Robert J. Motzer, MD
Durable responses were obtained with the immune checkpoint inhibitor nivolumab, with a manageable safety profile, in a phase II dose-ranging trial conducted in patients with previously treated metastatic renal cell carcinoma (mRCC). Responses were robust even in those patients who had received two or more prior lines of therapy.
There was no dose-response relationship observed for the primary endpoint of progression-free survival (PFS) across the three dosages of nivolumab studied, said lead investigator Robert J. Motzer, MD, at ESMO 2014.
“One of the most notable features of this drug is that durable responses were seen in these patients,” said Motzer, a medical oncologist at Memorial Sloan Kettering Cancer Center, in New York City.
Nivolumab, a fully human IgG4 PD-1 immune checkpoint-inhibitor monoclonal antibody that selectively blocks the PD-1 and PD-L1/PD-L2 interaction, had shown encouraging efficacy in patients with previously treated mRCC. Therefore, a randomized phase II clinical trial was conducted to assess dose-response relationship and activity of nivolumab in patients with mRCC. The results presented at ESMO were an update on previously reported results from the phase II study.
Eligibility for the trial included mRCC with a clear-cell component. All patients had received prior anti-angiogenic therapy—either a vascular endothelial growth factor receptor tyrosine kinase inhibitor or bevacizumab. Patients were allowed to have received up to three prior therapies, and all had experienced disease progression after their most recent therapy and within 6 months of enrollment.
Patients were randomized 1:1:1 to three different arms based on dosage: 0.3 mg/kg, 2 mg/kg, or 10 mg/kg of nivolumab intravenously administered every 3 weeks. Treatment was continued until disease progression or intolerance. Treatment beyond progression was allowed if there was clinical benefit noted by the treating physician. The primary objective was to assess whether a dose-response relationship existed between the three arms, as measured by PFS according to RECIST v1.1.
A total of 168 patients were enrolled. Thirty percent of patients had received one prior therapy; 37% had received two, and 33% had received three. The most common prior therapies were sunitinib (74%), everolimus (34%), pazopanib (27%), interleukin-2 (23%), and sorafenib (19%).
At time of assessment for the primary analysis, 86% of patients had discontinued the study, 75% for disease progression and 6% for drug-related toxicity.
The median PFS at the time of the analysis was 2.7 months in patients randomized to 0.3 mg/kg of nivolumab, 4.0 months in those randomized to 2 mg/kg, and 4.2 months in those randomized to 10 mg/kg. There was no dose-response relationship detected (P
“The rate of objective responses was similar between the three arms,” said Motzer. The rates of ORR were 20%, 22%, and 20% in the 0.3-mg/kg arm, 2-mg/kg arm, and 10-mg/kg arm, respectively. The median duration of response for the 10-mg/kg dosage arm was 22.3 months, and has not yet been reached for the two other dosage arms.
Most of the objective responses were partial responses (18% to 20% in each arm), he said. One patient (2%) in each of the two lowest-dosage arms achieved complete remission. Thirty seven percent to 44% in each arm had stable disease. “Across the study, there are 20 patients ongoing in response,” he said. “Fourteen of the 35 responders are in response for more than 24 months.”
The objective response rate (ORR) rate was similar regardless of the number of prior therapies—20% in patients who received one prior therapy and 21% in those who received two or more prior lines of therapy. “Durable responses were seen in both groups, including the heavily pretreated patients,” he said.
Most patients had a treatment-related adverse event, largely grade 1 and grade 2 events. There were no grade 4 or 5 treatment-related adverse events. “Only 19 patients (11%) had any grade 3 adverse event,” he said. “There wasn’t a difference in incidence of adverse events between the three arms, with the exception possibly of low-grade hypersensitivity reactions, which occurred at a higher frequency in patients treated with 10 mg/kg.” There was no grade 3 or 4 pneumonitis, which had been reported in an earlier study of nivolumab.
The median overall survival (OS) was 18.2 months, 25.5 months, and 24.7 months in the 0.3-mg/kg, 2-mg/kg, and 10-mg/kg arms, respectively. There was a trend, with a hazard ratio of 0.8 and 0.9, respectively, for improved survival with the two higher dosages compared with 0.3 mg/kg, said Motzer.
Median OS has not been reached among patients who received one prior therapy, and is 18.7 months for those who received two or more prior therapies. The 18.7 months with nivolumab as a third- or fourth-line agent “is really quite robust OS in this heavily pretreated population,” he said.