Common Immune-related Adverse Events Research Articles

Complete response to fifth-line anti-PD-1 rechallenge in fumarate hydratase-mutated papillary renal cell carcinoma

Fumarate hydratase (FH) mutated papillary renal cell carcinoma is an aggressive variant of kidney cancer that poorly responds to conventional targeted therapies and immunotherapy. Here, we present the 10-year follow-up of a heavily pre-treated patient with several lines of therapy, achieving a remarkable complete response to anti-PD-1 rechallenge. In addition, we highlight a common immune-related adverse event of anti-PD-1, eosinophilia, as a possible biomarker of response and using TCGA data analysis, provide proof-of-concept for tumor expression of the eosinophil-related gene SIGLEC8, as a promising powerful predictor of prognosis for papillary renal cell carcinoma patients.

Real-world efficacy and safety of durvalumab-tremelimumab as second-line systemic therapy after atezolizumab-bevacizumab in unresectable hepatocellular carcinoma.

The efficacy and safety of immune-checkpoint inhibitors (ICI) for the treatment of unresectable hepatocellular carcinoma are known. We explored ICI rechallenges with direct switching from 1 ICI regimen to another. This retrospective study included 16 patients who received atezolizumab-bevacizumab (Atezo+Bev) and durvalumab-tremelimumab (Dur+Tre) as the first-line and second-line combination therapy, respectively, at Hiroshima University Hospital. The radiological response and adverse event were evaluated in all patients. Of the 16 patients, 12 were male, and the median age at Atezo+Bev induction was 71 years. The reasons for medication changes were disease progression in 11 patients and adverse events in 5 patients. With Atezo+Bev and Dur+Tre initiation, the Barcelona-Clinic Liver-Cancer stage (A/B/C) progressed in 9/6/3 and 3/4/9 patients and the Child-Pugh classification (A/B/C) progressed in 12/4/0 and 9/6/3 patients, respectively. The disease control rate and overall response rate of Atezo+Bev were 87.5% and 58.3%, respectively, and of Dur+Tre were 62.5% and 0%, respectively. The most common immune-related adverse event in both the Atezo+Bev and Dur+Tre groups was colitis; 3 of the 5 patients with colitis on Atezo+Bev treatment had colitis with Dur+Tre, and 2 had exacerbations. Regarding liver function, ALBI score significantly decreased during Atezo+Bev, but not Dur+Tre, treatment. In patients with colitis following Atezo+Bev, subsequent Dur+Tre treatment may induce colitis recurrence or exacerbation. For immune-related adverse events other than colitis, Dur+Tre could provide relatively safe disease control while maintaining liver function.

Infliximab in steroid-refractory immune-related hepatitis does not demonstrate hepatotoxicity and may shorten time on steroids

BackgroundImmune-related hepatitis (irHepatitis) is a relatively common immune-related adverse event (irAE) of checkpoint inhibitors. Often, it responds well to steroids; however, in refractory cases, further therapy is needed. Anti-tumor necrosis...

Thyroid dysfunction caused by immune checkpoint inhibitors improves cancer outcomes.

A common immune-related adverse event (irAE) with immune checkpoint inhibitors (ICIs) is thyroid dysfunction (TD-irAEs). The clinical presentation can be varied, and its association with prognosis remains unclear. We investigated the characteristics of TD-irAEs and their association with clinical outcomes among cancer patients treated with ICIs in a real-life setting. Response to treatment was assessed using RECIST v1.1. We calculated the probability of recurrence and survival associated with TD-irAEs using multivariable-adjusted regression and Cox proportional hazards models. In this single-center retrospective analysis, we included 238 patients (72% male) with a median age of 69.5 years. Primary tumors were melanoma (23.1%), lung (60.5%), or urothelial cancer (16.4%), treated with atezolizumab (23.1%), pembrolizumab (44.5%), ipilimumab (0.4%), and/or nivolumab (25.6%). Seventy (29%) patients developed TD-irAEs in a median time of 69 days (41-181). The incidence of TD-irAEs with combination therapy was higher than with monotherapy (67% vs 6.3%, P = 0.011). TD-irAE patients showed a higher objective response rate (ORR) than those without TD-irAEs (60% vs 42.3%, P = 0.013) and longer overall survival (OS) 45 vs 16 months, P < 0.006. Patients who developed TD-irAEs had a relative reduction of 77% (OR 0.23, 95% CI 0.11-0.47) in the risk of progression and of 47% in the risk of mortality (HR 0.53, 95% CI 0.36-0.80), independent of age, sex, primary tumor, or ICI regimen. TD-irAEs occur in nearly 30% of our patients receiving ICIs. In our analysis, TD-irAEs appeared to be associated with higher ORR and longer OS and showed a reduction in the risk of progression and mortality.

