Monica Reddy Muppidi, MD & Saby George, MD

Advanced renal cell carcinoma (RCC) is a challenging disease with short survival. Conventional cytotoxic chemotherapy and radiotherapy are generally ineffective in RCC. The unspecific immunotherapy with interleukin-2 (IL-2) and interferon-&alpha; (IFN-&alpha;) was regarded as the first effective therapy in patients with RCC. It led to remarkable clinical benefit in attaining durable complete responses.

But these responses were seen in less than 10% of patients treated with high-dose IL-2. The objective response rate (ORR) was also minimal.

Targeted therapies such as inhibitors of vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) have shown better ORR, progression-free survival (PFS), and overall survival (OS).

The current standard of care for patients with advanced/metastatic RCC includes sunitinib, pazopanib, bevacizumab in combination with IFN, temsirolimus, sorafenib, axitinib, and everolimus. Despite the PFS benefit, the cancer becomes resistant to the targeted therapy, and progressive disease is imminent. Newer agents that can induce complete response and improve PFS and OS in a broad population are warranted. This has led to a quest to better understand T-cell activation and to the discovery of immune checkpoint inhibitors.

Immune checkpoints refer to regulatory pathways in the immunome that inhibit a portion of an active immune response against a specific target.

These are a normal part of the immune system. One such pathway is the programmed cell death (PD-1) and the programmed cell death 1 ligand (PD-L1). It involves the expression of the T-cell inhibitory ligand PD-L1 on the cell surface of tumor cells and infiltrating immune cells and PD-1 receptor on the tumor-infiltrating lymphocytes. The interaction between the PD-L1 and PD-1 receptors leads to inhibition of T-cell activation and effector function.

The inhibition of this interaction with antibodies directed against PD-1 and PD-L1 is being investigated in many tumors, including RCC.

Cytotoxic leukocyte antigen-4 (CTLA-4) is another widely studied immune checkpoint pathway. Immune activation occurs when the T-cell receptor (TCR) on the T cell interacts with the antigen on the antigen-presenting cell (APC) along with costimulation of CD28 on the T cell. This activation is kept under check through inhibitory signals from the interaction of CTLA-4 and its ligands, CD86 or CD80. Antibodies against CTLA-4 impede this inhibition, leading to unregulated T-cell activation (

). This article reviews immune checkpoint inhibitors with a focus on anti-PD-1/PD-L1 antibodies in RCC.

Tumoral PD-L1 expression in RCC is associated with worse prognosis and reduced survival.

In recent studies, it appears that higher expression of PD-L1 might be associated with higher chance of response.

However, the use of PD-L1 expression as a predictive biomarker has not been established because patients with negative PD-L1 also have shown decent responses. Furthermore, there is no standardized assay or definition for PD-L1 positivity.

Phase I Clinical Trials of Checkpoint Inhibitors in RCC

BMS-936558 (nivolumab) is a human immunoglobulin G4 monoclonal anti-PD-1 antibody. Its safety and tolerability were first studied in a dose-escalating phase I clinical trial with 39 patients with advanced solid tumors (NCT00441337). Only 1 of the 39 patients had RCC. The drug was well tolerated with no dose-limiting toxicities. Only 1 patient had a serious adverse effect (AE), inflammatory colitis; 1 patient had a durable complete response and 2 patients had partial responses, one of them the patient with RCC.

Nivolumab was also studied in another phase I trial involving 296 patients with advanced solid tumors; 34 of 296 patients had RCC (NCT0730639). Nivolumab was given in a starting dose of 1 mg/kg and then expanded to 3 mg/kg and 10 mg/kg in cohorts of 3 and 6 patients. Of the 34 patients with RCC, 17 received 1 mg/kg and 16 received 10 mg/kg. Cumulative ORR was 27% (9 of 33 patients). Five of 8 patients with response had a durable response greater than 1 year. Nine (27%) additional patients had stable disease, defined as stability longer than 24 weeks. Of all patients treated, 14% had grade 3 or 4 drug-related AEs, with rash (12%), diarrhea (11%), and pruritus (9%). Endocrine disorders of hypophysitis (2%) and hyperthyroidism (1%) are rare.

A long-term follow-up report of these patients with advanced RCC was reported by McDermott et al. In that study, 10 of 34 (29%) patients achieved objective response, with median response duration of 12.9 months. Median OS in all patients (34 patients) was 22.4 months. Survival rates of 1 year, 2 years, and 3 years were 71%, 48%, and 44%, respectively. Grade 3 to 4 treatment-related AEs occurred in 18% of patients, all of which were reversible.

