Patients with advanced renal cell carcinoma who received the checkpoint inhibitor combination nivolumab plus ipilimumab experienced longer treatment-free survival (TFS) over a 42-month period than patients who received the targeted therapy sunitinib, regardless of the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group, according to a new analysis of the CheckMate-214 clinical trial.

This study was published in Clinical Cancer Research, a journal of the American Association for Cancer Research.

The first and corresponding author of this study was Meredith Regan, ScD, associate professor at Harvard Medical School and Dana-Farber Cancer Institute.

TFS is the time between ending the protocol-assigned therapy and starting a subsequent therapy or death, for the entire trial cohort. The authors recently proposed this new outcome to incorporate the quality of survival time into the trial analysis to better inform clinical decision-making.

The authors evaluated TFS in the CheckMate-214 phase III trial. Results of this trial showed a significantly longer overall survival with the nivolumab and ipilimumab combination (nivolumab + ipilimumab) than with sunitinib in patients receiving their first therapy for advanced renal cell carcinoma with both intermediate and poor prognostic risk and favorable risk, assessed per the IMDC. At 42 months since initiating therapy, 52 percent and 39 percent of patients with intermediate/poor risk were alive with nivolumab + ipilimumab and sunitinib, respectively.

The TFS analysis was performed for the 42-month time period and included all patients (550 who received nivolumab + ipilimumab and 546 who received sunitinib). TFS was subdivided into treatment-free survival with and without toxicity by counting the days in which patients experienced moderate and severe treatment-related adverse events (TRAEs).

According to this analysis, over the 42-month period, the mean TFS was more than twice as long after nivolumab + ipilimumab than sunitinib for patients with intermediate/poor risk (6.9 months and 3.1 months, respectively), and three times as long for patients with favourable risk (11.0 months and 3.7 months, respectively). The mean TFS with severe TRAEs was a small fraction of time for both treatments and both risk groups (0.6 months and 0.3 months after nivolumab + ipilimumab and sunitinib, respectively, for intermediate/poor-risk patients; 0.9 months and 0.3 months after nivolumab + ipilimumab and sunitinib, respectively, for favourable-risk patients).

Notably, while the overall survival was similar with nivolumab + ipilimumab and sunitinib in patients with favourable risk, the TFS analysis revealed a difference in how this time was spent between the two treatments: at 42 months, 20 percent of patients treated with nivolumab + ipilimumab and 9 percent of patients treated with sunitinib were treatment-free.

Overall, patients with favourable risk who received sunitinib spent more time on protocol therapy and experienced moderate TRAEs for longer time than their counterparts who received nivolumab + ipilimumab.

“One of the great challenges in conducting clinical trials is that some of the endpoints we’ve been using to measure the efficacy and value of a treatment are not optimal, especially when evaluating immuno-oncology-based therapy regimens,” Regan said.

“As we continue to develop new treatments, we have an opportunity to think about new methods to better balance the efficacy and toxicity to the patients,” Regan added. “To do that, we needed a new endpoint to quantify those two aspects together—to continue to improve survival for patients while also focusing on how they are spending their time. That’s how TFS came to be.”

Regan commented that this analysis is very patient-centred and provides a new way to assess the value of new treatments to patients in clinical trials. “We knew from the previous CheckMate-214 analysis that nivolumab + ipilimumab improved survival compared with sunitinib; now, we are able to compare the way patients spent that overall survival time on these two different treatment approaches, and I think having this information is an important complement to the original trial results.”

The limitations of this study included that the researchers conducted the TFS analysis retrospectively, so the results had to be interpreted in the context of the existing protocol.   

Regan noted that the evaluation of toxicity needs to be better defined, since the researchers counted the days when patients experienced adverse events and registered their severity, but that didn’t take into account the type of adverse event or if more than one occurred on the same days.

Another potential limitation in the application of TFS in future clinical trials is that data collection could become more labor-intensive and costly. Furthermore, continuing to collect data on quality of life in the long run once patients stop the protocol-assigned treatment might be challenging.

Source: American Association for Cancer Research