Immune checkpoint inhibitor-induced inflammatory arthritis.

Immune-Related Adverse Events and Outcomes in Patients with Advanced Non–Small Cell Lung Cancer: A Predictive Marker of Efficacy?

Immune checkpoint inhibitors (ICIs) are improving prognoses in advanced stage cancers, but they also lead to immune-related adverse events (IRAEs). IRAEs targeting many organ systems have been reported, but musculoskeletal and rheumatic IRAEs have not been well-characterized. We systematically reviewed published literature on musculoskeletal and rheumatic IRAEs to better understand prevalence and clinical characteristics. Medline and CENTRAL databases were searched for articles reporting rheumatic and musculoskeletal IRAEs secondary to ICI treatment. After screening abstracts and full texts in duplicate, clinical features, prevalence, and treatment data were extracted and summarized. A total of 1,725 unique abstracts were screened; 231 contained original data and were about ICIs and went to full-text screening. Fifty-two of these contained information about musculoskeletal or rheumatic IRAEs or about treatment with ICIs in preexisting autoimmune disease. Of these, 33 were clinical trials, 3 were observational studies, and 16 were case reports or series. Arthralgia prevalence in clinical trials ranged 1-43%, and myalgia was reported in 2-20%. Arthritis was reported in 5 of 33 clinical trials, and vasculitis was reported in only 2. One observational study and 3 case reports described patients with preexisting autoimmune disease treated with ICIs. Case reports included development of inflammatory arthritis, vasculitis, myositis, and lupus nephritis. Arthralgia and myalgia have been reported commonly in patients treated with ICIs. The prevalence of rheumatic IRAEs such as inflammatory arthritis, vasculitis, and sicca syndrome is less clear from current evidence. There is limited observational and case-level evidence describing ICI use in patients with preexisting autoimmune disease.

Background:Patients with inflammatory arthritis (IA) exhibit altered immune regulation due to disease mechanisms and long-term immunosuppressant treatment. Several malignant diseases have shown significant improvement with immune checkpoint inhibitors (ICI), amongst...

BackgroundICIs (PD-1 inhibitors, PDL-1 inhibitors, CTLA-4 inhibitors) are increasingly used to treat various malignancies. The percentage of cancer patients in the US who may benefit from ICIs has increased from...

Immune checkpoint inhibitors (ICIs) are newly approved treatments for advanced malignancies that are increasing survival. The mechanism of these drugs, non-specifically activating T cells, also leads to immune-mediated damage of tissue or immune-related adverse events (IRAE). IRAEs with rheumatic phenotypes are increasingly being recognised. Inflammatory arthritis, sicca syndrome, inflammatory myopathy, vasculitis and lupus nephritis have been described as a result of ICIs. Use of ICIs will be expanding in the coming years for several reasons. ICIs will be used in earlier stage cancer, for more indications, and additional drugs will be approved. The rheumatologist plays a critical role in evaluating and treating these patients. The expertise of rheumatologists in evaluating rheumatic signs and symptoms and treating patients with immunosuppression are critical in ensuring the optimal outcomes for patients with rheumatic IRAE. Collaboration between oncology and rheumatology for clinical care and research will enhance understanding of these new disease entities.

Postherpes zoster programmed death-1 inhibitor−associated zosteriform granulomatous reactions

