Common Immune-related Adverse Events Research Articles

The risk of endocrine immune-related adverse events induced by PD-1 inhibitors in cancer patients: a systematic review and meta-analysis

ObjectiveEndocrinopathies are the most common immune-related adverse events (irAEs) observed during therapy with PD-1 inhibitors. In this study, we conducted a comprehensive systematic review and meta-analysis to evaluate the risk of immune-related endocrinopathies in patients treated with PD-1 inhibitors.MethodsWe performed a systematic search in the PubMed, Embase, and Cochrane Library databases to retrieve all randomized controlled trials (RCTs) involving PD-1 inhibitors, spanning from their inception to November 24, 2023. The comparative analysis encompassed patients undergoing chemotherapy, targeted therapy, or receiving placebo as control treatments. This study protocol has been registered with PROSPERO (CRD42023488303).ResultsA total of 48 clinical trials comprising 24,514 patients were included. Compared with control groups, patients treated with PD-1 inhibitors showed an increased risk of immune-related adverse events, including hypothyroidism, hyperthyroidism, hypophysitis, thyroiditis, diabetes mellitus, and adrenal insufficiency. Pembrolizumab was associated with an increased risk of all aforementioned endocrinopathies (hypothyroidism: RR=4.76, 95%CI: 3.55-6.39; hyperthyroidism: RR=9.69, 95%CI: 6.95-13.52; hypophysitis: RR=5.47, 95%CI: 2.73-10.97; thyroiditis: RR=5.95, 95%CI: 3.02-11.72; diabetes mellitus: RR=3.60, 95%CI: 1.65-7.88; adrenal insufficiency: RR=4.80, 95%CI: 2.60-8.88). Nivolumab was associated with an increased risk of hypothyroidism (RR=7.67, 95%CI: 5.00-11.75) and hyperthyroidism (RR=9.22, 95%CI: 4.71-18.04). Tislelizumab and sintilimab were associated with an increased risk of hypothyroidism (RR=19.07, 95%CI: 5.46-66.69 for tislelizumab and RR=18.36, 95%CI: 3.58-94.21 for sintilimab). For different tumor types, both hypothyroidism and hyperthyroidism were at high risks. Besides, patients with non-small cell lung cancer were at a higher risk of thyroiditis and adrenal insufficiency. Patients with melanoma were at a higher risk of hypophysitis and diabetes mellitus. Both low- and high-dose group increased risks of hypothyroidism and hyperthyroidism.ConclusionRisk of endocrine irAEs may vary in different PD-1 inhibitors and different tumor types. Increased awareness and understanding of the risk features of endocrine irAEs associated with PD-1 inhibitors is critical for clinicians.Systematic review registrationcrd.york.ac.uk/prospero, identifier PROSPERO (CRD42023488303).

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.

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.

The colitis may be microscopic, but the diarrhea is not: update on the treatment of microscopic colitis and immune checkpoint inhibitor colitis.

Microscopic colitis is an inflammatory disease of the colon that presents as watery diarrhea with minimal to normal endoscopic changes on colonoscopy. It encompasses two common subtypes, lymphocytic colitis and collagenous colitis, which are both treated similarly.Immune checkpoint inhibitor colitis is among the most common immune-related adverse events. Endoscopic and histological findings range from normal colonic mucosa to inflammatory bowel like changes. This review article provides update in treatment and management of microscopic colitis and immune checkpoint inhibitor colitis (ICPi colitis). Recent studies on microscopic colitis have focused on the successful use of immunomodulators such as biologics for treatment of budesonide refractory microscopic colitis cases. Microscopic colitis does not confer an added risk for colorectal cancer.With the increasing usage of immunotherapy agents, immune checkpoint inhibitor colitis is becoming more common. ICPi colitis can be successfully managed with steroids, with treatment stepped up to biologics for moderate to severe cases or for mild cases that do not respond to steroids. Immunotherapy agents can be carefully re-introduced in mild cases, after treatment of ICPi colitis. Biologics can be used to treat budesonide refractory microscopic colitis. ICPi colitis can be managed with steroids and biologics in moderate to severe cases.

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 <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.

A multicenter, open-label, single-arm, phase II trial to evaluate the efficacy and safety of geptanolimab (GB226) in the treatment of patients (pts) with programmed cell death ligand 1 (PD-L1)–positive recurrent or metastatic cervical cancer, for whom prior platinum-containing chemotherapy has failed.

