Immune Checkpoint Inhibitor Response in mRCC

Immune Checkpoint Inhibitor Response in Patients with mRCC

Chicago—Immune checkpoint inhibitors (ICIs) are standard of care for patients with metastatic renal cell carcinoma (mRCC). However, the data on biomarkers to predict patient response to ICIs are scarce. Results from trials of atezolizumab/bevacizumab suggest that tumors with high expression of an effector T-cell gene signature in the tumor (Teffhigh)/PD-L1+ are more likely to respond to ICI.

Researchers, led by Jason Zhu, MD, Duke University School of Medicine, used two gene panels in addition to other markers of inflammation in the tumor microenvironment to correlate with ICI responses. Results of the multicenter study were reported at the ASCO 2019 Annual Meeting in a poster titled Evaluation of Tumor Microenvironment and Biomarkers of Immune Checkpoint Inhibitor (ICI) Response in Metastatic Renal Cell Carcinoma (mRCC).

A total of 86 patients with mRCC treated with ICIs were included in the study. RNA sequencing was used to evaluate formalin-fixed paraffin-embedded (FFPE tumor) samples for Teff status. Based on the gene expression patterns of tumors in the study cohort, the researchers analyzed two gene panels: (1) a Teff gene panel (CD8, CD27, IFNG, GZMA, GZMB, PRF1, EOMES, CXCL9, CXCL10, CXCL11, CD274, CTLA4, FOXP3, TIGIT, IDO1, PSMB9, and TAP1); and (2) a 5-gene panel (FOXP3, CCR4, KLRK1, ITK, and TIGIT).

Objective response rates (ORRs), defined as complete responses (CRs) and partial responses (PRs), were correlated with programmed death-ligand 1 (PD-L1) status (positivity was defined as ≥1% TPS based on Dako 33C3 IHC Assay), and tumor mutational burden (TMB) (0-10, 10-20 ≥20 mut/Mb). Best response to ICI was determined using Response Evaluation in Solid Tumors Criteria version 1.1 criteria. was an association between ORR and inflamed tumor status, Teff gene panel, 5-gene panel PD-L1 status, and TMB.

For PD-L1 positive patients, ORR was 50% (n=4/8) compared with 14% (n=9/65) for PD-L1 negative patients (P=.042). Ninety-five percent of tumors (n=82/86) had TMB <10 mut/Mb.

Fifty percent of the patients (n=43) were classified as Teffhigh and 50% (n=43) were classified as Tefflow. In the Teffhigh cohort, ORR was 23% compared with 12% in the Tefflow cohort (P=.256). In the 5-gene high cohort, ORR was 31% (n=14/45), compared with 2% (n=1/41) in the 5-gene low cohort (P=.001).

In summary, the researchers said, “TMB and tumor inflammation based on CD8 did not reliably predict for objective responses in this study of mRCC patients treated with ICIs. Gene expression signatures provide a more comprehensive evaluation of the tumor microenvironment and may lead to better predictive biomarkers for ICI response than individual biomarkers such as PD-L1, TMB, or CD8 expression.”

Source: Zhu J, Pabla S, Labriola L, et al. Evaluation of tumor microenvironment and biomarkers of immune checkpoint inhibitor (ICI) response in metastatic renal cell carcinoma (mRCC). Abstract of a poster presented at the American Society of Clinical Oncology 2019 Annual Meeting, June 1, 2019, Chicago, Illinois.