Nivolumab plus Sunitinib or Pazopanib in Patients with Metastatic Renal Carcinoma
Targeting the vascular endothelial growth factor (VEGF) axis is an established antitumor strategy in the management of metastatic renal-cell carcinoma (mRCC). The VEGF receptor inhibitors sunitinib and pazopanib are standard of care in the treatment of patients with mRCC; however, their antitumor effects are not durable, underscoring the need for novel therapeutic strategies in this setting. It was hypothesized that anti-VEGF strategies suppress Tregs to attenuate tumor-induced immunosuppression, and might sensitize tumors to immunotherapy when used in combination. Nivolumab, a fully human monoclonal antibody that inhibits the programmed death-1 immune checkpoint receptor to restore T-cell antitumor immune responses, has shown clinical activity in mRCC. At ESMO 2014, Amin and colleagues reported preliminary results of a phase 1 trial of nivolumab plus either sunitinib (S+N) or pazopanib (P+N) in patients with mRCC (Amin et al. ESMO 2014: Abstract 1052PD).
In this pilot study, sunitinib 50 mg, 4 weeks on and 2 weeks off, or pazopanib 800 mg daily was administered until disease progression or until unacceptable toxicity, whereas previously treated patients received intravenous (IV) nivolumab 2 mg/kg and titrated up to 5 mg/kg IV every 3 weeks; nivolumab 5 mg/kg was expanded to treatment-naïve patients based on tolerability.
Overall, 7 patients were each initially treated with sunitinib plus nivolumab 2 mg/kg and 5 mg/kg, and this cohort was then expanded to an additional 19 treatment-naïve patients (total, n = 33) based on no reports of dose-limiting toxicities.
In the P+N arm, 4 dose-limiting toxicities, including elevations of ALT/AST in 3 patients and fatigue in 1 patient, were observed, leading to closure of this arm. Grade 3/4 treatment-related adverse events were reported in 27 of 33 patients (82%) and in 14 of 20 patients (70%) in the S+N and P+N groups, respectively. Common treatment-related grade 3 or 4 adverse events in the S+N group included elevated ALT (18%), hypertension (18%), hyponatremia (15%), and reduced lymphocyte count (15%); among the patients in the P+N group, these events included elevated ALT (20%), AST (20%), diarrhea (20%), and fatigue (15%). Grade 3 pneumonitis was reported in 1 patient in the S+N arm. Grade 3 or 4 treatment-related adverse events led to treatment discontinuations in 12 or 33 patients (36.4%) in the S+N cohort and 5 of 20 patients (25%) in the P+N cohort.
The objective response rates were 52% in the S+N arm and 45% in P+N arm, with median duration of response of 54.0 and 30.1 months, respectively. Many of the responses occurred by the time of first assessment at 6 weeks: in 41% of patients in the S+N cohort and in 56% of patients in the P+N cohort. At the time of the analysis, the authors reported that many of the responses were still ongoing: 10 in the S+N and 3 in the P+N groups, with 4 patients in the S+N group continuing to respond after treatment discontinuation that was not related to disease progression.
The median progression-free survival was 48.9 and 31.4 weeks for S+N and P+N arms, respectively. Amin and colleagues concluded that combination therapy with sunitinib plus nivolumab showed encouraging antitumor activity and was associated with a manageable safety profile in patients with mRCC. They also noted that the combination therapy resulted in responses that were higher than previously reported for monotherapy of either agent. However, the combination of pazopanib plus nivolumab is not a feasible treatment option at the dose and schedule studied here, because of dose-limiting toxicities.