Agent Immune Checkpoint Inhibitors Research Articles

40 Preclinical evaluation of a novel dendritic cell vaccine for kidney cancer

Abstract Background Dendritic cell (DC)-based vaccines have been previously shown to promote therapeutic T cell responses in both preclinical tumor models and in cancer patients, where extended patient overall survival has been noted in many cases. The goal of the present study is to develop a novel DC-based vaccine as an effective immuno-oncology (IO) agent for the prevention/treatment of kidney cancer. We previously demonstrated that actin-binding protein profilin1 (Pfn1) is overexpressed in tumor-associated vascular endothelial cells (ECs), where it may serve as a prognostic factor in human clear cell renal cancer (ccRCC). We further established a direct causal relationship between EC Pfn1 dysregulation, immune microenvironment alterations, and tumor progression in mouse models of RCC. The current work specifically explores whether Pfn1-targeted DC-based vaccines are effective in preventing orthotopic RCC in mice. Methods To generate Pfn1-targeted DC vaccines, we harvested and matured DCs from Balb/C mouse bone marrow-derived precursor cells in cultures containing rmIL4 and rmGM-CSF. DCs loaded with individual Pfn1 synthetic peptides (these sequences were identified using three MHC class I/II peptide-binding algorithms) were injected into syngeneic mice on days 0, 7 and 14. Spleens were harvested from immunized mice on day 21 to isolate CD4+ and CD8+ T cells, with T cells then stimulated with unmanipulated DCs or DCs pulsed with individual immunizing peptides to detect specific T cell activation, as measured by IFN-gamma release quantitated by ELISA. Tissue histology was performed to assess immune-related adverse events (iRAE) in vaccinated mice as a safety index. For cancer studies, Balb/c mice were immunized with DCs loaded with pooled Pfn1 peptides a few days prior to establishing either subcutaneous or orthotopic RCC tumors. Tumor-bearing mice were subjected to an identical booster vaccine prior one week later in advance of euthanasia and study end-point analyses. Results Our studies show that vaccination of Balb/c mice with DCs pulsed with Pfn1 peptides elicit specific CD4+ and/or CD8+ T cell responses without promoting irAEs. When applied in the prophylactic setting, DC-Pfn1 peptide vaccines substantially slow the growth of subcutaneous RCC tumors. In support of these findings, we have also developed preliminary data supporting the therapeutic effects of DC/Pfn1-peptide vaccines in a murine orthotopic model of RCC. Conclusions In summary, our studies provide first evidence for Pfn1-targeted IO agent in the cancer setting. Given that the survival benefit for dual immune-check point inhibitors (ICI)/anti-angiogenic therapy remains modest and is limited to a small minority of ccRCC patients, Pfn1-targeted vaccines could represent a novel therapeutic agent for improved patient outcomes when applied alone or in combination with in-clinic ICI agents. DOD CDMRP Funding: yes

Immune-related adverse events requiring hospitalization in patients with lung cancer: implications and insights.

Immune checkpoint inhibitors (ICI) are associated with a distinct spectrum of toxicities. Data on irAE hospitalization rates and clinical course of patients with thoracic malignancies are lacking. Patients with advanced thoracic malignancy treated with ICI (2/2016 to 6/2021) were retrospectively identified. Demographic and clinical data of confirmed irAE hospitalizations were extracted from the medical record and a descriptive analysis was performed. From February 2016 to June 2021, 1312 patients with thoracic malignancy received ICI (monotherapy, combination with 2nd ICI or other agents) with 102 patients (7.7%) hospitalized for irAEs. Treatment intent was first-line therapy in most patients (N = 50, 49%) with 9% (n = 9) receiving adjuvant ICI (N = 9). Sixty patients (59%) received ICI alone, 32% (N = 33) chemo plus immunotherapy, and 7% (N = 7) dual ICI. The median age on admission was 68 years. The median time between ICI initiation and admission was 64 days (1-935 days). Pneumonitis (32.3%; 33/102) was the most frequent indication for admission followed by gastroenterocolitis (19.6%; 20/102), hepatitis (12.7%; 13/102), myo/pericarditis (9.8%; 10/102), and endocrinopathies (9.8%; 10/102). Multi-organ toxicity occurred in 36% (N = 37) of patients. Overall, 85.2% (87/102) of patients received systemic corticosteroids and 17.6% (18/102) required additional lines of immunosuppression. The median length of hospitalization stay was 7 days (2-28 days) with a 25.5% (n = 26) readmission rate within 60 days and an 11.8% (n = 12) in house mortality rate. Severe irAE requiring inpatient admission, although infrequent, results in considerable morbidity, mortality, and healthcare utilization. Pneumonitis was the most common irAE requiring inpatient management in our patient population with a significant risk of mortality despite the use of guideline-directed systemic immunosuppression. This study highlights the continued need for collaborative efforts amongst medical specialties for improving the diagnostic and therapeutic management of patients with irAEs.

