Conference Coverage
CHICAGO – Nivolumab and nivolumab plus ipilimumab are superior to ipilimumab alone in first-line metastatic melanoma, results from the phase III CheckMate 067 study suggest.
After a minimum of 9 months follow-up, the risk of disease progression or death was reduced by 43% with nivolumab versus ipilimumab (hazard ratio, 0.57; P value < .001) and by 58% with nivolumab plus ipilimumab vs. ipilimumab (HR, 0.42; P < .001).
The study was not powered to compare nivolumab (Opdivo) plus ipilimumab (Yervoy) with nivolumab.
Patrice Wendling/Frontline Medical News
Dr. Jedd Wolchok
Median progression-free survival was 11.5 months with nivolumab plus ipilimumab, 6.9 months with nivolumab, and 2.9 months with ipilimumab alone, Dr. Jedd Wolchok said at the annual meeting of the American Society of Clinical Oncology.
Overall, 43.7% of patients in the nivolumab arm, 57.6% in the combination arm, and 19% in the ipilimumab arm had objective responses assessed by RECIST version 1.1. Complete responses were more common in the combination arm (11.5%) than in the nivolumab (9%) or ipilimumab (2.2%) arms, as were partial responses (46.2% vs. 34.8% vs. 16.8%).
The median duration of response has not been reached in any group, Dr. Wolchok, chief of melanoma and immunotherapeutics at Memorial Sloan-Kettering Cancer Center, New York, reported in the plenary session. The results were also simultaneously published in the New England Journal of Medicine (doi:10.1056/NEJMoa1504030).
Dr. Michael B. Atkins, deputy director of the Georgetown-Lombardi Comprehensive Cancer Center in Washington, who was invited to discuss CheckMate 067, said the principal take-home message is that, “Ipilimumab can no longer be considered as standard first-line immunotherapy for patients with advanced melanoma. This clearly has important implications for the field and for our patients.”
Combination nivolumab and ipilimumab, however, is “expensive treatment” and raises legitimate concerns about cost and value, he added. Judgment about whether the combination is worth it will need to be withheld until it’s determined if it “can produce more long-term responses or cures, which may reduce the need for other therapies. Further, because of its early toxicity, in contrast to the long duration of monotherapy, the combination may actually involve less treatment and expense.”
Ipilimumab, an anticytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) antibody, revolutionized the treatment of advanced melanoma just 5 years ago. But the landscape has changed with the 2014 approval of nivolumab and pembrolizumab (Keytruda), two anti–programmed death (PD-1) antibodies, and with recent phase III results reporting that pembrolizumab is superior to ipilimumab in advanced melanoma.
There are no clear-cut distinctions in efficacy or toxicity between nivolumab and pembrolizumab, so therefore, treatment decisions will be largely based on other factors such as dosing schedule, marketing cost, and experience, Dr. Atkins said. Pembrolizumab is FDA approved at 2 mg/kg every 3 weeks, while nivolumab is approved at 3 mg/kg every 2 weeks.
CheckMate 067 randomly assigned 945 previously untreated patients with unresectable stage III or IV melanoma to nivolumab 3 mg/kg every 2 weeks or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses then nivolumab 3 mg/kg every 2 weeks, or ipilimumab 3 mg/kg every 3 weeks for four doses. Patients were stratified at baseline by PD-ligand 1 expression, BRAF status, and American Joint Commission on Cancer M stage.
The impact of PD-L1 expression
As seen in other studies, PD-L1 expression enriched response. Objective response rates in patients with tumors showing less than 5% PD-L1 expression were 41.3% with nivolumab, 54.% with nivolumab plus ipilimumab, and 17.8% with ipilimumab. This increased to 57.5%, 72.1%, and 21.3% in patients with at least 5% PD-L1 expression in their tumors, Dr. Wolchok said.
In patients with PD-L1–negative tumors, median progression-free survival was 5.3 months with nivolumab, 11.2 months with nivolumab plus ipilimumab, and 2.8 months with ipilimumab. In patients with PD-L1–positive tumors, the median PFS was 14 months in both nivolumab groups and 3.9 months in the ipilimumab group.
The results suggest that nivolumab alone may have comparable efficacy to nivolumab plus ipilimumab in PD-L1–positive patients, Dr. Atkins said, but added several caveats. Notably, that median PFS is not the optimal way to evaluate immunotherapy because it can be compounded by pseudo progression. Better measures include overall survival and response duration, but those data are immature. Further, only 25%-28% of patients in the study were PD-L1 positive and two-thirds of responders to nivolumab alone were PD-L1 negative.
“PD-L1 expression is a weak biomarker,” he said.
Greater efficacy, greater toxicity
Both Dr. Wolchok and Dr. Atkins agreed that combining the two immunotherapies increased treatment-related adverse events, but that most events were manageable. Moreover, treatment interruption did not prevent tumor response, with 67.5% of patients who discontinued the nivolumab-ipilimumab combination because of a treatment-related adverse event developing a response.
