Dose Of Immune Checkpoint Inhibitors Research Articles

Abstract CT157: Combination of nivolumab with standard of care in the management of grade group 5 prostate cancer: Interim analysis of a phase II trial

Abstract Survival outcomes of grade group 5 (GG5) prostate cancer (PCa) after standard of care therapy (SOC) remain poor. Evidence suggest that high dose rate brachytherapy (HDR) and androgen depravation therapy (ADT) can serve as immune modulators. We hypothesize that the combination of HDR, ADT, and immune checkpoint inhibitors (ICI) may synergize to improve immune response and disease control. Here we report an interim analysis of a single-center single-arm phase II trial exploring this novel combination therapy with nivolumab for GG5 PCa. Patients were enrolled from 9/2018 to 4/2021 and required to have GG5 PCa with > 30% positive cores and receive ICI plus SOC regimen, comprising ADT, external beam RT (EBRT), and HDR. ICI (240 mg) was administered every 2 weeks for 4 doses beginning 4 weeks prior to HDR. HDR consisted of two 1150 cGy implants. EBRT followed HDR and consisted of 4500 cGy in 25 fractions. Total ADT length and elective nodal radiotherapy were per physician discretion. Biopsies were taken at time of diagnosis, HDR, and 1-month post HDR. Biopsy tumor samples underwent genomic profiling. Major pathologic response (MPR) was defined as < 17% positive cores. Wilcoxon test and Area Under the Curve (AUC) Receiver Operating Characteristics (ROC) curves were used for statistical analyses. Toxicity was evaluated according to CTCAE v5.0. The historic control cohort consisted of all patients treated with SOC between 1/2013 to 11/2021 and met all study inclusion/exclusion criteria. Cox regression was used to calculate 2-year (2Y) risk of metastasis with censorship at 24 months (m). Median follow up (mFUP) defined from diagnostic biopsy. Of 34 patients who received 2 or more doses of ICI, 1 patient (3%) experienced a dose limiting toxicity of autoimmune hepatitis (AH). The incidence of all grade 3 toxicity related to ICI at 3 and 6 months were both 3% (n=1; AH and QT prolongation, respectively). There was no grade 4+ toxicity at 3 m, nor any grade 3+ toxicity at 6 m. Two subjects were withdrawn from study, leaving 32 evaluable for clinical outcomes. mFUP of ICI cohort was 32 m with a 2Y PSA failure rate of 6%. CD8A, STING, ANPEP, and multiple immune signatures were associated with an early MPR (p < 0.05) with ICI. The Ricketts_Immunosuppression genomic signature strongly correlated with MPR to ICI (AUC = 0.7, p = 0.01). The control cohort consisted of 59 patients with a mFUP of 35 m and a 2Y PSA failure rate of 19%. ICI demonstrated an 88% reduction in 2Y risk of metastasis compared to controls (HR = 0.12, 95% CI, 0.02 - 1.0, p = 0.05). Combination of ICI with SOC for GG5 PCa is safe and associated with a clinically significant improvement in disease control. Key genomic features were identified to predict for early MPR to ICI. Ricketts_Immunosuppression was identified as a potential biomarker for ICI-sensitive tumor subtypes. Final analyses are anticipated in late 2023. Clinical trial information: NCT03543189. Citation Format: John Michael Bryant, Maria Sandoval, Ryan Putney, Corrado Caslini, Shivanshu Awasthi, Esther Katende, Angelina Fink, Syeda Mahrukh H Naqvi, Youngchul Kim, Jingsong Zhang, Jong Park, Amparo Serna, Julio Pow-Sang, Michael Poch, Roger Li, Brandon Manley, Arash Naghavi, Javier Torres-Roca, G. Daniel Grass, Sungjune Kim, Kujtim Latifi, Dylan Hunt, Peter A. Johnstone, Jasreman Dhillon, Rohit Jain, Daniel Fernandez, Kosj Yamoah. Combination of nivolumab with standard of care in the management of grade group 5 prostate cancer: Interim analysis of a phase II trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT157.

Clinical outcomes of patients with metastatic renal cell carcinoma who discontinued nivolumab +/- ipilimumab therapy electively or due to toxicity.

625 Background: Immune checkpoint inhibitor (ICI) based regimens are the standard of care for patients with metastatic renal cell carcinoma (mRCC). In other tumor types such as melanoma, there is evidence that cancer control can persist long after discontinuation of ICI therapy. Outcomes after ICI discontinuation for mRCC are less characterized. Our aim is to characterize the durability of treatment response in mRCC patients who discontinued ICI therapy electively or due to toxicity. Methods: We identified patients with mRCC who responded to nivolumab +/- ipilimumab and then discontinued ICI therapy either for elective reasons or due to toxicity. Patients who discontinued therapy due to progressive disease or who died within 3 months of their last ICI dose were excluded. Complete response (CR) duration was calculated from last ICI dose to the most recent documentation of CR status. Time to progression was defined as the time from last ICI dose to documentation of disease progression or initiation of next-line therapy. Durability of treatment response was calculated from the date of last ICI dose to the most recent follow up date at which sustained response was noted. Results: We identified a total of 56 patients treated with nivolumab +/- ipilimumab therapy who discontinued treatment for toxicity (n=30) or for elective reasons (n=26) and achieved CR or partial response/stable disease (PR/SD). Of the entire cohort, 19 patients (34%) achieved CR, and the majority (95%) were still alive and disease-free with a median follow up of 906 days (range 86-2143 days). Among all patients who discontinued treatment with best response of PR/SD, 49% experienced disease progression, with a median progression-free survival of 382 days (range 77-1267). 42% of patients who stopped ICI electively achieved CR and all (100%) were still alive with sustained CR (median follow-up = 735 days) at data collection. Among those with best response of PR/SD after elective discontinuation, about half (53%) maintained disease control while the rest had disease progression or death (47%). Conclusions: Patients with mRCC who achieve CR with nivolumab +/- ipilimumab and then subsequently discontinue therapy for reasons other than disease progression have excellent long-term cancer outcomes. Recurrence and subsequent progression are rare in this group. These results are similar to the durability of ICI treatment response observed in complete responders in melanoma. Outcomes were less favorable for patients who obtained PR/SD as best response prior to ICI discontinuation, although some patients had ongoing and durable cancer control for up to several years. More research is indicated to ascertain which disease/patient features predict long-term disease control after ICI discontinuation in patients who respond favorably to ICI therapy.

