Immune Checkpoint Inhibitor Treatment in Patients Aged 65 and Older With Advanced Melanoma: Association Between Sex and Survival

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In a study reported in JAMA Network Open, Jang et al found that women with advanced melanoma receiving combination immune checkpoint inhibitor therapy with nivolumab/ipilimumab as their most recent immune checkpoint inhibitor therapy (all with prior ipilimumab treatment) had a poorer survival outcome vs their male counterparts.

Study Details

The study used data from the Surveillance, Epidemiology, and End Results–Medicare linked database on patients aged ≥ 65 years with stage III to IV melanoma diagnosed through December 2015 with claims records showing nivolumab/ipilimumab combination immune checkpoint inhibitor therapy or anti–PD-1 therapy (single-agent pembrolizumab or nivolumab) as their last type of prescribed immune checkpoint inhibitor. Patients were followed through December 2017.

Key Findings

Among 1,369 patients included in the analysis (982 men, 71.7%; median age = 75 years, interquartile range = 69–82 years), 1,204 (87.9%) had received anti–PD-1 therapy as their last immune checkpoint inhibitor treatment and 165 (12.1%) had received combination immune checkpoint inhibitor treatment as their last immune checkpoint inhibitor treatment. All patients with combination immune checkpoint inhibitor treatment as their last treatment had received prior ipilimumab. Among patients receiving anti–PD-1 therapy, 362 vs 842 had prior vs no prior ipilimumab treatment.

After follow-up of up to 24 months, median overall survival was not reached for either sex in the total cohort, and there was no significant difference in survival between men and women. In subgroups, median survival was reached only among women receiving combination therapy (10.2 months, 95% confidence interval [CI] = 4.6–23.9 months), whereas > 50% of men receiving combination treatment and all patients receiving anti–PD-1 therapy irrespective of prior treatment with ipilimumab remained alive at the end of the study period.  

Survival with nivolumab/ipilimumab depended on sex (P = .009 for interaction). On multivariate analysis, hazard ratios for mortality were 2.82 (95% CI = 1.73–4.60) among women vs 1.32 (95% CI = 0.94–1.87) among men who received combination therapy with prior ipilimumab use vs those who received anti–PD-1-therpay with prior ipilimumab use. The hazard ratio for women vs men was 2.06 (95% CI = 1.28–3.32, P = .003).

For women vs men who received anti–PD-1 therapy as their last treatment, mortality hazard ratios were 1.06 (95% CI = 0.74–1.51) vs 1.21 (95% CI = 0.96–1.53) among those without vs with prior ipilimumab. There were no significant differences in mortality hazard ratios between women vs men receiving anti–PD-1 therapy with (0.97, 95% CI = 0.68–1.38, P = .85) or without prior ipilimumab (0.85, 95% CI = 0.67–1.07, P = .16).

The investigators concluded, “This cohort study suggests that female patients with advanced melanoma may not benefit as much from combination immune checkpoint inhibitors as male patients would. Tumor mutation burden or estrogen level may serve as an important biomarker associated with immune checkpoint inhibitor response in metastatic melanoma.”

Grace Lu-Yao, MPH, PhD, of Thomas Jefferson University, is the corresponding author for the JAMA Network Open article.

Disclosure: The study was supported by the National Cancer Institute. For full disclosures of the study authors, visit

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