Hair and nail adverse events during treatment with targeted therapies for metastatic melanoma

Immune-related adverse events (irAEs) are very prevalent when treating patients with ipilimumab and nivolumab in combination, and 30–40% of patients discontinue the treatment for this reason. It is of high clinical relevance to investigate the consequences of discontinuing the treatment early since combination therapy with ipilimumab and nivolumab is the first line of treatment for many patients with metastatic melanoma. In this follow-up study, with real-world data from the nationwide DAMMED database, we investigated whether there was a difference in progression-free survival (PFS) and overall survival (OS) for patients who discontinued or did not discontinue treatment within the first four doses of treatment due to irAEs. In total, 448 patients were treated with ipilimumab and nivolumab. Of these, 133 patients discontinued due to irAEs in the induction phase. Using the Cox proportional hazards model, there was no significant difference in PFS when comparing the group that discontinued with the group that did not discontinue. The group that discontinued had a significantly longer OS than the group that received the full length of treatment. Therefore, we conclude that there is no significant negative impact on efficacy for patients who discontinue due to irAEs in the induction phase of combination immunotherapy for metastatic melanoma.

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Adverse events of targeted therapies approved for women's cancers

International Journal of Women s Dermatology ◽

10.1016/j.ijwd.2021.10.006 ◽

2021 ◽

Author(s):

Mathilde Saint-Ghislain ◽

Chloé Levenbruck ◽

Audrey Bellesoeur

Keyword(s):

Adverse Events ◽

Targeted Therapies

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Checkpoint-blocker induced autoimmunity is associated with pretreatment T cell expression profiles and favourable outcome in melanoma

10.1101/2020.06.23.20138594 ◽

2020 ◽

Author(s):

W. Ye ◽

A Olsson-Brown ◽

R. A. Watson ◽

V. T. F. Cheung ◽

R. D. Morgan ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Clinical Outcome ◽

Adverse Events ◽

Metastatic Melanoma ◽

T Cell Receptor ◽

Immune Checkpoint ◽

Single Agent ◽

Cell Receptor ◽

Pre Treatment

1Abstract1.1BackgroundImmune checkpoint blockers (ICBs) activate CD8+ T cells to elicit anti-cancer activity but frequently lead to immune-related adverse events (irAEs). The relationship of irAE with baseline parameters and clinical outcome is unclear. We investigated associations between irAE development, CD8+ T cell receptor diversity and expression and clinical outcome in a non-trial setting.1.2MethodsPatients ≥18 years old with metastatic melanoma (MM) receiving combination ICB (ipilimumab plus nivolumab – cICB, n=60) or single-agent ICB (nivolumab/pembrolizumab – sICB, n=78) were prospectively recruited. We retrospectively evaluated the impact of irAEs on survival. This analysis was repeated in an independent cohort of MM patients treated at a separate institution (n=210, cICB:74, sICB:136). We performed RNA sequencing of CD8+ T cells isolated from patients prior to treatment, analysing T cell receptor clonality differential transcript expression according to irAE development.1.3Results48.6% of patients experienced treatment-related irAEs within the first 5 cycles of treatment. Development of irAE prior to the 5th cycle of ICB was associated with longer progression-free and overall survival (PFS, OS) in the primary cohort (log-rank test, PFS: P=0.00034; OS: P<0.0001), replicated in the secondary cohort (OS: P=0.00064). Across cohorts median survival for those patients not experiencing irAE was 14.4 (95% CI:9.6-19.5) months vs not-reached (95% CI:28.9 - Inf), P=3.0×10−7. Pre-treatment performance status and neutrophil count, but not BMI, were additional predictors of clinical outcome. Analysis of CD8+ T cells from 128 patients demonstrated irAE development was associated with increased T cell receptor diversity post-treatment (P=4.3×10−5). Development of irAE in sICB recipients was additionally associated with baseline differential expression of 224 transcripts (FDR<0.1), enriched in pro-inflammatory pathway genes including CYP4F3 and PTGS2.1.4ConclusionsEarly irAE development post-ICB is strongly associated with favourable survival in MM and increased diversity of peripheral CD8+ T cell receptors after treatment. irAE post-sICB is associated with pre-treatment upregulation of inflammatory pathways, indicating irAE development may reflect baseline immune activation states.Key messageImmune-related adverse events (irAEs) commonly occur in patients with metastatic melanoma treated with immune checkpoint blockade (ICB) therapy. In real world setting we find development of early irAEs post-ICB treatment is associated with survival benefit, indicative of a shared mechanism with anti-tumour efficacy. CD8+ T cells from patients who develop irAE show increased receptor diversity, and pre-treatment samples from patients who develop irAE post single-agent anti-PD1 show over-expression of inflammatory pathways, indicating baseline immune state can determine irAE development.