Association between pre-treatment chest imaging and pulmonary function abnormalities and immune checkpoint inhibitor pneumonitis.

Immune checkpoint inhibitors (ICIs) are a first-line treatment for various metastatic solid tumors. Pneumonitis is a potentially devastating complication of ICI treatment and a leading cause of ICI-related mortality. Here, we evaluate whether abnormal pre-treatment pulmonary function tests (PFTs) or interstitial abnormalities on computed tomography of the chest (CT chest) prior to ICI are associated with the development of ICI-pneumonitis (ICI-p). We conducted a retrospective cohort study of consecutive patients who received at least one dose of ICI from 2011 to 2017 at The Ohio State University. Potential risk factors for ICI-p, including abnormal PFTs and CT chest, were recorded. These risk factors were compared between patients with and without pneumonitis. In total, 1097 patients were included, 46 with ICI-p and 1051 without. Ninety percent of patients had pre-treatment chest imaging, while only 10% had pre-treatment PFTs. On multivariable analysis, interstitial abnormalities and reduced total lung capacity (TLC) were significantly associated with development of ICI-p (hazard ratio of 42.42 [95% CI; 15.04-119.67] and hazard ratio of 4.04 [95% CI; 1.32-12.37]), respectively. No other PFT abnormality was associated with increased risk of ICI-p. There was no significant difference in overall survival in patients who did or did not develop ICI-p (p = 0.332). Pre-existing interstitial abnormalities on CT chest and reduced TLC were strongly associated with developing ICI-p. Prospective studies are warranted to further explore the role of PFTs as a potential tool for identifying patients at highest risk for developing ICI-p.

Safety of COVID-19 vaccines in subjects with solid tumor cancers receiving immune checkpoint inhibitors

ABSTRACT The incidence of severe immune-related adverse events (irAEs) in cancer subjects receiving immune checkpoint inhibitors (ICIs) following COVID-19 vaccination and the relationship between the incidence of severe irAE and the interval between COVID-19 vaccination and ICI dose have not been established. We performed a retrospective study evaluating the incidence of irAEs in solid tumor subjects receiving ICI therapy who received any COVID-19 vaccinations since FDA authorization. irAEs were defined as severe with one or more grade 3 or above events (CTCAE v5.0), multiple organ involvement, or requiring hospitalization for management. Two hundred and eighty-four subjects who received COVID vaccinations from December 2020 and February 2022 were included in this analysis [median age at vaccination 67 years (IQR 59.0–75.0); 67.3% male]. Twenty-nine subjects (10.2%) developed severe irAEs, of which 12 subjects (41.4%) received ICI monotherapy, 10 subjects (34.5%) received combination ICI therapy with nivolumab and ipilimumab, and 7 subjects (24.1%) received ICI plus VEGFR-TKI therapy. Hospitalization occurred in 62% of subjects with severe irAEs, with a median duration of 3 days (IQR: 3.0–7.5 days). Immunosuppressive therapy was required in 79.3%, with a median duration of 103 days (IQR: 42.0–179.0). ICI therapy was discontinued in 51.7% of subjects with severe irAE; dosing was held or interrupted in 34.5%. Among severe irAEs, the median interval between vaccination and ICI treatment closest to the occurrence of severe irAE was 15.5 days (IQR: 10.0–23.0). In solid tumor cancer subjects receiving ICIs, COVID-19 vaccination is not associated with an increased incidence of severe irAEs compared to historical data and may be safely administered during ICI cancer therapy in subjects who lack contraindications.

Identifying Patients at Risk of Acute Kidney Injury among Patients Receiving Immune Checkpoint Inhibitors: A Machine Learning Approach.

Background: The benefits of immune checkpoint inhibitors (ICPis) in the treatment of patients with malignancies emerged recently, but immune-related adverse events (IRAEs), including acute kidney injury (AKI), cannot be ignored. The present study established and validated an ICPi-AKI prediction model based on machine learning algorithms to achieve early prediction of AKI events and timely intervention adjustment. Methods: We performed a retrospective study based on data from the First Medical Center of the PLA General Hospital. Patients with malignancy who received at least one dose of ICPi between January 2014 and December 2019 were included in the study. The characteristics of available variables were included after case review, and the baseline characteristics and clinical data of ICPi AKI and non-AKI patients were compared. After variable preprocessing, eight machine learning algorithms were used to construct a full variable availability model. Variable simplification models were constructed after screening important variables using the random forest recursive feature elimination method, and the performance of different machine learning methods and two types of modeling strategies were evaluated using multiple indicators. Results: Among the 1616 patients receiving checkpoint inhibitors, the overall incidence of AKI was 6.9% during the total follow-up time. Sixty-eight patients were associated with ICPi treatment after chart review, primarily in AKI stage 1 (70.5%), with a median time from first ICPi administration to AKI of 12.7 (IQR 2 to 56) weeks. The demographic characteristics, comorbidities, and proportions of malignancy types were similar between the ICPi-AKI and non-AKI groups, but there were significant differences in multiple characteristics, such as concomitant medications and laboratory test indicators. For model performance evaluation and comparison, the AUC values of all 38 variable availability models ranged from 0.7204-0.8241, and the AUC values of the simplicity model constructed using 16 significant variables ranged from 0.7528-0.8315. The neural networks model (NNs) and support vector machine (SVM) model had the best performance in the two types of modeling strategies, respectively; however, there was no significant difference in model performance comparison (p > 0.05). In addition, compared with the full variable availability model, the performance of the variable simplicity model was slightly improved. We also found that concomitant medications contributed more to the model prediction performance by screening the optimal feature combination. Conclusion: We successfully developed a machine learning-based ICPi-AKI prediction model and validated the best prediction performance of each machine model. It is reasonable to believe that clinical decision models driven by artificial intelligence can improve AKI prediction in patients with malignancies treated with ICPi. These models can be used to assist clinicians in the early identification of patients at high risk of AKI, support effective prevention and intervention, and ultimately improve the overall benefit of antitumor therapy in the target population.

