Dual Immune Checkpoint Inhibitors Research Articles

Intraperitoneal administration of dual immune checkpoint inhibitor therapy in recurrent gynecologic malignancies: Updated results of a phase 1b study

Intraperitoneal administration of dual immune checkpoint inhibitor therapy in recurrent gynecologic malignancies: Updated results of a phase 1b study

Dual Immune Checkpoint Inhibition in Patients With Aggressive Thyroid Carcinoma

Aggressive thyroid carcinoma, including radioiodine refractory (RAIR) differentiated thyroid carcinoma (DTC), medullary thyroid carcinoma (MTC), and anaplastic thyroid carcinoma (ATC), are associated with significant morbidity and mortality and have limited therapeutic options. Distinct immune profiles have been identified in thyroid cancer subtypes suggesting they may be susceptible to immune checkpoint inhibition. To evaluate the efficacy of anti-programmed cell death 1 nivolumab and anti-cytotoxic lymphocyte-associated protein 4 ipilimumab in patients with aggressive thyroid carcinoma. This phase 2 nonrandomized clinical trial enrolled patients with RAIR DTC in a single center from October 2017 to May 2019, with exploratory cohorts in MTC and ATC. The data were analyzed between June 2021 and September 2023. Intravenous nivolumab, 3 mg/kg, every 2 weeks and ipilimumab, 1 mg/kg, every 6 weeks until disease progression, intolerable adverse events, or a maximum duration of 2 years. The primary end point of the study was objective response rate (ORR) in RAIR DTC, which was scored according to RECIST (Response Evaluation Criteria in Solid Tumours), version 1.1. Key secondary end points included safety, progression-free survival, overall survival, and biomarker analyses. A total of 51 patients were registered, and 49 patients were evaluable for analysis. The median (range) age was 65 years (30-88 years), and 25 participants (51%) were female. ORR in the DTC cohort was 9.4% (3/32 [95% CI, 2.8%-28.5%]), with all partial responses in either oncocytic carcinoma (2/6 [33.0%]) or poorly differentiated thyroid carcinoma (1/5 [20.0%]). Clinical benefit rates were 62.5% (20/32) in the overall DTC cohort, including 83.3% (5/6) in oncocytic carcinoma and 40% (2/5) in poorly differentiated thyroid carcinoma. ORR in the exploratory ATC cohort was 30.0% (3/10 [95% CI, 6.7%-65.2%]), with a clinical benefit rates of 50.0% (5/10). No responses were observed in the exploratory MTC cohort. The safety profile was similar to prior reports with dual immune checkpoint inhibition (pruritus, rash, diarrhea, fatigue, and elevation of lipase and liver enzymes). The presence of NRAS tumor genetic sequence variations, but not BRAF V600E, was associated with worse outcomes. This phase 2 nonrandomized clinical trial reported clinical activity of dual immune checkpoint inhibition in aggressive thyroid cancer. The study did not meet its end point in the primary population of RAIR DTC and does not support further investigation in non-biomarker-selected DTC. However, the signal observed in ATC may merit further evaluation. ClinicalTrials.gov Identifier: NCT03246958.

Oral Lichenoid lesions induced by programmed cell death protein 1 and cytotoxic T-lymphocyte-associated protein 4 bispecific antibody: a case report

BackgroundCadonilimab is the first approved dual immune checkpoint inhibitor targeting programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), currently utilized for the treatment of various solid tumors. Oral mucosal adverse reactions, such as oral lichenoid lesions, represent one of the most prevalent immune-related adverse events associated with immune checkpoint antibodies. However, reports detailing oral side effects specifically linked to Cadonilimab are lacking. Documenting these side effects is essential to alert oncologists and stomatologists, facilitating timely intervention for affected patients.Case PresentationWe present a case involving a 35-year-old male patient diagnosed with hepatocellular carcinoma who received Cadonilimab following hepatectomy and subsequently developed extensive oral lichenoid lesions along with mucosal erosion at 13–14 weeks post-treatment initiation. A biopsy was conducted revealing immunohistochemical findings of CD3+, CD4+, CD8+, CD20 + lymphocytes, CD68 + macrophages, and α-SMA + myofibroblasts infiltrating the tissue of the oral lichenoid lesions. The patient’s oral lesions improved after administration of systemic and local glucocorticoid therapy alongside cessation of Cadonilimab treatment.ConclusionThis report marks the first documented instance of an oral adverse effect associated with Cadonilimab use. It underscores that administration of this agent may lead to significant lichenoid lesions and erosions within the oral cavity—an issue warranting increased vigilance from both oncologists and stomatologists.