Neoadjuvant anthracycline followed by toripalimab combined with nab-paclitaxel in patients with early triple-negative breast cancer (NeoTENNIS): a single-arm, phase II study

Toripalimab, a novel PD-1 antibody, is approved for treatment of multiple solid tumors; however, its neoadjuvant use with chemotherapy for triple-negative breast cancer (TNBC) remains unevaluated. Additionally, induction chemotherapy followed by de-escalation of neoadjuvant immunotherapy remains underexplored. Therefore, we conducted a phase II trial investigating a novel neoadjuvant chemoimmunotherapy regimen including de-escalation of immunotherapy for early-stage TNBC. Chemotherapy and anti-PD-1 therapy were sequentially administered in a neoadjuvant setting to female patients with histologically confirmed stage II-III TNBC between June 9, 2020, and March 24, 2022. Patients received neoadjuvant therapy with four cycles of epirubicin-cyclophosphamide every 2 weeks, followed by toripalimab (240mg) every 3 weeks plus nab-paclitaxel weekly for 12 weeks. The primary endpoint was total pathological complete response (tpCR; ypT0/is ypN0). Key secondary endpoints included breast pCR (bpCR; ypT0/is), event-free survival and biomarker analysis. Safety was also assessed. This study was registered with ClinicalTrials.gov (NCT04418154). Among 70 enrolled patients (median age, 51 years; 62.9% stage III), 66 completed treatment without progression and subsequently underwent surgery. The percentages of patients with a tpCR and bpCR were 39 of 70 (55.7%, 95% confidence interval [CI]: 43.3-67.6) and 41 of 70 (58.6%, 95% CI 46.2-70.2), respectively. Sixteen (22.9%) patients experienced grade ≥3 adverse events (AEs), frequently neutropenia (12, 17.1%) and leukopenia (11, 15.7%). The most common immune-related AE was hypothyroidism (5, 7.1%, all grade 1-2). Including 12 weeks of toripalimab in neoadjuvant chemotherapy conferred encouraging activity and manageable toxicity in patients with early TNBC, and this regimen warrants further investigation. National Natural Science Foundation of China, Junshi Biosciences, and Jiangsu Hengrui Pharmaceuticals.

Clinical characteristics, prognosis, and immunotherapy outcome in pediatric melanoma: Analysis from a large Chinese cohort.

10050 Background: Malignant melanoma in children and adolescents is rare, with limited data on Chinese populations.To assess the clinical characteristics, survival, prognostic factors, and the efficacy of immunotherapy in a real-world cohort of Chinese pediatric patients with melanoma. Methods: This is a retrospective, cohort study included pediatric melanoma patients between February, 2005 and May, 2021, with a median follow-up time of 76.7 months. Data analyses were conducted in May, 2023. This study enrolled patients from Sun Yat-sen University Cancer Center, the biggest cancer institution in South China for cancer prevention, diagnosis and treatment. Inclusion criteria for this study were as follows: 1) histopathologically confirmed diagnosis of melanoma; 2) Age ≤18 year; 3) with complete clinical data on sex, age, histopathological features, etc. The exclusion criteria was secondary malignant melanoma. Main outcomes and measures were patient’s OS and EFS. Results: 43 patients were enrolled, with median age of 138.9 (range 13.1-215.0) months, including 30 cutaneous melanoma, 7 meningeal melanoma, 5 mucosal melanoma, and 1 uveal melanoma. The frequency of BRAF V600E mutation was 16.7% (4/24). Mismatch repair proteins were normally expressed (7/7), and the positive rate of programmed cell death ligand 1 expression was 55.6% (5/9). The event-free survival and overall survival of cutaneous, mucosal and meningeal melanoma were 46.7±9.1% vs 75.0±21.7% vs 16.7±15.2% ( P = 0.010), 65.5±8.9% vs 75.0±21.7% vs 16.7±15.2% (P&lt; 0.001), respectively. Survival of cutaneous melanoma were associated with pathological type, ulceration, Clark level, disease spread, sentinel lymph node status, tumor stage and Ki-67 expression. 5 of 9 patients who were treated with PD-1 inhibitors (5 with PD-1 inhibitors alone, 3 with PD-1 inhibitors plus angiogenesis inhibitors, 1 with combination of anti-PD1, anti-angiogenic inhibitors plus chemotherapy) were evaluable with the overall response rate of 20%. The most common immune-related adverse event was hypothyroidism. Conclusions: This is the largest real-world study in pediatric melanoma patients in Asia. The prognosis of mucosal melanoma was favorable, followed by cutaneous melanoma, and meningeal melanoma had the worst prognosis. PD-1 antibody combined with angiogenesis inhibitors maybe a promising choice in pediatric melanoma.

