Phase 2 Trial of Nivolumab in Metastatic Renal Cell Carcinoma

Conference Correspondent - ASCO 2014 - Immuno-Oncology

Treatment of patients with progressing, recurring, or relapsing renal cell carcinoma (RCC) remains poor, regardless of stage or histology. Treatment options for recurrent RCC include surgical resection of localized metastatic disease, cytokine therapy with interferon-alpha or interleukin-2, and targeted therapies that block specific cancer cell growth pathways, including mammalian target of rapamycin (mTOR) and vascular endothelial growth factor (VEGF).1 None of these treatments, however, results in extended survival or cure. A recent retrospective study of patients with metastatic RCC who were treated with targeted therapy demonstrated overall survival (OS) medians that approach 3 years (range, 27-34 months).2

PD-L1 expression has been observed in most clear cell RCC and is associated with poorer cancer-specific survival.3 To exploit this potential mechanism of tumor responsiveness, Motzer and colleagues conducted a phase 2 trial to assess 3 doses of nivolumab (NIV), an anti-PD-L1 antibody, in metastatic RCC patients who had relapsed after treatment with agents targeting the VEGF pathway (ASCO 2014; Abstract 5009).

In this trial, patients with clear cell metastatic RCC who had received at least 1 agent that targeted VEGF and no more than 3 prior systemic therapies. They were randomized to NIV given at a dose of 0.3 mg/kg, 2 mg/kg, or 10 mg/kg every 3 weeks until disease progression or toxicity. The primary objective of the study was to evaluate the dose-response relationship as measured by progression-free survival (PFS). Secondary objectives included OS, objective response rate (ORR), and safety.

Most of the 168 relapsed RCC patients who enrolled in this trial of NIV had received prior systemic therapy, including VEGFR tyrosine kinase inhibitors (98%), mTOR inhibitors (34%), and immunotherapy (24%). One quarter (25%) were poor risk according to Memorial Sloan Kettering Cancer Center criteria.

After at least 16 months of follow-up, no relationship was noted between PFS and the dose of NIV; PFS and ORR results were similar across doses. Among the 168 patients, the ORR was 22%. The Table summarizes these efficacy outcomes. Dr Motzer noted that many objective responders in each of the NIV dosing cohorts continue to respond after 24 months or more. Median OS in the 2 higher-dose cohorts was approximately 25 months.

Rates of grade 3/4–related adverse events (AEs) were 17% or less for all doses of NIV. The most common grade 3/4 events varied among dosing cohorts. In the 10-mg/kg group, 2 patients experienced severe asthenia, while in the 3-mg/kg group, severe nausea and pruritus were reported (2 patients each). There was no grade 3/4 pneumonitis. In the NIV 0.3-mg/kg, 2-mg/kg, and 10-mg/kg cohorts, 2 (3%), 9 (17%) and 7 (13%) patients discontinued NIV due to treatment-related AEs, respectively.

Motzer and colleagues concluded that the promising activity of NIV in relapsed RCC warrants further evaluation. NIV is currently being compared with everolimus in a phase 3 trial as later-line therapy for RCC, as well as in a first-line trial in metastatic RCC combined with ipilimumab.

Table: Efficacy Outcomes of NIV in Patients with Relapsed RCC (n = 168)

  NIV 0.3 mg/kg
n = 60a
NIV 2 mg/kg
n = 54
NIV 10 mg/kg
n = 54
Median PFS, months (80% CI) 2.7 (1.9, 3.0) 4.0 (2.8, 4.2) 4.2 (2.8, 5.5)
ORR, n (%) 12 (20) 12 (22) 11 (20)
Median OS, months (80% CI) 18.2 (16.7, 24) 25.5 (19.8, 28.8) 24.7 (15.3, 26.0)
Treatment-related AE, n (%)
Grade 3/4 AE
44 (75)
3 (5)
36 (67)
9 (17)
42 (78)
7 (13)

aSafety analysis included 59 treated patients.


  1. National Cancer Institute website. Renal Cell Cancer Treatment: PDQ®. Stage IV and Recurrent Renal Cell Cancer. Last modified: February 21, 2014. Accessed June 1, 2014.
  2. Kroeger N, Choueiri TK, Lee JL, et al. Survival outcome and treatment response of patients with late relapse from renal cell carcinoma in the era of targeted therapy. Eur Urol. 2014;65(6):1086-1092.
  3. Thompson RH, Gillett MD, Cheville JC, et al. Costimulatory molecule B7-H1 in primary and metastatic clear cell renal cell carcinoma. Cancer. 2005;104:2084-2091.