Choosing the optimal therapy for metastatic renal cell carcinoma: Insights from a real-world comparative study.

The evolution of combination therapies integrating immune checkpoint inhibitors has revolutionized the first-line treatment of metastatic renal cell carcinoma (mRCC). Although these therapies are clinically approved, direct comparisons between dual immune checkpoint inhibitors (IOIO) and immune checkpoint inhibitors combined with tyrosine kinase inhibitors (IOTKI) in clinical trials are lacking. This gap creates uncertainties in selecting the most appropriate treatment based on patient-specific factors. This study employed the inverse probability of treatment weighting (IPTW) method to analyze progression-free survival (PFS) and overall survival (OS) for patients with mRCC receiving IOIO or IOTKI treatment regimens. A total of 171 patients were analyzed after applying inclusion criteria and propensity scoring. The study found no significant differences in PFS and OS between the two treatment modalities in the IPTW cohort. However, subgroup analyses revealed that IOTKI therapy was associated with better PFS and OS for patients without bone metastases and better OS for patients with a body mass index (BMI) over 25. IOIO therapy showed better OS for patients with a BMI below 18.5. Both IOIO and IOTKI therapies were effective. Therapy selection could be better tailored to patient characteristics by including factors such as the presence of bone metastases and BMI. This study enhances understanding of how patient-specific factors interact with different treatment modalities, potentially guiding more personalized treatment decisions in clinical practice for mRCC.

Exploring risk factors for endocrine-related immune-related adverse events: Insights from meta-analysis and Mendelian randomization.

This study utilized meta-analysis and Mendelian randomization (MR) to identify risk factors for endocrine-related immune-related adverse events (EirAEs) and to ascertain whether EirAEs confer better prognosis of immunotherapy. The meta-analysis identified several risk factors for EirAEs, including elevated baseline TSH (OR = 1.30, 95% CI 1.10-1.53), positive TgAb (OR = 14.23, p < .001), positive TPOAb (OR = 3.75, p < .001), prior thyroid-related medical history (OR = 4.19), increased BMI (OR = 1.11), combination immune checkpoint inhibitors (ICIs) therapy with targeted treatment (OR = 2.71, 95% CI 2.11-3.47), and dual ICI therapy (OR = 3.26, 95% CI 2.22-4.79). MR analysis further supported causalities between extreme BMI, hypothyroidism, and irAEs from a genetic perspective. In addition, cancer patients who experienced EirAEs exhibited significantly prolonged PFS (HR = 0.84, 95% CI 0.73-0.97) and OS (HR = 0.59, 95% CI 0.45-0.76) compared to those without. These findings provide valuable insights for clinical decision-making among healthcare professionals and offer direction for future research in this field.

Dual Immune Checkpoint Inhibition in Melanoma and PD-L1 Expression: The Jury Is Still Out.

This comment discusses the use of PD-L1 as a biomarker to guide treatment decisions for metastatic melanoma.

The role of cytoreductive nephrectomy in the era of immune checkpoint inhibitors: A review of current evidence and ongoing trials.

Renal cell carcinoma (RCC) was diagnosed in over 400 000 individuals globally in 2020, making it a significant global health concern. The incidence of RCC varies by region and overall mortality rates have been declining. This decline is attributed in part to advancements in early cancer detection through imaging and the development of more effective systemic therapies. Cytoreductive nephrectomy (CN) was adopted as a standard treatment for metastatic RCC (mRCC) based on clinical experience and early clinical trials. However, the treatment landscape has shifted with the introduction of tyrosine kinase inhibitors (TKI) in 2007 and, more recently, immune checkpoint inhibitors (ICIs). Dual ICI therapy and combinations of ICIs with TKIs are collectively referred to as immuno-combination therapies and have become standard first-line treatments. This review examines the evolving role of CN in the era of immuno-combination therapies, with a focus on patient selection and the timing of surgery. The immunogenic nature of RCC, characterized by spontaneous tumor regression and immune cell infiltration, suggests a potential benefit from combining CN with ICI therapy to enhance treatment outcomes. This is supported by several clinical studies that reported improved outcomes; however, these were limited by their retrospective nature. Ongoing clinical trials, such as NORDIC-SUN, PROBE, and SEVURO-CN, are expected to provide critical insights into the role of CN in the ICI era. Their findings will ultimately guide future clinical decision-making and further refine treatment strategies for mRCC.

