Resistance to anti-PD-1 immunotherapy for stage III and IV melanoma: a global chart review study

BACKGROUND: Anti-programmed cell death protein 1 (PD-1) immunotherapy has revolutionized the treatment of stage III and IV melanoma. Real-world data on its resistance is needed to facilitate the development of combinatorial approaches to overcome anti-PD-1 resistance. OBJECTIVES: To characterize anti-PD-1 resistance and assess whether progressive disease assigned by clinicians is concordant with scan data assessed by independent central reviewers (ICR). METHODS: A retrospective chart review was conducted in adult patients with stage III/IV melanoma who initiated anti-PD-1 therapy from January 2018 until 12 months before the start of data collection at 22 sites across six countries. Primary resistance and late relapse in the adjuvant setting, and primary, secondary resistance, and late progression in the advanced setting were assigned using Society for Immunotherapy of Cancer definitions. Demographic and clinical characteristics by type of resistance were compared with appropriate univariate tests. Time to resistance (TTR) and overall survival were analyzed using Kaplan-Meier. To compare the concordance of progression assigned by clinicians and ICR, the positive predictive value (PPV) was calculated in a subset of patients. RESULTS: Of 981 eligible patients, 738 were included. In the adjuvant setting (n=240), 53 (22.1%) patients developed primary resistance and 60 (25.0%) experienced late relapse. In the advanced setting (n=498), 222 (44.6%), 50 (10.0%), and 64 (12.9%) patients developed primary, secondary resistance, and late progression. Type of resistance significantly differed by country, race, type of BRAF mutation, and PD-L1 expression in both settings; and by sex, disease stage and tumor thickness in the adjuvant setting only (p<0.05). Mean (SD) TTR was 47.7 (1.3) and 24.2 (1.0) months in the adjuvant and advanced setting, respectively. Patients with primary resistance had the poorest overall survival. The PPV of progression assigned by clinicians was 87.2% (95% CI 72.6% to 95.7%). CONCLUSIONS: This study showed that a substantial proportion of patients with melanoma receiving anti-PD-1 therapy in the adjuvant (47.1%) and advanced (67.5%) settings developed resistance or late relapse/progression, highlighting an unmet medical need. Real-world clinical practice provided a reliable assessment of progression. Factors associated with different types of resistance were identified. Further study is warranted to evaluate their impact on patient risk stratification. (Graphical abstract).