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Pembrolizumab Cutaneous Adverse Events and Their Association With Disease Progression.

ABSTRACT: Immunomodulatory anticancer drugs, such as the anti-programmed death-1 drug pembrolizumab, have shown promising results in trials, and more patients will receive such treatments. Little is known about cutaneous adverse events (AEs) caused by these drugs and their possible correlation with treatment response.To describe the frequency and spectrum of cutaneous AEs linked with pembrolizumab and their possible correlation with treatment response.A single-institution, retrospective medical record review was conducted of patients with cancer who were treated with pembrolizumab from March 1, 2011, to May 28, 2014. The review comprised 83 consecutive patients who were enrolled in 2 clinical trials, received at least 1 dose of pembrolizumab, and had at least 1 follow-up visit. Patients were grouped according to the following therapeutic regimen for pembrolizumab: 43 received 10 mg/kg every 3 weeks, 24 received 10 mg/kg every 2 weeks, and 16 received 2 mg/kg every 3 weeks. Sixty-six patients were treated for melanoma, 15 patients for lung cancer, 1 patient for prostate cancer, and 1 patient for Merkel cell carcinoma. Median follow-up was 15 weeks (range, 2-105 weeks). The analysis was conducted from March 1 to September 30, 2014.Occurrence, severity, and type of cutaneous AEs, as well as disease progression and response to pembrolizumab treatment.Thirty-five patients (42%) developed cutaneous AEs attributed to pembrolizumab. The most common cutaneous AEs were macular papular eruption (24 [29%]), pruritus (10 [12%]), and hypopigmentation (7 [8%]). All 7 patients who developed hypopigmentation were treated for melanoma. Survival analyses showed that patients who developed cutaneous AEs had significantly longer progression-free intervals in all 3 groups (pembrolizumab, 10 mg/kg, every 3 weeks, P?=?.001; pembrolizumab, 10 mg/kg, every 2 weeks, P?=?.003; pembrolizumab, 2 mg/kg, every 3 weeks, P?=?.009) compared with patients who did not develop cutaneous AEs.Pembrolizumab therapy was associated with cutaneous AEs in 42% of patients. The development of cutaneous AEs, especially of hypopigmentation in patients with melanoma, could point toward better treatment response.

SUBMITTER: Sanlorenzo M

PROVIDER: S-EPMC5061067 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Pembrolizumab Cutaneous Adverse Events and Their Association With Disease Progression.

Sanlorenzo Martina M Vujic Igor I Daud Adil A Algazi Alain A Gubens Matthew M Luna Sara Alcántara SA Lin Kevin K Quaglino Pietro P Rappersberger Klemens K Ortiz-Urda Susana S

JAMA dermatology 20151101 11

<h4>Importance</h4>Immunomodulatory anticancer drugs, such as the anti-programmed death-1 drug pembrolizumab, have shown promising results in trials, and more patients will receive such treatments. Little is known about cutaneous adverse events (AEs) caused by these drugs and their possible correlation with treatment response.<h4>Objective</h4>To describe the frequency and spectrum of cutaneous AEs linked with pembrolizumab and their possible correlation with treatment response.<h4>Design, setti ...[more]

PMID: 26222619

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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:ImportancePembrolizumab, a monoclonal antibody targeting programmed cell death 1, is currently approved by the US Food and Drug Administration for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). The potential neoadjuvant role of programmed cell death 1 inhibitors in primary surgical management of HNSCC and effects on surgical outcomes are poorly understood.ObjectiveTo evaluate the incidence of postoperative adverse events in treatment-naive patients with advanced oral cavity cancer receiving neoadjuvant pembrolizumab when compared with matched controls, as part of a window-of-opportunity multi-institutional clinical trial assessing neoadjuvant pembrolizumab for locally advanced HNSCC.Design, setting, and participantsThis retrospective cohort study at a single tertiary academic institution included treatment-naive patients with local regionally advanced oral cavity squamous cell carcinoma (OCSCC) who were undergoing surgical resection.ExposuresPatients with local regionally advanced resectable OCSCC who received neoadjuvant pembrolizumab were retrospectively reviewed for postoperative adverse events. Controls were matched by age, race, smoking status, and overall cancer stage based on historical data at the same institution. Matched-cohort analysis was performed using a McNemar test to assess differences between the groups.Main outcomes and measuresIncidence of adverse events following surgical resection of advanced OCSCC within 30 days of surgery and on continued follow-up.ResultsA total of 64 patients (32 as part of the prospective clinical trial and 32 as controls; mean [SD] age, 59.6 [10.3] years; 28 [44%] women) were included in the analysis. Postoperative adverse events in the 32 patients receiving pembrolizumab included lymphedema (n = 20 [63%]), trismus (n = 7 [22%]), return to operating room (n = 7 [22%]), wound infection (n = 7 [22%]), fistula (n = 6 [19%]), wound dehiscence (n = 4 [13%]), flap failure (n = 3 [9%]), and hematoma (n = 2 [6%]). The matched control group demonstrated similar complication rates without considerable differences, except for trismus (n = 16 [50%]), which was greater by a difference of 28.1% (95% CI, 5.6%-50.6%) in the control group.Conclusions and relevanceThis cohort study examined surgical complications among patients with local regionally advanced OCSCC treated with neoadjuvant pembrolizumab and found that serious adverse events were similar to those in patients who underwent standard-of-care treatment. This suggests that there is no increased perioperative morbidity in the use of preoperative treatment with immunotherapy. Further prospective studies are needed to validate these findings for oral cavity cancer and other subsites of the head and neck.

