Baseline co-medications may alter the anti-tumoural effect of checkpoint inhibitors as well as the risk of immune-related adverse events

Abstract INTRODUCTION In several cancers treated with immune checkpoint inhibitors (ICIs), a remarkable association between the occurrence of immune-related adverse events (irAEs) and superior oncological outcomes has been reported. This effect has hitherto not been reported in the brain. This study aimed to investigate the relation between irAEs and outcomes in brain metastases (BM) patients treated with both local treatment to the brain (LT; i.e. surgery and/or radiation) and ICIs. METHODS This study is a retrospective cohort analysis of patients treated for non-small cell lung cancer (NSCLC) BMs in a tertiary institution in Boston, MA. Outcomes of interest were overall survival (OS) and intracranial progression-free survival (IC-PFS), measured from the time of LT. Sensitivity analyses were performed to account for immortal time bias (i.e., patients who live longer receive more cycles of ICIs and thus have more opportunity to develop an irAE). RESULTS A total of 184 patients were included; 62 (33.7%) were treated with neurosurgical resection and 122 (66.3%) with upfront brain radiation. irAEs occurred in 62 patients (33.7%). After adjusting for lung-Graded Prognostic Assessment, type of LT, type of ICI, newly diagnosed vs. recurrent BM, BM size and number, targetable mutations, and smoking status, irAEs were strongly associated with better OS (HR 0.33, 95% CI 0.19 – 0.58, p < 0.0001) and IC-PFS (HR 0.41; 95% CI 0.26 – 0.65; p = 0.0001). Landmark analysis including only patients who received more than 3 cycles of ICI (n = 133) demonstrated similar results for OS and IC-PFS, as did sensitivity analysis adjusting for the number of cycles administered (HR range 0.36 – 0.51, all p-values < 0.02). CONCLUSIONS After adjusting for known prognostic factors, irAEs strongly predict superior outcomes after LT in NSCLC BM patients. Sensitivity analysis suggests that this is unlikely due to immortal time bias.

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Prognostic significance of cutaneous immune-related adverse events in patients with melanoma and other cancers on immune checkpoint inhibitors

Journal of the American Academy of Dermatology ◽

10.1016/j.jaad.2021.03.024 ◽

2021 ◽

Author(s):

Leah L. Thompson ◽

Michael S. Chang ◽

Nicole J. Polyakov ◽

Amy E. Blum ◽

Nathaniel Josephs ◽

...

Keyword(s):

Adverse Events ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Prognostic Significance

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Rheumatic Immune-Related Adverse Events—A Consequence of Immune Checkpoint Inhibitor Therapy

Biology ◽

10.3390/biology10060561 ◽

2021 ◽

Vol 10 (6) ◽

pp. 561

Author(s):

Anca Bobircă ◽

Florin Bobircă ◽

Ioan Ancuta ◽

Alesandra Florescu ◽

Vlad Pădureanu ◽

...

Keyword(s):

Immune System ◽

Adverse Events ◽

Immune Checkpoint ◽

Multidisciplinary Approach ◽

Malignant Tumors ◽

Checkpoint Inhibitors ◽

Treatment Options ◽

Cancer Cell Growth ◽

Inhibitory Mechanisms ◽

Checkpoint Inhibitor Therapy

The advent of immunotherapy has changed the management and therapeutic methods for a variety of malignant tumors in the last decade. Unlike traditional cytotoxic chemotherapy, which works by interfering with cancer cell growth via various pathways and stages of the cell cycle, cancer immunotherapy uses the immune system to reduce malignant cells’ ability to escape the immune system and combat cell proliferation. The widespread use of immune checkpoint inhibitors (ICIs) over the past 10 years has presented valuable information on the profiles of toxic adverse effects. The attenuation of T-lymphocyte inhibitory mechanisms by ICIs results in immune system hyperactivation, which, as expected, is associated with various adverse events defined by inflammation. These adverse events, known as immune-related adverse events (ir-AEs), may affect any type of tissue throughout the human body, which includes the digestive tract, endocrine glands, liver and skin, with reports of cardiovascular, pulmonary and rheumatic ir-AEs as well. The adverse events that arise from ICI therapy are both novel and unique compared to those of the conventional treatment options. Thus, they require a multidisciplinary approach and continuous updates on the diagnostic approach and management.