Positive baseline thyroid autoantibodies as a predictive biomarker for thyroid immune-related adverse events: A systematic review and meta-analysis.

e24124 Background: Thyroid dysfunction is one of the most common immune-related adverse events (irAE) by immune checkpoint inhibitors (ICI). Given the known relationship between antithyroid autoantibodies (ATA), including antithyroid peroxidase (TPO Ab) and anti-thyroglobulin (Tg Ab), and autoimmune thyroid disease, they could also play a role as a predictive biomarker for thyroid irAE (T-irAE). We performed this meta-analysis to evaluate the association of positive baseline thyroid autoantibodies and T-irAE. Methods: Eligible studies were screened using Ovid Medline and Embase databases with search terms related to ATA and thyroid irAE. Studies must be case-control or cohort studies with patients who received ICI and report the numbers of patients who have thyroid dysfunction and do not have thyroid dysfunction by the pre-ICI treatment statuses of ATA, TPO Ab, or Tg Ab. The pooled odds ratio (OR) and the associated 95% confidence interval (95% CI) were calculated using the Mantel-Haenszel method. Subgroup analysis by types of ICI (anti-PD1, anti-PD-L1, or combination treatment) and study region were also performed. The presence of publication bias was assessed by direct visualization of funnel plots. Results: After two rounds of screening, 19 case-control and five retrospective cohort studies were included in the meta-analysis. Patients who had positive baseline ATA had increased odds of developing T-irAE, hypothyroidism, and hyperthyroidism (pooled OR 10.95, 95% CI 6.65-18.02, I2= 38%; 6.82, 95% CI 2.99-15.56, I2= 27%; and 7.59, 95% CI 2.51-22.96, I2= 42%; respectively). Positive pre-treatment TPO Ab and Tg Ab were also independently associated with higher odds of hypothyroidism (pooled OR 5.01, 95% CI 2.87-8.75, I2= 4%, and 18.73, 95% CI 9.04-38.80, I2= 0%, respectively) and hyperthyroidism (pooled OR 2.94, 95% CI 1.57-5.52, I2= 25%, and 8.36, 95% CI 1.18-59.31, I2= 82%, respectively). The associations did not significantly differ between the types of ICI utilized and the study region. Visualization of funnel plots did not reveal a presence of publication bias. Conclusions: Pre-ICI treatment statuses of ATA, TPO Ab, and Tg Ab are associated with both hypothyroidism and hyperthyroidism. Thyroid autoantibodies as a baseline predictive tool can be helpful for early detection of T-irAE in patients who receive ICI therapy.

Detection of immune-related adverse events among hospitalized patients using large language models.

2638 Background: Immune checkpoint inhibitor (ICI)-induced colitis, hepatitis, and pneumonitis are common immune-related adverse events (irAEs); however, the true incidence for these irAEs remains incompletely understood. Chart review is the gold standard for their detection but is time-consuming and cannot be implemented in large cohorts. The use of ICD codes is limited in sensitivity and specificity. Large language models (LLMs) are a scalable method of answering queries from human-generated text, though there is no data on the use of LLM for the identification of irAEs. Therefore, we investigated the application of a LLM to identify ICI-colitis, hepatitis, and pneumonitis among hospitalized patients, comparing its performance to manual chart review and ICD codes. Methods: Hospital admissions of patients on ICI therapy from February 5th, 2011, to November 3rd, 2021, were manually reviewed by a multidisciplinary immunotoxicity team using established published definitions for the presence of ICI colitis, hepatitis, and pneumonitis. Standard ICD codes and a LLM pipeline with retrieval-augmented generation (RAG) were used to detect irAEs. Performance was measured via sensitivity, specificity, and model runtime. The LLM was validated with a second dataset of inpatients with ICI colitis, hepatitis, and pneumonitis admitted from November 4th, 2021, to September 5th, 2023. Results: Among 5,677 hospitalized patients on ICI therapy in the initial cohort, there were 132 cases adjudicated with ICI colitis, 57 with ICI hepatitis, and 47 with ICI pneumonitis. The LLM was more sensitive in detecting all three irAEs compared to ICD codes (94.2% vs. 71.8%), achieving significance for ICI hepatitis (p&lt;0.001) and pneumonitis (p=0.006), while having similar specificities (92.5% vs 91.1%, Table 1). The LLM approach was also efficient, spending an average of 9.42s per chart, compared to an estimated 15 minutes per chart for individual chart review. The mean sensitivity and specificity of the LLM on the validation dataset for adjudicated ICI colitis (n=20), hepatitis (n=24), and pneumonitis (n=6) were 96.9% and 93.2%, respectively. Conclusions: LLMs serve as a useful tool for the detection of ICI colitis, hepatitis, and pneumonitis, significantly outperforming ICD-codes in accuracy and manual chart review in efficiency.[Table: see text]

Multi-ethnic genome-wide association study to identify a novel locus for susceptibility to immune-related adverse events from immune checkpoint inhibitors.

