The anti–programmed death 1 (PD-1) antibody nivolumab alone or in combination with another immune checkpoint antibody, ipilimumab, resulted in at least a doubling of the median time to disease progression in treatment-naïve metastatic melanoma patients compared with ipilimumab alone. These results were presented (abstract LBA1) by Jedd D. Wolchok, MD, PhD, chief of melanoma and immunotherapeutics service at Memorial Sloan Kettering Cancer Center in New York, at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting held May 29 to June 2 in Chicago.
In the phase III CheckMate 067 trial, nivolumab increased average progression-free survival (PFS) by 4.0 months compared with ipilimumab alone, from 2.9 months to 6.9 months (hazard ratio [HR], 0.57; P < .001). The benefit was even greater in the patients treated with the combination of nivolumab and ipilimumab. These patients had a median time to disease progression of 11.5 months (HR, 0.42; P < .001 compared with ipilimumab alone).
Advanced melanoma patients also had higher responses to nivolumab (43.7%) and the combination (57.6%) compared with ipilimumab alone (19%).
The complete response rates were 8.9%, 11.5%, and 2.2%, in the nivolumab, combination, and ipilimumab arms, respectively.
“The take home message is that the combination of nivolumab and ipilimumab, as well as nivolumab monotherapy, in metastatic melanoma are producing remarkable results compared to ipilimumab alone,” Steven O’Day, MD, clinical associate professor of medicine at the University of Southern California Keck School of Medicine and member of the John Wayne Cancer Institute, who was not involved in the trial, told Cancer Network. “This is a significant and practice-changing advance for doctors treating metastatic melanoma.”
Although the combination regimen appears to be slightly better than anti–PD-1 monotherapy, this comes with significant increased toxicity for patients, added O’Day.
The trial randomized 945 patients equally to nivolumab alone, ipilimumab alone, or the combination. Ipilimumab is currently approved by the US Food and Drug Administration (FDA) for both treatment-naïve and previously treated metastatic melanoma patients, and nivolumab is approved as a second-line metastatic melanoma therapy. Nivolumab is currently under review by the FDA for use as a monotherapy for previously untreated patients.
Nivolumab monotherapy was tested at the approved 3-mg/kg, every-2-week dosage, and ipilimumab was tested at the approved 3-mg/kg, every-3-week dosage. The combination arm tested the approved ipilimumab dose plus 1 mg/kg of nivolumab every 3 weeks for 4 doses followed by 3 mg/kg of nivolumab every 2 weeks for ≥ cycle 3.
Patients continue to be followed for the co-primary endpoint of overall survival.
High-grade treatment-related adverse events—diarrhea, and increased lipase and alanine aminotransferase levels—occurred most frequently in combination-treated patients (55.0%) compared with 27.3% and 16.3% in the ipilimumab and nivolumab arms, respectively. Discontinuation due to treatment-related adverse events occurred in 7.7%, 36.4%, and 14.8% of patients in the nivolumab, combination, and ipilimumab therapy arms, respectively. One death from neutropenia was related to nivolumab, and another death from cardiac arrest occurred in a patient in the ipilimumab arm.
“While the side effects are substantially greater with the combination, these are not side effects that we have not seen with these two agents alone, they are just increased in severity,” said O’Day.
For patients with PD-ligand 1 (L1)–positive tumors, the median PFS was 14.0 months in the nivolumab and combination arms combined. But for those with PD-L1–negative disease, the combination resulted in a longer PFS of 11.2 months compared with 5.3 months in the nivolumab monotherapy arm.
A total of 23.6% of the patients had PD-L1–positive tumors–25.3%, 21.7%, and 23.8% in the nivolumab, combination, and ipilimumab arms, respectively.
“It is promising that PD-L1 expression on the tumor may be a useful marker to identify patients who benefit most from the combination immunotherapy regimen,” said O’Day. Since the patients who have PD-L1 expression on their tumor cells responded equally well to nivolumab and the combination, these patients can likely forego the combination therapy and be treated with nivolumab alone, he added.
“We previously thought that all patients may need the combination to generate a maximal antitumor response,” concluded O’Day. “But what this study suggests is that the greatest benefit is for the PD-L1–negative patients.”