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JAVELIN Biomarker Analysis Identifies New Kidney Cancer Features Linked to Immunotherapy Response

NEW YORK – An international team of researchers has identified new biological features that could help determine how patients with advanced renal cell carcinoma (aRCC) will respond to combined PD-1/PD-L1 and angiogenic pathway inhibition.

In a study published on Monday in Nature Medicine, the researchers reported the results of molecular analyses of baseline tumor samples from the Phase III JAVELIN Renal 101 trial, which involves 886 previously untreated patients with aRCC. The Phase III results demonstrated significantly prolonged progression-free survival with first-line combination treatment with avelumab (Merck KGaA/Pfizer's Bavencio) plus axitinib (Pfizer's Inlyta) versus sunitinib (Pfizer's Sutent).

However, the researchers found that neither expression of PD-L1 nor tumor mutational burden differentiated progression-free survival in either study arm. Instead, they identified important biological features associated with differential progression-free survival, including new immunomodulatory and angiogenesis gene expression signatures (GESs), previously undescribed mutational profiles and their corresponding GESs, and several HLA types.

"These findings … may aid in the development of strategies for improved patient care in aRCC," the authors wrote.

Beginning with immunohistochemistry analysis, the researchers found that 69 percent of their tumor samples were PD-L1-positive. PD-L1 expression on immune cells did not differentiate progression-free survival in the combination treatment arm, though progression-free survival was shorter among patients with PD-L1-positive tumors relative to those with PD-L1-negative tumors in the monotherapy arm.

The researchers also examined the relationship between progression-free survival and the presence of CD8-positive cells within the total tumor area, the tumor center, and the invasive margin. They noted that progression-free survival was longer in the monotherapy arm for patients whose tumors had greater abundance of CD8-positive cells within the tumor center, as well as a nonsignificant trend favoring higher CD8-positive cell density within the invasive margin, but found no association between progression-free survival and CD8-positive cells in any tumor region in the combination arm.

An analysis of transcriptomic data allowed the researchers to identify four metabolic pathways of interest: oxygen transport, lipid metabolism, organic acid metabolism, and glucocorticoid metabolism. Higher expression of the genes in the oxygen transport and lipid metabolism pathways was associated with a trend toward improved progression-free survival in the combination arm. They also evaluated metabolic pathways described in the Kyoto Encyclopedia of Genes and Genomes (KEGG) — glycolysis, tricarboxylic acid (TCA) or Krebs cycle, fatty acid biosynthesis and pentose phosphate, and AMPK signaling pathways — which have previously been associated with survival in renal cell carcinoma, and found no significant association with progression-free survival in the combination arm.

Following the co-expression and network analyses, the researchers found elevated expression of an immune response cluster in patients with prolonged progression-free survival in the combination arm compared with those in the monotherapy arm. When they refined their module based on the expression of the genes most significantly associated with improved progression-free survival in the combination arm, the investigators identified a 26-gene subset, which they dubbed the Renal 101 Immuno signature.

This GES comprised regulators of both adaptive and innate immune responses (T cell and natural killer (NK) cell), cell trafficking, and inflammation. However, it had limited overlap with published GESs, including the IMmotion 150 effector T cell (Teff) signature and the interferon (IFN)-γ signature. Patients who had greater than or equal to the median expression of the Renal 101 Immuno signature had longer progression-free survival than those with less than the median expression in the combination therapy arm, the researchers said. The signature did not differentiate progression-free survival in the monotherapy arm, however.

The investigators verified the robustness and clinical relevance of the Renal 101 Immuno signature in an independent dataset from the JAVELIN Renal 100 study, an uncontrolled single-arm Phase Ib trial, where patients' samples that expressed the signature at the median level or higher tended to have better progression-free survival that those with lower expression levels. Further testing of Renal 101 Immuno in mixed-cohort data from the Phase I JAVELIN Solid Tumor trial of avelumab monotherapy showed that high expression of the signature was associated with improved progression-free survival.

Using a method similar to the one they used to define Renal 101 Immuno, the researchers also used gene expression data interrogation to identify a 26-gene angiogenesis GES that significantly differentiated progression-free survival in the monotherapy arm but not the combination therapy arm.

The researchers also explored whether the association between the immune-related GES and extended progression-free survival in the combination arm might mean that antigen presentation or major histocompatibility complex (MHC) expression could also affect progression-free survival. The DUX4 transcription factor and six-gene GES (ZSCAN4, PRAMEF1, TRIM51, KHDC1L, MBD3L2, and TRIM43) have been implicated as suppressors of MHC class I expression associated with resistance to anti-CTLA-4 therapy.

The investigators examined the clinical relevance of the DUX4 GES through its relation to progression-free survival in 720 patients. Among the 46 patients with high expression of the DUX4 GES, a trend toward reduced progression-free survival was observed in those in the combination therapy arm, while progression-free survival was not differentiated in those in the monotherapy arm. Further examination of the DUX4 GES in patients with high expression revealed significantly reduced expression of HLA-A, HLA-B and HLA-C relative to low expression.

Further analyses found that HLA type, but not tumor mutational burden, affected progression-free survival in both arms. Of the HLA alleles present in 5 percent or more of patients, five of them (A*01:01, A*03:01, B*40:02, B*57:01, and C*06:02) were associated with treatment-specific differences in progression-free survival. Tumor mutational burden, however, was not linked with the presence of other known mutations in renal cell carcinoma-associated genes, such as VHL or PBRM1, and did not differentiate progression-free survival in either arm.

"The composition of the Renal 101 Immuno signature, which comprises NK cell-related transcripts, as well as chemokine and cytotoxic T cell-related elements, suggests a biological link between improved progression-free survival associated with combination treatment and modulation of both the innate and adaptive immune systems," the authors concluded. "The implication of the adaptive and innate immune pathways as potential contributors and determinants of response may help explain the signature's limited overlap with other GESs previously associated with response to ICI-based treatments, such as atezolizumab plus bevacizumab."