3090 Background: Immune-related adverse events (IrAEs) arising from immune checkpoint inhibitors (ICIs) can be unpredictable. As genomic variation underlies both disease susceptibility and drug responses, genomic markers may predict for the development of IrAEs. We perform a pioneering pharmacogenomic study across a multi-ethnic Asian patient population to uncover genomic biomarkers associated with IrAEs from ICIs. Methods: From March 2018 – July 2023, cancer patients treated with ICIs from the National University Cancer Institute Singapore and Tan Tock Seng Hospital were recruited. IrAEs were 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 by SVS/HelixTree, PLINK and R. Genetic association was performed by logistic regression (additive model), accounting for all possible confounding factors. Bonferroni corrected P &lt; 1.28E-07 (0.05/390,925 SNPs passed QC) was considered statistically significant. Results: Genome-wide association study (GWAS) was conducted amongst 507 patients of Asian Ancestry (Chinese, Malay, Indian and Others). Median age was 63. Majority were male (66.5%), Chinese (76.7%), ECOG PS 0-1 (40.1%) and had stage IV cancer at diagnosis (67.2%). Non-small cell lung cancer (37.1%), renal cell carcinoma (12.2%) and hepatocellular carcinoma (7.7%) were the three most common cancers. Top four ICIs used were pembrolizumab, nivolumab, durvalumab and atezolizumab, respectively (47.1%, 23.9%, 12.5%, 11.3%). 0.8% of patients received dual ICIs concurrently. Median duration of treatment was 142 days and median follow-up was 147 days. IrAEs were seen in 43.7% of patients. Skin (24.1%), endocrine (8.1%) and hepatotoxicity (6.1%) were the most common IrAEs. 4.9% of patients had grade ≥3 toxicity, of which skin (3.6%), hepatotoxicity (3.0%) and pulmonary toxicity (1.8%) were the most common. Multi-ethnic GWAS analysis identified one potential novel genetic locus associated with CTCAE grade ≥3 IrAEs. chr3:163402331 rs146525069; P = 7.29E-08, OR (95%CI) = 17.08 (5.40- 54.04); minor allele = A, 10.91% in Cases vs 0.71% in Controls. Conclusions: This pharmacogenomics GWAS uncovered a novel locus for susceptibility to serious immune-related adverse events from immune checkpoint inhibitors. Further pharmacogenomic discovery/replication and functional validation studies are currently on-ongoing. Our study provides a potential biological mechanism for IrAEs and a step towards more effective clinical translation of pharmacogenetic testing to personalize ICI use.

Pembrolizumab plus nab-paclitaxel and platinum as first-line treatment in patients with recurrent or metastatic head and neck squamous-cell carcinoma: a prospective phaseⅡstudy

Objective: To evaluate the efficacy and safety of pembrolizumab plus nab-paclitaxel and platinum as first-line treatment in patients with recurrent or metastatic head and neck squamous-cell carcinoma (R/M HNSCC). Methods: This was a prospective, single-arm, open label, phase 2 clinical study enrolling patients at the Cancer Hospital of the Chinese Academy of Medical Sciences with R/M HNSCC treated with pembrolizumab plus nab-paclitaxel and cisplatin or carboplatin. After six cycles of treatment, patients received pembrolizumab as maintenance therapy until disease progression or intolerable toxicity or completion of 35 cycles of treatment. The primary endpoint was objective response rate, and secondary endpoints included overall survival, progression-free survival, and safety profile. Efficacy was evaluated according to the response evaluation criteria in solid tumors 1.1, survival analysis was performed using the Kaplan-Meier method, and adverse events were assessed using the America National Cancer Institute Common Terminology Criteria for Adverse Events 5.0. Results: A total of 30 patients with R/M HNSCC were enrolled from 23 April 2021 to 22 March 2023, including 28 males and 2 females, with a median age of 67 years. The median follow-up time was 14.5 months, the objective response rate was 70.0%, the disease control rate was 96.7%, and the median progression-free survival and overall survival of all patients were 11.6 months and 18.8 months, respectively. Median duration of response was up to 17.3 months. Grade≥3 treatment-related adverse events were leukopenia (26.7%), neutropenia (26.7%), peripheral neurotoxicity (3.3%), rash (3.3%), hyperalgesia (3.3%), and immune-related pneumonitis (3.3%). The most common immune-related adverse event was hypothyroidism (40.0%). Conclusion: Pembrolizumab combined with nab-paclitaxel and platinum shows encouraging antitumor activity accompanied with a manageable safety profile in untreated R/M HNSCC patients in China.

Diabetes Mellitus Induced by Nivolumab plus Regorafenib in a Patient with Esophageal Cancer

Abstract Nivolumab is now preferred as first-line and second-line treatment for advanced esophageal cancer, while regorafenib improves survival in refractory gastroesophageal cancer. The combined use of nivolumab and regorafenib has shown promising results. Nivolumab-induced thyroid dysfunction is a common immune-related adverse event (irAE), while type 1 diabetes mellitus induced by immune checkpoint inhibitors is rare and usually permanent. It is unclear whether the combination of regorafenib and nivolumab increases the risk of irAEs. We report a patient with recurrent esophageal squamous cell carcinoma who was treated with nivolumab plus regorafenib and developed thyroiditis and diabetic ketoacidosis. The rechallenge was successful, and the patient achieved a good treatment response.