Prognostic factors of toxicity of immune checkpoint inhibitors in nonsmall cell lung cancer and small cell lung cancer patients: The ToxImmune study.

Immunotherapy alone or in combination has clearly improved the survival of patients with lung cancer. However, it may also be responsible for adverse events impacting these patients' quality of life. The ToxImmune study aims to identify prognostic factors that can help to predict immune-related adverse events. We included all patients aged 18 years and older who had received at least one dose of immune checkpoint inhibitors, with or without other therapy, between June 2015 and December 2020 and were diagnosed with nonsmall cell lung cancer or small-cell lung cancer. Patients' baseline demographic characteristics, biological blood markers, and imaging by PET-scanner were collected from electronic medical records. All adverse events (AEs) and immune-related AEs (irAEs) were recorded (Common Terminology Criteria For Adverse Events V.5.0). Sixty-four patients were included, of whom 60 (94%) presented at least one irAE. The incidence of Common Terminology Criteria for Adverse Events (CTCAE) grade 2 and grade 3-4 was 34% and 8% respectively. Female sex, Primitive Tumor Standardized Uptake Value Max (SUVmax) <5, number of metastases ≥3 and immunotherapy received after the first line were found to be significant risk factors for immune-related adverse events. Based on the number of risk factors, the ToxImmune score predicts the risk of having a grade ≥2 adverse event (primitive tumor SUV ≥ 5=0 vs. primitive tumor SUV <5=1, number of metastases <3=0 vs. number of metastases ≥3=1 and L1=0 vs. L1 ≥ 1). The incidence of grade ≥2 adverse events was 20%, 55% and 90% with ToxImmune scores 0, 1 and=2 respectively (p=.003). Median progression-free survival (PFS) times were 19.2months, 6.64 months and 2.63 months for ToxImmune scores 0, 1 and=2 respectively, p=.13. Median overall survival times were 22.6months, 16.4months and 9.8months for ToxImmune scores 0, 1 and ≥2 respectively, p=.24. The disease control rate (DRR) was 78% in ToxIummune score 0 group, and 50% in ToxImmune score 1 and ≥2 groups (p=.363). The ToxImmune score, which is grounded on objective clinical parameters, indicates that cases with a high score had an advanced threat of severe adverse events. The ToxImmune score could therefore be used in clinical practice to identify patients treated for lung cancer with immunotherapy and at risk of severe AE.

Biomarker Trends, Incidence, and Outcomes of Immune Checkpoint Inhibitor–Induced Myocarditis

BackgroundMyocarditis is a dreaded and unpredictable complication of immune checkpoint inhibitors (ICI). We sought to determine whether routinely measured biomarkers could be helpful in monitoring for ICI myocarditis. ObjectivesThe authors examined biomarker trends of patients on ICI and their association with the incidence of ICI myocarditis and outcomes. MethodsWe conducted an observational cohort study of adults who received at least one dose of ICI at Michigan Medicine between June 2014 and December 2021 and underwent systematic serial testing for aspartate aminotransferase (AST) and alanine aminotransferase (ALT), creatine phosphokinase (CPK), and lactate dehydrogenase during ICI therapy. ResultsAmong 2,606 patients (mean age 64 ± 13 years; 60.7% men), 27 (1.0%) were diagnosed with ICI myocarditis. At diagnosis, patients with myocarditis had an elevated high-sensitivity troponin T (100%), ALT (88.9%), AST (85.2%), CPK (88.9%), and lactate dehydrogenase (92.6%). Findings were confirmed in an independent cohort of 30 patients with biopsy-confirmed ICI myocarditis. A total of 95% of patients with ICI myocarditis had elevations in at least 3 biomarkers compared with 5% of patients without myocarditis. Among the noncardiac biomarkers, only CPK was associated (per 100% increase) with the development of myocarditis (HR: 1.83; 95% CI: 1.59-2.10) and all-cause mortality (HR: 1.10; 95% CI: 1.01-1.20) in multivariable analysis. Elevations in CPK had a sensitivity of 99% and specificity of 23% for identifying myocarditis. ConclusionsICI myocarditis is associated with changes in AST, ALT, and CPK. An increase in noncardiac biomarkers during ICI treatment, notably CPK, should prompt further evaluation for ICI myocarditis.

Outcomes of Immune Checkpoint Inhibitor Administration in Hospitalized Patients With Solid Tumor Malignancies.

More oncologists desire to treat their patients with immune checkpoint inhibitors (ICIs) in the inpatient setting as their use has become more widespread for numerous oncologic indications. This is cost-prohibitive to patients and institutions because of high drug cost and lack of reimbursement in the inpatient setting. We sought to examine current practice of inpatient ICI administration to determine if and in which clinical scenarios it may provide significant clinical benefit and therefore be warranted regardless of cost. We conducted a retrospective chart review of adult patients who received at least one dose of an ICI for treatment of an active solid tumor malignancy during hospitalization at a single academic medical center between January 2017 and June 2018. Patient, disease, and admission characteristics including mortality data were examined, and cost analysis was performed. Sixty-five doses of ICIs were administered to 58 patients during the study period. Nearly 40% and 80% of patients died within 30 days and 180 days of ICI administration, respectively. There was a trend toward longer overall survival in patients with good prognostic factors including positive programmed death-ligand 1 (PD-L1) expression or microsatellite instability-high (MSI-H) status. Slightly over 70% of patients were discharged within 7 days of ICI administration. The total cost of inpatient ICI administration over the 18-month study period was $615,016 US dollars. Inpatient ICI administration is associated with high costs and poor outcomes in acutely ill hospitalized patients with advanced solid tumor malignancies and therefore should largely be avoided. Careful discharge planning to expedite outpatient treatment after discharge will be paramount in ensuring patients with good prognostic features who will benefit most from ICI therapy can be promptly treated in the outpatient setting as treating very close to discharge in the inpatient setting appears to be unnecessary, regardless of tumor features.