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Costs associated with adverse events for systemic therapies in metastatic melanoma

Journal of Comparative Effectiveness Research ◽

10.2217/cer-2018-0022 ◽

2018 ◽

Vol 7 (9) ◽

pp. 867-879 ◽

Cited By ~ 1

Author(s):

Alex Z Fu ◽

Zhiyi Li ◽

Jackson Tang ◽

Syed Mahmood ◽

Tyler Whisman ◽

...

Keyword(s):

Adverse Events ◽

Metastatic Melanoma ◽

Systemic Therapies

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AB0820 COMPARATIVE EFFICACY OF GUSELKUMAB IN PATIENTS WITH PSORIATIC ARTHRITIS: RESULTS FROM SYSTEMATIC LITERATURE REVIEW AND NETWORK META-ANALYSIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.6013 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1713-1714

Author(s):

I. Mcinnes ◽

P. J. Mease ◽

K. Eaton ◽

A. Schubert ◽

S. Peterson ◽

...

Keyword(s):

Psoriatic Arthritis ◽

Literature Review ◽

Adverse Events ◽

Systematic Literature Review ◽

Targeted Therapies ◽

Meta Analysis ◽

Tumor Necrosis Factor Inhibitor ◽

Forest Plot ◽

Research Support ◽

Phase 3

Background:The efficacy of the interleukin (IL)-23 subunit p19 inhibitor guselkumab (GUS) for psoriatic arthritis (PsA) has recently been demonstrated in two Phase 3 trials (DISCOVER-1 & -2) but has not been evaluated versus existing targeted therapies for PsA.Objectives:To compare GUS to targeted therapies for PsA through network meta-analysis (NMA).Methods:A systematic literature review was performed to identify PsA randomized controlled trials from 2000 to 2018. Bayesian NMAs were performed to compare treatments on American College of Rheumatology (ACR) 20/50/70 response, Psoriasis Area Severity Index (PASI) 75/90/100 response, Health Assessment Questionnaire Disability Index (HAQ-DI) score, resolution of enthesitis (RoE), resolution of dactylitis (RoD), adverse events (AEs) and serious adverse events (SAEs). Analyses used random effects models that adjusted for placebo response via meta-regression on baseline risk when feasible. Results are summarized by ranking treatments according to median absolute probabilities of response derived from NMAs.Results:Twenty-six Phase 3 studies were included in the quantitative synthesis. Studies were placebo-controlled up to 24 weeks and evaluated 13 targeted therapies for PsA. Absolute probabilities are reported for PASI 90 & ACR 20 responses according toFigure 1,and a forest plot of relative risks versus placebo for AEs is reported according toFigure 2. For ACR 20 response, GUS 100 mg every 4 weeks (Q4W) and every 8 weeks (Q8W) ranked 5th and 8th out of 20 interventions and were comparable to IL-17A inhibitor (IL-17Ai) and most tumor necrosis factor inhibitor (TNFi) agents. Similar findings were observed for ACR 50 and 70 responses. For PASI 90 response, GUS Q4W and Q8W ranked 1st and 2nd out of 15 interventions and were highly likely to provide a greater benefit than most other agents. Similar findings were observed for PASI 75 and 100 responses. For HAQ-DI score, GUS Q4W and Q8W ranked 6th and 10th out of 20 interventions and were comparable to IL-17Ai and most TNFi agents. For RoE, GUS Q4W and Q8W ranked 8th and 6th out of 13 interventions and were comparable to IL-17Ai and TNFi agents. For RoD, GUS Q4W and Q8W ranked 8th and 9th out of 13 interventions and were comparable to most IL-17Ai and TNFi agents. For AEs, GUS Q4W and Q8W ranked 3rd and 2nd out of 19 interventions and were comparable to IL-17Ai and TNFi agents. Likewise, for SAEs, GUS Q4W and Q8W ranked 4th and 5th out of 20 interventions and were comparable to IL-17Ai and TNFi agents. Analyses that controlled for previous exposure to biologics or assessed outcomes at alternative timepoints were broadly consistent with primary analysis results.Conclusion:NMA results indicate that GUS is comparable to most targeted PsA treatments for improvement in arthritis, soft tissue damage, physical function, and safety outcomes. For PASI outcomes, GUS is highly likely to provide a greater benefit than other targeted PsA treatments.Disclosure of Interests:Iain McInnes Grant/research support from: Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Janssen, and UCB, Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Gilead, Janssen, Novartis, Pfizer, and UCB, Philip J Mease Grant/research support from: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Eli Lilly, Novartis, Pfizer, Sun Pharmaceutical, UCB – grant/research support, Consultant of: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Eli Lilly, Novartis, Pfizer, Sun Pharmaceutical, UCB – consultant, Speakers bureau: Abbott, Amgen, Biogen Idec, BMS, Eli Lilly, Genentech, Janssen, Pfizer, UCB – speakers bureau, Kiefer Eaton Shareholder of: Test Pharma, Consultant of: Janssen, Agata Schubert Employee of: Janssen-Cilag, Steve Peterson Employee of: Janssen Research & Development, LLC, Tim Disher Consultant of: Janssen, Wim Noel Employee of: Janssen Pharmaceuticals NV, Hassan Fareen Employee of: Janssen, Chetan Karyekar Shareholder of: Johnson & Johnson, Consultant of: Janssen, Employee of: Janssen Global Services, LLC. Previously, Novartis, Bristol-Myers Squibb, and Abbott Labs., Suzy Van Sanden Employee of: Janssen, Christopher T. Ritchlin Grant/research support from: UCB Pharma, AbbVie, Amgen, Consultant of: UCB Pharma, Amgen, AbbVie, Lilly, Pfizer, Novartis, Gilead, Janssen, Wolf-Henning Boehncke Grant/research support from: Janssen Research & Development, LLC, Consultant of: Janssen