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Ocular adverse events associated with immune checkpoint inhibitors: a novel multidisciplinary management algorithm

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835921992989 ◽

2021 ◽

Vol 13 ◽

pp. 175883592199298

Author(s):

Orthi Shahzad ◽

Nicola Thompson ◽

Gerry Clare ◽

Sarah Welsh ◽

Erika Damato ◽

...

Keyword(s):

Adverse Events ◽

Checkpoint Inhibitors ◽

Case Reports ◽

Case Series ◽

Simple Algorithm ◽

Cancer Therapeutics ◽

Management Algorithm ◽

Ocular Symptoms ◽

Systemic Corticosteroids ◽

Permanent Loss

Ocular immune-related adverse events (IrAEs) associated with use of checkpoint inhibitors (CPIs) in cancer therapeutics are relatively rare, occurring in approximately 1% of treated patients. Recognition and early intervention are essential because the degree of tissue damage may be disproportionate to the symptoms, and lack of appropriate treatment risks permanent loss of vision. International guidelines on managing ocular IrAEs provide limited advice only. Importantly, local interventions can be effective and may avoid the need for systemic corticosteroids, thereby permitting the continuation of CPIs. We present a single institution case series of eight affected patients managed by our multidisciplinary team. Consistent with previously published series and case reports, we identified anterior uveitis as the most common ocular IrAE associated with CPIs requiring intervention. Based on our experience, as well as published guidance, we generated a simple algorithm to assist clinicians efficiently manage patients developing ocular symptoms during treatment with CPIs. In addition, we make recommendations for optimising treatment of uveitis and address implications for ongoing CPI therapy.

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Anti-PD-1-Induced Hidradenitis Suppurativa

Dermatopathology ◽

10.3390/dermatopathology8010007 ◽

2021 ◽

Vol 8 (1) ◽

pp. 37-39

Author(s):

Alexia Maillard ◽

Damien Pastor ◽

Rastine Merat

Keyword(s):

Adverse Events ◽

Hidradenitis Suppurativa ◽

Checkpoint Inhibitors ◽

Latency Period ◽

The Body ◽

Skin Reactions ◽

Zinc Gluconate ◽

Severe Acne ◽

Bowel Diseases ◽

Inflammatory Bowel

Mucocutaneous adverse events are commonly observed under immune checkpoint inhibitors (ICIs) therapy. Here, we report the case of a 43-year-old male patient with a stage IIIC melanoma disease who developed hidradenitis suppurativa (HS) three months after the beginning of an anti-PD-1 (nivolumab) adjuvant therapy. The patient had no comorbidities other than obesity and severe acne during adolescence. After an unsuccessful course of lymecycline while he was still treated with nivolumab, he gradually improved under zinc gluconate therapy and, more importantly, after nivolumab cessation. HS is a recurrent follicular inflammatory disease in the apocrine gland-bearing areas of the body often associated with obesity, metabolic syndrome, tobacco smoking, inflammatory bowel diseases, psoriasis, and arthritis. In our patient, the latency period between drug initiation and onset of HS symptoms and the improvement after immunotherapy discontinuation, argued strongly in favor of an anti-PD-1-induced HS. Anti-PD-1 therapies often trigger T cells-mediated adverse events that mimic Th17-mediated inflammatory and neutrophilic diseases. We suggest that HS, as other pustular skin reactions and ICIs-induced neutrophilic colitis, can be part of the anti-PD-1 mucocutaneous adverse event spectrum.

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