Real-world assessment of attenuated dosing anti-PD1 therapy as an alternative dosing strategy in a high-income country (as defined by World Bank).

The rising cost of oncological drugs poses a global challenge to patients, insurers, and policy makers, with the leading drugs worldwide by revenue from immune checkpoint inhibitors (ICIs). Despite its cost, ICI is marked as a paradigm shift, offering the potential of a long-term cure. To reduce cost, an attenuated dose of ICI based on pharmacological principles can be used while maintaining efficacy. This real-world study aims to examine the prescribing patterns, the effect of financial constraints, and the outcomes in non-small cell lung cancer (NSCLC). All patients receiving palliative intent ICI treatment for advanced NSCLC between January 2014 and April 2021 in National University Hospital, Singapore were recruited. Demographics, prescription trends, factors affecting the prescription of attenuated dose ICI (AD ICI) versus standard dose ICI (SD ICI), and the effect of dose on survival outcomes, toxicities, and costs were examined. Two hundred seventy-four received ICI. The majority of them were treated in first-line setting. One hundred sixty-two (59%) of patients received AD ICI, whereas 112 (41%) received SD ICI. Patients who did not have a supplemental private as-charged health insurance plan were more likely to have received AD ICI (OR: 4.53 [2.69-7.61] p < 0.001). There was no difference in progression-free survival (PFS) and overall survival (OS)-adjusted HR 1.07 CI [0.76, 1.50] p = 0.697 and HR 0.95 CI [0.67, 1.34] p = 0.773, respectively, between patients who received AD versus SD ICI. A cost minimization analysis evaluating the degree of cost savings related to drug costs estimated a within study cost saving of USD 7,939,059 over 7 years. Our study provides evidence for AD-ICI as a promising strategy to maximize the number of patients who can be treated with ICI. This has the potential to make significant economic impact and allow more patients to benefit from novel therapies.

Plasma Exchange for Immune-Related Adverse Events Due to Immune Checkpoint Inhibitor Therapy: Implications for Clinical Care and Clinical Trial Design

Therapeutic plasma exchange (TPE) is increasingly utilized for Grade 3-4 immunotherapy adverse events (irAEs) to accelerate elimination of drug, autoantibodies, and cytokines. Immune checkpoint inhibitors (ICI) are IgG1 or IgG4 constructs with long half-lives (t1/2) and volume of distributions (Vd) favorable for clearance by apheresis. As drug levels are not readily available, the number of sessions needed to eliminate ICIs is estimated based on the interval from last drug dose, drug Vd, and drug t1/2. Increased use of TPE is anticipated as ICIs are now given despite preexisting autoimmunity, prior organ transplantation, and/or prior irAEs. TPE protocols are well established for the management of diseases that can also present as irAEs [e.g. thrombotic thrombocytopenic purpura (TTP), chronic inflammatory demyelinating polyneuropathy (CIDP), myasthenia gravis (MG), hemophagocytic lymphohistiocytosis (HLH)] and for drug removal (e.g. natalizumab). While TPE is included in irAE management guidelines as second line therapy or later (Brahmer JR, et al, J Immunother Cancer, 2021 PMID: 34172516), no randomized controlled trial (RCT) data are available. TPE can reduce the level of clinical biomarkers for irAE monitoring: creatinine kinase (CK), aspartate aminotransferase (AST), alanine aminotransferase (ALT),fibrinogen, platelet count, ferritin. We treated 4 adults (median age 66 years, range 65-77 years) with TPE for steroid-refractory irAEs [myositis (2), myocarditis (1)] and, as part of initial therapy, in combination with dexamethasone and anakinra, for ICI-associated HLH. ICI constructs were IgG1 anti-PD-L1 (envafolimab, durvalumab) and IgG4 anti-PD-1 (nivolumab, cemiplimab). Data collection was IRB approved and with patient written consent. ICI indications were sarcoma, thymic carcinoma, cutaneous squamous cell carcinoma (SCC), and lung SCC. Only one patient (HLH irAE) had preexisting autoimmunity (thyroiditis). Median time from last ICI dose to first irAE symptoms or signs was 16 days (range 5-29 days). Three of 4 patients developed irAE after the first ICI dose. One patient (myocarditis) required full systemic anticoagulation (heparin, then enoxaparin) for atrial fibrillation and deep venous thrombosis, and dual antiplatelet therapy (DAPT) for a new coronary stent. The two myositis patients received prophylactic enoxaparin. All TPE sessions were one plasma volume exchange through central venous access, utilized Anticoagulant Citrate Dextrose Solution A (ACDA), and scheduled daily or every other day. Number of sessions ranged from 2-4. Except for the patient with HLH, TPE was initiated with 5% albumin replacement. Fibrinogen levels and estimated bleeding risk guided the need for fresh frozen plasma (FFP) replacement. Session intervals, exchange fluid, transfusion, biomarkers, changes in fibrinogen and platelet count, anticoagulation, and functional response are detailed in Table 1. Three of 4 patients, who had normal baseline fibrinogen and platelet counts, experienced clinically significant hypofibrinogenemia resulting in discontinuation of chemical DVT prophylaxis and/or cryoprecipitate transfusion, but did not have clinically significant thrombocytopenia. The fourth patient (HLH) required ongoing transfusion support due to pre-TPE hypofibrinogenemia and thrombocytopenia. TPE confounded interpretation of biomarkers in all. All irAEs demonstrated prompt clinical improvement, however, due to rapid corticosteroid tapers, 2 patients (myositis, HLH) relapsed within 1 month from last TPE. Both responded to additional immunosuppression. One patient (myositis) did not relapse. Grade 4 bleeding occurred in the patient receiving enoxaparin and DAPT and led to discontinuation of TPE after 2 sessions. Our experience supports the following when considering TPE for irAEs: 1) exclusion of patients with high bleeding risk, or use of 100% FFP replacement and every other day TPE; 2) meticulous non-biomarker irAE assessment during and after TPE; 3) RCT design includes irAE relapse timing and rates and long term follow-up to assess cumulative immunosuppression and tumor outcome; 4) serial drug levels and correlative studies (e.g. cytokines, autoantibodies) to better understand TPE mechanisms, persistence of irAEs, and long term ICI anti-tumor benefit. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

