Updated results of the CheckMate 067 trial continue to indicate that treatment with nivolumab plus ipilimumab or nivolumab alone significantly prolonged progression-free survival (PFS) in patients with treatment-naive advanced melanoma compared with ipilimumab alone.
An updated analysis with a median of 18 months follow-up was presented June 6 by Jedd D. Wolchok, MD, PhD, of Memorial Sloan Kettering Cancer Center, during the “Melanoma/Skin Cancers” Oral Abstract Session.
Dr. Jedd D. Wolchok
“I think these results do cement the role of checkpoint inhibitors in the treatment of patients with melanoma,” Dr. Wolchok told the ASCO Daily News. “They point toward the possibility that longer-term outcomes for the combination could be better, but we do not know yet for sure because overall survival data are not mature.”
The study randomly assigned 945 patients with unresectable or metastatic melanoma to treatment with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg for four doses followed by nivolumab, nivolumab 3 mg/kg plus placebo, or ipilimumab 3mg/kg plus placebo.
Initial results from the CheckMate 067 trial were presented by Dr. Wolchok last year during the ASCO Annual Meeting Plenary Session. Those results showed a median PFS of 11.5 months for patients on the combination of nivolumab and ipilimumab compared with 6.9 months for nivolumab alone and 2.9 months for ipilimumab alone.
With longer follow-up, updated results show that both the combination of nivolumab and ipilimumab and nivolumab alone result in a significant improvement in PFS compared with ipilimumab alone. The combination therapy reduced patients risk for progression by 58% compared with ipilimumab alone (HR 0.42, 99.5% CI [0.31, 0.57]; p < .00001) and nivolumab monotherapy reduced the risk for progression by 45% (HR 0.55, 99.5% CI [0.43, 0.76]; p < .00001). Although the study was not powered for the comparison, an exploratory endpoint analysis showed that combination therapy reduced the risk for progression by 24% compared with nivolumab monotherapy (HR 0.76, 95% CI [0.60, 0.92]).
Median PFS in all arms has not changed since last year’s initial presentation of the results. Overall response rate for both nivolumab arms are significantly higher compared with the ipilimumab monotherapy group. The overall response rate was 19% for ipilimumab monotherapy compared with 57.6% for nivolumab plus ipilimumab (p < .001) and 43.7% for nivolumab alone (p < .001). In a descriptive analysis the response rate for the combination group was numerically higher than in the nivolumab monotherapy group.
“Although the response rates have not changed, some partial responses have evolved into complete responses over time,” Dr. Wolchok noted.
With a median follow-up of 20.7 months, the median duration of response was not reached in the combination arm, whereas, the median was 22 months for nivolumab monotherapy and 14 months for ipilimumab monotherapy.
Subgroup analyses demonstrated improved PFS across all subgroups for the combination and nivolumab alone arms. Similar results were also observed for overall response rates across all subgroups.
The researchers also stratified patients at baseline for PD-L1 expression using a 5% PD-L1 expression level. In those patients who had PD-L1 expression less than 5%, the median PFS for the combination of nivolumab and ipilimumab was 11.1 months compared with 5.3 months for nivolumab-alone group and 2.8 months for the ipilimumab group.
“Interestingly, the group with at least 5% PD-L1 expression, PFS appeared comparable for the nivolumab and the nivolumab plus ipilimumab combination groups with a hazard ratio of 0.87,” Dr. Wolchok said. “Note that in the original analysis done last year, the hazard ratio for this comparison was 0.96 with an identical 14-month median reported for both subgroups. Now, with an additional 9 months of follow-up, the median for the combination group has still not yet been reached, while for nivolumab the median is 22 months, which indicates the very dynamic nature of these curves even with over 20 months follow-up.”
In contrast to the PFS results, treatment with the nivolumab combination resulted in numerically higher response rates compare with nivolumab alone regardless of PD-L1 expression. Patients with tumors with at least 5% PD-L1 expression had a 72.1% overall response rate compared with 57.5% in patients assigned nivolumab alone. Additionally, the median duration of response for both levels treated with the combination have not yet been reached.
“The fact that the median duration of response has not been reached with a minimum of 18 months of follow-up is very impressive in a disease where overall survival was previously 7 months,” Dr. Wolchok told the ASCO Daily News.
Updated safety data with additional follow-up are consistent with the previously reported results for nivolumab plus ipilimumab, with no cumulative toxicity noted and no new safety signals identified.
“The combination seems to be delivering durable responses in a majority of patients, but 55% of patients will have high-grade adverse events,” Dr. Wolchok said.
According to Dr. Wolchok, clinicians will have to have meaningful discussions with patients and their families about the risks and benefits of the combination treatment.