Phase II Clinical Trials of Checkpoint Inhibitors in RCC

In a randomized, phase II, dose-ranging clinical trial, 168 patients with metastatic renal cell carcinoma (mRCC) were assigned to nivolumab 0.3 mg/kg, 2 mg/kg, or 10 mg/kg cohorts (NCT01354431); 70% of the patients had received more than one prior therapy. Median PFS was similar in all the cohorts, with 2.7 months, 4.0 months, and 4.2 months, respectively. Median OS ranged from 18.5 months, 25.5 months, and 24.8 months, respectively, with 3-year survival rates of 33%, 40%, and 32%, respectively. The ORR was 20%, 22%, and 20%, respectively. Of these, 75% (9/12), 50% (6/12), and 45% (5/11) were ongoing responders at the time of analysis, respectively. Fourteen of 35 were responding at 24 months from the start of study therapy, 7/35 were ongoing responders who had not yet reached the 24-month mark, and 14 of 35 stopped responding.

In all, 73% of the patients experienced treatment-related AEs, with 11% of them being grade 3 to 4. The incidence of AEs was similar across all cohorts. Fatigue was the most common treatment-related AE. No treatment-related deaths were recorded. Treatment-related discontinuation occurred in 7% of patients. Nivolumab demonstrated OS benefit across all dose cohorts as well as in PD-L1-positive and PD-L1-negative patients in this study with 3 years minimum follow-up. It also demonstrated durable long-term benefit in a handful of patients. This seems to be a favorable result in heavily pretreated patients with mRCC.

Based on these results, a phase III randomized trial (CheckMate 025) was initiated in patients with advanced or metastatic clear-cell RCC who received prior antiangiogenic therapy. The goal of the trial was to compare the clinical benefit of nivolumab versus everolimus, with OS the primary outcome measure (NCT01668784). The study has completed recruitment of patients, and the final data collection for primary outcome measure is expected in February 2016.

Combination Trials of Immune Checkpoint Inhibitors

Nivolumab is being studied in combination with other agents, including VEGF-tyrosine kinase inhibitor (TKI), sunitinib and pazopanib and CTLA-4 antibody ipilimumab. Data of these phase I/II trials were presented at the 2014 American Society of Clinical Oncology (ASCO) meeting.

A phase I trial was conducted with nivolumab plus sunitinib or pazopanib in patients with mRCC who received more than one prior therapy, with the primary aim to assess overall tolerability and safety (NCT01472081). Nivolumab (N) was given in dose escalation, while standard doses of sunitinib and pazaponib were used. In the sunitinib (S) arm (S + N; n = 33), nivolumab was dose escalated from 2 mg/kg (n = 7) to 5 mg/kg (n = 7) and then expanded in another 19 patients who were treatment-na&iuml;ve. In the pazopanib (P) arm (P + N ; n = 20) 10 patients were treated with 2 mg/kg with no further escalation after it was determined as the maximum tolerated dose. The limiting toxicities with this dose included elevated aspartate aminotransferase/alanine aminotransferase (AST/ALT) (n = 3) and fatigue (n = 1). Grade 3 to 4 AEs led to therapy discontinuation in 24% of patients in the sunitinib arm and in 20% of the patients in the pazopanib arm. Immune-mediated renal and hepatic AEs were higher in combination groups than in monotherapy. At the first assessment in 6 weeks, durable responses were noted in 41% in arm S and 56% in arm P. The ORR was 52% in arm S and 45% in arm P. This study showed that combination therapy has a manageable safety profile with reasonable antitumor activity.

Nivolumab (N) in combination with the CTLA-4 antibody, ipilumumab (I), is being studied in a phase I trial (CheckMate 016, NCT01472081).&nbsp;The trial&rsquo;s expanded cohort results were presented at the 2015 ASCO meeting. Patients with mRCC were randomized to N 3 mg/kg plus I 1 mg/kg (N3 + I1), to N 1 mg/kg plus I 3 mg/kg (N1 + I3), or to N 3 mg/kg plus I 3 mg/kg (N3 + I3) IV given every 3 weeks for 4 doses. Following that, all cohorts received N 3 mg/kg IV every 2 weeks until progression or toxicity. Cohorts N1 + I3 and N3 + I1 were expanded to 47 patients per arm while cohort N3 + I3 showed early toxicity and did not proceed to expansion. The primary endpoint was safety. Treatment-related AEs occurred in 88% of patients. Grade 3 to 4 treatment-related AEs occurred in 34% and 64% of patients in N3 + I1 and N1 + I3 arms, respectively, most common of which were gastrointestinal and hepatic. Discontinuation of therapy due to AEs occurred in 16% of patients. Most common AEs were elevated lipase and amylase, transaminitis, diarrhea, and colitis. Efficacy results are summarized in

. These results show promising antitumor activity for this combination therapy, with encouraging OS results. These data also support the development of this combination, leading to initiation of a phase III clinical trial in first-line setting.

