JAVELIN Renal 101 biomarker analysis may help personalize patient care
medwireNews: Biomarker analysis has given fresh insight into the response achieved with avelumab plus axitinib among advanced renal cell carcinoma (RCC) patients participating in the JAVELIN Renal 101 trial.
Initial results from the phase III study were presented at the ESMO 2018 meeting, demonstrating a significant improvement in progression-free survival (PFS) with the combination regimen compared with sunitinib monotherapy.
Now findings for the prespecified biomarker analysis of tumor samples taken before initiation of systemic therapy have been reported at the 2019 ASCO Annual Meeting in Chicago, Illinois, USA.
Presenting author Tony Choueiri, from Dana-Farber Cancer Institute in Boston, Massachusetts, USA, told delegates that immunohistochemistry analysis of 804 participants did not find a significant difference in PFS by PD-L1 expression among patients who were given avelumab plus axitinib.
Among sunitinib-treated patients, however, those with at least 1% of PD-L1-positive immune cells within the tumor area had significantly shorter PFS than those whose tumors did not express the biomarker, he said, at 8.2 versus 11.1 months and a hazard ratio (HR) of 1.57.
When tumor-infiltrating T cells at the invasive margin were examined in samples from 795 patients, median PFS among participants given avelumab plus axitinib was significantly longer in those with CD8 expression on or above than below the median, at inestimable versus 9.8 months and a HR of 0.59.
But the opposite was true among sunitinib-treated patients, with a median PFS of 7.1 months for patients with a CD8 expression on or above the median versus 11.1 months for those with expression below the median, giving a HR of 1.42, albeit that was not significant.
“So this finding […], in part, supports the biologic response to checkpoint blocker in that patients with tumors with a high level of tumor-infiltrating cells typically have a more robust immune response to checkpoint blockade, and also probably reflects the […] negative prognostic significance of immune infiltrate in the absence of [immune-oncology] therapy in the presence, for example, of VEGF-targeted therapy,” Choueiri commented.
Gene expression analysis performed for 720 patients identified the top 26 genes associated with immune-related function and PFS, creating a JAVELIN Renal 101 signature composed of five groups of genes associated with T-cell receptor signaling; T-cell activation, proliferation, and differentiation; natural killer cell-mediated cytotoxicity; chemokines; and other immune response genes.
Among the patients given avelumab plus axitinib, those with expression of this signature on or above the median had significantly longer PFS than those with expression below the median, at 15.2 versus 9.8 months and a HR of 0.60, whereas PFS was not correlated with expression among the sunitinib-treated patients.
Choueiri reported that the JAVELIN Renal 101 signature’s prediction of enhanced response to avelumab plus axitinib was verified in an independent data set from the phase Ib JAVELIN Renal 100 trial. And when gene signatures from the IMmotion150 trial were applied to the JAVELIN Renal 101 patients, the benefit of the combination regimen was predicted.
There was also correlation between expression of genes grouped by function and PFS, the researchers said. For example, patients with high expression of immune-related genes, including CD8, had better PFS with combination treatment than sunitinib, whereas the opposite was true for patients with high expression of angiogenesis-related genes, such as VEGFR-1 and -2.
Finally, whole-exome sequencing of 733 patients showed that PFS in the combination treatment arm was better in patients with several key protein-altering somatic mutations, including in CD163L1, interleukin-16, and MC1R, whereas PTEN mutation carriers given avelumab plus axitinib had poorer PFS than wild-type patients.
“Overall, we feel that these findings provide novel insight into the biology of response to avelumab and axitinib,” said Choueiri, who believes that by defining molecular features that will predict first-line response to immunotherapy and tyrosine kinase inhibitors in patients with advanced RCC, it will be possible to “inform personalized therapy strategies” in this population.
He added: “Examination of blood-based biomarkers in serial samples as well as further investigation of the relevance and significance of these findings is ongoing.”
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This independent article was supported by an educational grant from Pfizer and Merck KGaA