DNA-Demethylating Agents Combined with Anti-PD-1 Inhibitors Showed Activity in Patients with Relapsed or Refractory Extranodal NK/T Cell Lymphoma Who Have Failed Immunotherapy: An Exploratory Study

Background: Extranodal natural killer (NK)/T-cell lymphoma (ENKTL) is a rare aggressive type of non-Hodgkin's lymphoma associated with Epstein-Barr virus infection. Relapse or refractory (RR)-ENKTL cases are characterized by a high rate of relapse and dismal prognosis with limited therapeutic options. Immune check point inhibitors (ICIs) represent the cornerstone of treatment for RR-ENKTL; however, limited information is available of a rechallenge with ICIs after ICIs are discontinued due to disease progression. Epigenetic aberrations are critical as genetic abnormalities is the hallmarks of ENKTL. One of current promising strategies is that combining epigenetic and ICIs can overcome tumor resistance and enhance immunotherapy responses. Here, we assess the efficacy and safety of DNA methyltransferases inhibitors (DNMTi) plus anti-PD-1 therapy in RR-ENKTL. Methods: This trial enrolled eligible patients with histologically confirmed RR-ENKTL failing from asparaginase-based regimen or ICIs therapy; adequate organ function and bone marrow function; and at least one measurable or evaluable lesion or symptoms. Patients received standard dosage of anti-PD-1 antibodies plus decitabine (10mg/d, d1-5) or azacytidine (100mg/d, d1-5) every 21 days until disease progression, death, intolerable toxicity. Patients accept ASCT as consolidation after they obtained CR. The primary endpoints were objective response rate (ORR) based on Lugano 2016 criteria and clinical benefit rate. Secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. Adverse events (AEs) were defined according to CTCAE 5.0. Results: From March 2020 to May 2022, 27 eligible patients were enrolled. Median age 40 years (range, 12-77), 15 (55.6%) male, 13 (48.1%) patients with stage IV of disease at screening, 11 (40.7%) patients with PINK-E score ≥ 3 points. Among them, 5(18.5%) patients had no imaging lesions, but all peripheral blood ctDNA were positive, they had high plasma EBV-DNA level(n=3), persistent fever(n=2) associated with ENKTL. The median number of prior systemic therapies was 2 (1-5), 21（77.8%）patients received ≥ 2 lines of prior systemic therapy. Twenty-two (81.5%) patients experienced prior ICIs therapy, 23(85.2%) previously received HDACi. The median time between the last dose of prior ICIs and initiation of this trial was 0.8 months (0.8 -23). Seven (25.9%) patients received decitabine, 20 (74.1%) received azacytidine. Of 22 imaging objective response evaluable patients, 13 (59.1%) achieved response (iORR) including 10 (45.5%) patients with CR (iCR). Clinical benefit analysis of 27 patients showed that clinical response(cORR) was 63.0% (17/27), 14 (59.1%) got CR (cCR). Among 5 patients with positive ctDNA alone, 4 patients achieve clinical improvement ,ctDNA negativity(n=4), EBV clearance(n=2) or fever disappearance (n=2). Among 22 patients previously received ICIs (20 patients previously received anti-PD-1 antibody plus HDACi), of these, 11 (50%) had response. After anti-PD-1 antibodies rechallenge plus DNMTi, iORR and cORR were 58.8% (10/17), 63.6% (14/22), iCR and cCR were 41.2% (7/17), 50.0% (11/22), respectively. Anti-PD-1 antibodies rechallenge plus DNMTi yielded iORR were 72.7% (8/11) and 55.6% (5/9) in patients responded to prior ICIs therapy. The difference of efficacy between decitabine and azacytidine was no significant, iORR and cORR were 60% (3/5), 58.8% (10/17) and 71.4% (5/7), 60.0% (12/20), respectively in this study. The median follow-up time was 12.1 (1.9-28.0) months, 1-year OS rate was 70.4%, median PFS rate was 12.8months. Survival results were similar with decitabine and azacytidine cohort. Sixteen (59.3%) patients reported treatment-related AEs (TRAEs). The most frequently observed (≥10%) TRAEs were lymphopenia (44.4%), neutropenia (37.0%), hypothyroidism (25.9%), nausea (18.5%), hyperglycemia (11.1%). Conclusion: DNMTi combined with anti-PD-1 immunotherapy showed promising efficacy and manageable safety profile in RR-ENKTL for the first time. ICIs rechallenge is still an active and feasible strategy, further prospective studies are needed to clarify the role of rechallenge ICIs in this population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abstract 12324: Biomarker Trends in Patients With Immune-Checkpoint Inhibitor Myocarditis