Ipilimumab with nivolumab in molecularly selected patients with castration-resistant prostate cancer: primary analysis of the phase II INSPIRE trial

Metastatic castration-resistant prostate cancer (mCRPC) typically exhibits resistance to immune checkpoint inhibitors (ICIs). However, a subset of mCRPC patients displays a more immunogenic profile. This study examines efficacy and safety of dual ICI therapy in molecularly selected mCRPC. This single-arm, phase II trial included 69 molecularly selected mCRPC patients with mismatch repair deficiency (dMMR), non-synonymous tumour mutational burden ≥7.1 muts/Mb (hTMB), a BRCA2 mutation (BRCAm), or biallelic CDK12 inactivation (CDK12i). Efficacy was assessed in ICI-naïve patients (cohort A) with RECIST 1.1 (A1) and Prostate Cancer Working Group 3 (A2) measurable disease. Safety was evaluated in cohorts A and B (prior ICI monotherapy). Treatment included nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks for four cycles, followed by nivolumab 480 mg every 4 weeks for up to 1 year. The primary endpoint was disease control rate beyond 6 months (DCR > 6), aiming to surpass a DCR > 6 of 22%. Patients initiated treatment between January 2021 and February 2024. Cohort A included 65 patients. Of these, 21 had dMMR (32%), 8 had hTMB (12%), 20 had BRCAm (31%), and 16 had CDK12i (25%). DCR > 6 was achieved in 38% of patients [95% confidence interval (CI) 27% to 51%], and was highest in dMMR (81%), followed by hTMB (25%), CDK12i (19%), and BRCAm (15%). Objective response rate in cohort A was 38% (95% CI 22% to 55%) and 47% (95% CI 34% to 60%) exhibited a 50% decline in prostate-specific antigen levels. Median progression-free survival (PFS) was 4.0 months (95% CI 3.5-12.0 months) in cohort A, and 32.7 months (95% CI 21.8 months-not reached) in dMMR patients. Treatment-related adverse events (TRAEs) led to permanent discontinuation in 14 of 69 patients (20%). Grade ≥3 TRAEs occurred in 48% of patients, with diarrhoea and elevated transaminases each in 10%. There was one treatment-related death due to a bowel perforation and a second following euthanasia after grade 4 toxicity. This trial of dual ICIs in molecularly selected mCRPC met its primary endpoint, showing DCR > 6 in 38% of patients. Dual ICIs exhibited modest responses in the hTMB, BRCAm, and CDK12i subgroups, but demonstrated exceptional efficacy in dMMR.

Engineered Nanoparticles for Enhanced Antitumoral Synergy Between Macrophages and T Cells in the Tumor Microenvironment.

T cells and macrophages have the potential to collaborate to eliminate tumor cells efficiently. Macrophages can eliminate tumor cells through phagocytosis and subsequently activate T cells by presenting tumor antigens. The activated T cells, in turn, can kill tumor cells and redirect tumor-associated macrophages toward an antitumoral M1 phenotype. However, checkpoint molecules expressed on tumor cells impede the collaborative action of these immune cells. Meanwhile, monotherapy with a single immune checkpoint inhibitor (ICI) for either macrophages or T cells yields suboptimal efficacy in cancer patients. To address this challenge, here a nanoparticle capable of efficiently delivering dual ICIs to tumors for both macrophages and T cells is developed. These programmed cell death protein 1 (PD-1)-transfected macrophage membrane-derived nanoparticles (PMMNPs) can target tumors and provide signal-regulatory protein alpha and PD-1 to block CD47 and programmed cell death-ligand 1 (PD-L1), respectively, on tumor cells. PMMNPs enhance macrophage-mediated cancer cell phagocytosis and antigen presentation, promote T cell activation, and induce the reprogramming of macrophages toward an antitumoral phenotype. In syngeneic tumor-bearing mice, PMMNPs demonstrate superior therapeutic efficacy compared to nanoparticles delivering single ICIs and non-targeted delivery of anti-CD47 and anti-PD-L1 antibodies. PMMNPs capable of augmenting the antitumoral interplay between macrophages and T cells may offer a promising avenue for cancer immunotherapy.

