Resistance to anti-PD-1 immunotherapy for stage III and IV melanoma: Results from a global multi-site chart review.

Abstract

9532 Background: Anti-PD-1 immunotherapy has been approved for 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 estimate the percentage and understand patient/disease characteristics and survival of those receiving anti-PD1 therapy who experience primary resistance and late relapse in the adjuvant (resectable) setting, and primary, secondary resistance and late progression in the advanced (unresectable/metastatic) setting. Methods: A retrospective chart review was conducted in 22 sites in Australia, France, Germany, South Korea, UK and USA. Adult patients who began anti-PD-1 therapy for stage III or IV melanoma from 1 Jan 2018 until 12 months before the start of data collection were included. SITC Immunotherapy Resistance Taskforce definitions of resistance were used, and late relapse/progression defined if occurring more than 12 weeks after last dose of anti-PD-1. The percentage of patients with primary, secondary resistance or late relapse/progression were calculated. Time to death was analysed using Kaplan-Meier. Univariate tests were used to compare baseline characteristics and survival by type of resistance. Results: Of 981 eligible patients, 738 were included in the full analysis set. 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, respectively. In the adjuvant setting, a greater proportion of patients with primary resistance (66%) or late relapse (75%) were male than in those with no relapse (52%) (p=0.007). Asian patients experienced less late relapse (0.0%) than White patients (28.2%) but more primary resistance (61.5% vs. 18.4%) (p<0.001). In the advanced setting, 48.6% of Asian patients developed primary resistance, 37.8% secondary resistance, 5.4% late progression vs. 40.8%, 8.8% and 12.7% of White patients (p<0.001). No significant difference was observed in age, BMI, disease severity, Charlson index score and comorbid conditions by type of resistance. In both settings, time to death varied significantly by type of resistance (p<0.001). Patients with primary resistance had the poorest survival: a mean of 42 months in the adjuvant setting and 31 months in the advanced setting (39 months in those with secondary resistance). Conclusions: A large proportion of patients developed resistance or late relapse/progression and require alternative therapy after anti-PD-1, highlighting a substantial unmet medical need. A greater proportion of Asian patients developed resistance compared to White patients, possibly due to differences in melanoma subtype. Patients with primary resistance had the poorest survival.