Preliminary data for combinations based on PD-1/PD-L1 antagonists suggest further improvements in outcome will be observed in the near future. Also at the 2014 ASCO annual meeting, Hammers and colleagues presented the initial results of a phase 2 study evaluating two-dose combinations of nivolumab and ipilimumab (anti-cytotoxic T-lymphocyte-associated protein 4).6
In the 46 patients enrolled in the trial, the ORR was 45%, and 65% of all patients remained progression-free at 24 weeks. The addition of ipilimumab to nivolumab increased the rate and severity of immune-related AEs but the toxicities were manageable and reversible. A randomized phase 3 trial of the ipilimumab/nivolumab combination versus sunitinib is planned. In another study that was also presented at the 2014 ASCO meeting, Amin and colleagues presented the first data from a trial combining nivolumab with either sunitinib or pazopanib.7
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The ORR of 52% and 45% in the sunitinib and pazopanib cohorts, respectively, exceeded the expected activity of either agent in this population, where many patients had progressed on a prior VEGF receptor inhibitor. Combinations of MPDL3280A with bevacizumab have also been explored in metastatic renal cancer, and a large randomized phase 2 trial studying MPDL3280 in combination with bevacizumab compared with MPDL3280A alone compared with sunitinib is currently accruing previously untreated patients.
Immune therapies hold substantial promise to improve therapeutic options for patients with metastatic renal cancer. Other immune checkpoint inhibitors (eg, anti-B7-H4), combinations of two or more immune checkpoint inhibitors (eg, anti-PD1 or anti-PD-L1 with anti-LAG3 or anti-TIM3), combinations of immune checkpoint inhibitors with costimulatory agonists (eg, anti-PD1 or anti-PD-L1 with either anti-CD27, anti-OX40, or anti-CD137), and combinations of immune checkpoint inhibitors with cytokines (eg, IL-2 or interferon) merit development in advanced renal cancer.
We observed an outstanding response in patients with non-clear cell metastatic renal cancer treated with anti-PD-L1 and further study in the latter subpopulations of metastatic renal cancer is also warranted.
- Fyfe GA, Fisher RI, Rosenberg SA, et al. Long-term response data for 255 patients with metastatic renal cell carcinoma treated with high-dose recombinant interleukin-2 therapy. J Clin Oncol. 1996;14:2410-2411.
- Drake CG, McDermott DF, Sznol M, et al. Survival, safety, and response duration results of nivolumab (Anti-PD-1; BMS-936558; ONO-4538) in a phase I trial in patients with previously treated metastatic renal cell carcinoma (mRCC): Long-term patient follow-up. J Clin Oncol. 2013;31(suppl): Abstract 4514.
- Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443-2454.
- Herbst RS, Gordon MS, Fine GD, et al. A study of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic tumors. J Clin Oncol. 2013;31(suppl): Abstract 3000.
- Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab for metastatic renal cell carcinoma (mRCC): Results of a randomized, dose-ranging phase II trial. J Clin Oncol. 2014;32(suppl):5s. Abstract 5009.
- Hammers HJ, Plimack ER, Infante JR, et al. Phase I study of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2014;32:(suppl):5s. Abstract 4504.
- Amin A, Plimack ER, Infante JR, et al. Nivolumab (anti-PD-1; BMS-936558, ONO-4538) in combination with sunitinib or pazopanib in patients (pts) with metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2014;32(suppl):5s. Abstract 5010.
Mario Sznol is Professor of Medicine and Clinical Research Program Leader of the Melanoma Program at the Yale Cancer Center in New Haven, CT, and a member of the Cancer Therapy Advisory Board.