The approval of multiple inhibitors of either the VEGF or mTOR pathway provided an incremental advance in the treatment of metastatic clear cell renal cancer. However, the agents have several important limitations: For example, the optimal clinical effect appears to be dependent on chronic administration, chronic drug toxicity can impact quality of life in many patients, and almost all patients eventually develop resistance and succumb to the disease.
High-dose interleukin (IL)-2 can produce long and unmaintained remissions in approximately 5% to 10% of selected patients with metastatic renal cancer and remains an important option for treatment of the disease. However, multiple approaches to improve on IL-2 activity or to combine it with other agents either have failed or have met with limited success. New effective therapies are desperately needed for both clear cell and non–clear cell metastatic renal cancers.
PD-1/PD-L1 Antagonists
In multiple trials, including the recently reported study by Motzer et al reviewed in this issue of The ASCO Post, antibody antagonists of the immune regulatory checkpoint PD-1 (programmed cell death protein 1) or its ligand PD-L1 demonstrated clinically meaningful activity in metastatic clear cell renal cancer.1,2 Objective response rates have been in the range of 20%, and responses can persist for long periods in a subset of patients.
Moreover, PD-1/PD-L1 antagonists were generally well tolerated in the clinical trials, with a favorable risk/benefit profile. In the Motzer et al trial, all enrolled patients progressed on a prior systemic antiangiogenic agent, and 70% had received two or more prior therapies. In the latter population, in which additional treatment with other VEGFR or mTOR inhibitors produced at best temporary benefit, the activity of nivolumab (Opdivo), particularly the durable objective responses, appeared particularly striking.
Accrual to a phase III trial of nivolumab vs everolimus (Afinitor) in patients progressing on a prior antiangiogenic agent was recently completed and will eventually address the impact of nivolumab on progression-free and overall survival more definitively. Even prior to the availability of the phase III data, it could be argued that the activity and safety profile observed by Motzer et al provide sufficient evidence of clinical benefit to consider nivolumab as a second-line treatment option in patients with metastatic clear cell renal carcinoma.
In Combination With Immunotherapy
Although substantial time and resources will be expended to refine predictive biomarkers for single-agent PD-1/PD-L1 antagonists and to debate the best sequence for immunotherapy vs targeted therapy or the relative roles of IL-2 vs the PD-1/PD-L1 antagonists, the most important clinical need is to develop even more effective immunologic agents and combinations.
At the 2014 ASCO Annual Meeting, Hammers et al reported an overall objective response rate of 45% among 44 patients with metastatic clear cell renal carcinoma treated with one of two dose/schedules of nivolumab combined with ipilimumab (Yervoy).3 Eighty percent had received a prior therapy and 57%, a prior antiangiogenic agent. Follow-up was short, but 16 of 20 responders had ongoing response at the time of analysis. The rate of grade 3 to 4 adverse events was high, but the adverse events were manageable, as shown in prior studies of the combination in melanoma. If the activity is confirmed in a planned phase III trial vs sunitinib (Sutent), the combination of ipilimumab and nivolumab could be an important treatment advance for patients with advanced clear cell renal carcinoma.
Multiple other immunotherapy combinations merit exploration in metastatic renal cancer, with or without the inclusion of a PD-L1/PD-1 antagonist. The highest priority will likely be given to combinations of active cytokines such as interferon alfa (Roferon-A, Intron A) or IL-2 with a PD-1/PD-L1 antagonist, combinations of inhibitors of immunosuppressive pathways, and combinations of immune costimulatory antibodies with PD-1/PD-L1 antagonists. It seems likely that other highly active and tolerable combinations will be discovered, although the challenge will be to select the best combination for each individual patient. Evaluation of all the potential combinations exceeds the capacity of the clinical trials system, and the best endpoints for go/no-go decisions beyond the initial trials remain unclear.
More Combinations Under Study
Promising clinical data were also recently presented for combinations of PD-1/PD-L1 antagonists with antiangiogenic agents. The mechanisms by which these two classes of agents could interact to produce improved antitumor activity are unknown but could be related to potential beneficial effects of the antiangiogenic agents on the immune tumor microenvironment or on traffic of lymphocytes into tumor.
At the 2014 ASCO Annual Meeting, Amin et al reported the results of a trial combining nivolumab with either sunitinib or pazopanib (Votrient).4 Objective response rates were high for both combinations, from 45% to 52%, which included patients who had progressed on a prior VEGFR tyrosine kinase inhibitor. Rates of grade 3 to 4 toxicity were high in both arms, and therefore, further adjustments in dose and schedule may be necessary to define an optimal regimen.
At the 2014 ESMO Meeting, early encouraging data were also presented by McDermott et al for the combination of bevacizumab (Avastin) with the anti–PD-L1 agent MPDL3280A.5 Among the 10 evaluable patients, 4 met criteria for objective response, and another 4 achieved stable disease for at least 24 weeks. The MPDL3280A/bevacizumab combination was well tolerated, with a low rate of grade 3 adverse events. A phase II randomized trial of MPDL3280A with or without bevacizumab vs sunitinib will complete accrual soon, and phase III trials are likely to follow. It remains to be seen whether responses to combinations of immunotherapies with antiangiogenic agents will persist beyond discontinuation of the VEGF pathway inhibitor.
Overall, the immune checkpoint inhibitors, and particularly the PD-1/PD-L1 inhibitors, represent an important new class of agents for treatment of metastatic renal cancer. We observed significant tumor regression in a patient with non–clear cell renal cancer treated with anti–PD-L1, suggesting that trials in non–clear cell renal cancer should also be pursued. ■
Disclosure: Dr. Sznol is a paid consultant for Genentech/Roche, Bristol-Myers Squibb, Astra-Zeneca/Medimmune, Pfizer, Novartis, Kyowa-Kirin, Merus, Seattle Genetics, Immune Design, Prometheus, Anaeropharma, Astellas-Agensys, Immunova, Nektar, Neostem, and Pierre-Fabre and is on the advisory board of Symphogen, Lion Biotechnologies Amphivena, and Adaptive Biotechnologies.
References
2. Herbst RS, Soria JC, Kowanetz M, et al: Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515:563-567, 2014.
3. Hammers HJ, Plimack ER, Infante JR, et al: Phase I study of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma. 2014 ASCO Annual Meeting. Abstract 4504.
4. Amin A, Plimack ER, Infante JR, et al: Nivolumab (anti-PD-1; BMS-936558, ONO-4538) in combination with sunitinib or pazopanib in patients with metastatic renal cell carcinoma. 2014 ASCO Annual Meeting. Abstract 5010.
5. McDermott DF, Sznol M, Sosman JA, et al: Immune correlates and long term follow up of a phase Ia study of MPDL3280A, an engineered PD-L1 antibody, in patiens with metastatic renal cell carcinoma (mRCC). 2014 Annual ESMO Conference. Abstract 809O.
Dr. Sznol is Professor of Internal Medicine at Yale Cancer Center in New Haven, Connecticut.