Immune Checkpoint Inhibitor–Induced Cardiotoxicity

Immune checkpoint inhibitors (ICIs) improve outcomes in a wide range of cancers; however, serious adverse effects, including cardiovascular adverse effects (CVAEs), can occur. To determine the incidence of CVAEs and analyze data on the management of myocarditis in patients exposed to ICIs. PubMed, Embase, and Cochrane Central Register of Controlled Trials from inception were searched on April 4, 2023. Two separate studies were performed. Key inclusion criteria for study 1 were phases 1 to 4 trials involving adults with malignant neoplasms treated with an ICI and toxicity data; for study 2, publications (case reports and retrospective analyses) on clinical manifestations and treatment of patients with ICI-induced CVAEs. Studies with dose escalation or fewer than 11 patients in each group and all case reports, retrospective analyses, letters, reviews, and editorials were excluded from study 1. Studies not published in English were excluded from study 2. The PRISMA guidelines and Cochrane Handbook for Systematic Reviews were followed. Data were extracted independently by 2 researchers. A meta-analysis of the incidence of CVAEs in clinical trials and a systematic review of the evidence for the management of myocarditis were performed. Data were pooled using a random-effects model. In study 1, the primary outcome was incidence CVAEs in clinical trials with ICIs and ICI combination therapies. Study 2 examined evidence supporting specific management strategies that may decrease the mortality rate of myocarditis. The primary outcomes were planned before data collection began. In study 1, a total of 83 315 unique participants in 589 unique trials were included in the meta-analysis. Incidence of CVAEs induced by anti-programmed cell death 1 and/or programmed cell death ligand 1 was 0.80% (95% CI, 0%-1.66%) in clinical trials, with no differences between the compounds, except for cemiplimab, which was associated with a higher risk of CVAEs. Incidence of CVAEs following ipilimumab treatment was 1.07% (95% CI, 0%-2.58%). The incidence of myocarditis was significantly higher following treatment with dual ICIs. However, CVAE incidence was not higher with dual ICIs, ICI combination with chemotherapy, or tyrosine kinase inhibitors. Evidence from randomized clinical trials on recommended monitoring and treatment strategies for ICI-induced myocarditis was lacking. Study 2 showed that myocarditis-associated mortality occurred in 83 of 220 patients (37.7%). Prospective data from 40 patients with myocarditis indicated that systematic screening for respiratory muscle involvement, coupled with active ventilation, prompt use of abatacept, and the addition of ruxolitinib, may decrease the mortality rate. Immune checkpoint inhibitor-induced CVAEs and/or myocarditis were recorded in 1.07% of patients in clinical trials. The CVAE mortality risk remains high, justifying the need for monitoring and management strategies for which evidence from randomized clinical trials is absent. Early recognition, ICI therapy cessation, prompt initiation of corticosteroid therapy, and escalation of therapy are all crucial elements for achieving optimal outcomes. Prospective clinical trials or at least prospective registration of treatments and outcomes are highly warranted.

Efficacy and safety of immune checkpoint inhibitors for individuals with advanced EGFR-mutated non-small-cell lung cancer who progressed on EGFR tyrosine-kinase inhibitors: a systematic review, meta-analysis, and network meta-analysis

