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CHICAGO -- An immunotherapy combination for untreated melanoma reduced the risk of death or progression by more than half as compared with a drug currently used as a standard of care, a large randomized trial showed.
Patients treated with nivolumab (Opdivo) and ipilimumab (Yervoy) had a median progression-free survival (PFS) of 11.5 months compared with 2.9 months for ipilimumab alone and 6.9 months with nivolumab monotherapy. Median PFS with the combination and with nivolumab alone increased to 14 months -- more than four times greater than the PFS of patients who received only ipilimumab -- among patients whose tumors tested positive for programmed death receptor ligand 1 (PD-L1), the target of nivolumab.
The PFS improvement came at a price of increased toxicity, as grade 3/4 adverse events occurred twice as often with the combination as with ipilimumab monotherapy, but even patients who discontinued treatment because of side effects did better with the combination, as reported here at the American Society of Clinical Oncology meeting.
"The majority of adverse events were managed and resolved with established algorithms, so based upon the available evidence, the combination represents a means to improve outcomes, particularly for patients whose tumors have less than 5% PD-L1 expression," Jedd D. Wolchok, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York City, said during a press briefing.
The findings were reported simultaneously online in the New England Journal of Medicine. The outcome of the phase III trial corroborates and extends results from a phase II study reported in April, also showing a significant PFS advantage for the combination over ipilimumab alone.
The rationale for combining the two drugs comes from recognition that cytotoxic T-lymphocyte antigen 4 (CTLA-4) and PD-1 represent distinct but complementary pathways involved in the negative regulation of anti-tumor immunity. Ipilimumab targets CTLA-4 and nivolumab targets PD-L1. Preclinical and phase I and II clinical studies have consistently shown greater activity (including response, complete response, and survival) with the combination than with ipilimumab alone.
Wolchok reported findings from the first phase III trial to compare nivolumab alone or in combination with ipilimumab versus ipilimumab alone. Investigators in the multicenter trial enrolled almost 1,000 patients with untreated, unresectable, or metastatic melanoma. Patients were randomized to ipilimumab, nivolumab, or the combination. Treatment continued until disease progression or development of unacceptable toxicity.
Data were stratified by PD-L1 expression, BRAF expression, and melanoma stage (by American Joint Commission on Cancer criteria). The trial had co-primary endpoints of PFS and overall survival, and Wolchok reported data for PFS. Secondary endpoints included objective response rate, correlation between PD-L1 expression and efficacy, and safety.
The primary comparison was nivolumab monotherapy and the combination versus ipilimumab alone, which is a current standard of care for the patient population enrolled in the study. The results showed that the combination reduced the hazard for death or progression by 58% versus ipilimumab alone (P
- Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
- Combination immunotherapy with nivolumab and ipilimumab in untreated melanoma reduced the risk of death or disease progression by more than half compared with ipilimumab (standard therapy) alone.
- Grade 3/4 adverse events (AEs) were much more common with the combination therapy, but most AEs were managed and resolved by established treatment algorithms.
CHICAGO -- An immunotherapy combination for untreated melanoma reduced the risk of death or progression by more than half as compared with a drug currently used as a standard of care, a large randomized trial showed.
Patients treated with nivolumab (Opdivo) and ipilimumab (Yervoy) had a median progression-free survival (PFS) of 11.5 months compared with 2.9 months for ipilimumab alone and 6.9 months with nivolumab monotherapy. Median PFS with the combination and with nivolumab alone increased to 14 months -- more than four times greater than the PFS of patients who received only ipilimumab -- among patients whose tumors tested positive for programmed death receptor ligand 1 (PD-L1), the target of nivolumab.
The PFS improvement came at a price of increased toxicity, as grade 3/4 adverse events occurred twice as often with the combination as with ipilimumab monotherapy, but even patients who discontinued treatment because of side effects did better with the combination, as reported here at the American Society of Clinical Oncology meeting.
"The majority of adverse events were managed and resolved with established algorithms, so based upon the available evidence, the combination represents a means to improve outcomes, particularly for patients whose tumors have less than 5% PD-L1 expression," Jedd D. Wolchok, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York City, said during a press briefing.
The findings were reported simultaneously online in the New England Journal of Medicine. The outcome of the phase III trial corroborates and extends results from a phase II study reported in April, also showing a significant PFS advantage for the combination over ipilimumab alone.
The rationale for combining the two drugs comes from recognition that cytotoxic T-lymphocyte antigen 4 (CTLA-4) and PD-1 represent distinct but complementary pathways involved in the negative regulation of anti-tumor immunity. Ipilimumab targets CTLA-4 and nivolumab targets PD-L1. Preclinical and phase I and II clinical studies have consistently shown greater activity (including response, complete response, and survival) with the combination than with ipilimumab alone.
Wolchok reported findings from the first phase III trial to compare nivolumab alone or in combination with ipilimumab versus ipilimumab alone. Investigators in the multicenter trial enrolled almost 1,000 patients with untreated, unresectable, or metastatic melanoma. Patients were randomized to ipilimumab, nivolumab, or the combination. Treatment continued until disease progression or development of unacceptable toxicity.
Data were stratified by PD-L1 expression, BRAF expression, and melanoma stage (by American Joint Commission on Cancer criteria). The trial had co-primary endpoints of PFS and overall survival, and Wolchok reported data for PFS. Secondary endpoints included objective response rate, correlation between PD-L1 expression and efficacy, and safety.
The primary comparison was nivolumab monotherapy and the combination versus ipilimumab alone, which is a current standard of care for the patient population enrolled in the study. The results showed that the combination reduced the hazard for death or progression by 58% versus ipilimumab alone (P
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