Emerging Insights into Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Induced by Immune Checkpoint Inhibitor and Tumor-Targeted Therapy.

Anticancer drugs have revolutionized tumor therapy, with cutaneous toxicities such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) being common immune-related adverse events. The debate over the efficacy of systemic corticosteroids in treating these conditions persists, while tumor necrosis factor (TNF)-alpha inhibitors show promise. This study aims to evaluate the effectiveness and safety of combination therapy involving the TNF-α inhibitor adalimumab for SJS/TEN induced by anticancer drugs. A literature review of SJS/TEN cases induced by anticancer drugs from 1992 to 2023 was conducted, alongside an analysis of patients admitted to the First Affiliated Hospital of Fujian Medical University during the same period. Clinical characteristics, skin healing time, mortality, and adverse events were evaluated in two treatment groups: SJS/TEN patients treated with targeted anticancer therapies and immunotherapies. Among the 27 patients studied (18 with SJS or SJS-TEN overlapping and 9 with TEN), combination therapy with adalimumab significantly reduced mucocutaneous reepithelization time and healing duration compared to corticosteroid monotherapy. Patients receiving adalimumab combined with corticosteroids had lower actual mortality rates than those on corticosteroid monotherapy. The combination therapy also showed a trend towards reducing standardized mortality rates based on the Score of Toxic Epidermal Necrolysis (SCORTEN). The findings suggest that adalimumab in combination with corticosteroids provides significant clinical benefits and is safer than corticosteroids alone for treating SJS/TEN induced by targeted anticancer therapies and immunotherapies. This study contributes valuable insights into potential treatment strategies for severe cutaneous adverse reactions to anticancer drugs, highlighting the importance of exploring alternative therapies such as TNF-α inhibitors in managing these conditions effectively.

Risk of reactive cutaneous capillary endothelial proliferation induced by camrelizumab in patients with non-small cell lung cancer: a retrospective study.

Reactive cutaneous capillary endothelial proliferation (RCCEP) is a common immune-related adverse event (irAE) related to camrelizumab. This study aimed to investigate the risk factors of RCCEP and its association with patients' survival. This retrospective study collected the data of consecutive patients with non-small cell lung cancer (NSCLC) who received camrelizumab between January 2019 and December 2021. Baseline characteristics and peripheral blood biomarkers were collected. The outcomes were the occurrence of RCCEP and progression-free survival (PFS). The factors associated with RCCEP were analyzed using univariable and multivariable logistic regression. The association between PFS and RCCEP occurrence was analyzed by the log-rank test. Among the 80 patients included, 24 (30.0%) developed RCCEP, and 56 did not. Among the patients with RCCEP, only four reported the occurrence of grade 3-4 RCCEP. The multivariable analysis revealed that a percentage of eosinophil (EOS%) >1.75% was significantly associated with a higher risk of RCCEP [odds ratio (OR) =4.484; 95% confidence interval (CI): 1.139-17.651] and camrelizumab combined with an anti-angiogenic agent was significantly associated with a lower risk of RCCEP (OR =0.188; 95% CI: 0.055-0.639). The median PFS was numerically longer in patients with RCCEP than in those who did not (17 vs. 9 months, P=0.069). Patients who had baseline EOS% >1.75% and received camrelizumab without an anti-angiogenic agent had a longer median PFS than those who did not (17 vs. 9 months, P=0.011). Baseline EOS% >1.75% and camrelizumab without an anti-angiogenic agent were risk factors of RCCEP and might be associated with better survival in patients with NSCLC.

A case report and literature review on reactive cutaneous capillary endothelial proliferation induced by camrelizumab in a nasopharyngeal carcinoma patient

Camrelizumab, a monoclonal antibody, blocks programmed cell death protein-1 from binding to T cells and programmed cell death ligand 1 on tumor cells, thereby ensuring sustained T cell activation and blocking immune escape of various types of cancer, including nasopharyngeal carcinoma. Reactive cutaneous capillary endothelial hyperplasia (RCCEP) is the most common immune-related adverse event in patients treated with camrelizumab. We report a case nasopharyngeal carcinoma in a patient with camrelizumab-induced RCCEP. A 68-year-old man diagnosed with nasopharyngeal carcinoma developed RCCEP at multiple locations after 3 months of camrelizumab treatment. RCCEP of the right lower eyelid affected closure of the right eye. In this report, we also reviewed previous literature on camrelizumab-induced RCCEP. In summary, the mechanism underlying camrelizumab-induced RCCEP remains unclear. RCCEP typically gradually subsides after discontinuing camrelizumab treatment. Larger nodules can be treated with lasers, ligation, or surgery. Although surgical excision is effective, RCCEP may recur in patients undergoing camrelizumab treatment. RCCEP management may not be required in the absence of adverse effects on the patient’s daily life.