CheckMate 214 (NCT02231749) is a phase III trial comparing nivolumab (N) 3 mg/kg IV plus ipilimumab (I) 1 mg/kg IV given every 3 weeks for 4 doses, followed by N monotherapy 3 mg/kg every 2 weeks and sunitinib monotherapy (50 mg orally once a day for 4 weeks followed by 2 weeks off). The trial expects to randomize about 1070 treatment-na&iuml;ve patients stratified by International mRCC Database Consortium prognostic score and by region. Primary endpoints are PFS and OS. Secondary endpoints include ORR and safety. Treatment will be continued beyond progression if it is well-tolerated and if investigator-assessed clinical benefit is achieved. Treatment will be discontinued for unacceptable toxicity or withdrawal of consent.

Pembrolizumab (MK3475) is another PD-1 antibody that is being studied extensively. In patients with treatment-na&iuml;ve mRCC, it is being studied in combination with the TKI axitinib in a phase Ib dose-finding study to evaluate the safety, pharmacokinetics, and pharmacodynamics of this combination (NCT02133742). The study plans to initiate axitinib at a starting dose of 5 mg twice a day, and MK3475 with 2 mg/kg and 1 mg/kg every IV 3 weeks, to find the maximum tolerated dose and continue treatment in a dose-expansion phase. The study, which is recruiting participants, will enroll an estimated 60 patients and is expected to be completed in March 2017.

BMS-936559 is a fully humanized PD-L1-specific antibody. It was evaluated in a phase I trial (NCT00729664) with 207 patients with advanced solid tumors, of which 17 had RCC. Patients were administered 10 mg/kg of PD-L1 antibody IV on days 1, 15, and 29 in a 6-week cycle, up to 16 cycles or until complete response or confirmed progression of disease. Two of 17 patients had objective response with duration of 4 and 17 months; 7 of 17 patients had stable disease at 24 weeks. The most common drug-related AEs were fatigue, rash, arthralgia, nausea, and headache. Treatment-related grade 3 to 4 AEs occurred in 19 of the 207 patients (9%).

Ipilimumab and tremelimumab are the two humanized CTLA-4 antibodies studied in various malignancies. Ipilimumab has been approved in advanced melanoma based on OS benefit in phase III trials, while tremelimumab failed to demonstrate any survival benefit in these patients. Both drugs were also studied in RCC in phase I and II trials. In a phase II trial with ipilimumab, the association between autoimmune toxicity and objective tumor response was found to be significant.

Tremelimumab was studied in combination with sunitinib in a phase I dose-escalating trial to evaluate drug safety. The continuance of this trial was not recommended because the combination caused significant dose-limiting toxicities.

summarizes the salient features of these trials.

PD-1/PD-L1 is regarded as the lead axis for immune checkpoint inhibition. Numerous antibodies targeting this pathway are being investigated at various stages in many tumors, especially in mRCC, where immunotherapy has proven to be beneficial (

). Preliminary results from these trials demonstrated acceptable and manageable toxicity along with promising efficacy. But we await the results of the ongoing phase III trials to see if there is any significant improvement in durable responses and in OS. The antitumor responses of these drugs are heterogeneous and are distinct from cytotoxic chemotherapy. Responses beyond disease progression, which are commonly seen with these drugs, are not captured by the response criteria for solid tumors. Hence, Wolchok et al evaluated a novel immune-related response criteria to assess these responses.

Nevertheless, prospective studies of these criteria and their association to OS are necessary. With better and broader patient selection in clinical trials, identification of predictive biomarkers, better response evaluation criteria, and superior combination therapies, we can envisage a significant shift in the treatment of RCC with immune checkpoint inhibitors.

Fyfe GA, Fisher RI, Rosenberg SA, Sznol M, Parkinson DR, Louie AC. Long-term response data for 255 patients with metastatic renal cell carcinoma treated with high-dose recombinant interleukin-2 therapy.

McDermott DF, Cheng SC, Signoretti S, et al. The high-dose aldesleukin &ldquo;select&rdquo; trial: a trial to prospectively validate predictive models of response to treatment in patients with metastatic renal cell carcinoma.

Articles

Unspecific immunotherapy with interleukin-2 (IL-2) and interferon-alpha was regarded as the first effective therapy in patients with RCC, leading to remarkable clinical benefit in attaining durable complete responses.

Monica Reddy Muppidi, MD & Saby George, MD | Authors

Articles

Immune Checkpoint Inhibitors in Renal Cell Carcinoma