Dataset Information

Primary Resistance to PD-1-Based Immunotherapy-A Study in 319 Patients with Stage IV Melanoma.

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.

SUBMITTER: Amaral T

PROVIDER: S-EPMC7226601 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Publications

Primary Resistance to PD-1-Based Immunotherapy-A Study in 319 Patients with Stage IV Melanoma.

Amaral Teresa T Seeber Olivia O Mersi Edgar E Sanchez Stephanie S Thomas Ioannis I Meiwes Andreas A Forschner Andrea A Leiter Ulrike U Eigentler Thomas T Keim Ulrike U Garbe Claus C

Cancers 20200422 4

<h4>Background</h4>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.<h4>Patients and methods</h4>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 ...[more]

PMID: 32331243

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Project description:PurposeWe tested the hypothesis that the combination of tremelimumab and interferon alfa-2b acting via different and possibly synergistic mechanisms would overcome tumor immune tolerance and lead to significant and durable clinical responses.Patients and methodsWe conducted a phase II study in which patients were administered tremelimumab 15 mg/kg/course (three cycles [one cycle = 4 weeks]) intravenously every 12 weeks. High-dose interferon alfa-2b (HDI) was administered concurrently, including intravenous induction at 20 MU/m2/d for 5 d/wk for 4 weeks followed by maintenance at 10 MU/m2/d subcutaneously three times a week for 8 weeks per course. From course 2 onward, HDI maintenance was administered subcutaneously.ResultsThirty-seven patients with American Joint Committee on Cancer stage IV (9M1a, 6M1b, and 22M1c) were enrolled. Two patients had previously treated brain metastases. Grades 3 and 4 toxicities included neutropenia (six patients; 17%), diarrhea/colitis (four patients; 11%), liver enzyme increase (four patients; 11%), rash (four patients; 11%), fatigue (15 patients; 40%), and anxiety/depression (five patients; 14%). Response data were available for 35 patients. The best objective response rate (RR; Response Evaluation Criteria in Solid Tumors) by intention to treat was 24% (90% CI, 13% to 36%; four complete responses [CRs] and five partial responses [PRs] that lasted 6, 6, > 12, > 14, > 18, 20, > 28, 30, and > 37 months, respectively). Fourteen patients (38%) had stable disease (SD) that lasted 1.5 to 21 months. The median progression-free survival was 6.4 months (95% CI, 3.3 to 12.1 months). The median overall survival (OS) was 21 months (95% CI, 9.5 to not reached). There was a weak association between therapy-induced autoimmunity and clinical benefits (CR/PR/SD; P = .0059), baseline C-reactive protein (CRP) less than or equal to 2.7× the upper limit of normal and clinical benefits (P = .0494) and improved probability of survival (P = .0032), and baseline lymphocyte count of at least 1,000/μL and response (CR/PR; P = .0183) and clinical benefits (CR/PR/SD; P = .0255). Biomarker associations were not significant after adjustment for multiple comparisons.ConclusionHDI can be administered combined with tremelimumab with acceptable toxicity and promising durable antitumor efficacy that warrant further testing in a randomized trial.

Dataset Information

Primary Resistance to PD-1-Based Immunotherapy-A Study in 319 Patients with Stage IV Melanoma.

Background

Patients and methods

Results

Conclusions

Publications

Primary Resistance to PD-1-Based Immunotherapy-A Study in 319 Patients with Stage IV Melanoma.

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