Phase 2 Trial of Nivolumab and VEGF Inhibitors in First-Line Metastatic Renal Cell Carcinoma

Conference Correspondent - ASCO 2014 - Immuno-Oncology

Today, antiangiogenic agents, including sunitinib (S) and pazopanib (P), are standard treatment options for patients with metastatic renal cell carcinoma (mRCC). Despite the introduction of these new therapies, patients with mRCC relapse after initial therapy with limited survival benefit. None of today’s treatments for mRCC extend survival or cure.1 A recent retrospective study of patients with mRCC who were treated with targeted therapy demonstrated overall survival (OS) medians that approach 3 years (range, 27-34 months).2

Amin and colleagues presented results of a trial designed to determine the maximum tolerated dose (MTD), safety, and activity of nivolumab (NIV), a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, in combination with either sunitinib or pazopanib in patients with mRCC that was treatment-naïve or relapsed after 1 line of therapy. Their preliminary data show that NIV plus S or P has encouraging antitumor activity and a manageable safety profile.

In this study, patients with mRCC (0 or 1 prior systemic therapies) received NIV in combination with S (50 mg, 4 weeks on, 2 weeks off; Arm S) or P (800 mg daily; Arm P), until progression or unacceptable toxicity. The starting dose of NIV was 2 mg/kg every 3 weeks (N2), with planned escalation to 5 mg/kg (N5). Based on tolerability, the Arm S N5 cohort was expanded to include treatment-naïve patients.

Seven patients were assigned to Arm S N2 and Arm S N5. No dose-limiting toxicities (DLTs) were observed, and MTD was not reached. Arm S N5 was then expanded with 19 additional patients (total n = 33). Patients in Arm P, which enrolled 20 patients at N2, had 4 DLTs (elevated liver enzymes [n = 3]; fatigue [n = 1]), leading to closure of this arm.

Grade 3/4 treatment-related adverse events (AEs) were observed in 24 of 33 patients (73%) in Arm S and 12 of 20 patients (60%) in Arm P. The most common grade 3/4 AEs included elevated liver enzymes (18%), hypertension (18%), and hyponatremia (15%) in Arm S, and elevated liver enzymes and fatigue in Arm P (20% each). Grade 3 pneumonitis occurred in 1 patient (Arm S N5). Grade 3/4 AEs led to discontinuation of the tyrosine kinase inhibitor or both drugs in 36% of patients in Arm S and 25% of patients in Arm P (N5). Dr Amin noted that renal AEs, including acute renal failure, and hepatic AEs were higher than expected with these agents used alone.

The Table summarizes response rate and PFS data for the 2 arms of this phase using RECIST 1.1 criteria.

Table: Efficacy Outcomes of NIV + VEGF Inhibitor (S or P) in Patients with RCC (n = 53)

  S + NIV
(n = 33)
(n = 20)
Confirmed ORR, n (%) 17 (52) 9 (45)
Median duration of response (weeks) 37.1 30.1
Best overall response, n (%)
Unable to determine

1 (3)
16 (48)
10 (30)
1 (3)
4 (12)

9 (45)
7 (35)
4 (20)
Median PFS, weeks
(95% CI)
(41.6, 66.0)
(12.1, 48.1)

Amin and colleagues concluded that the combination of PD-1 inhibition with NIV and VEGF inhibition with S or P warrants further investigation, but should be approached with caution in light of the higher-than-expected rates of renal and hepatic AEs.


  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.