The Resurgence of Interest in Immune Therapy for Metastatic Renal Carcinoma
Immune therapies hold substantial promise to improve therapeutic options for mRCC.
Since the approval of high-dose interleukin-2 (IL-2; aldesleukin) in 1992, no other immune therapy has been registered for the treatment of metastatic renal carcinoma.
In contrast, since December 2005, multiple agents designed to inhibit vascular endothelial growth factor (VEGF) or mammalian target of rapamycin (mTOR) signaling. Sorafenib, sunitinib, pazopanib, axitinib, bevacizumab/interferon, everolimus, and temsirolimus were approved by U.S. Food and Drug Administration for the same indication because of improvements in progression-free survival (PFS) (and in the case of temsirolimus a modest increase in overall survival).
High-dose IL-2 remains a valuable option for patients with metastatic clear cell renal carcinoma because of its unique ability to produce long-term complete remissions in approximately 5% to 10% of patients.1
However, IL-2 administration is associated with acute severe toxicity requiring expert management in an inpatient setting, for this reason it is currently offered by a limited number of centers in the United States and around the world.
Renewed interest in immune therapy of metastatic renal cancer was stimulated by the activity of nivolumab, an antibody that blocks the PD-1 inhibitory receptor on T-lymphocytes, in a cohort of 34 previously treated patients.2,3
Mario Sznol, MD
At doses of 1 to 10 mg/kg intravenously (IV) every 2 weeks, the objective response rate (ORR) was 29% and an additional 27% had stable disease for 24 weeks or more. Grade 3 to 4 adverse events (AEs) were observed in only about 17% of patients and, overall, treatment was well tolerated. MPDL3280A, an antibody blocking the PD-L1 ligand for PD-1, was also well tolerated in a cohort of 47 patients with metastatic renal cancer accrued to a phase 1 trial. MPDL3280A produced an ORR of 13% and 53% of patients displayed PFS at 24 weeks.4
In a subsequent randomized phase 2 trial presented by Motzer and colleagues at the 2014 American Society of Clinical Oncology (ASCO) annual meeting, 168 previously treated patients with metastatic clear cell renal cancer were randomized to receive nivolumab IV q3w at doses of 0.3 mg/kg, 2 mg/kg, or 10 mg/kg.5
The ORR was 20% to 22% among the cohorts and median survival exceeded the results produced in similar patient populations enrolled in prior phase 3 trials of targeted therapies. A subset of the patients who responded to the PD-1/PD-L1 antagonists remained progression-free for long periods even after discontinuation of treatment. The results of the randomized phase 3 trial of nivolumab versus everolimus in patients progressing on a VEGFR inhibitor are anxiously awaited.