The clinical benefits of immune checkpoint inhibitor (ICI)-based treatments in treating individuals with advanced EGFR-mutated non-small-cell lung cancer (NSCLC) who have progressed on EGFR tyrosine-kinase inhibitors (TKIs) remain controversial. We aimed to review the literature to comprehensively investigate the individual and comparative clinical outcomes of various ICI-based treatment strategies in this population. In this systematic review and meta-analysis, we used single-arm, pairwise, and network meta-analytical approaches. We searched PubMed, Embase, Cochrane Library, Web of Science, ClinicalTrials.gov, and relevant international conference proceedings from database inception to Jan 31, 2024, without language restrictions, to identify eligible clinical trials that assessed ICI-based treatments for individuals with advanced EGFR-mutated NSCLC who progressed on EGFR-TKIs. Studies considered eligible were published and unpublished phase 1, 2, or 3 clinical trials enrolling participants with histologically or cytologically confirmed advanced EGFR-mutated NSCLC who had progressed after at least one EGFR-TKI treatment, and that evaluated ICI-based treatment strategies on at least one of the clinical outcomes of interest. The primary outcome analysed was progression-free survival. The protocol is registered with PROSPERO, CRD42021292626. 17 single-arm trials and 15 randomised controlled trials, involving 2886 participants and seven ICI-based treatment strategies (ICI monotherapy, ICI plus chemotherapy [ICI-chemo], ICI plus antiangiogenesis [ICI-antiangio], ICI plus antiangiogenesis plus chemotherapy [ICI-antiangio-chemo], dual ICIs [ICI-ICI], dual ICIs plus chemotherapy [ICI-ICI-chemo], and ICI plus EGFR-TKI [ICI-TKI]), were included. Three of these strategies-ICI monotherapy, ICI-antiangio-chemo, and ICI-chemo-had sufficient data across the included studies to perform a pairwise meta-analysis. The pairwise meta-analysis showed that, compared with chemotherapy, ICI monotherapy led to shorter progression-free survival (hazard ratio [HR] 1·73 [95% CI 1·30-2·29], I2=0%), whereas ICI-antiangio-chemo (HR 0·54 [0·44-0·67], I2=0%) and ICI-chemo (HR 0·77 [0·67-0·88], I2=0%) prolonged progression-free survival. The network meta-analysis showed that ICI-antiangio-chemo yielded the best progression-free survival results, with substantial benefits over ICI-chemo (HR 0·71 [95% credible interval 0·59-0·85]), ICI monotherapy (HR 0·30 [0·22-0·41]), and non-ICI treatment strategies including antiangio-chemo (HR 0·76 [0·58-1·00]) and chemotherapy alone (HR 0·54 [0·45-0·64]). ICI-antiangio-chemo was associated with higher risks of both any-grade and grade 3 or worse adverse events over ICI-chemo and chemotherapy in the network meta-analysis. For individuals with advanced EGFR-mutated NSCLC who progressed on EGFR-TKIs, ICI-antiangio-chemo was identified as the optimal treatment option. The toxicity of this treatment was acceptable but needs careful attention. ICI-chemo showed appreciably greater efficacy than the standard-of-care chemotherapy. These findings clarified the roles of ICI-based treatment strategies in this difficult-to-treat refractory population, potentially complementing recent guidelines. None.

Infusion-related reactions from immune checkpoint inhibitors: A proportional and network meta-analysis.

38 Background: Immune checkpoint inhibitors (ICIs) have become the standard of care for the treatment of patients with solid tumors. Infusion-related reactions (IRRs) to ICIs have been reported in up to 20%, but the incidence varies among ICIs. Therefore, we aimed to report and compare the incidence of IRRs to each ICI therapy. Methods: We searched PubMed/MEDLINE, Embase, and Web of Science to identify phase 3 randomized controlled trials (RCTs) evaluating ICIs (CTLA-4, PD-1, PD-L1, and LAG-3 inhibitors) in solid tumors. We performed a random-effects model network meta-analysis to compare the odds ratio (OR) of IRRs by using RCTs comparing dual ICIs, ICI monotherapy, and placebo/observation. For a proportional meta-analysis, treatment arms evaluating ICI monotherapy, or dual ICIs, were selected to pool the incidence of IRRs. Results: A total of 25,250 patients from 47 phase 3 RCTs were included in the analysis. A network meta-analysis of treatment-related IRRs included 10 RCTs and showed that avelumab (OR 70.2, 95% confidence interval [CI]: 4.32-1140) and atezolizumab (40.72, 2.47-671.4) had a significantly higher risk of treatment-related IRRs compared with placebo/observation. Network ranking revealed that avelumab, atezolizumab, and relatlimab plus nivolumab were the top three therapies with risk of treatment-related IRRs. Proportional meta-analyses revealed that the pooled incidence of treatment-related IRRs was 5.39% for PD-1 plus CTLA-4 inhibitors, 8.25% for PD-L1 (avelumab: 13.1%, non-avelumab: 1.93%), 1.97% for CTLA-4, and 1.95% for PD-1 inhibitors. Results of immune-related IRRs were relatively consistent with those of treatment-related IRRs (Table). Conclusions: Avelumab has the highest risk of IRRs followed by atezolizumab and dual ICIs. This comparative study provides insight into the incidence of IRRs with ICI regimens. These results are useful in assessing which systemic therapies are responsible for IRRs, particularly when ICIs are combined with other agents. [Table: see text]

Early circulating tumor DNA (ctDNA) changes during treatment with immune checkpoint inhibitors (ICI) as a predictor of clinical outcomes in patients (pts) with advanced stage melanoma/skin cancer.