Real-world incidence of incident noninfectious uveitis in patients treated with BRAF inhibitors: a nationwide clinical cohort study

To compare the incidence of noninfectious uveitis in skin melanoma or lung cancer patients who received BRAF inhibitors with that in those who received immune checkpoint inhibitors (ICIs) or conventional cytotoxic chemotherapy. Nationwide population-based retrospective clinical cohort study METHODS: From the Health Insurance Review and Assessment Service database of South Korea, we retrospectively defined 77,323 patients with skin melanoma or lung cancer who received BRAF inhibitor therapy (BRAF inhibitor-exposed group; n = 396), ICIs (ICI-exposed group; n = 22,474), or conventional cytotoxic chemotherapy (unexposed group; n = 54,453). We calculated the 1-year cumulative incidence of noninfectious uveitis in each group from the first day of BRAF inhibitor, ICI, or cytotoxic agent administration. During the first year of treatment initiation, the cumulative incidence of uveitis was 0.33%, 0.35%, and 2.27% in the unexposed, ICI-exposed, and BRAF inhibitor-exposed groups, respectively. Adjusted hazard ratios (aHR) indicated a 7.52-fold and 5.68-fold increased risk of uveitis in the BRAF inhibitor-exposed group compared with that in the unexposed and ICI-exposed groups (95% confidence interval [CI] 3.83-14.75, P < 0.001 and 95% CI 2.81-11.47, P < 0.001, respectively). After 1:4 propensity score matching, aHRs showed a 35.51-fold and 15.80-fold increased risk (95% CI 4.49-280.48, P = 0.001 and 95% CI 1.76-141.00, P = 0.014) of uveitis and severe uveitis, respectively, in the BRAF inhibitor-exposed versus unexposed patients. Crossover analysis within the BRAF inhibitor-exposed group showed a 3.71-fold increase in uveitis risk during 1-year post index date in comparison with 1-year prior to index date (95% CI 1.03-13.40, P = 0.046). In the BRAF inhibitor-exposed group, female sex, chronic kidney disease, and melanoma were associated with a trend of increased, albeit nonsignificant, risk of uveitis. Melanoma or lung cancer patients treated with BRAF inhibitors showed significantly higher risk of noninfectious uveitis than patients treated with conventional cytotoxic drugs or ICIs. These findings emphasize the importance of pretreatment patient education on BRAF-inhibitor-associated uveitis risk to enable prompt ophthalmic evaluation and treatment if symptoms arise during drug administration.

Genomic and Epigenomic Biomarkers of Immune Checkpoint Immunotherapy Response in Melanoma: Current and Future Perspectives.

Immune checkpoint inhibitors (ICIs) demonstrate durable responses, long-term survival benefits, and improved outcomes in cancer patients compared to chemotherapy. However, the majority of cancer patients do not respond to ICIs, and a high proportion of those patients who do respond to ICI therapy develop innate or acquired resistance to ICIs, limiting their clinical utility. The most studied predictive tissue biomarkers for ICI response are PD-L1 immunohistochemical expression, DNA mismatch repair deficiency, and tumour mutation burden, although these are weak predictors of ICI response. The identification of better predictive biomarkers remains an important goal to improve the identification of patients who would benefit from ICIs. Here, we review established and emerging biomarkers of ICI response, focusing on epigenomic and genomic alterations in cancer patients, which have the potential to help guide single-agent ICI immunotherapy or ICI immunotherapy in combination with other ICI immunotherapies or agents. We briefly review the current status of ICI response biomarkers, including investigational biomarkers, and we present insights into several emerging and promising epigenomic biomarker candidates, including current knowledge gaps in the context of ICI immunotherapy response in melanoma patients.

Treatment strategy for HER2-negative advanced gastric cancer: salvage-line strategy for advanced gastric cancer.

After immune checkpoint inhibitor (ICI) comes into third-line treatment of advanced gastric cancer, the therapeutic strategy has been dramatically changed. Recent first-line regimen, which consists of ICI and chemotherapeutic agents, prolonged progression-free survival, and subsequent treatment options enabled continuous treatment beyond second-line therapy. Moreover, the advent of vascular endothelial growth factor (VEGF)-targeted agents including angiogenesis inhibitors and TKIs provides an opportunity of considering the interaction between ICI and anti-VEGF agents, and facilitating novel treatment proposal. Although clinical benefit of prolonged VEGF blockade after disease progression has not been confirmed in gastric cancer, combination therapy of cytotoxic agents and anti-VEGF agent, such as irinotecan plus ramucirumab demonstrated favorable objective response rate and progression-free survival in third- or later-line setting. In this review, we discuss recent progress and future directions of later-line treatments of HER2-negative advancer gastric cancer.