Project description:Background & aimsHepatic steatosis has been associated with increased risk of major adverse cardiovascular events (MACE) but it is not clear whether steatosis is independently associated with risk of MACE. We investigated whether steatosis is associated with risk of MACE independently of the presence and extent of baseline coronary artery disease, assessed by comprehensive contrast-enhanced computed tomography angiography (CTA).MethodsWe conducted a nested cohort study of 3756 subjects (mean age, 60.6 years; 48.4% men) who underwent coronary CTA at 193 sites in North America, from July 2010 through September 2013, as part of the PROMISE study, which included noninvasive cardiovascular analyses of symptomatic outpatients without coronary artery disease. Independent core laboratory readers measured hepatic and splenic attenuation, using non-contrast computed tomography images to identify steatosis, and evaluated coronary plaques and stenosis in coronary CTA images. We collected data on participants' cardiovascular risk factors, presence of metabolic syndrome, and body mass index. The primary endpoint was an adjudicated composite of MACE (death, myocardial infarction, or unstable angina) during a median follow-up time of 25 months.ResultsAmong the 959 subjects who had steatosis (25.5% of the cohort), 42 had MACE (4.4%), whereas among the 2797 subjects without steatosis, 73 had MACE (2.6%) (hazard ratio [HR] for MACE in subjects with steatosis, 1.69; 95% CI, 1.16-2.48; P = .006 for MACE in subjects with vs without steatosis). This association remained after adjustment for atherosclerotic cardiovascular disease risk scores, significant stenosis, and metabolic syndrome (adjusted HR, 1.72; 95% CI, 1.16-2.54; P = .007) or obesity (adjusted HR, 1.75; 95% CI, 1.19-2.59; P = .005). Steatosis remained independently associated with MACE after adjustment for all CTA measures of plaques and stenosis.ConclusionsHepatic steatosis is associated with MACE independently of other cardiovascular risk factors or extent of coronary artery disease. Strategies to reduce steatosis might reduce risk of MACE. ClinicalTrials.gov no: NCT01174550.

Project description:ImportanceCutaneous immune-related adverse events (cirAEs) are some of the earliest toxic reactions to emerge following immune-checkpoint inhibitor (ICI) initiation. As an early indicator of robust inflammatory response, cirAEs may be associated with patterns of immune-mediated toxic effects, but associations between these events and noncutaneous immune-related adverse events (irAEs) remain underexplored.ObjectivesTo characterize patterns of cirAEs and irAEs across care settings and examine associations between the features of first cirAE, overall irAE risk, and risk of specific irAE subtypes.Design, setting, and participantsA retrospective cohort study was conducted at a single academic medical center. The cohort included 358 patients with cancer who initiated anti-programmed death 1/ligand 1 and/or anticytotoxic-T-lymphocyte-4 ICI therapy between January 1, 2016, and March 8, 2019, and developed 1 or more cirAEs, identified using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes and confirmed via manual medical record review. All relevant information documented before March 31, 2020, was included.ExposuresAnti-programmed death 1/ligand 1 and/or anticytotoxic-T-lymphocyte-4 therapy.Main outcomes and measuresAssociations between specific cirAE morphologic classes and patterns of irAEs (occurrence, timeline, organ class, and specific toxic effects). Given the potential that shared underlying factors are associated with the risk of both noncutaneous and cutaneous toxic effects, the presence of observed positive associations between certain cirAE and irAE subtypes was hypothesized.ResultsOf the 358 patients, 213 were men (59.5%); median age was 65 years (interquartile range, 55-73 years). Nearly half of the patients (177 [49.4%]) with cirAE also developed a noncutaneous irAE. Most patients (128 [72.3%]) experienced their first cirAE before developing any irAE. Several cirAE morphologic classes were found to be associated with overall, organ-based, and specific irAEs. More specifically, mucositis was found to be associated with overall irAE risk (odds ratio [OR], 5.28; 95% CI, 1.11-24.26; P = .04), gastrointestinal irAEs (OR, 5.70; 95% CI, 1.11-29.40; P = .04), and the specific diagnosis of gastroenterocolitis (OR, 6.80; 95% CI, 1.24-37.39; P = .03). In addition, psoriasis was associated with an increased risk of endocrine irAEs (OR, 4.54; 95% CI, 1.21-17.04; P = .03).Conclusions and relevanceIn this cohort study, these findings underscore the risk of multisystem toxic effects in patients experiencing cirAEs and highlight potential opportunities for dermatologists in the management of noncutaneous toxic effects.

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Pembrolizumab Cutaneous Adverse Events and Their Association With Disease Progression.

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Pembrolizumab Cutaneous Adverse Events and Their Association With Disease Progression.

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