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Renal Cell Carcinoma
Center of Excellence
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TAKE-HOME MESSAGE
In 168 patients with clear cell metastatic renal cell carcinoma previously treated with agents targeting the VEGF pathway, nivolumab at three doses (0.3, 2, and 10 mg/kg) demonstrated antitumor activity and manageable toxicity. A total of 19/168 (11%) patients experienced grade 3/4 treatment-related adverse events, the most common of which was fatigue.
The authors conclude that the results support further study of nivolumab in metastatic renal cell carcinoma in phase III clinical trials.
In a recently published randomized phase II study, Motzer and colleagues evaluated the efficacy and safety of monotherapy with nivolumab, a novel PD-1 checkpoint inhibitor that restores T-cell immunity against tumors.1 In this study, 168 patients (70% had prior treatment) with RCC were randomized to three dose levels: 0.3, 2, or 10 mg/kg IV every 3 weeks. Median progression-free survivals (PFS) were 2.7, 4, and 4.2 months, respectively (P = .9); objective response rates (ORR) were 20%, 22%, and 20%; and median overall survivals (OS) were 18.2, 25.5, and 24.7 months. Approximately 11% of patients had grade 3/4 treatment-related adverse events, but, overall, the therapy was well-tolerated. As occurs in patients with other malignancies, patients who responded seemed to have quite durable and ongoing responses. At the time of data cutoff, 40% of patients who responded were still having a response >2 years on therapy. Of note, prior studies on various therapies in this patient population yielded OS of 11 to 17 months; so, a therapy that produces an OS of 18 to 25.5 months seems quite remarkable.
Of note, early data on NCT01472081 were presented at ASCO 2014,2 in which the researchers utilized a strategy combining nivolumab with VEGF TKIs (sunitinib and pazopanib) for patients with RCC. PFS was 48.9 months (29 patients) for patients who received sunitinib and 31.4 months (19 patients) for patients who received pazopanib. The toxicities were mainly the expected toxicities of the respective VEGF TKIs. Early data from the same study were also presented, in which the researchers utilized a dual immunotherapy strategy with nivolumab and ipilimumab in two alternative dosing arms. A total of 21 patients received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg, and 23 patients received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg. The first group demonstrated a 43% ORR, and the second demonstrated a 48% ORR. The 24-week PFS was around 65% in each. Those who responded generally had very durable responses. There was clearly significantly more gastrointestinal toxicity with the higher doses of ipilimumab.
Immune checkpoint inhibitors, specifically PD-1 inhibitors, clearly represent a class of therapy that is emerging for patients with RCC. There are still many more studies underway for RCC. Of note, patients who respond tend to have durable responses. The main challenge is developing unique identifiers that enable us to preselect patients who are most likely to benefit from therapy from the outset; this will alter our treatment paradigm, and we are moving rapidly to this new era.
abstract
This abstract is available on the publisher's site.
Nivolumab for Metastatic Renal Cell Carcinoma: Results of a Randomized Phase II Trial
J. Clin. Oncol 2014 Dec 01;[EPub Ahead of Print], RJ Motzer, BI Rini, DF McDermott, BG Redman, TM Kuzel, MR Harrison, UN Vaishampayan, HA Drabkin, S George, TF Logan, KA Margolin, ER Plimack, AM Lambert, IM Waxman, HJ Hammers
In a recently published randomized phase II study, Motzer and colleagues evaluated the efficacy and safety of monotherapy with nivolumab, a novel PD-1 checkpoint inhibitor that restores T-cell immunity against tumors.1 In this study, 168 patients (70% had prior treatment) with RCC were randomized to three dose levels: 0.3, 2, or 10 mg/kg IV every 3 weeks. Median progression-free survivals (PFS) were 2.7, 4, and 4.2 months, respectively (P = .9); objective response rates (ORR) were 20%, 22%, and 20%; and median overall survivals (OS) were 18.2, 25.5, and 24.7 months. Approximately 11% of patients had grade 3/4 treatment-related adverse events, but, overall, the therapy was well-tolerated. As occurs in patients with other malignancies, patients who responded seemed to have quite durable and ongoing responses. At the time of data cutoff, 40% of patients who responded were still having a response >2 years on therapy. Of note, prior studies on various therapies in this patient population yielded OS of 11 to 17 months; so, a therapy that produces an OS of 18 to 25.5 months seems quite remarkable.
Of note, early data on NCT01472081 were presented at ASCO 2014,2 in which the researchers utilized a strategy combining nivolumab with VEGF TKIs (sunitinib and pazopanib) for patients with RCC. PFS was 48.9 months (29 patients) for patients who received sunitinib and 31.4 months (19 patients) for patients who received pazopanib. The toxicities were mainly the expected toxicities of the respective VEGF TKIs. Early data from the same study were also presented, in which the researchers utilized a dual immunotherapy strategy with nivolumab and ipilimumab in two alternative dosing arms. A total of 21 patients received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg, and 23 patients received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg. The first group demonstrated a 43% ORR, and the second demonstrated a 48% ORR. The 24-week PFS was around 65% in each. Those who responded generally had very durable responses. There was clearly significantly more gastrointestinal toxicity with the higher doses of ipilimumab.
Immune checkpoint inhibitors, specifically PD-1 inhibitors, clearly represent a class of therapy that is emerging for patients with RCC. There are still many more studies underway for RCC. Of note, patients who respond tend to have durable responses. The main challenge is developing unique identifiers that enable us to preselect patients who are most likely to benefit from therapy from the outset; this will alter our treatment paradigm, and we are moving rapidly to this new era.