Especially because of the durability of responses, tolerability, and promising overall survival data, I think anti–PD-1 agents should be developed in [renal cell carcinoma].
—Lauren C. Harshman, MD
In her discussion of the renal cell carcinoma studies at the ASCO Annual Meeting, Lauren C. Harshman, MD, Assistant Professor of Medical Oncology at Dana-Farber Cancer Institute, Boston, suggested, “Given the plateau in efficacy with current treatments, there is space and need for agents with new modes of activity. Especially because of the durability of response, tolerability, and promising overall survival data, I think anti–PD-1 agents should be developed in [renal cell carcinoma].”
But Dr. Harshman pointed out that as monotherapy, the results with nivolumab were less robust than were seen in a previous phase I trial. “The progression-free survival data were somewhat disappointing compared to the phase I results, but they do confirm the activity of nivolumab, at least in a subset of patients,” she said. “Especially at the higher doses, the overall survival [associated with] nivolumab was encouraging.”
With the cautions of comparing a phase II trial to more rigorously tested phase III studies, she noted that the median overall survival at over 2 years was favorable compared to upwards of 16 months for the targeted therapies in their phase III second and third-line trials.
Greater Promise in Combinations
Dr. Harshman said the greater promise may lie in combining anti–PD-1 agents with tyrosine kinase inhibitors, as was done in the study by Amin and colleagues. The combination of nivolumab with an anti–vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor makes sense, she suggested, as VEGF inhibition “may induce a more hospitable immune environment.” The response rate with the combination therapy was 52%, compared with 20% to 22% in the nivolumab monotherapy trial, and some degree of tumor elimination was observed in almost all patients.
“What was exciting was the lack of treatment-refractory disease. We saw primary tumor escape in only 3%, vs 40% in the phase II [monotherapy] study,” she pointed out.
Nevertheless, she reminded listeners that in treatment-naive patients sunitinib alone can produce response rates of 25% to 47%, and achieve median progression-free survival times of 9.5 to 11 months. In the nivolumab/tyrosine kinase inhibitor combination study, median progression-free survival was 12 months, which was encouraging, but it must be noted that 60% of patients were treatment-naive.
The efficacy, however, “comes at a cost,” she continued. Grade 3/4 adverse events were observed in 70% to 80% of patients, and in the sunitinib arm, which will go on to further study, 35% of patients discontinued treatment due to adverse events.
“Durability of response is a distinct feature of PD-1 blockade that we should build upon. We can see continued response or disease stabilization, even off therapy,” she said.
There remains a need to identify the optimal candidate for this strategy, the optimal timing of the VEGF inhibitor, and the best and simplest combinations, “and move these forward,” she said. ■
Disclosure: Dr. Harshman has participated on advisory boards for Bristol Myers Squibb, Pfizer, and Aveo and has received research funding from Bristol Myers Squibb and Genentech. Dr. Harshman participated in the Motzer phase 2 study (abstract 5009) as site PI at Stanford (2011-2012).