Introduction: Immune checkpoint inhibitors (ICIs) are associated with myocarditis; however, there is no consensus on strategies to identify or monitor for myocarditis. We sought to characterize longitudinal biomarkers in patients receiving ICIs. Methods: We conducted an observational cohort study of adult (≥18 years) patients who had received at least one dose of single or dual ICI at Michigan Medicine between June 2014 - December 2021. Patients were identified as having myocarditis if a clinical diagnosis was noted in the medical record by the cardiovascular consult team. Laboratory values (i.e., high-sensitivity troponin-T [hsTnT], aspartate transaminase [AST], alanine transaminase [ALT], lactate dehydrogenase [LDH], and creatinine phosphokinase [CPK]) were collected from medical records for 12 months after beginning ICI. Results: In 2,606 patients (mean (SD) age 64 (13) years; 60.8% male), 27 (1.0%) developed myocarditis at a median (IQR) time of 28 (18,40) days after starting ICIs. At diagnosis, most patients with myocarditis had a non-cardiac immune-related adverse event (88.9%) and an elevated ALT (88.9%), AST (85.2%), CPK (88.9%), and LDH (92.6%). All patients with myocarditis had an elevated hsTnT. Compared to patients without myocarditis, patients with myocarditis had significant elevations in ALT, AST, CPK, and LDH after starting ICIs (all P&lt;0.001) (Figure). In patients with myocarditis, average concentrations of AST and ALT remained elevated at 12 months, whereas CPK peaked at 1 month then rapidly declined. Average concentrations of all biomarkers in patients without myocarditis were in the normal range. CPK values greater than the upper limit of normal had a sensitivity and specificity of detecting myocarditis of 99% and 23%, respectively. Conclusions: Myocarditis rarely occurs in the absence of other immune-related adverse events. Elevated AST, ALT and CPK should prompt measuring hs-TnT and initiating further evaluation for ICI myocarditis.

Gastrostomy, tracheostomy, opioid, and health care utilization among patients with recurrent/metastatic head and neck cancer receiving immunotherapy.

296 Background: Immune checkpoint inhibitors (ICI) are approved for recurrent and/or metastatic squamous head and neck cancers (R/M HNSCC). Landmark trials have shown stable or improved patient (pt) reported quality of life outcomes. It is unclear how these translate into gastrostomy (G) and tracheostomy (T) dependence, opioid use, or ER/unplanned hospitalizations (UH) in an unselected population. We sought to explore these in our large single institution cohort. Methods: We reviewed R/M HNSCC pts receiving ICI at a tertiary referral NCI designated cancer center. Outcomes were assessed between the first dose of ICI and 100 days after the last dose of ICI. Overall survival (OS) was estimated via Kaplan-Meier estimation. Differences between groups were assessed via log-rank testing procedure and adjusted for age, tumor characteristics, and smoking status. Results: Between 1/2012 and 12/2019, we treated 152 pts with ICI, mostly male (n = 142, 82%), partnered/married (n = 103, 68%), with median age 64 years (range 23 – 90). The most common primary sites were oropharynx (n = 55, 36%) and oral cavity (n = 33, 22%). 50 (35%) had ≥2 lines of prior systemic therapy and 29 (19%) had an ECOG ≥2. The most common pt races were white (n = 114, 75%), Asian (n = 14, 9%), and Hispanic, any race (n = 6, 4%). 83 (55%) and 23 (15%) had history of smoking and heavy alcohol use respectively. Median duration of ICI therapy was 95 days (range 1-1720). Prior to ICI, 49 (32%) had G, 17 (11%) had T, and 15 (10%) had both. While on ICI, 6 (4%) had G placed, and 1 (1%) had a G removed; 1 (1%) had T placed, and 2 (1%) had T removed. 69 (45%) had ER visits and 57 (38%) had UH; 11 (7%) were directly related to ICI adverse effects. Prior to ICI, 104 (68%) were on opiates; requirements increased in 58 (41%) pts and decreased in 17 (12%) pts. Pre-existing G prior to ICI had worse OS on log-rank testing, but significance was lost when adjusted for variables. Pre-existing T prior to ICI (p = 0.001, HR 3.08, 95% Cl [1.56,6.08]), and pts with increasing opiate requirements on ICI (p value = 0.0007, HR 2.13, 95% Cl [1.38,3.28]) had worse OS. Conclusions: In our cohort, ICI did not change G or T usage. Pre-existing T and increasing opiate use were also associated with worse survival. Our data supports augmentation of palliative care and advanced care planning in the R/M HNSCC population.

Socioeconomic factors and outcomes among patients with recurrent/metastatic head and neck cancer receiving immunotherapy.

153 Background: Immune checkpoint inhibitors (ICI) are now a therapeutic standard for recurrent/metastatic head and neck squamous cell cancer (R/M HNSCC). There is limited data on the impact of demographics and socioeconomic (SES) factors on outcomes in this population, and we sought to evaluate these in our single institution cohort. Methods: R/M HNSCC patients (pts) receiving ICI were retrospectively reviewed from an institutional database. SES factors included income, distance to center (dist), marital status, race, and insurance. Median household income by residence zip code was obtained from the US Census Bureau. Time to ICI initiation (TTI) was time from initial visit recommending ICI and first ICI dose. Opiate use was calculated using morphine equivalents prior to ICI initiation and either at best response or end of ICI if no response. Associations between SES factors with overall survival (OS) and TTI were assessed using Cox proportional hazards regression. Binary outcomes were assessed using logistic regression and included ER visits/unplanned hospitalizations (UH) and increase in opioid use. Analyses were adjusted for disease characteristics, smoking status, ECOG, and demographics. Results: Between 1/2012-12/2019, 152 pts received ICI; 124 (82%) were male, with median age of 64 years (range 23-90), and 103 (68%) were partnered/married. The most common races were 114 white (75%), 14 Asian (9%) and 6 Hispanic, any race (4%). Out of 149 (98%) insured pts, 27 (18%) were Medicaid and 69 (46%) Medicare. Median dist was 39 miles (Q1 21, Q3 100), and median income was $80,586 (Q1 $61,202, Q3 $103,059). The most common primary sites were oropharynx (36%), oral cavity (22%), and nasopharynx (7%); 29 (19%) had an ECOG ≥2. While on or within 100 days of ICI, 69 (45%) had ER visits, and 57 (38%) had UH. Increased dist was associated with improved OS (4th vs 1st quartile, p = 0.0002; HR 0.33; 95% CI [0.18,0.59]); we observed no other SES association with OS. Increased opioid use was associated with Medicaid/no insurance (p = 0.05; OR 2.89; 95% CI [1.02,8.77]). No SES association with TTI was found, although there was a nonsignificant trend of higher TTI with increasing dist. We saw no correlation with ER/UH and any SES variables. Conclusions: Among R/M HNSCC pts receiving ICI, insurance had an impact on opiate usage, suggesting more advance disease/higher burden of symptoms and indicating need for augmentation of supportive care in this group. Higher dist was associated with improved OS, even accounting for performance status, which may reflect increased resources in this group. Further studies should examine pt factors that may contribute to disparities in the setting of novel therapies for R/M HNSCC pts.

