Abstract
Background: Primary resistance to immunotherapy can be observed in approximately 40–65% of the stage IV melanoma patients treated with immune checkpoint inhibitors. A minority of the patients receive a second-line therapy, and the clinical benefit is small. Patients and methods: Stage IV melanoma patients treated with first-line PD-1-based immunotherapy between January 2015 and December 2018 were investigated. Primary resistance was defined as progressive disease (PD) at the time of the first tumor assessment after starting immunotherapy. Patients with complete response, partial response, and stable disease were classified as having disease control (DC). Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan–Meier estimator. Univariate and multivariate logistic regression analyses were performed to determine prognostic factors associated with OS. Results: Three hundred and nineteen patients were included, and 40% had primary resistance to immunotherapy. The median follow-up time was 22 months. Patients with primary resistance had 1-, 2-, and 3-year OS rates of 41%, 15%, and 10%, respectively, compared to 91%, 81%, and 65% for the patients who achieved DC. The following independently significant prognostic factors for OS were identified: protein S100B level and primary tumor localization. There was a statistically significant difference for OS (p < 0.0001) but not for PFS (p = 0.230) when analyzing risk groups formed with a combination of these two variables (low-, intermediate-, and high-risk subgroups). Conclusions: Melanoma patients with primary resistance to immunotherapy have a dismal prognosis. Response at the first tumor assessment after starting immunotherapy is a stronger prognostic factor for the further course of the disease than pretreatment risk factors.
Highlights
Immunotherapy with checkpoint inhibitors is currently the most effective therapy for metastatic melanoma, achieving high remission rates and long-term survival [1]
We focus on the clinical outcomes of stage IV melanoma patients with primary resistance to first-line progressive disease (PD)-1-based immunotherapy, pembrolizumab, nivolumab, and nivolumab plus ipilimumab
We evaluate the course of the disease in patients prospectively registered in the Central Malignant Melanoma Registry (CMMR) of the German Dermatological
Summary
Immunotherapy with checkpoint inhibitors is currently the most effective therapy for metastatic melanoma, achieving high remission rates and long-term survival [1]. These therapies include ipilimumab, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody, nivolumab and pembrolizumab, both programmed cell death protein 1 (PD-1) antibodies, and the dual combination of anti-PD-1 and anti-CTLA-4 antibodies nivolumab plus ipilimumab. Primary resistance is typically assumed in the clinical practice if tumor progression is observed at the first tumor assessment after therapy starts, which in our center takes place around week 12 (+/−5 days) It is observed in a rather high percentage of patients, estimated to be between 40% and 65%, depending on whether patients receive first-line immunotherapy or immunotherapy after progression under other systemic therapies [3,9,10].
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