Clinical Activity of Ipilimumab Plus Nivolumab in Patients With Metastatic Non–Clear Cell Renal Cell Carcinoma

Abstract

Introduction

Ipilimumab plus nivolumab has been approved for intermediate- and poor-risk metastatic renal cell carcinoma (RCC). However, the activity in non–clear cell RCC (nccRCC) is unknown.

Patients and Methods

Patients from Cleveland Clinic and the University of Texas Southwestern who had received ipilimumab plus nivolumab for metastatic nccRCC from October 2017 to May 2019 were retrospectively identified. Ipilimumab plus nivolumab was administered in accordance with the CHECKMATE 214 trial. Imaging was obtained at baseline and every 12 weeks. The baseline patient characteristics, objective response per Response Evaluation Criteria in Solid Tumors, version 1.1, and treatment-related adverse events (TRAEs) per Common Terminology Criteria for Adverse Events, version 5.0, were analyzed.

Results

Eighteen patients were identified. The median age was 59 years (range, 32-81 years), 77.8% were men, and the Eastern Cooperative Oncology Group performance status was 0 (38%) or 1 (50%). The median treatment duration was 2.4 months (range, 0.7-12.3 months). The non–clear cell histologic types included 6 papillary, 5 chromophobe, 3 unclassified, 2 adenocarcinoma of renal origin, 1 translocation, and 1 medullary. Most had an intermediate (66%) or poor (22%) International Metastatic Database Consortium risk. The best objective response included 6 partial responses (PRs; 33.3%) and 3 with stable disease (16.7%). Of the patients with a PR, the median time to the best response was 3.0 months, and median duration of the PR was 4.3 months. The median progression-free survival was 7.1 months. All-grade TRAEs were noted in 11 patients (61.1%) and included colitis (22%), hepatotoxicity (16%), rash (11%), and fatigue (11%). Eleven patients (61%) had TRAEs requiring high-dose glucocorticoids (> 40 mg of prednisone equivalent daily).

Conclusions

Ipilimumab plus nivolumab demonstrated objective responses and notable toxicity in patients with nccRCC.

Introduction

Nearly 75% of kidney cancer cases will be the clear cell histologic subtype and 25% will be non–clear cell histologic subtypes (non–clear cell renal cell carcinoma [nccRCC]).¹ The emergence of tyrosine kinase inhibitors² and immune check point inhibitors^3,4 in the past decade has revolutionized the treatment of kidney cancer. However, these have been predominantly investigated in patients with clear cell RCC (ccRCC). With the recent advances in molecular biology, the understanding of the oncogenic mechanisms and patterns of response to systemic treatments in nccRCC is evolving.⁵

nccRCC is a heterogeneous group of diseases with multiple histologic subtypes, including papillary, chromophobe, unclassified, adenocarcinoma, translocation, medullary, and collecting duct RCC.⁶ These histologic types have been found to be relatively resistant to the systemic treatments used for ccRCC.⁷ In a retrospective review from the International Metastatic Database Consortium (IMDC), patients with nccRCC were found to have worse outcomes compared with those with ccRCC, with a median survival of 12.8 months compared with 22.3 months for those with ccRCC.⁸ The exact reason for this difference is not yet known but could be attributed to distinct pathologic and molecular features that resulted in less activity of systemic therapy in nccRCC.

Three randomized prospective studies evaluated vascular endothelial growth factor receptor inhibitors and mammalian target of rapamycin inhibitors for advanced nccRCC, with sunitinib and everolimus showing modest clinical activity in these patients and lower response rates compared with those with ccRCC. The largest trial was ASPEN (everolimus vs. sunitinib for patients with metastatic non–clear cell renal cell carcinoma), which randomized 108 patients with advanced nccRCC to receive either sunitinib or everolimus.⁹ The median progression-free survival (PFS), the primary endpoint of the trial, was longer for the patients assigned to sunitinib (8.3 vs. 5.6 months; hazard ratio, 1.41; P = .16). In a second trial, ESPN (everolimus vs. sunitinib prospective evaluation in metastatic non–clear cell renal cell carcinoma), 73 patients were randomly assigned to treatment with everolimus or sunitinib, with crossover to the alternate agent at disease progression.¹⁰ That trial also found that the overall response rate (ORR) was greater with sunitinib than with everolimus (9% vs. 3%) and the median PFS with first-line therapy was 6.1 months with sunitinib and 4.1 months with everolimus (P = .6).¹⁰ In the third phase II trial RECORD-3 (renal cell cancer treatment with oral RAD001 given daily) trial, the sequence of sunitinib followed by everolimus was compared with the sequence of everolimus followed by sunitinib for patients with metastatic RCC.¹¹ In the subset of patients with nccRCC (n = 66), a trend was found toward a longer PFS for the patients initially treated with sunitinib compared with those initially treated with everolimus (7.2 vs. 5.1 months; hazard ratio, 1.54; 95% confidence interval [CI], 0.86-2.75). A meta-analysis of the 3 studies concluded that sunitinib results in favorable outcomes compared with everolimus for first-line therapy.⁷ Owing to the lack of prospective clinical evidence for the treatment of nccRCC, treatments decisions have often been extrapolated from the results of prospective trials of ccRCC.

nccRCC expresses immune checkpoint programmed cell death ligand (PD-L1) on tumor cells and tumor-infiltrating mononuclear cells.¹² This has allowed for multiple clinical trials using immune checkpoint inhibitors either as a single agent or in combinations for patients with nccRCC. In a recent multicenter retrospective study of 41 patients with various histologic subtypes of nccRCC treated with nivolumab (a humanized monoclonal anti-programmed cell death 1 [PD-1] antibody), patients with nccRCC were found to have an ORR of 20% and PFS of 3.5 months.¹³

Ipilimumab is a humanized monoclonal IgG1 anti-cytotoxic T-lymphocyte antigen-4 antibody, which, in combination with nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, has recently been approved by the Food and Drug Administration as first-line treatment of IMDC intermediate- and poor-risk metastatic ccRCC after the Checkmate 214 trial⁴ showed significantly improved PFS and overall survival (OS) with the combination therapy. Updated data showed a 30-month OS rate of 60% with the ipilimumab plus nivolumab combination compared with 47% with sunitinib in the intermediate- and poor-risk population (hazard ratio, 0.66; 95% CI, 0.54-0.80; P < .0001).¹⁴ The investigator-assessed ORRs were 42% versus 29% (P = .0001), including a complete response (CR) rate of 11% versus 1% for the combination versus sunitinib alone, respectively. Among the responders, 52% of the patients receiving nivolumab plus ipilimumab had a response duration of ≥ 18 months compared with 28% of patients in the tyrosine kinase inhibitor arm. That trial had included only ccRCC; thus, the activity of ipilimumab plus nivolumab for nccRCC remains unknown.