Clinical activity of nivolumab in combination with eribulin in HER2-negative metastatic breast cancer: A phase IB/II study (KCSG BR18-16)

AimWe evaluated the efficacy and safety of nivolumab and eribulin combination therapy for metastatic breast cancer (BC) in Asian populations. MethodsIn this parallel phase II study, adult patients with histologically confirmed recurrent/metastatic hormone receptor-positive/HER2-negative (HR+HER2-) or triple-negative BC (TNBC) were prospectively enroled from 10 academic hospitals in Korea (ClinicalTrials.gov Identifier: NCT04061863). They received nivolumab (360 mg) on day 1 plus eribulin (1.4 mg/m2) on days 1 and 8 every 3 weeks until disease progression or intolerable toxicity. The primary endpoint was the investigator-assessed 6-month progression-free survival (PFS) rate in each subtype. Secondary endpoints included investigator-assessed objective response rate (ORR) as per Response Evaluation Criteria in Advanced Solid Tumors version 1.1, disease control rate, overall survival, and treatment toxicity. The association between PD-L1 expression and efficacy was investigated. ResultsForty-five patients with HR+HER2- BC and 45 with TNBC were enroled. Their median age was 51 (range, 31–71) years, and 74 (82.2%) received one or two prior treatments before enrolment. Six-month PFS was 47.2% and 25.1% in the HR+HER2- and TNBC cohorts, respectively. Median PFS was 5.6 (95% confidence interval [CI]: 5.3–7.4) and 3.0 (95% CI: 2.1–5.2) months in the HR+HER2- and TNBC groups, respectively. ORRs were 53.3% (complete response [CR]: 0, partial response [PR]: 24) and 28.9% (CR: 1, PR: 12). Patients with PD-L1+ tumours (PD-L1 expression ≥1%) and PD-L1- tumours (ORR 50% versus 53.8% in HR+HER2-, 30.8% versus 29.0% in TNBC) had similar ORRs. Neutropenia was the most common grade 3/4 adverse event; the most common immune-related adverse events (AEs) were grades 1/2 hypothyroidism and pruritus. Five patients discontinued therapy because of immune-related AEs. ConclusionNivolumab plus eribulin showed promising efficacy and tolerable safety in previously treated HER2- metastatic BC. Trial registrationNCT04061863

FRI539 Vitamin D and Endocrine Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitors

Abstract Disclosure: Z. He: None. A. Leiter: None. E. Carroll: None. G. Santiago Pichardo: None. I. Khanna: None. E. Gutowski: None. E.J. Gallagher: Research Investigator; Self; Novartis Pharmaceuticals, Flare Therapeutics, Seagen. Background: Low vitamin D levels have been previously associated with the development of thyroid dysfunction in non-cancer populations. Thyroid dysfunction is one of the most common immune-related adverse events (irAEs) induced by immune checkpoint inhibitors (ICIs). Currently, the effect of vitamin D deficiency or vitamin D supplementation on the development of ICI-induced thyroid dysfunction is unknown. This study was design to examine the association between baseline vitamin D levels and vitamin D supplementation, and the development of ICI-induced thyroid dysfunction. Methods: In this IRB-approved, retrospective cohort study, we collected demographic and clinical characteristics in addition to TSH, free T4, and vitamin D levels from patients with melanoma, multiple myeloma (MM), and transitional cell carcinoma (TCC) treated with ICIs between 2011 and 2020, in a large urban hospital system. The primary outcome was the occurrence of thyroid dysfunction defined by abnormal TSH or free T4 level after ICI initiation. Vitamin D deficiency / insufficiency was defined as serum 25-hydroxy-vitamin D level &amp;lt;30ng/mL. Patients were followed until the first occurrence of the primary outcome or the date of the most recent normal TSH level. Descriptive data are presented as n(%) and median±SD. Univariate and multivariate analysis were performed to examine the association between the primary outcome and vitamin D deficiency/ insufficiency or supplementation. Results: 288 patients with melanoma (n=111), MM (n=86) or TCC (n=91) were identified, with a median age of 65±13 years, and 64% were male. 110 (38%) patients experienced thyroid dysfunction. Among the TCC subgroup, the mean baseline TSH levels for patients who experienced the outcome was significantly higher than that for patients who did not (p = 0.0066). No statistical significance was found for the melanoma (p=0.42) or MM subgroups (p=0.30). Amongst patients with baseline vitamin D levels measured, we found no statistically significant association between thyroid dysfunction and baseline vitamin D deficiency (OR = 0.62, p = 0.34). In the entire cohort, the 1-year outcome-free rates for patients taking and not taking vitamin D supplementation were 68% and 61%, respectively (p=0.07). Vitamin D supplementation was found to reduce the risk of ICI-induced thyroid abnormality by approximately 40% (RR = 0.606, p=0.03) in the multivariate analysis. No difference in mortality was found between those who developed thyroid dysfunction and those who did not. Conclusions: In individuals with melanoma, MM and TCC, vitamin D supplementation may have a protective effect against ICI-induced thyroid dysfunction. Whether vitamin D supplementation impacts cancer response to ICIs is unknown at this time. Presentation: Friday, June 16, 2023