Abstract 4073: Decoy-resistant IL-18 enhances checkpoint inhibitor combinations beyond anti-PD-1 in vitro and in vivo

Abstract Background: Interleukin-18 (IL18) is a proinflammatory cytokine that modulates both innate and adaptive immune responses. Historically, wild-type recombinant IL-18 has shown limited anti-tumor efficacy in preclinical models and clinical trials, likely due to upregulation of IL-18 binding protein (IL-18BP), a negative regulator of the IL-18 signaling axis. Accordingly, an engineered IL-18 cytokine capable of interacting with the IL-18 receptor, but resistant to IL-18BP interactions (i.e., “Decoy-Resistant IL-18”, DR-18), has demonstrated enhanced therapeutic potential in mouse tumor models, both as a single agent and in combination with anti-PD-1 [1, 2]. Here we evaluated murine DR-18 in combination with additional checkpoint inhibitors beyond anti-PD-1 in a set of mouse tumor models, and tested human DR-18 activity in vitro/ex vivo for activation of human immune cells and anti-tumor activity. Results: Treatment with mDR-18 elicited strong efficacy as a single agent and combination activity with immune checkpoint inhibitors (ICIs) across diverse syngeneic mouse models of solid tumors. As a single agent, mDR-18 demonstrated robust single agent activity in tumor growth inhibition for MC38 (&amp;gt;80%), CT26 (&amp;gt;60%) and B16-F10 (&amp;gt;55%). Combination treatment of mDR-18 with anti-PD-1, anti-CTLA-4, or anti-LAG-3 increased the efficacy for the MC38 (&amp;gt;85-95%), CT26 models (&amp;gt;80-85%), while the B16-F10 (&amp;gt;60%) showed smaller efficacy enhancement with the combinations. In vitro assays revealed human DR-18 (ST-067) activated immune cells and enhanced A549 tumor cell killing over 72hrs. Furthermore, ex vivo studies of 3D patient-derived tumor spheroids demonstrated that ST-067 impaired growth and increased immune cell infiltration, highlighting the potential of hDR-18 to enhance immune activity within the human tumor microenvironment. Conclusion: These studies expand the breadth of IL-18/checkpoint synergism beyond anti-PD-1 and confirm enhanced human immune response in vitro with the clinical candidate ST-067. Taken together, these findings strengthen the rationale for clinical combination of ST-067 with ICI agents in patients with solid tumors. 1.Zhou T, Damsky W, Weizman OE, et al. IL-18BP is a secreted immune checkpoint and barrier to IL-18 immunotherapy. Nature. 2020;583(7817):609-614. doi:10.1038/s41586-020-2422-62.Minnie SA, Waltner OG, Ensbey KS, et al. Depletion of exhausted alloreactive T cells enables targeting of stem-like memory T cells to generate tumor-specific immunity. Sci Immunol. 2022;7(76):eabo3420. doi:10.1126/sciimmunol.abo3420 Citation Format: Jeffrey N. Lindquist, Kai Qin, Aaron M. Ring, Hirdesh Uppal. Decoy-resistant IL-18 enhances checkpoint inhibitor combinations beyond anti-PD-1 in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4073.

Impact of immunotherapy time-of-day infusion on survival and immunologic correlates in patients with metastatic renal cell carcinoma: a multicenter cohort analysis

BackgroundRecent studies have demonstrated that earlier time-of-day infusion of immune checkpoint inhibitors (ICIs) is associated with longer progression-free survival (PFS) and overall survival (OS) among patients with metastatic melanoma and...

PD-1/PD-L1 inhibitor-induced immune thrombocytopenia: A pharmacovigilance study and systematic review

IntroductionProgrammed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) immune checkpoint inhibitors (ICIs) are used for a variety of cancers and are associated with a risk of developing immune-related adverse events, most commonly dermatitis, colitis, hepatitis, and pneumonitis. Immune-mediated hematologic toxicities have been reported, but are less well-described in the literature. Immune thrombocytopenia (ITP) is a rare autoimmune, hematologic adverse event that has been reported with PD-1/PD-L1 inhibitors. MethodsWe performed a retrospective observational analysis of the United States Food and Drug Administration Adverse Event Reporting System (FAERS) data. We searched for cases of ITP reported with exposure to PD-1/PD-L1 inhibitors from initial FDA approval for each agent to September 30, 2022. Disproportionality signal analysis was done by calculating the reporting odds ratio (ROR). Oxaliplatin was used as a positive control for sensitivity analysis as it is an anticancer therapy that has been associated with drug-induced ITP. A systematic review of the PubMed database was also conducted to identify published cases of PD-1/PD-L1 inhibitor-induced ITP. ResultsThere were 329 reports of ITP with ICIs in the FAERS database that were reviewed for a disproportionality signal, including atezolizumab (n = 27), durvalumab (n = 17), nivolumab (n = 160), and pembrolizumab (n = 125). The ROR was significant for atezolizumab (ROR 5.39, 95 % CI 3.69–7.87), avelumab (ROR 10.32, 95 % CI 4.91–21.69), durvalumab (ROR 7.91, 95 % CI 4.91–12.75), nivolumab (ROR 9.76, 95 % CI 8.34–11.43), and pembrolizumab (ROR 12.6, 95 % CI 10.55–15.06). In our systematic review, we summated 57 cases of ICI-induced ITP. Nivolumab and pembrolizumab had the most reported cases of ITP in the literature. Most cases reported (53 %) included ITP-directed therapies beyond corticosteroids for the management of ICI-induced ITP. ConclusionThere is a significant reporting signal of ITP with several ICI agents. Clinicians should be aware of and monitor for signs of this potentially serious adverse event.