5535 Background: Geptanolimab (GB226) is a novel anti-programmed cell death 1 (PD-1) antibody, exhibiting good tolerance and promising efficacy in pts with advanced/recurrent solid tumor/lymphoma in previous phase I/II studies. This study is a two-part, multicenter, single-arm phase II study of GB226 in pts with recurrent or metastatic cervical cancer recruited from 28 clinical sites in China. In Part 1, we observed encouraging antitumor activity of GB226 with 11 PRs in 46 PD-L1 positive (combined positive score, CPS≥1) pts. Here we report the efficacy and safety results from Part 2 of this trial. Methods: In part 2, PD-L1 positive (CPS≥1) pts with recurrent or metastatic cervical cancer who had received one or more lines of platinum-containing chemotherapy were enrolled and treated with GB226 (intravenous infusion, 3 mg/kg) once every 2 weeks until disease progression or intolerable toxicity. The primary endpoint was objective response rate (ORR) assessed by Independent Review Committee (IRC) per RECIST 1.1. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS) and safety. Results: In Part 2, 123 pts were enrolled. As of July 28, 2022, after a median follow-up of 16.69 months (95%CI: 11.07, NR), 100 pts who met the study population criteria were eventually included in the full analysis set (FAS). 46% (46/100) of pts had received ≥2 lines of prior systemic therapy and 90% (90/100) had squamous cell carcinoma. The ORR was 18.0% (18/100; 95%CI: 11.03%, 26.95%) assessed by IRC, including 5 pts with CR (5.0%) and 13 pats with PR (13.0%); Median DOR was not reached (95%CI: 7.16, NR), median PFS was 1.91 months (95%CI: 1.87, 3.55), and median OS was 16.69 months (95%CI: 11.07, NR). Clinical benefit was observed across most patient subgroups, with a trend of higher ORR in pts with squamous cell carcinoma, no previous bevacizumab use and higher CPS. Among 123 safety-evaluable pts, 97 (78.9%) pts experienced a treatment-related adverse event (TRAE). The most common TRAE (≥10%) were hypothyroidism (24.4%), anemia (21.1%) and hyperthyroidism (13.8%), most of which were grade 1 and 2. Treatment-related grade 3/4 adverse events occurred in 25 (20.3%) and 2 (1.6%) pts, respectively. No grade 5 TRAEs occurred. 7 (5.7%) pts discontinued treatment due to a TRAE. The most common immune-related adverse events (irAE, ≥5%) were hypothyroidism 27 (22.0%) and hyperthyroidism 16 (13.0%). Conclusions: GB226 demonstrated durable antitumor activity and manageable safety profile in pts with recurrent or metastatic cervical cancer. Clinical trial information: NCT03808857 .

The study of immune-related adverse events in a community-based centre.

2642 Background: The effectiveness of immunotherapy is often hindered by the development of immune-related adverse events (IrAE). Racial minorities were under-represented in the key clinical trials that led to the approval of different immune checkpoint inhibitors (ICI). In this study, we explore the side effect profile of immune checkpoint inhibitors in our patient population that comprises almost entirely of minorities, mostly African Americans (AA) and Hispanics. We hypothesize that due to race-based differences in immune milieu of the body and disease susceptibility, the timing and severity of immunotherapy-related IrAE would be different in AA and Hispanics compared to Caucasians. This can translate into a difference in clinical outcomes as well. There have been some suggestions of a positive association of the development of IrAE with cancer survival, although the data is limited and heterogeneous. The purpose of our study is to study the frequency and severity of IrAEs in racial minority groups, compare them with previous clinical trials population, and add valuable real-world data in this underrepresented group of patients. Methods: A retrospective chart review was performed on adult patients with solid malignancies treated with any ICI between January 1, 2015 and April 30, 2022. Patients were classified according to age (greater/equal to 65y or younger), sex, race (self-identified), primary cancer, and type of immunotherapy received. Outcome data using type and severity of IrAE, time to development of IrAE, and any association with clinical outcomes was collected and analyzed using descriptive statistics as well as univariate analysis. Results: A total of 78 patients were included in the final analysis. The mean age was 68 years; 51% were males; 42.3% were Hispanics, 37% were AA, 19.7% were others, and 1% were Whites. Most common malignancy was lung cancer (65.5%). Most common ICI agent used was Pembrolizumab (n = 52) and 2 patients were treated with combination therapy using Ipilimumab and Nivolumab. 41 (52.5%) patients had IrAE of any grade while 9 (11.5%) patients experienced grade 3 side effects. None of the patients experienced grade 4 side effects. Most common IrAE of any grade was hypothyroidism (n = 14) while most common grade 3 side effect was colitis (n = 6). 31 patients were less than 65y of age. There was no significant difference in IrAE in patients less than 65 years of age vs ≥ 65 years (51.6% vs 53.1%) or grade 3 IrAE (9.6% vs 12.7%). Conclusions: In our study population consisting mostly of AA and Hispanics, the rate of IrAE of any grade as well as grade 3 or 4 IrAE with ICI therapy was comparable to what was seen in clinical trials involving these drugs. This data and its potential effects on survival outcomes need to be analyzed in prospective studies involving a larger number of patients.

