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Ipilimumab Plus Anti–PD-1 Therapy vs Ipilimumab Alone for Patients With Advanced Melanoma Resistant to Anti–PD-1/PD-L1 Monotherapy


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In a retrospective cohort study reported in The Lancet Oncology, da Silva et al found that better outcomes were achieved with the combination of an anti–PD-1 agent plus ipilimumab vs ipilimumab alone in patients with advanced melanoma who were resistant to prior anti–PD-1 or anti–PD-L1 monotherapy.

Study Details

The study involved data from patients treated at 15 melanoma centers in Australia, Europe, and the United States. Patients had unresectable stage III or stage IV disease with innate or acquired resistance to anti–PD-1/PD-L1 monotherapy (nivolumab, pembrolizumab, or atezolizumab) and subsequently received either ipilimumab monotherapy or ipilimumab plus anti–PD-1 treatment with pembrolizumab or nivolumab between February 2011 and February 2020. All patients had received nivolumab, pembrolizumab, or atezolizumab in the adjuvant or metastatic setting, with disease progression or recurrence of disease during or after treatment.

In patients who are resistant to anti–PD-1/L1, ipilimumab plus anti–PD-1 [therapy] seemed to yield higher efficacy than ipilimumab, with a higher objective response rate, longer progression-free and longer overall survival, with a similar rate of grade 3 to 5 toxicity.
— da Silva et al

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Key Findings

Among the total of 355 patients included in the analysis, 193 received ipilimumab plus anti–PD-1 treatment and 162 received ipilimumab alone. Median follow-up was 22.1 months (interquartile range = 9.5–30.9 months).

Objective response was observed in 60 patients (31%) in the combination group vs 21 patients (13%) in the ipilimumab group (P < .0001), including complete response in 11% vs 2%. The disease control rate was 40% vs 27% (P = .016).    

Median overall survival was 20.4 months (95% confidence interval [CI] = 12.7–34.8 months) in the combination group vs 8.8 months (95% CI = 6.1–11.3 months) in the ipilimumab group (hazard ratio [HR] = 0.50, 95% CI = 0.38–0.66, P < .0001), with 1-year rates of 58% (95% CI = 51%–66%) vs 38% (95% CI = 31%–48%).

Median progression-free survival was 3.0 months (95% CI = 2.6–3.6 months) in the combination group vs 2.6 months (95% CI = 2.4–2.9 months) in the ipilimumab group (HR = 0.69, 95% CI = 0.55–0.87, P = .0019), with 1-year rates of 24% (95% CI = 19%–32%) vs 12% (95% CI = 8%–19%).

Grade ≥ 3 treatment-related adverse events occurred in 31% of patients in the combination group vs 33% in the ipilimumab group, with the most common being diarrhea or colitis (12% vs 20%) and increased alanine or aspartate aminotransferase (12% vs 9%). Death occurred in one patient in the ipilimumab group at 26 days after the last treatment, with the cause consisting of colon perforation due to immune-related pancolitis.

Grade 3 to 4 treatment-related adverse events had occurred in five patients in the combination group and six in the ipilimumab group during anti–PD-1/PD-L1 monotherapy before the study treatments. Of these, two patients in the combination group and three in the ipilimumab group had grade 3 to 4 events during study treatment, with four having relapse of the same event (grade 3 pneumonitis, pancreatitis, hepatitis, and hemolytic anemia).

The investigators concluded, “In patients who are resistant to anti–PD-1/L1, ipilimumab plus anti–PD-1 [therapy] seemed to yield higher efficacy than ipilimumab, with a higher objective response rate, longer progression-free and longer overall survival, with a similar rate of grade 3 to 5 toxicity. Ipilimumab plus anti–PD-1 should be favored over ipilimumab alone as a second-line immunotherapy for these patients with advanced melanoma.”

Georgina Long, PhD, of the Melanoma Institute Australia, University of Sydney, is the corresponding author for The Lancet Oncology article.

Disclosure: The investigators reported that there was no external funding for the study. For full disclosures of the study authors, visit thelancet.com.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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