Exploring the Landscape of Immune Checkpoint Inhibitor-Induced Adverse Events Through Big Data Mining of Pan-Cancer Clinical Trials.

Immune checkpoint inhibitors (ICIs) have significantly improved the survival of patients with cancer and provided long-term durable benefit. However, ICI-treated patients develop a range of toxicities known as immune-related adverse events (irAEs), which could compromise clinical benefits from these treatments. As the incidence and spectrum of irAEs differs across cancer types and ICI agents, it is imperative to characterize the incidence and spectrum of irAEs in a pan-cancer cohort to aid clinical management. We queried >400 000 trials registered at ClinicalTrials.gov and retrieved a comprehensive pan-cancer database of 71 087 ICI-treated participants from 19 cancer types and 7 ICI agents. We performed data harmonization and cleaning of these trial results into 293 harmonized adverse event categories using Medical Dictionary for Regulatory Activities. We developed irAExplorer (https://irae.tanlab.org), an interactive database that focuses on adverse events in patients administered with ICIs from big data mining. irAExplorer encompasses 71 087 distinct clinical trial participants from 343 clinical trials across 19 cancer types with well-annotated ICI treatment regimens and harmonized adverse event categories. We demonstrated a few of the irAE analyses through irAExplorer and highlighted some associations between treatment- or cancer-specific irAEs. The irAExplorer is a user-friendly resource that offers exploration, validation, and discovery of treatment- or cancer-specific irAEs across pan-cancer cohorts. We envision that irAExplorer can serve as a valuable resource to cross-validate users' internal datasets to increase the robustness of their findings.

Single agent vs combination immunotherapy in advanced melanoma: a review of the evidence.

The aim of this review is to outline the current landscape of advanced melanoma treatment options, provide insights on selecting combination therapies within different clinical scenarios, capture clinical relevance of anti-programmed cell death protein 1 (PD-1) monotherapy, and explore the unmet needs with immune check-point inhibitors (ICI) in advanced melanoma. ICI based treatment consisted of single agent ICI or dual combination ICI-ICI is the standard of care of front-line treatment of metastatic or unresectable melanoma. PD-1 inhibitors (Pembrolizumab and Nivolumab) improved progression free survival (PFS) and overall survival (OS) compared to chemotherapy and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) inhibitors (Ipilimumab and Tremelimumab). The dual ICI combination (Nivolumab and Ipilimumab) provided profound and durable responses better than monotherapy, and the longest overall survival ever achieved in advanced disease, including in patients with murine sarcoma viral oncogene homolog B (BRAF)-mutated disease, but at the cost of a high risk of severe toxicity. The new dual blockage of LAG-3 and PD-1 (Nivolumab-Relatlimab) emerges as a valid option with promising efficacy outcomes and a favourable toxicity profile. Mature survival data is still needed to capture the real benefit. These new plethora of options pose new challenges not only for optimal treatment sequencing strategies but especially for management of adverse effects, endorsing the need to integrate a holistic and personalized approach for patient care.

Abstract PR012: Underrepresentation and underreporting of minoritized racial and ethnic groups in clinical trials on immune checkpoint inhibitors

