CHICAGO—At the 2016 ASCO Annual Meeting, David McDermott, MD, Director of the Biologic Therapy Program and Co-Director of the Kidney Tumor Program at Beth Israel Deaconess Medical Center, Boston, presented results of a study he co-authored on long-term overall survival with nivolumab in patients previously treated for advanced renal cell carcinomas.
In the phase III Checkmate 025 study, patients who'd received prior anti-angiogenic therapy then nivolumab experienced a longer overall survival than those in an everolimus treatment regimen. McDermott and his team questioned if nivolumab's benefits are maintained in the long-term.
Hence, the clinicians set out on what turned out to be the longest follow-up with an anti-PD-1 agent to date in renal cell carcinoma. The phase I and II studies on survival and safety results spanned 4 years and ultimately reinforced the advantages of nivolumab.
The phase I and II studies were broken into two treatment arms and both sets of patients required failing prior treatments. The phase I population was more heavily pre-treated.
Dosing and scheduling were different in the two arms, but McDermott assured audiences this didn't alter clinical outcomes. Unacceptable toxicity was cause to discontinue treatment, as was confirmed tumor progression. According to McDermott, for patients who achieved clinical benefit, treatment was limited to 96 weeks on phase I and given continuously until progression on phase II.
In the phase I study, the primary endpoint was safety and tolerability. A key secondary endpoint was objective response rate. In the phase II study, the primary endpoint was dose response by progression-free survival and the key secondary endpoints were response rate, overall survival, and toxicities.
Understanding Long-Term Overall Survival
All told on both trials, median long-term overall survival data was greater than 22 months.
“With follow-up over 48 months, approximately one-third of patients are still alive at 4 years in both studies,” shared McDermott. “At 5 years, 34 percent were alive on the phase I trial. We look forward to seeing whether nivolumab produces similar long-term survival in the phase III study.”
Separating patients by baseline and response characteristics shed more light on the nivolumab versus everolimus debate. In phase II, the team used Sloan Kettering criteria to classify patients by outcomes of good, intermediate, and poor risk.
“In the phase II clinical trial, encouraging long-term survival was seen in both favorable and unfavorable sub-groups,” he noted. “Long-term survival was seen in patients with excellent or reduced performance status. In patients with objective response, stable disease or progressive disease as their best response, these data suggest that long-term survival is achievable in all sub-groups.”
When compared with everolimus in the large, randomized Checkmate 025 study, patients taking nivolumab demonstrated significantly improved overall survival. The median survival was 25 months for patients taking nivolumab versus 19.6 months for patients prescribed everolimus. Even those in traditionally unfavorable risk groups experienced benefits, although McDermott expressed enthusiasm for validating survival benefits in a longer follow-up.
Adverse Effects & Toxicities
By way of context, safety outcomes in the larger phase III Checkmate 025 study were reported at grade 3-4 toxicities in 19 percent of patients receiving nivolumab. Treatment-related adverse effects leading to discontinuation were seen in less than 8 percent of patients in the nivolumab regimen.
After studying the issue for 4 years, grade 3 and 4 toxicities occurred in less than 20 percent of patients, and treatment-related adverse effects leading to discontinuation were experienced in less than 10 percent of patients.
“These results are notable because they remain similar to the safety outcomes in the larger phase III study, even with an additional 3 years of follow-up,” McDermott stated.
Furthermore, nivolumab was well-tolerated in the phase I and II trials, and side effects were reversible. The most common adverse effects included endocrine, gastrointestinal, hepatic, pulmonary, renal, and skin toxicities occurring in 40 percent of patients in the phase II trial. The highest percentage of patients who experienced side effects did so within the first 6 months of treatment and this was consistent with nivolumab's known safety profile. No adverse effects occurred after 30 months of treatment initiation.
The adverse effect trend followed a similar plot for treatment-related adverse effects in the phase II study, as was the median time to onset.
“While most side effects were well-managed with immune modulating therapy, not all resolved completely,” noted McDermott.
For example, while grade 3 and 4 endocrine toxicities resolved with treatment, half the patients with grade 1 and 2 toxicities required ongoing hormonal replacement therapy. Some patients, including those with gastrointestinal adverse effects, required 2-3 months of immune modulating therapy to resolve symptoms.
All told, though, responses remained durable even after treatment was discontinued. In some patients, tumor shrinkage was substantial and the benefit of nivolumab persisted for months after treatment was stopped.
Unconventional responses of tumor regression after initial progression of target lesions or persistent reduction in the presence of new lesions were experienced by some patients.
“The combined impact of conventional and unconventional responses with nivolumab contributed to long-term survival in this cohort,” explained McDermott.
Ultimately, he told the audience it comes down to the number of patients still alive more than 4 years. “For the 48 patients on phase II trial alive 4 or more years, long-term survival occurs in all sub-groups,” he remarked. “Interestingly, stable and progressive disease was the best response for patients who achieved the best response for more than 50 percent of the patients who achieved long-term survival in this trial. Fifteen of the 48 patients alive for more than 4 years have not required therapy other than nivolumab.”
He clarified that, after treatment with nivolumab in a second-line or later setting, one-third of patients are still alive at 4 years (phase I and II) and 5 years (phase I).
McDermott advised future investigators to focus on identifying predictors of long-term survival, determination of optimal treatment duration, and innovative trial designs to understand the clinical impact of sequential, adjuvant, and combination approaches.
Robin Hocevar is a contributing writer.