The Lynx Group

Gene Signature May Identify Nonresponders to Nivolumab

September 2016, Vol 7, No 8

Immunotherapies have changed the way many patients with cancers, including patients with renal-cell carcinoma (RCC), are treated. Although some patients have a dramatic response to immunotherapies that appears to be sustained over the long-term, a large proportion of patients do not respond to treatment with programmed death (PD)-1 or PD ligand 1 (PD-L1) inhibitors. Therefore, the search continues for biomarkers that can help to determine which patients will likely respond to available checkpoint inhibitors, optimizing treatment selection.

A recent study by Maria Libera Ascierto, PhD, MS, Department of Oncology, John Hopkins School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, and colleagues focused on a gene signature that may identify patients with renal-cell carcinoma whose tumor expresses PD-L1 who are unlikely to benefit from nivolumab therapy (Ascierto ML, et al. Cancer Immunol Res. 2016;4:726-733).

The study showed that patients with PD-L1–positive RCC that did not respond to nivolumab had a significantly higher expression of genes associated with metabolism in their archived tumor tissue compared with PD-L1–positive tumors that responded to nivolumab.

“We found high expression levels of metabolic genes in PD-L1–positive renal cell carcinomas from patients who did not respond to nivolumab. If these data are reproduced in larger groups of patients, we could potentially use the information to guide treatment decisions for patients with renal cell carcinoma,” said senior author Suzanne L. Topalian, MD, Professor of Surgery and Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, in a news release from the American Association for Cancer Research. Dr Topalian added that she is hopeful that this small retrospective study will provide a basis for future exploration.

Identifying Biomarkers of Response to PD-1 Inhibitors

An important aspect of these findings is that the gene signature was associated with metabolism, not immune-related mechanisms. “Given that nivolumab works by releasing the brakes on the immune system, most studies of treatment resistance so far have focused on looking for immune system–related mechanisms. Our data suggest that resistance can also be caused by tumor-specific mechanisms,” Dr Topalian added in the press release.

Between 15% and 30% of patients with RCC have substantial and durable responses to immunotherapies, such as nivolumab, that target the PD-1 and PD-L1 pathway (Weinstock M, et al. Ther Adv Urol. 2015;7:365-377). Research efforts are focused on identifying biomarkers that predict whether patients will respond to immunotherapy, sparing patients from treatments of no benefit, and allowing patients to receive treatment with other potentially beneficial therapies.

Some studies suggest that patients with RCC with PD-L1–positive tumors are more likely than those with PD-L1–negative tumors to respond to PD-1 pathway inhibitors, but the dilemma is that not all PD-L1–positive tumors respond. “A significant number of patients with PD-L1+ RCC do not respond to PD-1 pathway blockade, suggesting that additional intratumoral factors may influence treatment outcomes,” wrote Dr Topalian and colleagues.

In this study, Dr Topalian and colleagues analyzed archived tumor samples obtained before treatment from 13 patients with metastatic RCC and PD-L1–positive tumors. All patients received treatment with nivolumab in clinical trials. Overall, 4 patients were classified as responders, and 9 patients were classified as nonresponders.

Whole-genome expression profiling of 29,377 genes revealed significantly elevated levels of 110 genes in tumors of patients who did not respond to nivolumab. Further analysis revealed that genes expressed at elevated levels in tumors of patients who responded to nivolumab therapy were primarily those associated with metabolism.

“Given the success of our unbiased whole-genome expression profiling approach, we are looking to extend these studies to analyze other types of cancer, as well as to confirm our current results in additional renal cell carcinomas from patients receiving anti–PD1-1 therapies. Such studies may also reveal new drug targets for combination therapies with anti–PD-1,” said Dr Topalian in the press release.

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