Abstract Background: In the last decade, a fast-growing number of clinical trials on immune checkpoint inhibitors (ICIs) have led to their wide approval and clinical use with substantial improvement in patient outcomes across multiple cancer types. Historically, minoritized racial and ethnic groups have been underrepresented in clinical trials. Such disparities may be exacerbated in trials of new therapies such as ICIs. Our study aimed to examine the representation and reporting of the racial and ethnic composition of participants in clinical trials involving ICIs. Methods: Clinical trials published in full text in English from 2007 to 2022, with ICI as an active intervention for any malignancy, were reviewed. Information on trial characteristics and racial and ethnic composition of participants were extracted from published papers or ClinicalTrials.gov. Differences in participation in terms of year of publication, trial phase, ICI agent, and cancer type were analyzed. Enrollment-incidence ratio (EIR) was calculated using the proportion of minoritized racial/ethnic group patients among trial participants versus the age-adjusted cancer incidence by race and ethnicity for each cancer type and year from the National Cancer Institute Surveillance, Epidemiology, and End Result (SEER) database. An EIR greater than 1 signifies overrepresentation while less than 1 signifies underrepresentation. Results: A total of 471 clinical trials were identified and included in the analysis, with the majority published between 2019 and 2022 (68%) and conducted in Phase 2 (41%) or Phase 3 (26%). The most investigated ICI was pembrolizumab (28%), and lung cancer was the most studied malignancy (22%). Racial composition was unreported in 31% of the trials, while 59% did not report Hispanic/Latinx ethnic composition. Only 6.4% of the trials reported race/ethnicity-specific results. Overall, Hispanics/Latinx were the most underrepresented (EIR 0.30, 95% CI 0, 1.45), followed by Blacks/African Americans (EIR 0.40, 95% CI 0, 1.95), and American Indians/Alaska Natives (EIR 0.92, 95% CI 0, 8.98), while Whites (EIR 1.13, 95% CI 0.63, 1.43) and Asians (EIR 1.88, 95% CI 0, 8.11) were overrepresented. Subgroup analyses revealed consistent overrepresentation of only Whites across the years of publication (EIR 1.11-1.23), trial phases (EIR 1.07-1.22), ICIs agents (EIR 1.03-1.21), and cancer types (EIR 1.02-1.30), while Hispanics/Latinx and Blacks/African Americans were consistently underrepresented across these categories. Excluding phase 1 trials (31.9%) in the analyses did not significantly alter these findings. Conclusions: Disparities in the representation and reporting of minoritized racial and ethnic groups persist in recent trials on ICIs. Whites and Asians were overrepresented; Hispanics/Latinx, Blacks, and Native Americans were underrepresented. Concerted efforts from the clinical, research, patient, and advocate communities are warranted to improve diversity in trial representation and reporting and ensure safe and beneficial treatment with ICIs for all patients. Citation Format: Alfredo V. Chua Jr., Jennifer Delmerico, Haiyang Sheng, Shipra Gandhi, Igor Puzanov, Lori C. Sakoda, Gary R. Morrow, Christine B. Ambrosone, Charles Kamen, Song Yao. Underrepresentation and underreporting of minoritized racial and ethnic groups in clinical trials on immune checkpoint inhibitors [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr PR012.

Complications of immunotherapy in advanced hepatocellular carcinoma.

Immune checkpoint inhibitors (ICIs) are highly effective in cancer treatment. However, the risks associated with the treatment must be carefully balanced against the therapeutic benefits. Immune-related adverse events (irAEs) are generally unpredictable and may persist over an extended period. In this review, we analyzed common irAEs reported in highly cited original articles and systematic reviews. The prevalent adverse reactions include fatigue, pyrexia, rash, pruritus, diarrhea, decreased appetite, nausea, abdominal pain, constipation, hepatitis, and hypothyroidism. Therefore, it is crucial to conduct evaluations not only of gastrointestinal organs but also of cardiac, neurologic, endocrine (including the frequently affected thyroid), and ophthalmic systems before commencing ICIs. This review further explores commonly reported types of irAEs, specific irAEs associated with each ICI agent, rare yet potentially fatal irAEs, and available treatment options for managing them.

Text intervention to minimize time burden of cancer care (TIME).

301 Background: Innovative strategies to mitigate the time toxicity of cancer therapy are desperately needed. We have shown that a text-based e-triage can utilize patient-reported outcomes to identify patients without immune checkpoint inhibitor (ICI) toxicity who could safely fast-track to ICI infusion without a pre-infusion office visit. We report the efficacy of e-triage versus usual care to minimize the time toxicity of cancer care. Methods: This hybrid type 1 effectiveness-implementation randomized controlled trial was conducted at Penn Medicine between December 2021 and December 2022. Eligible patients spoke English, were receiving single agent ICI for a solid tumor, and had access to a mobile device with text messaging. The e-triage arm included ICI toxicity symptom assessment via two-way text messaging 96 hours prior to scheduled ICI and routine laboratory testing. Patients on the e-triage arm with normal bloodwork and no symptoms identified by the e-triage were eligible to fast-track to ICI infusion, bypassing the pre-treatment office visit. Usual care was standard office visits. Primary endpoint was care time (total time per ambulatory encounter including commute-, wait-, infusion-, and lab-times). Secondary endpoints were patient wait time per encounter, incident emergency department (ED) or hospital visits during follow-up, health related quality of life (HRQOL) measured by The Functional Assessment of Cancer Therapy-General, and patient satisfaction measured by PSQ-18. Differences in proportions of ED or hospital visits between arms were evaluated by the Fisher’s exact test. Linear mixed-effects models with random intercepts for each individual evaluated differences in all other endpoints between arms, accounting for within-patient correlation. Implementation outcomes were adoption (# patients who participated in the trial out of # approached) and fidelity (# patients on the intervention arm who followed their triage assignment). Acceptability, feasibility, and appropriateness outcomes were reported previously. Results: Among 152 eligible patients, 51 consented onto study (adoption rate 33.6%) and 40 were randomized (n=21, usual care; n=19, e-triage). Patient characteristics will be presented. Of 52 encounters on the e-triage arm, 23 adhered to their e-triage assessment (fidelity rate 44.2%). Compared with the usual care arm, patients on the e-triage arm had an average of 70 minutes less care time per encounter (95% CI -123.7 to –8.08 minutes, p=0.03) and 30.1 minutes less wait time (95% CI -61 to 1.1 minutes, p=0.08). The incidence of ED or hospital visits did not differ by treatment arm (usual care, n=2, 12.5% vs. intervention, n=3, 20%, p=0.65). HRQOL and patient satisfaction scores were similar by treatment arm. Conclusions: Results from this pilot trial support further work to optimize the design and implementation of a mobile e-triage program to personalize cancer care delivery and minimize time toxicity. Clinical trial information: NCT05134636 .

