Biomarkers suggestive of adaptive immune activity were observed in patients with metastatic renal cell carcinoma (mRCC) who had better clinical outcomes with nivolumab in a phase I clinical trial. In addition, significant upregulation of CTLA-4 and PD-L2 was seen during treatment with nivolumab, suggesting the potential for combination therapy with ipilimumab in patients with mRCC, said Toni K. Choueiri, MD, of Dana-Farber Cancer Institute, during the Genitourinary (Nonprostate) Cancer Oral Abstract Session, held on Monday, June 1 (Abstract 4500).
Dr. Toni K. Choueiri
“In this exploratory study, nivolumab provided a meaningful survival benefit in patients with mRCC, mirroring prior results, consistent with other reports, and irrespective of PD-L1 expression,” Dr. Choueiri said.
The changes in biomarkers that appeared to be related to better outcomes included increased serum markers of interferon gamma activation, increased tumor gene expression indicating lymphoid and myeloid infiltration with active checkpoint regulation, decreased clonality of circulating T-cell receptors (TCR), and increased T-cell counts in the tumor.
Nivolumab, an anti–PD-1 immune checkpoint inhibitor, has previously been shown to provide an overall survival (OS) of 18.2-25.5 months in patients with previously treated mRCC. The primary objective of this study was to assess the pharmacodynamic activity of nivolumab on tumor-infiltrating T-cells and serum chemokines in patients with mRCC. Investigators assessed associations between PD-L1 expression at baseline, as well as changes during therapy in key exploratory objectives, including serum cytokines, gene expression, TCR repertoire, and other biomarkers associated with clinical outcomes.
Patients previously treated with one to three therapies were randomly assigned to receive 0.3, 2.0, or 10.0 mg/kg of intravenous nivolumab every 3 weeks. Patients with treatment-naive disease received 10 mg/kg of intravenous nivolumab every 3 weeks. Specimens used for analysis were obtained at baseline and at day 8 of cycle two. Patients were treated until complete response (CR), progression, or intolerable toxicity were reached.
Patient characteristics were well balanced among the groups, however, 21% of patients with treatment-naive disease underwent radiotherapy compared with 37% of patients in the previously treated arms. In total, 91 patients were treated. Among patients who were previously treated, median OS was 16.4 months (95% CI [10.1, not reached]) in the 0.3 mg/kg arm, not reached for the 2.0 mg/kg arm, and 25.2 months (95% CI [12.0, not reached]) for the 10.0 mg/kg arm. Among patients with treatment-naive disease, the median OS was not yet reached.
PD-L1 positivity was defined as 5% or greater of tumor cell membrane staining in one or more biopsies. Of 56 evaluable baseline biopsies, 18 had PD-L1–positive expression, and 38 had PD-L1–negative expression. When OS was calculated by PD-L1 expression, median OS was not reached in the patients with PD-L1–positive disease. Median OS was 23.4 months (95% CI [13.1, 33.3]) in the patients with PD-L1–negative disease (Fig. 1). OS at 12 months was similar regardless of PD-L1 status, with 71% in patients who had PD-L1–positive and PD-L1–negative disease (95% CI [44, 87] and [52, 83], respectively). However, the 24-month OS rate was 64% (95% CI [37%, 82%]) among patients with PD-L1–positive disease compared with 48% (95% CI [30%, 64%]) among patients with PD-L1–negative disease.
Although there was no significant association between PD-L1 status and survival, discussant Noah M. Hahn, MD, of Johns Hopkins Medical Institutions, said “we need to look at these curves and see if there is a story emerging.” At 1 year, the curves are superimposable, he observed, but at 2 years, the curves separate, and the PD-L1 curve begins to plateau. “So, although there is not a statistically significant association with PD-L1 status and survival, there is a trend present that I think is worth investigating in further data sets,” he concluded.
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