225 Background: ctDNA monitoring has shown promising results in predicting relapse in resected solid tumors. Its role in treatment response assessment and predicting survival outcomes in the unresectable or metastatic disease setting merits further investigation. In our study, we attempt to assess the role of early ctDNA changes in predicting disease response, progression, and overall survival outcomes in pts with advanced stage melanoma/skin cancer treated with ICI therapy. Methods: A retrospective analysis using a personalized, tumor-informed ctDNA assay (Natera) on prospectively collected plasma samples from pts with unresectable stage III/IV melanoma/skin cancer treated with anti-PD-1 based therapy at the University of Wisconsin (Madison) was performed. Baseline ctDNA levels were assessed prior to the start of treatment and at 3-4 weeks (i.e. prior to the second treatment dose). A logistic regression model was used to evaluate the odds of overall disease control [complete response + partial response + stable disease, per RECIST version 1.1] based on the change in ctDNA levels (decrease vs increase) between both time points. Cox proportional hazard models were used to investigate the effects of ctDNA level change on progression free survival (PFS) and overall survival (OS). Results: 46 pts were evaluated. 82% melanoma, 14% Merkel cell carcinoma, 2% skin adenocarcinoma and 2% squamous cell carcinoma. 77% were treated with dual ICI (anti-PD-1 based) therapy and 23% with anti-PD-1 monotherapy. Median follow up was 12.1 months. Median change in ctDNA levels from baseline were -4.83 MTM/mL among pts with ctDNA decrease and +37.39 MTM/mL among pts with ctDNA increase. A qualitative decrease in ctDNA level was associated with overall disease control (OR 65.00, 95% CI 11.88-587.89, p&lt;0.0001), longer PFS (HR 0.08, 95% CI 0.03-0.22, p&lt;0.0001), and longer OS (HR 0.17, 95% CI 0.05-0.54, p=0.0008) compared to an increase in ctDNA level from baseline to 3-4 weeks after starting ICI therapy. Median PFS was not reached (NR) and 1.63 months; and median OS was NR and 5.57 months among pts with ctDNA decrease and ctDNA increase, respectively. Conclusions: We found that early ctDNA dynamics after 3-4 weeks of ICI initiation in pts with advanced melanoma/skin cancer appears to be a candidate strategy to predict treatment response, risk of progression, and potentially long-term survival. Larger prospective studies are warranted to validate the utility of ctDNA in treatment monitoring.

Comparative analysis of dual immune checkpoint inhibitor combination therapy versus immune checkpoint inhibitor plus tyrosine kinase inhibitor combination therapy for renal cell carcinoma with inferior vena cava tumor thrombosis.

Whether immune checkpoint inhibitor (ICI) plus ICI combination therapy or ICI plus tyrosine kinase inhibitor (TKI) combination therapy is useful for renal cell carcinoma (RCC) with inferior vena cava tumor thrombosis (IVCTT) remains unclear. We retrospectively evaluated the therapeutic effects and incidence of treatment-related adverse events (TRAEs) associated with ICI-based combination therapy in 36 patients with advanced RCC with IVCTT. The median age at initiation of treatment was 71years; the IVCTT stages were cT3b in 22 patients and cT3c in 14. The ICI-ICI and ICI-TKI groups comprised 15 and 21 patients, respectively. Median tumor shrinkage at the best response showed that the primary tumor diameter decreased by 1.8cm (22%), and the IVCTT height decreased by 1.5cm (26%). A higher proportion of patients in the ICI-TKI group experienced tumor shrinkage than those in the ICI-ICI group (primary tumor, p = 0.0325; IVCTT, p = 0.0112). Approximately 27% of patients experienced an increase in the IVCTT height with ICI-ICI combination therapy. No significant difference was observed in the relative tumor shrinkage of IVCTT, primary or level-down staging of IVCTT, other treatment effects, incidence of TRAEs, surgical outcomes, or prognosis between the groups. ICI-based combination therapy is effective against IVCTT and primary RCC. Although ICI-ICI is associated with a higher probability of tumor growth compared with ICI-TKI in the frequency of tumor regression, both therapies may be almost equally effective against primary RCC with IVCTT.