<h3></h3> Immune checkpoint inhibitors have transformed the treatment of various cancers including metastatic melanoma. Immune checkpoints are regulatory mechanisms which modulate the immune system and prevent overwhelming autoimmune attack. This may be exploited by certain tumour types, leading to attenuation of T cell activation and thus expansion and growth of tumour cells. Blockade of pathways including CTLA-4, PD-1 and PDL-1 has emerged as an approach to remove this inhibitory immune checkpoint mechanism and allow host to mount immune responses against tumour cells.^{1 2} Immune related adverse events (irAEs) are important, as high grade toxicities may require corticosteroids and discontinuation of treatment. The incidence of high grade irAEs is greater with CTLA-4 inhibitors (ipilimumab) than PD-1 inhibitors (nivolumab), and risk is increased further in combination (Ipi/Nivo). Ipi/Nivo induced hepatitis is an important irAE occurring in 17.6% patients (any grade) with 8.3% experiencing grade 3/4 hepatitis, based on previous trial data.^3–6 Continued analysis of real-world data is important to better establish the natural history of immunotherapy related hepatitis. Lancashire Teaching Hospitals is the tertiary cancer centre for Lancashire and South Cumbria. Electronic records, biochemistry results and oncology prescribing databases were retrospectively analysed for 68 patients treated with Ipi/Nivo between August 2016 and October 2020. 36 (52.9%) patients experienced hepatotoxicity (any grade) with n= 11 (16.2%) patients developing grade 3 or 4 hepatitis. The median time of onset of hepatotoxicity from the first dose (all grades) was 40 days (range 8–322). Amongst patients who experienced hepatotoxicity, the proportion treated with intravenous, oral or nil corticosteroids was 47.2%, 38.9% and 13.9% respectively. 4 patients required escalation to MMF and 1 patient needed tacrolimus as a third agent. Of patients who developed hepatotoxicity, n=29 had combination treatment discontinued prior to completion of 4 cycles. 15 patients were re-challenged with single agent nivolumab. Of the patients re-challenged, n=9 (60%) did not experience any further hepatotoxicity. This data demonstrated Ipi/nivo induced hepatitis occurring at a higher rate than in reported studies. This highlights the importance in monitoring real world data with novel anti-cancer therapies however, larger collaborative datasets are required. In addition, further comparative effectiveness research regarding treatment with oral vs intravenous corticosteroids will be important. The latter usually requires hospital admission, which has cost, service and patient experience implications. Finally, further analysis of phenotypic and biochemical variables associated with hepatotoxicity may identify important trends to allow better prediction and thus appropriate counselling and informed discussion when planning treatment. <h3>References</h3> Wei S, <i>et al</i>. Fundamental mechanisms of immune checkpoint blockade therapy. <i>Cancer Discov</i> 2018;<b>8</b>(9):1069–1086. Marin-Acevedo JA, <i>et al</i>. Next generation of immune checkpoint therapy in cancer: new developments and challenges. <i>J Haematol Oncol</i> 2018:<b>11</b>:39. Zhou X, et al. Are immune-related adverse events associated with the efficacy of immune checkpoint inhibitors in patients with cancer? A systematic review and meta-analysis. <i>BMC Med</i> 2020;18:87. Larkin J, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. <i>N Eng J Med</i> 2015;373:23–34. Hodi F, et al. Improved survival with ipilimumab in patients with metastatic melanoma. <i>N Eng J Med</i> 2010;363:711–723. Wolchok J, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol 2010;11(2):155–64. U.S Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. November 2017. Haanen J, et al. Management of toxicities from immunotherapy: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. <i>Ann Oncol</i> 2017;28(suppl 4):119–142. Cheung V, et al. Immunotherapy-related hepatitis: real-world experience from a tertiary centre. <i>Frontline Gastroenterology</i> 2019;10:364–371. Eun Y, <i>et al</i>. Risk factors for immune-related adverse events associated with anti-PD-1 pembrolizumab. <i>Sci Rep</i> 2019;<b>9</b>:14039. Owen D, <i>et al</i>. Incidence, risk factors, and effect on survival of immune-related adverse events in patients with non-small-cell lung cancer. <i>Clin Lung Cancer</i> 2018;<b>19</b>(6):893–900. Parmanande A, <i>et al</i>. Risk factors for immune related adverse events: a retrospective study. <i>Ann Oncol</i> 2019;<b>30</b>(suppl11). Barata M, <i>et al</i>. Predictors of immunotherapy induced immune-related adverse events. <i>Eur Respir J</i> 2019:<b>54</b>(suppl63). Aimono Y, <i>et al</i>. Evaluation of risk factors for immune-related adverse events associated with treatment with immune checkpoint inhibitors. <i>Gan To Kagaku Ryoho</i> 2021;<b>48</b>(1):57–61. Angum F, <i>et al</i>. The prevalence of autoimmune disorders in women: a narrative review. <i>Cureus</i> 2020;<b>15</b>(5):e8094. Fairweather D, <i>et al</i>. Women and autoimmune diseases. <i>Emerg Infect Dis</i> 2004;<b>10</b>(11):2005–2011. Ozdemir B, <i>et al</i>. Immune-related adverse events of immune checkpoint inhibitors and the impact of sex- what we know and what we need to learn. <i>Ann Oncol</i> 2018;<b>29</b>(4):1067.

