Introduction Defects in immunological self-tolerance result in an increased risk for development of autoimmune paraneoplastic diseases (AD) and immune-mediated toxicity in response to immune stimulation in individuals with thymic epithelial tumors (TETs). We conducted a survey to evaluate the tolerability of Covid-19 messenger RNA (mRNA) vaccines in patients with TETs, including individuals with pre-existing AD. Methods After reviewing published data on adverse events (AEs) associated with the BNT162b2 (Pfizer, Inc., and BioNTech) and mRNA-1273 (ModernaTX, Inc.) mRNA vaccines, we designed and administered a questionnaire to participants at three timepoints: after each dose of vaccination and one month following the final dose. Questions related to AD and use of immunosuppressive drugs were included. Descriptive statistics were used to analyze data and results were compared with previously described results related to the BNT162b2 and mRNA-1273 vaccines. Results From February 26 th and June 1 st , 2021, we administered the survey to 54 participants (median age: 58 years; thymoma: 33; pre-existing AD: 19). Common AEs included injection-site pain, fatigue, and headaches. There were no vaccination-related hospitalizations or deaths. Autoimmune flares occurred in three (16%) patients after the first dose and three (17%) patients after the second dose. The majority of AD flares were mild and self-limited. One patient (2%) was diagnosed with a new AD following vaccination. Conclusions Tolerability of COVID-19 mRNA vaccines in patients with TETs is comparable to the general population. Most patients with pre-existing AD did not experience disease flares and the development of new AD was rare. Patients with TETs should be encouraged to get vaccinated against COVID-19 due to the documented benefits of vaccination and manageable risk profile.
The emergence of immunotherapy as a modern pillar of cancer treatment has changed the treatment landscape for various cancers. Immune checkpoint inhibitors directed at programed death-1 (PD-1) or its ligand (PD-L1), in particular, have found widespread clinical applications and have resulted in durable responses and an improvement in survival of patients with advanced or metastatic disease. Tumor cell PD-L1 expression and tumor mutation burden (TMB) are biomarkers of response and efforts are underway to identify other biomarkers that might predict benefit with these drugs. Most patients tolerate immunotherapy well, although a subset of patients develop immune-mediated toxicity due to excessive immune stimulation. Thymic epithelial tumors (TETs) have a unique biology which can predispose to development of autoimmune paraneoplastic disease, especially in patients with thymoma. Due to defects in immunological self-tolerance, the use of immunotherapy in TET patients is associated with an increased risk of immune-mediated adverse events, which can be potentially life-threatening. Development of biomarkers of response and toxicity is particularly important for the treatment of TETs since it is important to identify patients who might benefit from treatment and be at low risk for development of severe immune toxicity. The use of immunotherapy in patients with autoimmune disorders and those who have previously experienced immune-mediated toxicity is currently an area of active research. Various risk mitigation strategies are under evaluation in prospective clinical trials, including trials of immune checkpoint inhibitors in patients with thymic cancers.
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced cancers. However, activation of the immune system can occasionally cause life-threatening toxicity involving critical organs. Induction of immune-mediated toxicity is a significant concern for patients with thymic epithelial tumors (TETs) due to defects in immune tolerance. An increased risk of skeletal and cardiac muscle inflammation following treatment with ICIs is well recognized in patients with advanced TETs. However, uncommon musculoskeletal and rheumatic complications can also occur. The cases presented in this report highlight the spectrum of presentation of immune-mediated, joint-predominant musculoskeletal adverse events in patients with advanced TETs treated with ICIs, including polymyalgia rheumatica-like illness and inflammatory arthritis.
e21153 Background: Poly (ADP-ribose) polymerase inhibitors (PARPi) show variable clinical activity in individuals with advanced cancers. In the lung-MAP substudy S1400G, talazoparib alone was not sufficiently active in squamous lung cancers with homologous recombinant repair deficiency. Combinations of PARPi with immune checkpoint inhibitors (ICIs) are under investigation since preclinical studies show an immunostimulatory effect of PARPi that can potentially increase responsiveness to ICIs. To test this hypothesis, we evaluated the PARPi, O with the ICI, D in individuals with advanced NSCLC who had received at least one prior platinum-based regimen. Methods: Eligible participants were enrolled in an expansion cohort of a proof-of-concept phase I/II study (NCT02484404) and received O 300 mg PO BID with D 1500 mg IV every 4 weeks until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Results: Between July 2016 and July 2021, 15 participants with recurrent NSCLC were enrolled (median age: 66 years; stage IV: 12; adenocarcinoma 11; prior ICI: 9). After median potential follow-up of 39.6 months (mo), median PFS (mPFS) was 3.2 mo (95% CI: 0.9-7.6). Among 14 subjects with known EGFR mutation status, mPFS was longer in 11 individuals with EGFR-WT tumors (5.7 vs. 0.9 mo; p = 0.001). DNA repair mutation ( APC, BAP1, BRCA1, BRCA2, CHEK2, FANCI, FANCL and PALB2) status was known for 9 subjects; mPFS of subjects with (n = 7) or without (n = 2) DNA repair mutations was 3.2 vs. 18.1 mo (p = 0.68), respectively. Tumor PD-L1 expression > 50% (n = 3/10) and prior ICI therapy (n = 9/15) was associated with longer, albeit not statistically significant, mPFS: 7.6 vs. 1.8 mo; p = 0.22, and 5.7 vs. 1.8 mo; p = 0.39, respectively. Two (13%) partial responses, 7 (47%) stable disease and 6 (40%) cases of progressive disease were observed. Four (27%) subjects, including 3 previously treated with ICIs, achieved durable response or stability for up to 3 years. Treatment-related adverse events (TRAEs) were generally mild (grade 1 or 2). The most common TRAEs were anemia (40%), thrombocytopenia (27%), anorexia, fatigue, pain, and hypophosphatemia (each observed in 20%). Grade > 3 TRAEs occurred in 4 (27%) subjects (all hematologic). Immune-related AEs occurred in 4 (27%) individuals. Two subjects developed myelodysplasia after 12 and 36 mo of treatment. Three (20%) subjects required dose reductions or discontinuation of O due to anemia. There were no treatment-related deaths. Accrual will continue until 20 eligible participants are enrolled. Conclusions: O+D has acceptable safety and modest efficacy in an unselected population with recurrent NSCLC. Sufficient clinical activity is not observed in individuals with EGFR-mutated tumors. Genomic and immunological analyses are being performed to identify predictive biomarkers in individuals with durable benefit and will be reported. Clinical trial information: NCT02484404.
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