Safety and effectiveness of combination versus monotherapy with immune checkpoint inhibitors in patients with preexisting autoimmune diseases

ABSTRACT Patients with preexisting autoimmune disease (pAID) are generally excluded from clinical trials for immune checkpoint inhibitors (ICIs) for cancer due to concern of flaring pAID. In this multi-center, retrospective observational study, we compared safety of ICI combination (two ICI agents) versus monotherapy in cancer patients with pAIDs. The primary outcome was time to AEs (immune-related adverse events (irAEs) and/or pAID flares), with progression-free survival (PFS) and overall survival as secondary outcomes. Sixty-four of 133 patients (48%) received ICI combination and 69 (52%) monotherapy. Most had melanoma (32%) and lung cancer (31%). Most common pAIDs were rheumatic (28%) and dermatologic (23%). Over a median follow-up of 15 months (95%CI, 11-18 mo), the cumulative incidence of any-grade irAEs was higher for combination compared to monotherapy (subdistribution hazard ratio (sHR) 2.27, 95%CI 1.35–3.82). No statistically significant difference was observed in high-grade irAEs (sHR 2.31 (0.95–5.66), P = .054) or the cumulative incidence of pAID flares. There was no statistically significant difference for melanoma PFS between combination versus monotherapy (23.2 vs. 17.1mo, P = .53). The combination group was more likely to discontinue or hold ICI, but > 50% of the combination group was still able to continue ICI therapy. No treatment-related deaths occurred. In our cohort with pAIDs, patients had a tolerable toxicity profile with ICI combination therapy. Our results support the use of ICI combination if deemed necessary for cancer therapy in patients with pAIDs, since the ICI toxicities were comparable to monotherapy, able to be effectively managed and mostly did not require ICI interruption.

SAT443 Prevalence Of Immune Checkpoint Inhibitor-related Endocrinopathies In Patients With Cancers

Abstract Disclosure: S. Pittampalli: None. S.R. Lubin: None. R. Acharya: None. Background: Immune checkpoint inhibitors (ICIs), emerged as the primary treatment modality for a wide range of cancers improving overall survival. Nevertheless, improved overall survival is complicated by endocrine dysfunctions including thyroid dysfunction, adrenalitis, diabetes mellitus, and hypophysitis. Such adverse events offset the benefits of ICI therapy and are associated with significant morbidity and mortality. Limited data exists concerning the burden of the ICI-related endocrinopathies in cancer treatment.Objective: To identify the prevalence and timing of onset of various endocrinopathies in patients with cancers receiving ICIs. Methods: A retrospective study was conducted at SUNY Upstate Medical University, NY comprising of adult patients. The study population consisted of all patients age 18 and above seen at Upstate Medical University between 1 January 2019 and 31 December 2021. Anonymized aggregate-level data was collected using an EPIC Slicer Dicer to identify all adult patients with cancer who underwent ICI therapy and a total of 199 patients were included. Demographic, clinical, histopathological, laboratory data were examined. The study was reviewed by IRB and deemed exempt. The following ICI-related endocrinopathies were considered: Hypothyroidism, hyperthyroidism, diabetes mellitus, adrenal insuffiency, and hypophysitis. ICI treatments included: anti-PD-1 (nivolumab, pembrolizumab, cemiplimab), anti-PD-L1 (atezolizumab, avelumab, durvalumab), and combination therapy (ipilimumab and nivolumab, or any other ICI combinations). Statistical analysis including descriptive statistics, ANOVA was conducted using IBM SPSS software.Results: A total of fifty patients (25%) developed ICI-related endocrinopathy (n=28 M, 22 F) with a mean age of onset 63.69 years. Majority of the patients were being treated for lung cancers (51%) and had hypothyroidism (88%) followed by adrenal insufficiency (9%) and diabetes (2%). There were no cases of hyperthyroidism or hypophysitis observed. The average time of onset of endocrinopathies after initiation of ICI therapy was 22 weeks (anti-PD-1=122 days, anti-PD-L1=180 days and combination therapy= 252 days) with a significantly later onset with combined therapy when compared to anti-PD-1 inhibitors (252 vs 122 days, p= 0.004). Conclusion: With the increasing use of immune checkpoint inhibitors in cancer therapy, there is increased prevalence of endocrinopathies. Periodic hormonal assessment along with close monitoring of new symptoms results in early detection of endocrinopathies as the time of onset varies significantly with the type of ICI agent and the use of single vs combination therapy. Presentation: Saturday, June 17, 2023

