Concerns Raised About Patient-Reported Outcomes in CheckMate 214 Trial

February 13, 2019

An exploratory analysis showed that patients who received nivolumab plus ipilimumab had better patient-reported outcomes. Do the results hold up?

Individuals with advanced renal cell carcinoma who received nivolumab plus ipilimumab had better patient-reported outcomes (PROs), according to an exploratory analysis of the CheckMate 214 trial recently published in The Lancet Oncology. However, concerns have been raised that the results may be biased in favor of the combination arm due to the trial’s open-label nature.

The CheckMate 214 trial previously showed that patients with advanced renal cell carcinoma who received nivolumab plus ipilimumab had improved overall survival compared with standard-of-care sunitinib, ultimately establishing a new standard of care. The immunotherapy combination was approved in April 2018 as the first-line therapy for treatment-naive patients at intermediate or poor risk with advanced renal cell carcinoma.

“It’s kind of hard to imagine that [knowing the treatment] isn’t going to color the opinions of someone filling out a quality-of-life survey when they know that they’re getting this new treatment,” said Wesley Mayer, MD, assistant professor of urology at Baylor College of Medicine, during an interview with Cancer Network.

CheckMate 214 is an ongoing, randomized, open-label, multicenter, international phase III trial that enrolled adult patients with treatment-naïve advanced or metastatic clear-cell renal cell carcinoma. Patients were from 175 sites throughout 28 counties. On the basis of risk status, patients were divided into favorable, intermediate, and poor risk subgroups.

A total of 847 patients who were intermediate or poor risk were randomly assigned to treatment with either nivolumab plus ipilimumab every 3 weeks for 4 doses followed by nivolumab every 2 weeks (n = 425) or sunitinib alone for 4 weeks of each 6-week cycle (n = 422).

PROs were assessed as an exploratory endpoint and gathered using three instruments: the Functional Assessment of Cancer Therapy–Kidney Symptom Index-19 (FKSI-19), Functional Assessment of Cancer Therapy-General (FACT-G), and EuroQol five-dimensional, three-level (EQ-5D-3L) tools.

At a median follow-up of 25.2 months, for two of the three assessment tools, patients in the combination arm reported better PROs than patients in the sunitinib arm from the start of treatment through 103 weeks, or about 2 years. For the FKSI-19 tool, which is validated for kidney cancer, the average change in the overall score between baseline and 103 weeks was 4.00 (95% CI, 1.91 to 6.09) for the combination arm compared with −3.14 (95% CI, –6.03 to –0.25) for the sunitinib arm (P < .0001). For the FACT-G tool, which is validated for cancer in general, the average change in overall score was 4.77 (95% CI, 1.73 to 7.82) for the combination arm vs −4.32 (95% CI, −8.54 to −0.11) for the sunitinib arm (P = .0005). For the EQ-5D-3L tool, however, PROs were not significantly different between treatment groups; EQ-5D-3L is validated for measuring general health status.

In addition to the potential bias of the open-label design, Mayer pointed out another concern. Despite showing better PROs, the combination arm had a higher discontinuation rate due to treatment-related adverse events vs the sunitinib arm (22% vs 12%).

“It’s hard to reconcile,” Mayer said. “[That] makes it difficult for me to go running to Ipi Nivo [ipilimumab plus nivolumab] as a drug regimen that’s going to give my patients better quality of life on the therapy,” he said.

A possible explanation for the higher discontinuation rate could be the inability to dose reduce the ipilimumab plus nivolumab combination. “If a patient can’t tolerance sunitinib, you might have some adjustments you can make to their therapy and they may still be able to stay on protocol, whereas in this particular trial, that might not have been true for Ipi Nivo,” Mayer explained.

Despite these study limitations, Mayer said that because the field is moving so quickly, he is not focused specifically on whether this one particular combination regimen is superior to sunitinib in terms of PROs. “We’ll probably find out in 6 months from now that it’s one big regimen-it’s all three of these [drugs]-so I try not to get too lost in those weeds,” he said.