Two Clinical Trials of Advanced Renal Cell Carcinoma Therapies Report Positive Results

Cleveland Clinic participated in two multisite clinical trials of advanced renal cell carcinoma (RCC) treatments which recently reported encouraging results for the 30 percent of RCC patients worldwide with advanced-stage or metastatic disease and historically poor prognosis.

Since 2005, the RCC treatment landscape has undergone a major evolution: moving from cytokine-based immunotherapy, which achieved little clinical benefit, to targeted therapy against vascular endothelial growth factor (VEGF) and today to novel immunotherapy agents. As a cancer with immunogenic properties, RCC has responded well to immunotherapy. “We are in the midst of another transition in RCC treatment with the advances in immunologic drugs,” says Brian Rini, MD, Director, Genitourinary Program, Cleveland Clinic Cancer Center.

The standard of care for metastatic RCC (mRCC) has been treatment with the anti-VEGF drugs pazopanib and sunitinib, which also inhibit platelet-derived growth factor (PDGF) and other kinases. While outcomes have improved with the use of multiple targeted therapies, durable and complete responses are uncommon, as most patients eventually become resistant to targeted therapies and develop disease progression or metastatic disease.

In recent studies, single-agent treatments with monoclonal antibodies that block the interaction between the programmed cell-death protein PD-1 and its ligand PD-L1 have shown anti-tumor activity in heavily pretreated patients with advanced RCC.

Current trials are focusing on combination therapies of antibodies against PD-1 or PD-L1 and VEGF tyrosine kinase inhibitors which have shown improved activity over single-agent therapy.

JAVELIN Renal 100 phase 1b trial

Conducted at 14 medical centers in the U.S., U.K. and Japan, JAVELIN Renal 100 is an ongoing open-label, dose-finding and dose-expansion phase 1b study that is evaluating the combination therapy of avelumab, an immunoglobulin G1 monoclonal antibody against PD-L1; and axitinib, a VEGF receptor inhibitor approved for second-line treatment of advanced RCC.

Eligible patients were age 18 or older and had histologically or cytologically confirmed advanced RCC with a clear-cell component, a life expectancy of at least three months, an Eastern Cooperative Oncology Group performance status score of 1 or lower, no previous systemic treatment for advanced RCC and a resected primary tumor.

Between October 2015 and September 2016, the study enrolled six patients in the dose-finding phase and 49 in the dose-expansion phase. As of the study cut-off date (April 2017), all six patients in the dose-finding phase and 26 (53 percent) of the 49 patients in the dose-expansion phase had confirmed objective responses. Of the 55 participants, 32 (58 percent) had grade 3 or worse treatment-related adverse events, the most common being hypertension in 16 patients.

Overall, the combination therapy of avelumab/axitinib in treatment-naive patients with advanced RCC had promising anti-tumor activity and a manageable safety profile consistent with the profiles of the individual agents when administered as monotherapy. Based on the clinical benefits shown in this trial, first-line standard-of-care for RCC is likely to transition from sunitinib to avelumab/axitinib, reports Dr. Rini.

A phase 3 trial comparing avelumab/axitinib with sunitinib is in progress.

CheckMate 214 phase 3 trial

The CheckMate 214 randomized phase 3 trial compared sunitinib and combination therapy with nivolumab, a PD-1 immune checkpoint antibody approved for advanced RCC treatment after treatment with antiangiogenic therapy; and ipilimumab, an anticytotoxic T-lymphocyte-associated antigen 4 antibody approved for the treatment of metastatic melanoma. This combination has shown promising efficacy in multiple tumor types, resulting in higher response rates than either agent alone.

Eligible patients were age 18 or older with previously untreated advanced RCC with a clear cell component, measurable disease according to RECIST version 1.1 and a Karnofsky performance-status score of at least 70. Patients were characterized according to International Metastatic Renal Cell Carcinoma (IMDC) risk: favorable, intermediate or poor. Approximately 75 percent of patients with advanced RCC have intermediate- or poor-risk features; in this trial, it was 77 percent. Of the 1096 participants, 550 received nivolumab and ipilimumab and 546 sunitinib.

At a median follow-up of 25.2 months in intermediate- and poor-risk patients, the 18-month overall survival rate was 75 percent with nivolumab/ipilimumab and 60 percent with sunitinib. The objective response rate was 42 percent vs 27 percent, and the complete response rate was 9 percent vs 1 percent. Treatment-related adverse events occurred in 509 of 547 patients in the nivolumab/ipilimumab group and 521 of 535 patients in the sunitinib group.

“The combination therapy of nivolumab and ipilimumab showed advantages across the board in all efficacy parameters and is as tolerable as sunitinib,” says Dr. Rini. “Both nivolumab/ipilimumab and avelumab/axitinib are big advances in treating renal cell carcinoma that will change the way we approach patients.”