In phase 1b/2 trials conducted in mRCC, combinations of axitinib with avelumab (anti-PD-L1) or pembrolizumab (anti-PD-1) produced high objective response rates.9,10 In the phase 1b trial of axitinib in combination with avelumab, the objective response rate was 58.2%, and was 65.9% in the subset with tumor cells positive for PD-L1 (greater than 1%) by the SP263 assay. For the combination of axitinib and pembrolizumab, the objective response rate was 73% and median progression-free survival was 20.9 months. Phase 3 randomized trials are in progress.
Other VEGF pathway inhibitors, such as cabozantinib, which shows superior activity to sunitinib in previously untreated patients, are being combined with PD-1 or PD-L1 antagonists.11,12
Overall, data from trials conducted to date with combinations of VEGF and PD-1 pathway inhibitors show promising improvements in objective response rates and median durations of progression-free survival compared with single-agent VEGF pathway inhibitors. The specific subgroups that derive the most benefit from the combinations remain undefined, and future studies will likely evaluate potential predictive biomarkers using both clinical (IMDC) and tumor-related features (for example, PD-L1-positive expression and gene signatures for angiogenesis and immune cell infiltrates).
Longer follow-up from phase 3 trials will be required to assess effects on overall survival and the ability of the combinations to produce durable and treatment-unmaintained responses. Additional data will, furthermore, be necessary to determine whether the different VEGF pathway inhibitors (for example, bevacizumab vs the small molecule inhibitors, or different small molecule inhibitors) produce different outcomes in combination with PD-1 pathway inhibitors.
Other important questions include the relative efficacy of ipilimumab/nivolumab or other immune agent combinations vs combinations of PD-1/VEGF pathway inhibitors, and optimal sequencing of these therapies. Studies have been initiated to assess the safety and activity of triplets including ipilimumab, nivolumab, and a VEGF pathway inhibitor.12
- Osorio JC, Motzer RJ, Voss MH. Optimizing treatment approaches in advanced renal cancer. Oncology (Williston Park). 2017;31(12):919-26, 928-30.
- Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803-13. doi: 10.1056/NEJMoa1510665
- Escudier B, Tannir NM, McDermott DF, et al. CheckMate 214: efficacy and safety of nivolumab + ipilimumab (N+I) v sunitinib (S) for treatment-naïve advanced or metastatic renal cell carcinoma (mRCC), including IMDC risk and PD-L1 expression subgroups. Ann Oncol. 2017;28(suppl_5). doi: 10.1093/annonc/mdx440.029
- 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):5010.
- Sznol M, McDermott DF, Jones SF, et al. Phase Ib evaluation of MPDL3280A (anti-PDL1) in combination with bevacizumab (bev) in patients (pts) with metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2015;33(suppl):410.
- McDermott DF, Atkins MB, Motzer RJ, et al. A phase II study of atezolizumab (atezo) with or without bevacizumab (bev) versus sunitinib (sun) in untreated metastatic renal cell carcinoma (mRCC) patients (pts). J Clin Oncol. 2017;35(suppl):431.
- Atkins MB, McDermott DF, Powles T, et al. IMmotion150: A phase II trial in untreated metastatic renal cell carcinoma (mRCC) patients (pts) of atezolizumab (atezo) and bevacizumab (bev) vs and following atezo or sunitinib (sun). J Clin Oncol. 2017;35(suppl):4505.
- Motzer RJ, Powles T, Atkins MB, et al. IMmotion151: a randomized phase III study of atezolizumab plus bevacizumab vs sunitinib in untreated metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2018;36(suppl):578.
- Choueiri TK, Larkin JMG, Oya M, et al. First-line avelumab + axitinib therapy in patients (pts) with advanced renal cell carcinoma (aRCC): results from a phase Ib trial. J Clin Oncol. 2017;35(suppl):4504.
- Atkins MB, Plimack ER, Puzanov I, et al. Safety and efficacy of axitinib (axi) in combination with pembrolizumab (pembro) in patients (pts) with advanced renal cell cancer (aRCC). J Clin Oncol. 2018;36(suppl):579.
- Choueiri TK, Halabi S, Sanford BL, et al. Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the Alliance A031203 CABOSUN trial. J Clin Oncol. 2017;35:591-7.
- Nadal RM, Mortazavi A, Stein M, et al. Results of phase I plus expansion cohorts of cabozantinib (Cabo) plus nivolumab (Nivo) and CaboNivo plus ipilimumab (Ipi) in patients (pts) with with metastatic urothelial carcinoma (mUC) and other genitourinary (GU) malignancies. J Clin Oncol. 2018;36(suppl):515.