PD-1/PD-L1 in Renal Cell Carcinoma: Projecting the Way Forward

Abstract

At the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting, data were presented from several key studies in metastatic renal cell carcinoma evaluating inhibitors of programmed cell death 1 (PD-1) (PDCD1) and programmed cell death 1 ligand 1 (PD-L1) (CD274). This commentary evaluates the implications of these data and potential avenues forward for this promising class of agents. Novel immunotherapeutic agents have captured headlines across all domains of oncology, with nearly US $1.3 billion in recent investments across multiple pharmaceutical companies. This funding will span 78 clinical trials including an estimated 19,000 patients. The bulk of this spending may center on agents that abrogate the interaction between programmed cell death 1(PD-1) (PDCD1) and its associated ligands, programmed cell death 1 ligand 1 (PDL1) (CD274) and programmed cell death 1 ligand 2 (PD-L2) (PDCD1LG2). Perhaps the most promising data thus far are in the setting of metastatic melanoma, with a large proportion of patients achieving prolonged responses to the PD-1 inhibitors nivolumab (BMS-936558) and lambrolizumab (MK-3475). For genitourinary cancers, there is increasing interest surrounding the activity of these agents in both renal cell carcinoma (RCC) and bladder cancer. The idea of approaching metastatic RCC (mRCC) with immunotherapy may elicit a sense of deja vu; after all, agents such as interferon alfa and interleukin-2 have been used now for over 2 decades. However, early data from PD-1 and PD-L1 inhibitors have suggested a higher clinical benefit rate, also with the potential for long-term responses. In a phase I trial of the PD-1 inhibitor nivolumab, a total of 34 patients were enrolled, and 44% had received 3 or more prior therapies. At the last report of these data, an objective response rate (ORR) of 29% was observed, with a median progression-free survival (PFS) of 7.3 months. Impressively, 2-year overall survival (OS) was 50% in this heavily pretreated population. Of course, phase I data require further validation. At the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting, 2 abstracts offered a further perspective on nivolumab monotherapy (Table 1). The first was a randomized, phase II study including 168 patients with mRCC exploring 3 dose levels of nivolumab (0.3 mg/ kg, 2 mg/kg, and 10 mg/kg intravenously every 3 weeks). In this experience, 70% of patients had 2 prior therapies. Median PFS was in the range of 2.7 to 4.2 months across cohorts, and the ORR was in the range of 20% to 22%. Of 35 patients who incurred a response, 19 patients might be considered “durable responders,” with responses maintained for over 1 year. As in the phase I experience, toxicities were manageable, with < 17% of patients in each arm incurring grade 3 or 4 toxicity. A second abstract included a smaller number of patients with mRCC (n1⁄4 91) but offered more correlative data, with baseline biopsies in all patients and sequential biopsies in a subset of individuals. In this study, a response rate (RR) of just 16% was observed. A similar rate of grade 3 or 4 events (15%) was reported. At first glance, the RR and PFS data reported in these 2 large experiences seem a bit less encouraging compared with the aforementioned phase I data. A phase III trial comparing everolimus and nivolumab in patients with mRCC and 3 prior therapies (with 2 prior antiangiogenic agents) recently completed accrual. The investigators hope to find a substantial improvement in OS with nivolumab; given that OS will likely be driven by responding patients, the lower RR observed in more recent studies may challenge the primary endpoint. If monotherapy with nivolumab is not the optimal strategy, what are other potential paths forward? The 2014 ASCO Annual Meeting also offered a first glimpse at potential combinations with nivolumab. As vascular endothelial growth factor (VEGF)-directed