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Baseline Biomarkers for Outcome of Melanoma Patients Treated with Pembrolizumab.

ABSTRACT: PURPOSE:Biomarkers for outcome after immune-checkpoint blockade are strongly needed as these may influence individual treatment selection or sequence. We aimed to identify baseline factors associated with overall survival (OS) after pembrolizumab treatment in melanoma patients. EXPERIMENTAL DESIGN:Serum lactate dehydrogenase (LDH), routine blood count parameters, and clinical characteristics were investigated in 616 patients. Endpoints were OS and best overall response following pembrolizumab treatment. Kaplan-Meier analysis and Cox regression were applied for survival analysis. RESULTS:Relative eosinophil count (REC) ?1.5%, relative lymphocyte count (RLC) ?17.5%, ?2.5-fold elevation of LDH, and the absence of metastasis other than soft-tissue/lung were associated with favorable OS in the discovery (n = 177) and the confirmation (n = 182) cohort and had independent positive impact (all P < 0.001). Their independent role was subsequently confirmed in the validation cohort (n = 257; all P < 0.01). The number of favorable factors was strongly associated with prognosis. One-year OS probabilities of 83.9% versus 14.7% and response rates of 58.3% versus 3.3% were observed in patients with four of four compared to those with none of four favorable baseline factors present, respectively. CONCLUSIONS:High REC and RLC, low LDH, and absence of metastasis other than soft-tissue/lung are independent baseline characteristics associated with favorable OS of patients with melanoma treated with pembrolizumab. Presence of four favorable factors in combination identifies a subgroup with excellent prognosis. In contrast, patients with no favorable factors present have a poor prognosis, despite pembrolizumab, and additional treatment advances are still needed. A potential predictive impact needs to be further investigated. Clin Cancer Res; 22(22); 5487-96. ©2016 AACR.

SUBMITTER: Weide B

PROVIDER: S-EPMC5572569 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Baseline Biomarkers for Outcome of Melanoma Patients Treated with Pembrolizumab.

Weide Benjamin B Martens Alexander A Hassel Jessica C JC Berking Carola C Postow Michael A MA Bisschop Kees K Simeone Ester E Mangana Johanna J Schilling Bastian B Di Giacomo Anna Maria AM Brenner Nicole N Kähler Katharina K Heinzerling Lucie L Gutzmer Ralf R Bender Armin A Gebhardt Christoffer C Romano Emanuela E Meier Friedegund F Martus Peter P Maio Michele M Blank Christian C Schadendorf Dirk D Dummer Reinhard R Ascierto Paolo A PA Hospers Geke G Garbe Claus C Wolchok Jedd D JD

Clinical cancer research : an official journal of the American Association for Cancer Research 20160516 22

<h4>Purpose</h4>Biomarkers for outcome after immune-checkpoint blockade are strongly needed as these may influence individual treatment selection or sequence. We aimed to identify baseline factors associated with overall survival (OS) after pembrolizumab treatment in melanoma patients.<h4>Experimental design</h4>Serum lactate dehydrogenase (LDH), routine blood count parameters, and clinical characteristics were investigated in 616 patients. Endpoints were OS and best overall response following p ...[more]

PMID: 27185375

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Project description:ContextImmune checkpoint blockade is associated with endocrine-related adverse events. Thyroid dysfunction during pembrolizumab therapy, an anti-programmed cell death 1 (PD-1) receptor monoclonal antibody, remains to be fully characterized.ObjectiveTo assess the incidence and characteristics of pembrolizumab-associated thyroid dysfunction.Design and settingThyroid function was monitored prospectively in melanoma patients who initiated pembrolizumab within an expanded access program at a referral oncology center. 18Fluorodeoxyglucose uptake on positron emission tomography/computed tomography (18FDG-PET/CT) was reviewed in cases compatible with inflammatory thyroiditis.PatientsNinety-nine patients with advanced melanoma (age, 26.3-93.6 years; 63.6% females) who received at least one administration of pembrolizumab.Main outcome measuresPatient characteristics, thyroid function (TSH, free T4), thyroid autoantibodies, and 18FDG-PET/CT.ResultsEighteen adverse events of thyroid dysfunction were observed in 17 patients. Thyrotoxicosis occurred in 12 patients, of which nine evolved to hypothyroidism. Isolated hypothyroidism was present in six patients. Levothyroxine therapy was required in 10 of 15 hypothyroid patients. Thyroid autoantibodies were elevated during thyroid dysfunction in four of 10 cases. Diffuse increased 18FDG uptake by the thyroid gland was observed in all seven thyrotoxic patients who progressed to hypothyroidism.ConclusionsThyroid dysfunction is common in melanoma patients treated with pembrolizumab. Hypothyroidism and thyrotoxicosis related to inflammatory thyroiditis are the most frequent presentations. Serial measurements of thyroid function tests are indicated during anti-PD-1 monoclonal antibody therapy. Thyrotoxicosis compatible with inflammatory thyroiditis was associated with diffuse increased 18FDG uptake by the thyroid gland. The prospective role of thyroid autoantibodies should be further investigated, together with the histopathological correlates.

Project description:BackgroundPembrolizumab demonstrated robust antitumor activity and safety in the phase Ib KEYNOTE-001 study (NCT01295827) of advanced melanoma. Five-year outcomes in all patients and treatment-naive patients are reported herein. Patients whose disease progressed following initial response and who received a second course of pembrolizumab were also analyzed.Patients and methodsPatients aged ≥18 years with previously treated or treatment-naive advanced/metastatic melanoma received pembrolizumab 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks until disease progression, intolerable toxicity, or patient/investigator decision to withdraw. Kaplan-Meier estimates of overall survival (OS) and progression-free survival (PFS) were calculated. Objective response rate and PFS were based on immune-related response criteria by investigator assessment (data cut-off, September 1, 2017).ResultsKEYNOTE-001 enrolled 655 patients with melanoma; median follow-up was 55 months. Estimated 5-year OS was 34% in all patients and 41% in treatment-naive patients; median OS was 23.8 months (95% CI, 20.2-30.4) and 38.6 months (95% CI, 27.2-not reached), respectively. Estimated 5-year PFS rates were 21% in all patients and 29% in treatment-naive patients; median PFS was 8.3 months (95% CI, 5.8-11.1) and 16.9 months (95% CI, 9.3-35.5), respectively. Median response duration was not reached; 73% of all responses and 82% of treatment-naive responses were ongoing at data cut-off; the longest response was ongoing at 66 months. Four patients [all with prior response of complete response (CR)] whose disease progressed during observation subsequently received second-course pembrolizumab. One patient each achieved CR and partial response (after data cut-off). Treatment-related AEs (TRAEs) occurred in 86% of patients and resulted in study discontinuation in 7.8%; 17% experienced grade 3/4 TRAE.ConclusionsThis 5-year analysis of KEYNOTE-001 represents the longest follow-up for pembrolizumab to date and confirms the durable antitumor activity and tolerability of pembrolizumab in advanced melanoma.Clinical trial registryClinicalTrials.gov, NCT01295827.

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Baseline Biomarkers for Outcome of Melanoma Patients Treated with Pembrolizumab.

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Baseline Biomarkers for Outcome of Melanoma Patients Treated with Pembrolizumab.

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