Clonally expanded, thyrotoxic effector CD8+ T cells driven by IL-21 contribute to checkpoint inhibitor thyroiditis.

Autoimmune toxicity occurs in up to 60% of patients treated with immune checkpoint inhibitor (ICI) therapy for cancer and represents an increasing clinical challenge for expanding the use of these treatments. To date, human immunopathogenic studies of immune-related adverse events (IRAEs) have relied on sampling of circulating peripheral blood cells rather than affected tissues. Here, we directly obtained thyroid specimens from individuals with ICI-thyroiditis, one of the most common IRAEs, and compared immune infiltrates with those from individuals with spontaneous autoimmune Hashimoto's thyroiditis (HT) or no thyroid disease. Single-cell RNA sequencing revealed a dominant, clonally expanded population of thyroid-infiltrating cytotoxic CXCR6+ CD8+ T cells (effector CD8+ T cells) present in ICI-thyroiditis but not HT or healthy controls. Furthermore, we identified a crucial role for interleukin-21 (IL-21), a cytokine secreted by intrathyroidal T follicular (TFH) and T peripheral helper (TPH) cells, as a driver of these thyrotoxic effector CD8+ T cells. In the presence of IL-21, human CD8+ T cells acquired the activated effector phenotype with up-regulation of the cytotoxic molecules interferon-γ (IFN-γ) and granzyme B, increased expression of the chemokine receptor CXCR6, and thyrotoxic capacity. We validated these findings in vivo using a mouse model of IRAEs and further demonstrated that genetic deletion of IL-21 signaling protected ICI-treated mice from thyroid immune infiltration. Together, these studies reveal mechanisms and candidate therapeutic targets for individuals who develop IRAEs.

Clonally-Expanded, Thyrotoxic Autoimmune Mediator CD8 +T cells Driven by IL21 Contribute to Checkpoint Inhibitor Thyroiditis

Abstract Autoimmune toxicity occurs in up to 60% of patients treated with immune checkpoint inhibitor (ICI) cancer therapy and is an increasing clinical challenge with the expanding use of these treatments. Previous human studies into the cause of immune related adverse events (IRAEs) have often evaluated only circulating immune cells rather than affected tissues. Here, we directly sampled thyroid specimens from subjects with ICI-thyroiditis, one of the most common IRAEs, to determine driving mechanisms. We compared immune infiltrates in ICI-thyroiditis to those in subjects with spontaneous autoimmune Hashimoto’s thyroiditis (HT) or no thyroid disease. Single cell RNA sequencing revealed a dominant, clonally expanded population of thyroid-infiltrating cytotoxic CXCR6 +CD8 +T cells (“CD8 +autoimmune mediators”) present in ICI-thyroiditis, but not HT or healthy subjects. Furthermore, we identified a crucial role for interleukin 21, a cytokine secreted by intrathyroidal T follicular (Tfh) and T peripheral helper (Tph) cells, as a driver of these thyrotoxic CD8 +autoimmune mediators. In the presence of IL21, human CD8 +T cells acquired the autoimmune mediator phenotype with upregulation of cytotoxic molecules (IFNg, granzyme); the chemokine receptor CXCR6; and thyrotoxic capacity. We validated these findings in vivo using a novel mouse model of IRAEs, and further demonstrated that genetic inhibition of IL21 signaling protected ICI-treated mice from thyroid autoimmunity. Taken together, our data reveal novel mechanisms by which IL21 +Tfh/Tph cells drive thyrotoxic CD8 +autoimmune mediators for the development of IRAEs in humans. Furthermore, these studies highlight IL21 as a potential therapeutic target in patients to prevent IRAEs. Supported by grants from the NIH NIDDK (K08 DK129829), the American Thyroid Association, and the Aramont Charitable Foundation.

Predictors of thyroid adverse events during cancer immunotherapy: a real-life experience at a single center.