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

2547 Background: Immune checkpoint inhibitors (ICIs) have ushered in a unique entity known as immune-related adverse events (IrAEs) that can be debilitating and challenging for physicians. Given that genomic variation underlies both disease susceptibility and drug response, there is reasonable cause to believe that genomic markers are predictive of IrAEs. We perform a pioneering pharmacogenomic study to uncover genomic biomarkers associated with IrAEs from ICIs. Methods: Since March 2018, we recruited cancer patients treated with ICIs from the National University Cancer Institute Singapore and Tan Tock Seng Hospital. IrAEs were clinical characterized and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5. DNA was extracted and genotyped by Infinium Global Screening Array (700K markers). Statistical analyses were performed using SVS/HelixTree. Genetic association was performed by logistic regression. Bonferroni corrected P &lt; 7.1E-08 was considered statistically significant. Results: We conducted a pilot pharmacogenomic genome-wide association study (GWAS) on 307 patients of Asian Ancestry. Median age was 62. Majority were male (68.1%), Chinese (75.9%), ECOG PS 0-1 (91.6%), stage IV cancer at diagnosis (64.6%). Non-small cell lung cancer (36.2%), renal cell carcinoma (12.4%) and hepatocellular carcinoma (7.2%) were the three most common cancers. Top four ICIs used were pembrolizumab, nivolumab, atezolizumab and durvalumab, respectively (44.6%, 26.1%, 10.1% and 10.1% respectively). Nine percent of patients received dual ICIs concurrently. Median duration of treatment was 152 days and median follow up was 212 days. IrAEs were seen in 50.5% of patients. Skin (21.8%), endocrine (6.8%) and hepatotoxicity (5.9%) were the most common IrAEs. Eight percent of patients had CTCAEv5 grade ≥3 toxicity, of which hepatotoxicity (2.6%), skin (1.6%) and pulmonary toxicities (1.3%) were the most common. A preliminary pharmacogenomic investigation revealed one potential novel genetic locus associated with IrAEs: LOC105373202 rs5915369; Unadjusted P= 6.6E-08, OR (95%CI) = 27.8 (3.7-206.5), minor allele = A, 10.7% in cases vs 0.4% in controls. We also identified an additional 3 independent SNPs (rs167609, rs2341687, DMDrs5928214) with nominal significance (7.1E-0-8≤ P&lt; 5.0E-7). Conclusions: This pilot pharmacogenomics GWAS uncovered 4 potential novel genetic loci predictive of IrAEs from ICIs amongst Asian patients. Further pharmacogenomic discovery/replication and functional validation studies are currently on-ongoing to identify specific genomic biomarkers that predispose individual patients to IrAEs.

Features of polymyalgia rheumatica–like syndrome after immune checkpoint inhibitor therapy

Limitations of morphology-based management for immune checkpoint inhibitor-related cutaneous adverse events