The Inpatient Immunotherapy Outcomes study: A multicenter retrospective study of patients treated with immune checkpoint inhibitors in the inpatient setting.

300 Background: Immune checkpoint inhibitors (ICIs) have revolutionized the care of patients (pts) with cancer. However, median time to response is 2-6 months and many pts derive no benefit from ICIs. Pts are often admitted to the hospital with complications of advanced disease or its treatment, and many have prognoses limited to months. Several recent studies have demonstrated a limited benefit of anticancer therapy at end of life. ICIs are also associated with significant financial toxicity for both pts and the health care system. The role of ICI therapy in the inpatient (IP) setting is unclear. To begin to address this gap in knowledge, we conducted the Inpatient Immunotherapy Outcomes Study (IIOS) to describe characteristics and outcomes of pts who received IP ICIs. Methods: IIOS is a multicenter, retrospective study of pts treated with PD-(L)1 and CTLA-4 inhibitors during IP hospitalization between 2012-2021 at 4 large academic institutions: Mount Sinai Hospital, Yale-New Haven Hospital, University of Pennsylvania, and Georgetown University Hospital. Manual data collection was performed using each institution’s EMR and was approved by each institution’s IRB. Descriptive statistics were used to characterize the population and demonstrate pt outcomes. Results: A total of 159 pts received IPI ICI. Median age was 61 years. 54.7% of pts were white and 17.6% were Black; 12.6% were Hispanic. Thoracic/head and neck malignancies were most common (26.4%), followed by gastrointestinal (19.5%) and hematologic malignancies (17.6%). Most pts (73%) initiated ICIs in the IP setting while 27% continued an outpatient ICI regimen. 129 pts (81.1%) had stage IV solid malignancies at the time of ICI initiation in any setting; median prior lines of systemic therapy was 1 (range, 0-11). The most commonly administered IP ICI was pembrolizumab (49.1%) followed by nivolumab (34.0%), with ICIs administered with non-curative intent in 91.8% of pts. In 44.7% of pts, the ICI given did not have an FDA approval for that cancer type and stage at the time of administration. PD-L1 expression was available on tumors from 60 pts, 32 (53.3%) of whom had expression of 50% or higher. 112 pts (70.4%) had no documented clinical or imaging-based response to ICI therapy. Discharge disposition included home (47.2%), IP death (27%), rehabilitation centers (15.1%), and hospice (10.1%). Median days between first IP ICI dose and death was 47 (95% CI, 33-68). Conclusions: This is the largest multi-institutional effort to understand pt outcomes following IP ICI administration. Preliminary data, as outlined above, is concerning for poor clinical outcomes which should give clinicians pause when considering IP ICI use. Further analysis is ongoing to determine predictors of overall survival and discharge to home.

From Bad to Worse: The Clinical Spectrum of Immune Checkpoint Inhibitor Myocarditis and Associated 3M Syndrome with Concomitant Myositis and Myasthenia

Immune checkpoint inhibitors (ICIs), though revolutionizing cancer care, are well known to cause a diverse array of autoimmune side effects termed immune-related adverse events (IRAEs). ICI Myocarditis is a rare manifestation of IRAE associated with high mortality. We report two cases of fulminant ICI myocarditis refractory to potent immunosuppressants. Our first patient received pembrolizumab for lymphoma, small cell lung cancer and renal cell carcinoma. After 13 doses of ICIs, he developed fulminant myocarditis with concomitant lower-motor neuron type facial nerve palsy. Despite receiving triple immunosuppressive therapies with pulse steroid, mycophenolate mofetil and basiliximab, his cardiac condition progressively worsened and eventually died of heart failure. Our second patients received dual ICIs with pembrolizumab and ipilimumab for inoperable hepatocellular carcinoma. Shortly after first doses of ICIs, he developed 3M syndrome with the classically described triad of Myocarditis, Myositis and bulbar Myasthenia gravis. Despite receiving pulse steroid, mycophenolate mofetil, tacrolimus, plasmapheresis and intravenous immunoglobulin, he had persistent myocardial inflammation with elevated troponin level, and refractory bulbar myasthenia requiring mechanical ventilation and nasogastric tube feeding. Our case series illustrates challenges with managing ICI myocarditis and its associated clinical syndromes including the 3M syndrome. Given the wide application of ICIs, clinical trials as well as preclinical studies are urgently needed to find out the optimal therapy for ICI myocarditis. As early identification of ICI myocarditis allows prompt cessation of ICIs and initiation of immunosuppressants, which may potentially improve cardiovascular outcome of these patients, it is also crucial to determine to optimal strategies for screening ICI myocarditis.

Association between germ-line HLA and immune-related adverse events.