Thyroid dysfunction is among the most common immune-related adverse events (irAEs) of immune checkpoint inhibitors (ICIs) therapy. Data regarding potential predictors of the development of thyroid irAEs are still limited and sometimes conflicting. We assessed potential risk factors and clinical outcomes associated with the onset of thyroid irAEs in a cohort of patients with different types of cancer treated with ICIs at a single center. Clinical and biochemical data, including thyroid function tests and autoantibodies at baseline and during treatment, were collected, and the onset of thyroid irAEs was recorded. Patients with thyroid dysfunction and/or under levothyroxine therapy before starting ICI were excluded. 110 patients (80M, 30 F, aged 32-85years; 56.4% non-small-cell lung cancer, 87% treated with anti-PD-1) with complete information were included in the study. Among them, 32 (29%) developed thyroid irAEs during ICIs therapy. Primary hypothyroidism was the most common irAEs, occurring in 31 patients (28.18% of the whole cohort), including 14 patients who experienced a transient thyrotoxicosis. About 60% of irAEs occurred within the first 8weeks of therapy. At multivariate analysis, anti-thyroid autoantibodies positivity at baseline (OR 18.471, p = 0.022), a pre-existing (autoimmune and non-autoimmune) thyroid disorder (OR 16.307, p < 0.001), and a family history of thyroid diseases (OR = 9.287, p = 0.002) were independent predictors of the development of thyroid irAEs. Our data confirm the high frequency of thyroid dysfunctions (mostly hypothyroidism) during ICIs, and provide data on valuable predictors of thyroid toxicities that may help clinicians in identifying patients at risk for developing irAEs.

Immune checkpoint inhibitor-induced hypophysitis: clinical and biochemical features.

Immune checkpoint inhibitors are a very promising novel class of immune response-regulating drugs for cancer treatment. Hypophysitis is one of their most common immune-related adverse events, occurring in a significant proportion of patients. Since this is a potentially severe entity, regular hormone monitoring is recommended during treatment to allow for a timely diagnosis and adequate treatment. Identification of clinical signs and symptoms, such as headaches, fatigue, weakness, nausea and dizziness, can also be key for its recognition. Compressive symptoms, such as visual disturbances, are uncommon, as is diabetes insipidus. Imaging findings are usually mild and transient and can easily go unnoticed. However, the presence of pituitary abnormalities in imaging studies should prompt closer monitoring, as these can precede clinical manifestations. The clinical importance of this entity relates mainly to the risk of hormone deficiency, especially ACTH, which occurs in the majority of patients and is rarely reversible, requiring lifelong glucocorticoid replacement therapy.

Abstract PD11-11: PD11-11 Results from ALICE – Atezolizumab Combined with Immunogenic Chemotherapy in Patients with Metastatic Triple Negative Breast Cancer, a Randomized Phase IIb Trial

