Checkpoint Inhibitors Generate Renewed Excitement in RCC

David F. McDermott, MD

With several novel therapies approaching regulatory approval, the treatment landscape for renal cell carcinoma (RCC) is facing a major upheaval championed by growing excitement for checkpoint inhibitors, vaccines, recombinant T-cell receptors, and bi-specific T-cell engagers, according to David F. McDermott, MD, at the 7th European Multidisciplinary Meeting on Urological Cancers (EMUC).¹

“Single-agent PD-1 pathway blockade improves survival in RCC. It improves quality of life for these patients and has made ‘treatment-free survival’ possible,” said McDermott, from Beth Israel Deaconess Medical Center. “However, predictive biomarkers need to be refined to expand the application of immunotherapies to first-line and adjuvant settings.”

Multiple complex and often overlapping mechanisms are employed by tumors to evade and suppress the immune system. For example, tumors can downregulate MHC1, which inhibits tumor antigen presentation. Additionally, tumor cells also secrete TGF-ß and other immunosuppressive factors. More recently, PD-L1’s function in immunosuppression has also been defined.

“Many tumors express PD-L1, which can act like barbed wire surrounding the tumor and preventing immune cells from interacting with it,” commented McDermott.

McDermott pointed out that nivolumab, a PD-1 blocking antibody, demonstrated greater benefit in RCC compared to everolimus in a phase III trial. In this study, nivolumab improve overall survival (OS) but not progression-free survival (PFS) compared with everolimus.² Data from this study for nivolumab in RCC were granted a priority review by the FDA.

In this trial, 822 patients with RCC who had undergone 1 or more prior anti-angiogenic therapies were randomized between the two therapies. The median OS was 25.0 versus 19.5 months (HR, 0.73; P = .0018) and PFS was 15.6 versus 11.7 months (HR 0.88; P = .1135) with nivolumab compared with everolimus, respectively.

A clinically meaningful and statistically significant improvement from baseline in quality of life was also reported with nivolumab versus everolimus. This may be attributed to the earlier response seen with nivolumab, McDermott pointed out.

Nivolumab and other similar agents react with T-cells that are already at the tumor site, which may partially explain the quick response that is often seen. Furthermore, the response often continued after patients who responded to the treatment went off nivolumab.

“These remissions are deeper, in many cases, and treatment-free survival is what patients really want to see,” he said.

While quality of life was improved, unique immunological toxicities were sometimes seen nivolumab. Treatment-related adverse events were similar and sometimes lower with nivolumab than with everolimus. However, McDermott pointed out that the median time to resolution of events in this trial using immunomodulatory medication was from 0.4 to 18.6 weeks and some endocrine events were not resolved.

“When they occur, immunological adverse effects can be very challenging; not all of them resolve and some can cause significant distress, as in the case of colitis,” he remarked.

The next frontiers for immunotherapy in RCC are biomarkers and combination strategies. A leading biomarker for the PD-1 inhibitors is PD-L1. Additionally, studies have sought to combine PD-1 inhibitors with CTLA-4-targeted agents, TKIs, and chemotherapy.

An analysis of PD-L1 expression in the phase III nivolumab data revealed that PD-L1 expression ≤1% was associated median OS was 21.8 compared with 27.4 months with nivolumab in patients with PD-L1 expression ≥1%. Everolimus results were similar, with median OS of 18.8 versus 21.2 months, respectively.

“Tumor heterogeneity complicates biomarker development in RCC. Biomarkers can not yet guide clinical development but will be essential for pursuing frontline and adjuvant trials of immunotherapeutics,” McDermott cautioned. “Multiple investigators have shown that PD-L1 expression alone cannot reliably predict responders.”

Several ongoing studies are exploring the use of combinations in RCC, including nivolumab plus bevacizumab or ipilimumab (NCT02231749; NCT02210117). In addition to nivolumab, trials continue to assess other checkpoint inhibitor in combinations, including pembrolizumab (NCT02014636; NCT02133742), atezolizumab (NCT01984242; NCT02420821), and avelumab (NCT02493751).

The CheckMate-214 trial is of particular interest, which will evaluate nivolumab plus ipilimumab compared with sunitinb in 1070 patients with advanced metastatic RCC who have had no prior systemic treatment. CheckMate-214 is scheduled for completion in January 2018, and has primary endpoints of PFS and OS, with overall response rate and safety for secondary endpoints.

“Combinations improve outcomes but can increase toxicity, making the refinement of management algorithms essential,” McDermott emphasized.

Reference

1. McDermott DF. Understanding the immunology of advanced RCC: The role of checkpoint inhibitors. Presented at: 7th European Multidisciplinary Meeting on Urological Cancers (EMUC), Barcelona, Spain, November 12—15, 2015.
2. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal cell carcinoma. N Engl J Med. 2015;373(19):1803-1813.