BackgroundIn recent years, significant progress has been made in immune checkpoint inhibitors (ICIs). However, accompanied by remarkable efficacy, a growing number of immune-related adverse events (irAEs) also arose. The mechanism of irAEs remains unclear. Previous studies indicated a positive association between specific human leukocyte antigen (HLA) variants and irAEs. Therefore, we planned and initiated a large cohort study aiming to uncover the relationship between irAEs and divergent HLA types.MethodsWe screened all patients who have been treated in the clinical research ward, Cancer Hospital of the Chinese Academy of Medical Sciences. All participants were diagnosed with malignant tumors with complete AE follow-up data in the original electronic medical records. Sequencing libraries were generated using a customized panel, and four-digit formatted HLA alleles were extracted for further analysis. Association analysis was performed between HLA variants and different irAEs. We introduced two external reference groups and a non-irAE control group within the study cohort to control the type I error. We also explored the relationship between the zygosity of HLA genes, the evolutionary divergence of HLA class I genotype (HED), and irAEs.Results530 participants received at least two doses of ICIs. The median follow-up time was 10.3 months. 97% of patients received anti-PD-1/PD-L1 treatment. The occurrence of overall irAEs showed no significant difference between the HLA homozygous group and the HLA heterozygous group. We did not find any significant association between irAEs and HED. We found that some HLA types are associated with irAEs of different organs and detected a significant association between HLA-DRB3*01:01 and thrombocytopenia (OR 3.48 (1.19,9.42), p = 0.011), HLA-DPB1*04:02 and hypokalemia/hyponatremia (OR 3.44 (1.24,9.1), p = 0.009), leukopenia (OR 2.1 (0.92,4.8), p = 0.037), anemia (OR 2.33 (1.0,5.41), p = 0.026), HLA-A*26:01 and bilirubin elevation (OR 2.67 (0.92,8.31), p = 0.037).ConclusionsIrAEs in specific organs and tissues may be associated with certain HLA types, while HLA heterogeneity has no significant influence on the happening of irAEs. More research is needed to explore the role of germline genetic changes in the risk assessment of irAEs.

The role of immune checkpoint inhibitors in clinical practice: an analysis of the treatment patterns, survival and toxicity rates by sex

PurposeOur aim is to describe the role of immune checkpoint inhibitors (ICI) in clinical practice by providing the patient and tumor characteristics as well as survival and toxicity rates by sex.MethodsWe used electronic health records to identify patients treated at the Cancer Center of the University Hospital Bern, Switzerland between January 1, 2017 and June 16, 2021.ResultsWe identified 5109 patients, 689 of whom (13.5%) received at least one dose of ICI. The fraction of patients who were prescribed ICI increased from 8.6% in 2017 to 22.9% in 2021. ICI represented 13.2% of the anticancer treatments in 2017 and increased to 28.2% in 2021. The majority of patients were male (68.7%), who were older than the female patients (median age 67 vs. 61 years). Over time, adjuvant and first line treatments increased for both sexes. Lung cancer and melanoma were the most common cancer types in males and females. The incidence of irAEs was higher among females (38.4% vs. 28.1%) and lead more often to treatment discontination in females than in males (21.1% vs. 16.8%). Independent of sex, the occurrence of irAEs was associated with greater median overall survival (OS, not reached vs. 1.1 years). Female patients had a longer median OS than males (1.9 vs. 1.5 years).ConclusionsICI play an increasingly important role in oncology. irAEs are more frequent in female patients and are associated with a longer OS. More research is needed to understand the association between patient sex and toxicity and survival.

Salvage chemotherapy in patients with nonsmall cell lung cancer after prior immunotherapy: a retrospective, real-life experience study.

Patients with advanced nonsmall cell lung cancer (NSCLC) who progress with immune checkpoint inhibitors (ICIs), salvage chemotherapy remains the only viable option for tumors that do not harbor genomic alterations. Data on the efficacy of salvage chemotherapy after immunotherapy (SCAI) are scarce. Our main objective in the current study was to evaluate the efficacy of SCAI. All consecutive patients who were diagnosed as having metastatic NSCLC and received at least one dose of ICIs were retrospectively reviewed. We computed progression-free survival (PFS), overall survival (OS) and objective response rate (ORR) with SCAI. We also analyzed associations between survival and various clinicopathologic factors. We identified 35 patients with advanced NSCLC who received at least one dose of SCAI. The median age was 66 years. Most of patients were male ( n = 26, 74.3%) and former or current smokers ( n = 33, 94.3%). The majority of the patients were Eastern Cooperative Oncology Group Performance Status (ECOG PS) 2 ( n = 22; 62.9%), and there were no patients with driver mutations. SCAI was administered as second-line therapy in 21 (60.0%) patients and third-line in 14 (40.0%) patients. The ORR to SCAI was 20.0% with median PFS and OS were 2.43 (95% CI, 1.69-3.16) months and 4.40 (95% CI, 2.17-6.62) months, respectively. In multivariate analysis, ECOG PS 2 was confirmed as being independently associated with inferior OS. We demonstrated that patients with NSCLC who progressed to ICIs had limited clinical benefit with salvage chemotherapy, particularly for patients who were ECOG PS 2.

The rest period between chemotherapy and immunotherapy influences the efficacy of immune checkpoint inhibitors in lung cancer.

BackgroundThe use of immune checkpoint inhibitors (ICIs) as first‐line treatment rather than as second‐line treatment makes a big difference in the drug efficacy and progression‐free survival. However, the mechanism for this is still not clear. This study aimed to analyze the effects of the rest period between chemotherapy and immunotherapy on the efficacy of ICIs.MethodsThis study included 100 patients with advanced NSCLC treated with PD‐1/PD‐L1 inhibitors at Chungnam National University Hospital (CNUH) between May 2016 and August 2019. The rest period was defined from the last dose of cytotoxic chemotherapy to the first dose of ICIs. We retrospectively reviewed patients' clinical data and blood test records and analyzed lymphocyte subsets using flow cytometry.ResultsThe median rest period was 64 days. The long rest period group (≥36 days) showed significantly higher clinical benefits than the short rest period group (<36 days) (69.4% vs. 39.5%, p = 0.003). White blood cell (WBC) count, absolute neutrophil count (ANC), absolute lymphocyte count (ALC), and neutrophil‐lymphocyte ratio (NLR) just before chemotherapy were not different between the two groups. However, the blood test after chemotherapy immediately before immunotherapy showed significantly higher ANC and NLR in the short rest period group than in the long rest period group. The frequency of the Th1 subset and PD‐1 + CD8+ T cells were significantly higher in the long rest period group than in the short rest period group.ConclusionTime interval from chemotherapy to immunotherapy may affect immune cell status and efficacy of ICIs.