Abstract Background: Immune checkpoint inhibitors (CPI) have shown efficacy against metastatic triple negative breast cancer (mTNBC), but only for PD-L1 positive tumors. It is not known if so-called immunogenic chemotherapies may yield clinical relevant synergies with CPI. We addressed these issues, by conducting a trial evaluating atezolizumab (anti-PD-L1) in combination with doxorubicin, which has been reported to provoke immunogenic cell death, and low-dose metronomic cyclophosphamide, which has been reported to counter immunosuppressive cells. The pegylated liposomal form of doxorubicin (PLD) was selected to avoid steroids and allow for long term therapy in responders. To our knowledge, this is the first randomized trial reporting on the concomitant addition of CPI to antracyclines in mTNBC. Methods: The trial enrolled patients with mTNBC and maximum one previous line of chemotherapy in the metastatic setting. Patients were randomized 2:3 into arm A (n=28), receiving chemotherapy alone, or arm B (n=40), receiving chemotherapy in combination with atezolizumab (840 mg every 2nd week). The chemotherapy consisted of PLD (20mg/m2 every 2nd week) + oral cyclophosphamide (cyclo; 50mg/day, 2/4 weeks) in both arms. The per protocol (PP) population was defined as patients receiving &amp;gt; 3 doses of atezolizumab and &amp;gt;2 doses of PLD. The primary efficacy endpoint was progression-free survival (PFS) in the PP population. The protocol power analysis focused on durable response, as measured by 15 months PFS. Safety, a co-primary endpoint, was evaluated in all patients that started therapy (Full Analysis Set; FAS). Secondary endpoints included PFS in FAS, objective response rate (ORR), clinical benefit rate (CBR), durable response rate (&amp;gt;6 months; DRR), overall survival (OS) and biomarkers. PD-L1 status was determined retrospectively by the Ventana SP142 assay, as tumor-infiltrating immune cells with cut-off ≥ 1%. Efficacy data are given in the PP population unless stated otherwise. Hazard ratios (HR) are given with 95% confidence intervals (CI). Results: A total of 68 patients started therapy (FAS), of which 59 were in the PP population and 57% had not received previous chemotherapy in the metastatic setting. PFS was significantly improved in arm B compared to arm A in both the PP population (HR 0.57; CI 0.33-0.99; p=0.0477) and in the FAS (HR 0.56; CI 0.33-0.95; p=0.0326). Median PFS was 4.3 months in arm B versus 3.5 months in arm A. The progression-free proportion after 15 months was 14.7% (CI 6.4-30.1%) in arm B versus 0% in arm A. The ORR was 30.6%/21.7%, CBR was 52.8%/43.5% and DRR was 13.9%/4.3% in arm B/A. The PFS advantage was observed for both PD-L1+ (n=27; HR 0.58) and PD-L1- subjects (n=31; HR 0.66). All five patients without progression after 15 months belonged to arm B, and three out of these patients were PD-L1 negative. Serious adverse events occurred for 48% in arm B and 29% in arm A (FAS). The most common immune related adverse events of any grade in arm B/A were hypothyroidism (10.0%/7.1 %), pneumonitis (10.0%/3.6%), hyperthyroidism (5.0%/7.1%) and rash (7.5%/3.6%). Further biomarker analyses and assessments of immunological changes during therapy are ongoing. Conclusions: The addition of atezolizumab to PLD and low-dose metronomic cyclophosphamide significantly improved PFS. A benefit was indicated also in patients with PD-L1 negative disease. The combination regimen was well tolerated with no new safety signals. Results from the ongoing analyses of consecutive tumor and blood samples will be important to assess the hypothesized immunological effects of the chemotherapy and to investigate biomarkers associated with the response to the combined treatment. Citation Format: Jon Amund Kyte, Andreas H. Røssevold, Nikolai K. Andresen, Christina Annette Bjerre, Bjørnar Gilje, Erik Hugger Jakobsen, Sunil Xavier Raj, Ragnhild Sørum Falk, Elin Borgen, Thea Jahr, Øystein Garred, Jon Lømo, Randi Margit Mathiesen, Bjørn Naume. PD11-11 Results from ALICE – Atezolizumab Combined with Immunogenic Chemotherapy in Patients with Metastatic Triple Negative Breast Cancer, a Randomized Phase IIb Trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD11-11.

Identification of risk factors for gastrointestinal irAEs associated with immune checkpoint inhibitors.

791 Background: Immune checkpoint inhibitors (ICIs) are widely used in tumor-agnostic therapy showing remarkable survival benefit in various cancer types. Gastrointestinal (GI) toxicities are common immune-related adverse events (irAEs) with limited reports for risk factors. In this study, we investigated potential risk factors for GI-irAEs in patients receiving immunotherapy. Methods: We retrospectively reviewed medical records of cancer patients treated with ICIs between January 2020 and December 2021 at Tokyo Medical and Dental University hospital, and analyzed the relationship between GI-irAEs and patients’ clinicopathological characteristics, treatment duration or the number of treatment cycles. Results: Among 474 patients, 136 were eligible for analysis. Patient characteristics were as follows: the median age, 68 years (range, 32-92); male/female, 104 (76.5%)/32 (23.5%); and cancer types were mainly GI in 36 (26.5%), head and neck in 33 (24.3%), urinary tract in 35 (25.7%), and others in 32 (23.5%). Details of ICIs were nivolumab in 47 (34.6%), pembrolizumab in 61 (44.9%), atezolizumab in 17 (12.5%), and nivolumab + ipilimumab in 11 (8.1%). GI-irAEs was observed in 29 patients (21.3%), and more frequent in female than male (OR: 3.07, 95% CI: 1.31-7.68, P=0.0146). The median number of treatment cycles to the onset of GI-irAEs from ICIs initiation was 4 (range, 1-70). Female had a shorter event-free survival than male (HR: 2.12, 95% CI: 0.914-4.9, P=0.041). There was no significant difference in gender for the number of treatment cycles to the onset of GI-irAEs from ICIs initiation. Of 17 patients (12.5%) with grade 2≤ GI-irAEs, female had trend toward higher incidence (OR: 2.63, 95% CI: 0.99-7.22, P = 0.122). The outcomes after the GI-irAEs onset were as follows: treatment continuation in 9 patients (52.9%), treatment discontinuation followed by observation in 1 (5.9%) and administration of corticosteroids in 7 patients (41.2%). Of 7 patients receiving corticosteroids, 2 resumed chemotherapy with other drugs, 2 resumed chemotherapy with same drugs, and 3 discontinued chemotherapy. Conclusions: Our results suggest that female is a potential risk factor for GI-irAEs during ICI treatment regardless of cancer types.