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Behcet’s-like syndrome following pembrolizumab: An immune-related adverse event associated with programmed death receptor-1 inhibitor therapy

Journal of Oncology Pharmacy Practice ◽

10.1177/1078155219877219 ◽

2019 ◽

Vol 26 (4) ◽

pp. 995-999 ◽

Cited By ~ 1

Author(s):

Steffi Thomas ◽

Chay Bae ◽

Tabanor Joy-Ann ◽

William Traverse

Keyword(s):

Adverse Events ◽

Metastatic Melanoma ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Death Receptor ◽

Programmed Death ◽

Organ Systems ◽

Wide Range ◽

The Right

Introduction The landscape for the treatment of metastatic melanoma has been revolutionized with the introduction immune checkpoint inhibitors. Immune checkpoint inhibitors have now become the standard of care for the treatment of cancers. These immune agents including programmed death receptor-1 inhibitors, programmed death-ligand 1 inhibitors and cytotoxic T-lymphocyte antigen-4 inhibitors have shown promising results but have been associated with numerous immune-related complications. Pembrolizumab, a programmed death receptor-1 inhibitor, has been associated with a number of immune-related adverse events affecting multiple organ systems including integument, ocular, endocrine, cardiovascular, pulmonary, renal, gastrointestinal, and musculoskeletal system. Case report We present a case of an 88-year-old Caucasian male with metastatic melanoma of the face with metastasis to the right fifth cranial nerve and into the right cavernous sinus. He underwent resection of the melanoma and was placed on pembrolizumab at 2 mg/kg every three weeks. Interestingly, 24 months on pembrolizumab therapy, he developed corneal erosions, oral and genital ulcerations. Management and outcome Patient completed his 24 months of pembrolizumab and was started on prednisone and colchicine with improvement in his symptoms. At his follow-up eight months, he had recurrence of an oral ulcer. Discussion Here we present a rare case of an elderly male on pembrolizumab who suffered from corneal erosions, oral and genital ulcers, a syndrome similar to Behcet’s disease. Given that pembrolizumab and other immune checkpoint inhibitors are being utilized in the treatment of cancers, physicians should be aware of the wide range immune-related adverse events including the possible Behcet’s-like syndrome presentation.

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