Thyroid dysfunction induced by anti-PD-1 therapy is associated with a better progression-free survival in patients with advanced carcinoma

PurposeThyroid dysfunction is the most common immune-related adverse event during anti-programmed cell death 1 (anti-PD-1) therapy. In this study, we monitored patients with advanced malignant tumors who received anti-PD-1 therapy to observe the characteristic of anti-PD-1 therapy-induced thyroid dysfunction and its correlation with prognosis.MethodsPatients with advanced carcinoma treated with anti-PD-1 therapy were evaluated for thyroid function at baseline and after treatment initiation from August 2020 to March 2022. Seventy-three patients were finally included in the study.ResultsAmong these patients, 19 (26.03%) developed thyroid dysfunction after receiving anti-PD-1 therapy. Primary hypothyroidism and thyrotoxicosis were the most common clinical manifestation. Anti-PD-1-induced thyroid dysfunction occurred 63 (26–131) days after administration; thyrotoxicosis appeared earlier than primary hypothyroidism. In Kaplan–Meier survival analysis, the progression-free survival (PFS) of the thyroid dysfunction group was better than that of the no thyroid dysfunction group (227 (95% confidence interval (CI) 50.85–403.15) days vs 164 (95% CI 77.76–250.24) days, p = 0.026). Male patients had better PFS than female patients (213 (95% CI 157.74–268.26) days vs 74 (95% CI 41.23–106.77) days, p = 0.031). In cox proportional hazards regression model, anti-PD-1-induced thyroid dysfunction remained an independent predictor of better PFS (hazard ratio (HR) = 0.339(0.136–0.848), p = 0.021).ConclusionThyroid dysfunction is a common immune-related adverse events in advanced cancer patients treated with anti-PD-1 therapy and predicts a better prognosis.Trial registrationThis study was retrospectively registered with Trial ClinicalTrials.gov (NCT05593744) on October 25, 2022.

Real-world ANASTASE study of atezolizumab+nab-paclitaxel as first-line treatment of PD-L1-positive metastatic triple-negative breast cancer

The combination of atezolizumab and nab-paclitaxel is recommended in the EU as first-line treatment for PD-L1-positive metastatic triple-negative breast cancer (mTNBC), based on the results of phase III IMpassion130 trial. However, ‘real-world’ data on this combination are limited. The ANASTASE study (NCT05609903) collected data on atezolizumab plus nab-paclitaxel in PD-L1-positive mTNBC patients enrolled in the Italian Compassionate Use Program. A retrospective analysis was conducted in 29 Italian oncology centers among patients who completed at least one cycle of treatment. Data from 52 patients were gathered. Among them, 21.1% presented de novo stage IV; 78.8% previously received (neo)adjuvant treatment; 55.8% patients had only one site of metastasis; median number of treatment cycles was five (IQR: 3–8); objective response rate was 42.3% (95% CI: 28.9–55.7%). The median time-to-treatment discontinuation was 5 months (95% CI: 2.8–7.1); clinical benefit at 12 months was 45.8%. The median duration of response was 12.7 months (95% CI: 4.1–21.4). At a median follow-up of 20 months, the median progression-free survival was 6.3 months (95% CI: 3.9–8.7) and the median time to next treatment or death was 8.1 months (95% CI: 5.5–10.7). At 12 months and 24 months, the overall survival rates were 66.3% and 49.1%, respectively. The most common immune-related adverse events included rash (23.1%), hepatitis (11.5%), thyroiditis (11.5%) and pneumonia (9.6%). Within the ANASTASE study, patients with PD-L1-positive mTNBC treated with first-line atezolizumab plus nab-paclitaxel achieved PFS and ORR similar to those reported in the IMpassion130 study, with no unexpected adverse events.