Outcomes of Consolidative Thoracic Radiation within First-Line Chemoimmunotherapy in Extensive-Stage Small-Cell Lung Cancer: Results from a Single Cancer Center

Thoracic radiation (TRT) benefits local control undoubtedly and survival with some minor controversy in extensive-stage small-cell lung cancer (ES-SCLC) patients undergoing radiotherapy in the chemoradiotherapy era. However, whether TRT could further enhance the benefit of immune checkpoint inhibitors (ICIs) maintenance on outcomes in the immunotherapy era is still unclear. This study aims to investigate the role of consolidative TRT in ES-SCLC patients receiving first-line chemoimmunotherapy followed by immunotherapy maintenance. Outcomes of patients who were treated with first-line chemo-immunotherapy followed by ICIs maintenance for ES-SCLC were reviewed. Based on TRT or not, patients were allocated to TRT group or non-TRT group. Progression-free survival (PFS), overall survival (OS) and local-recurrence free survival (LRFS) were calculated by the Kaplan-Meier method and compared by log-rank test. A total of 100 patients with no progressive disease after 4 cycles of chemotherapy were retrospectively analyzed between January 2020 and December 2021 and were allocated into TRT group (n = 47) and non-TRT group (n = 53). The median follow-up time was 20.3 months. The median PFS and OS in TRT were 9.1 months and 21.8 months, versus 8.8 months (p = 0.93) and 24.3 months (p = 0.63), respectively, in non-TRT. ICIs agents consisted of Durvalumab (59.0%) and Atezolizumab (41.0%). The median dose of TRT is 50 Gy (IQR: 45 - 54), while the median interval time from chemotherapy completion to TRT was 31 days (IQR: 12 - 44.5). Only 10 (21.3%) patients terminated ICIs in the period of TRT. The rate of intrathoracic progression after the first-line therapy in TRT significantly decreased compared to that with non-TRT (20.0% versus 55.9%, p = 0.003). The median LRFS time in TRT was not reached, but significantly longer than 10.8 months in non-TRT (HR = 0.27, p < 0.01). Second-line chemotherapy significantly prolonged survival compared to that with chemo-free patients (mOS: 24.5 vs. 21.4 months, p = 0.026). The subgroup analysis showed a trend of patients with brain metastases benefit from TRT (21.8 versus 13.7 months, HR 0.61, p = 0.38) while liver metastases did not (13.3 versus 15.0 months, HR 1.80, p = 0.21). Of 47 patients with TRT, only 10.6% of patients experienced grade 3 radiation-induced pneumonitis, while no grade 4 or 5 adverse events occurred. None of patients experienced grade ≥ 3 treatment-related cardiac events. Consolidative TRT in the period of immunotherapy maintenance followed first-line chemo-immunotherapy did not prolong OS and PFS but increased LRFS in ES-SCLC.

Differential outcomes and immune checkpoint inhibitor response among endometrial cancer patients with MLH1 hypermethylation versus MLH1 “Lynch-like” mismatch repair gene mutation

ObjectivesTo identify differential survival outcomes and immune checkpoint inhibitor (ICI) response in MLH1 hypermethylated versus MLH1 mutated (“Lynch-like”) endometrial tumors and determine whether their molecular profiles can elucidate the differential outcomes. Methods1673 mismatch repair deficient endometrial tumors were analyzed by next-generation sequencing and whole transcriptome sequencing (Caris Life Sciences, Phoenix, AZ). PD-L1, ER, and PR were tested by immunohistochemistry and immune cell infiltrates were calculated using MCP-counter. Significance was determined using Chi-square and Mann-Whitney U tests and adjusted for multiple comparisons. Overall survival (OS) was depicted using Kaplan-Meier survival curves. ResultsThe endometrial cancer cohort comprised 89.2% patients with MLH1 hypermethylated tumors and 10.8% with MLH1 mutated tumors, with median ages of 67 and 60 years, respectively (p < 0.01). Patients with MLH1 hypermethylated tumors had significantly worse OS and trended toward worse OS following ICI treatment than patients with MLH1 mutated tumors. The immune microenvironment of MLH1 hypermethylated relative to MLH1 mutated was characterized by decreased PD-L1 positivity, immune checkpoint gene expression, immune cell infiltration, T cell inflamed scores, and interferon gamma (IFNγ) scores. MLH1 hypermethylation was also associated with decreased mutation rates in TP53 and DNA damage repair genes, but increased rates of JAK1, FGFR2, CCND1, and PTEN mutations, as well as increased ER and PR positivity. ConclusionsEndometrial cancer patients with MLH1 hypermethylation display significantly decreased survival and discrepant immunotherapy responses compared to patients with MLH1 mutated tumors, which was associated with differential mutational profiles, a more immune cold phenotype, and increased ER/PR expression in MLH1 hypermethylated tumors. Providers may consider early transition from single agent ICI to a multi-agent regimen or hormonal therapy for patients with MLH1 hypermethylated tumors.

