessed on-therapy biomarkers, finding differential post-treatment changes in T-cell numbers and clones at cycle 2, day 1.

Further, treatment-specific differences were also seen in non–T-cell populations such as monocytes and neutrophils at multiple time points through cycle 3, day 1. Additionally, both pre-treatment and on-treatment serum levels of VEGF, CRP, and several interleukins showed differential associations with PFS (for example, higher pre-treatment levels of VEGF were associated with shorter PFS only among those treated with sunitinib).

Finally, the authors identified specific genomic alterations in tumor tissues that were associated with differences in several pre-treatment and on-treatment angiokines and cytokines.

The authors conclude that the response to treatment with first-line avelumab and axitinib or sunitinib in advanced renal cell carcinoma was associated with immune fitness and treatment-specific immunomodulation. These biomarkers can be detected based on peripheral blood samples.