Ipilimumab Plus Nivolumab Improves Progression-Free Survival in Advanced Melanoma

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Patients with advanced melanoma whose cancer does not respond to treatment with PD-1 inhibitors are often switched to treatment with a second type of immunotherapy drug, a CTLA-4 inhibitor such as the drug ipilimumab. In a phase II trial presented by Vanderwalde et al during the American Association for Cancer Research (AACR) Annual Meeting 2022, patients who received a combination of ipilimumab and nivolumab achieved longer progression-free survival than those who were treated with ipilimumab alone, with 6-month progression free survival estimates of 34% vs 13% (Abstract CT013). The overall rate of response to treatment was also greater in the combination arm (28% vs 9%).

In addition, analysis of patient-derived biopsies allowed researchers to test the hypothesis that primary anti–PD-1 resistance due to a lack of preexisting T-cell infiltrate could be overcome by adding treatment with the anti–CTLA-4 antibody ipilimumab.

“We have known for more than 7 years that patients receiving PD-1 inhibitor monotherapy do better than patients receiving ipilimumab alone in the front-line setting,” said Ari Vanderwalde, MD, MPH, a SWOG investigator with the West Cancer Center and Research Institute in Germantown, Tennessee, who was study chair and presented findings at the meeting. “But we still don’t know what the appropriate therapy is for patients without BRAF mutations in the second-line setting. This study answers the question of whether patients who [have disease progression] on a PD-1 agent can continue the PD-1 agent in combination with ipilimumab, or if they should be switched to ipilimumab altogether.” 

Study Details

SWOG S1616 enrolled 92 patients with advanced melanoma who had been treated with anti–PD-1 or anti–PD-L1 immunotherapy drugs and had not received an anti–CTLA-4 drug. In all cases, the patients’ cancer had not responded to this therapy and had become worse or had spread, either during treatment or after the patient had stopped therapy. 

These patients were randomly assigned in a 1:3 ratio to receive either ipilimumab alone at 3 mg/kg every 3 weeks for 12 weeks (23 patients) or a combination of ipilimumab at 3 mg/kg every 3 weeks and nivolumab at 1 mg/kg every 3 weeks for 12 weeks followed by monthly nivolumab at 480 mg for up to 2 years (69 patients). 

Side effects were consistent with what has been previously described for these agents.

“More than 50% of patients don’t achieve a response to PD-1 inhibitors in the front-line setting,” Dr. Vanderwalde said. “These primary refractory patients have had limited evidence-based options. SWOG S1616 should establish the combination of ipilimumab and nivolumab as the standard in patients who have [had disease progression] on first-line therapy that did not contain ipilimumab.”

Disclosures: For full disclosures of the study authors, visit

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