Metastatic triple-negative breast cancer (mTNBC) is an aggressive disease with particularly poor outcomes [1]. Over&#13;\nthe past few years, relevant gains in knowledge concerning the molecular landscape of this disease have allowed&#13;\nto considerably broaden the available therapeutic armamentarium. Poly ADP-ribose polymerase-1 inhibitors,&#13;\nepigenetic agents, anti-androgens, tyrosine kinase inhibitors and immune checkpoint inhibitors (ICIs) may all&#13;\noptimally exemplify the targeted therapeutic weapons recently gained in the fight against mTNBC [2].&#13;\nTargeting of immune checkpoints through their respective monoclonal antibodies translates into effective antitumor responses not only in widely recognized ‘immunogenic’ tumor types, for example, melanoma and renal cell&#13;\ncarcinoma, but also in other solid tumors including breast cancer [3]. PD-1 is an immune checkpoint expressed on&#13;\nthe surface of B cells, T cells and natural killer T cells, with a critical role in modulating self tolerance, immune&#13;\nhomeostasis and inflammation. When activated by PD-L1 or -L2, PD-1 mediates downregulation of T-cell activity,&#13;\ncauses T-cell lysis and reduces cytokine production significantly

Concurrent Immune Checkpoint Inhibitors and Stereotactic Radiosurgery for Brain Metastases in Non-Small Cell Lung Cancer, Melanoma, and Renal Cell Carcinoma

Disclosure: A.K. Fernando: None. R. Cheema: None. Introduction: Immune checkpoints are proteins expressed by immune cells and are crucial for maintaining self-tolerance. Immune checkpoint inhibitors (ICIs) are antibodies that inhibit these checkpoints and enhances T-cell activation and antitumor activity. This emerged as a powerful tool in treating cancer, however its use is jeopardized by various immune related adverse events (IRAEs). Secondary hypophysitis, although rare, is associated with immunotherapy. The incidence of hypophysitis is considerably lower with PD-1 inhibitors such as pembrolizumab (0.5-1.5%) than with CTLA-4 inhibitors. We present a case of hypophysitis following initiation of pembrolizumab for NSCLC. Case: A 64-year-old Caucasian male was seen in Endocrinology for evaluation of abnormal TFTs with nonspecific symptoms of fatigue and malaise. He was recently diagnosed with poorly differentiated lung carcinoma with metastasis to brain. After completing XRT, he was started on pembrolizumab/trastuzumab. TFTs prior to initiation of treatment were unremarkable. He developed a mild rash and fatigue post treatment but otherwise treatment was well tolerated. TFTs at week 8 after starting ICIs showed TSH 0.09 uIU/mL (0.27-4.2), T4 0.8 ng/dL (0.9-1.7) and T3 2.2 pg/mL (2.5-4.3). MRI Sella showed enlargement of the pituitary gland and stalk suggestive of hypophysitis. Pembrolizumab was discontinued. Additional studies showed low total testosterone 19.5 ng/dL (193-740) and free testosterone 4.5 pg/mL (35-130) with inappropriately normal gonadotropins suggestive of central hypogonadism. Other pituitary axis were intact. Cosyntropin stimulation test confirmed intact HP Adrenal axis. He was started on levothyroxine and hydrocortisone (20 mg AM and 10 mg PM) for hypophysitis. His symptoms improved. He is closely being monitored with plan to repeat MRI Sella in 3 months and to re-evaluate his HP adrenal prior to weaning off steroids. Discussion: IRAEs from ICIs typically present within 6 to 12 weeks but can present several months to years later. The non-specific nature of symptoms in patients on PD-1 inhibitors can delay clinical recognition with dire consequences. Treatment involves hormone replacement and stopping immunotherapy. Though benefit of GC in patients with grades 1-2 hypophysitis is unclear, low dose corticosteroids have been used to mitigate pituitary inflammation. High dose GC although commonly used in patients with critical illness (grades 3-4), its use remains controversial as they have not shown to significantly alter overall survival. Some degree of pituitary function may recover 4-12 weeks following withdrawal of ICIs. Given the increase in use of ICIs and the serious nature of IRAEs, it is critical to be aware of clinical manifestations, diagnosis, and management of this entity. Presentation: Friday, June 16, 2023

BackgroundCutaneous immune-related adverse events (cirAEs) are the most common form of immune-related adverse events after immune-checkpoint inhibitor (ICI) treatment, affecting up to 40% of ICI recipients and ranging in severity...