BI20 Generalized pustular psoriasis in a patient receiving pembrolizumab for metastatic lung adenocarcinoma

Abstract Skin toxicities are the most common immune-related adverse events (irAEs) associated with immune checkpoint inhibitor (ICI) treatment, an emerging field in dermatology. A wide spectrum of skin irAEs, including lichenoid reactions, vitiligo, bullous pemphigoid and other autoimmune skin diseases, have been reported. Psoriasiform irAEs may occur as an exacerbation of pre-existing disease or de novo and often occur later than other skin irAEs. Most cases reported to date are of chronic plaque and palmoplantar psoriasis. Generalized pustular psoriasis has been reported in fewer than 10 cases. We present a patient with mild pre-existing psoriasis who developed plaque psoriasis, evolving into severe pustular psoriasis after 4 months of pembrolizumab therapy for lung cancer. A 67-year-old man with stage 4 lung adenocarcinoma developed a widespread, itchy psoriasiform rash 3 months after starting pembrolizumab. He had a history of rheumatoid arthritis (RA) and pembrolizumab was started when he had progressed through chemotherapy. The RA was controlled on prednisolone, which was increased when methotrexate was discontinued shortly after diagnosis of lung cancer. He had a family history of psoriasis, and although he had previously been noted to have limited plaque and nail psoriasis, this had required minimal treatment. Within 2 months of starting pembrolizumab, he developed scaly, red plaques affecting more than 30% body surface area (BSA). The oncology team diagnosed a grade 3 skin toxicity and increased doses of oral steroids. Upon steroid tapering, the rash flared and was diagnosed in dermatology as consistent with exacerbation of pre-existing plaque psoriasis secondary to pembrolizumab and high-dose steroids. He partially responded to skin-directed treatment, but 2 months later following his sixth cycle of pembrolizumab, he progressed to generalized suberythrodermic pustular psoriasis. He was treated with acitretin and methotrexate. The incidence of ICI-mediated psoriasis and psoriasiform irAEs is approximately 4% of all skin toxicities. A cohort study by the European Network for Cutaneous Adverse Event to Oncologic Drugs group reported that 70% of 115 patients had no history of psoriasis. Ten per cent of psoriasiform irAEs were categorized as severe, involving more than 30% BSA. However, only eight (7%) had pustular involvement and 2% erythroderma. Treatment options include acitretin, methotrexate, apremilast and biologics. Guttate psoriasis and grade 2/3 disease were significant positive predictors for the antitumour response of ICIs. In summary, ICI-related psoriasis is an increasingly common problem with widespread use of immunotherapy. Early diagnosis and adequate management with agents that do not interfere with immunotherapy, or with the underlying malignancy, and close liaison with oncology are crucial.

Ustekinumab for the treatment of immune related cutaneous adverse events (ircAEs).

e14702 Background: IrcAEs are one of the most common immune related adverse events (irAEs) associated with immune checkpoint inhibitors (ICI). Ustekinumab, a monoclonal antibody that targets IL12/IL23, is FDA approved for the treatment of autoimmune diseases including psoriasis and inflammatory bowel disease. The IL12/23 pathway may mediate a subset of ircAEs, and ustekinumab may be effective for the treatment of these events. Methods: Patients at Memorial Sloan Kettering Cancer Center who received ustekinumab for treatment of ircAEs were identified from 8/18/2017 to 2/17/2022. Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 was used to grade ircAEs. Patient response to ustekinumab was subcategorized into complete resolution (CR, improvement of symptoms to baseline or grade 0), partial resolution (PR, improvement in CTCAE grade but not CR), or no response/worsening (NR, no clinical improvement or worsening of ircAEs). Results: A total of 11 patients were included in the study. The median age was 72 years (IQR 69.5-77) and 45% of patients were female. The most common ICIs were pembrolizumab (64%, n=7), nivolumab (18%, n=2), atezolizumab (9%, n=1), and avelumab (9%, n=1). Melanoma (27%, n=3) and bladder (27%, n=3) cancer were the two most common neoplasms. All patients had psoriasiform ircAEs (n=10), except one who had a pyoderma gangrenosum (PG) ircAE; most were either grade 2 (46%) or grade 3 (36%) at the time of ustekinumab initiation. The majority of patients (73%, n=8), including the one with PG, noted some improvement with ustekinumab, with 55% (n=6) and 18% (n=2) achieving CR and PR, respectively. The median duration of ustekinumab treatment was 169 days (0 – 1774), and among those with PR or CR, the median time to initial response was 27 days (21 – 39). In addition, the proportion of patients on topical and systemic steroids before and after ustekinumab decreased from 91% (n=10) to 56% (n=6) and from 64% (n=7) to 36% (n=3), respectively. Four patients (36.4%) discontinued ICIs because of severe ircAEs, with 1 (25%) successfully recontinuing their ICI following control of ircAE symptoms with ustekinumab. We noted progression of disease among 55% (n=6) of patients at any point after ustekinumab treatment. Among them, median time to next treatment was 345.5 days (70-925), with a median of 347.5 days (70-576) and 601 days (277-925 days) for patients with non-metastatic (33.3%) and metastatic tumors (66.7%), respectively. Conclusions: Ustekinumab has shown encouraging clinical activity especially for psoriasiform ircAEs and can be an effective steroid-sparing treatment for specific ircAEs. Despite the occurrence of cancer progression in some of our cohort, it was difficult to interpret the ICI anti-tumor activity post ustekinumab given the small numbers and multiple tumor types. Further prospective studies are needed to validate our findings given the significant potential of ustekinumab for the management of ircAEs.