Pre-existing Interstitial Lung Abnormalities and Immune Checkpoint Inhibitor-Related Pneumonitis in Solid Tumors: A Retrospective Analysis.

Immune checkpoint inhibitors (ICIs) have demonstrated efficacy over previous cytotoxic chemotherapies in clinical trials among various tumors. Despite their favorable outcomes, they are associated with a unique set of toxicities termed as immune-related adverse events (irAEs). Among the toxicities, ICI-related pneumonitis has poor outcomes with little understanding of its risk factors. This retrospective study aimed to investigate whether pre-existing interstitial lung abnormality (ILA) is a potential risk factor for ICI-related pneumonitis. Patients with non-small cell lung cancer, malignant melanoma, renal cell carcinoma, and gastric cancer, who was administered either nivolumab, pembrolizumab, or atezolizumab between September 2014 and January 2019 were retrospectively reviewed. Information on baseline characteristics, computed tomography findings before administration of ICIs, clinical outcomes, and irAEs were collected from their medical records. Pre-existing ILA was categorized based on previous studies. Two-hundred-nine patients with a median age of 68 years were included and 23 (11.0%) developed ICI-related pneumonitis. While smoking history and ICI agents were associated with ICI-related pneumonitis (P = .005 and .044, respectively), the categories of ILA were not associated with ICI-related pneumonitis (P = .428). None of the features of lung abnormalities were also associated with ICI-related pneumonitis. Multivariate logistic analysis indicated that smoking history was the only significant predictor of ICI-related pneumonitis (P = .028). This retrospective study did not demonstrate statistically significant association between pre-existing ILA and ICI-related pneumonitis, nor an association between radiologic features of ILA and ICI-related pneumonitis. Smoking history was independently associated with ICI-related pneumonitis. Further research is warranted for further understanding of the risk factors of ICI-related pneumonitis.

SETBP1 mutation determines sensitivity to immune checkpoint inhibitors in melanoma and NSCLC.

SET binding protein 1 (SETBP1) plays crucial roles in various biological processes; however, its involvement in cancer immune checkpoint inhibitor (ICI) treatments has never been studied. In this study, we collected a total of 631 melanoma and 109 non-small cell lung cancer (NSCLC) samples treated with ICI agents (i.e., anti-CTLA-4, anti-PD-1/PD-L1, or combination therapy). Additionally, we obtained their corresponding somatic mutational profiles. We observed that SETBP1 mutated (SETBP1-MUT) melanoma patients exhibited significantly prolonged ICI survival outcomes compared to wild-type patients (HR: 0.56, 95% CI: 0.38-0.81, P = 0.002). Consistently, an elevated ICI response rate was also noticed in the SETBP1-MUT group (42.9% vs. 29.1%, P = 0.016). The Association of SETBP1 mutations with favorable immunotherapeutic prognosis and response was further supported by an independent NSCLC cohort (both P < 0.05). Additional immunological analyses revealed that favorable immune infiltration, tumor immunogenicity, and immune response circuits were enriched in SETBP1-MUT patients. Overall, our findings suggest that SETBP1 mutations may serve as a new biomarker for stratifying beneficiaries of ICI treatments in melanoma and NSCLC, which provides possible evidence for tailoring clinical immunotherapeutic strategies.

Immune checkpoint inhibitors promising role in cancer therapy: clinical evidence and immune-related adverse events.

The advent of immune checkpoint inhibitors (ICIs) has led to noteworthy progressions in the management of diverse cancer types, as evidenced by the pioneering "ipilimumab" medication authorized by US FDA in 2011. Importantly, ICIs agents have demonstrated encouraging potential in bringing about transformation across diverse forms of cancer by selectively targeting the immune checkpoint pathways that are exploited by cancerous cells for dodging the immune system, culminating in progressive and favorable health outcomes for patients. The primary mechanism of action (MOA) of ICIs involves blocking inhibitory immune checkpoints. There are three approved categories including Programmed Death (PD-1) inhibitors (cemiplimab, nivolumab, and pembrolizumab), Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) (Ipilimumab), and Programmed Death-Ligand 1 (PDL-1) (Avelumab). Although ICIs promisingly increase therapeutic response and cancer survival rates, using ICIs has demonstrated some limitations including autoimmune reactions and toxicities, requiring close monitoring. The present review endeavors to explicate the underlying principles of the MOA and pharmacokinetics of the approved ICIs in the realm of cancer induction, including an appraisal of their level of practice-based evidence.