59 Risk Factors of Immune Related Adverse Events in Patients with Metastatic Renal Cell Carcinoma Treated with Immune Checkpoint Inhibitors

Abstract Background Immune checkpoint inhibitor (ICI) based combinations have become the standard of care for first-line treatment in patients with metastatic renal cell carcinoma (mRCC). However, ICI can be responsible for immune-related adverse events (irAEs). Herein, we aimed to identify risk factors of immune related adverse events (irAEs) in patients treated with current first line (1L) combination of ICIs (ICI+ICI) or ICI with vascular endothelial growth factor (VEGF) targeted therapy (ICI+VEGF). Methods Data was collected retrospectively from patients treated for mRCC at Dana-Farber Cancer Institute, either receiving dual ICI or ICI+VEGF as 1L treatment regimen. Patients were categorized into two groups: those who developed grade ≥ 2 irAEs and those with grade 1 or no AEs. Time to toxicity (TT) was defined as the primary outcome. Univariate Cox regression analysis was initially conducted to identify potential predictive factors associated with irAEs. Subsequently, significant variables related to treatment adverse events were included in a multivariate Cox regression analysis with adjustments for multiple baseline factors. Results Among the 158 patients included, 122 (77.2%) were male, and 36 (22.8%) were female. Median age of patients at the treatment start date of therapy was 61 years (Q1-Q3: 62-69). A total of 57 (36.1%) patients developed grade ≥ 2 irAEs. The median follow-up of patients was 25.7 months. Univariate analysis showed that diabetes, male sex, and ccRCC may indeed influence the development of irAEs with a trend towards significance. However, thrombocytosis could be a protective factor against developing irAEs (p &amp;lt;0.05, Table). Upon multivariate analysis, only ccRCC remained significant as a risk factor for irAEs compared to other subtypes, with a HR of 2.93 (95% CI:1.05-8.18, p = 0.04) (Table). Table: Cox regression analysis for assessment of risk factors associated with irAEs Conclusions In this real-world study, we investigated potential clinical risk factors at baseline related to irAEs in patients with mRCC undergoing ICI-combination therapy. ccRCC histology was significantly associated with a higher risk of developing irAEs compared to other RCC subtypes. The retrospective design and the number of patients could be potential limitations of our findings.

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.

Diaphragmatic Myopathy Associated with Dual Immune Checkpoint Inhibitors in a Patient with Renal Cell Carcinoma

ABSTRACT Immune-related adverse events (irAEs) have become increasingly prevalent with immune checkpoint inhibitor (ICI) cancer treatment. We present a 79-year-old man with metastatic renal cell carcinoma who developed shortness of breath and hypercapnic respiratory insufficiency after his first cycle of nivolumab and ipilimumab. Laboratory data showed elevated creatinine kinase, troponins, and transaminases. Computed tomography of the chest demonstrated bilateral lower lobe atelectasis. Heart catheterization and endomyocardial biopsy were unremarkable. Electromyogram (EMG) and nerve conduction studies (NCS) of the limb muscles revealed mild diffuse myopathy, normal sensory nerve conductions, and low-amplitude motor responses. Subsequent diaphragmatic EMG and NCS demonstrated severe myopathy. ICI-mediated myopathy predominantly affecting diaphragmatic muscles was diagnosed. Treatment included intravenous methylprednisolone, infliximab, abatacept, rituximab, and plasmapheresis. He underwent tracheostomy placement on hospital day 11 due to minimal improvement. He was discharged to a long-term acute care hospital, but unfortunately, he died less than 1 month later due to recurrent infections. irAEs can affect any organ system, but diaphragmatic dysfunction is uncommon. Use of diaphragmatic EMG, NCS, ultrasound study, or biopsy can support the diagnosis. Treatment includes systemic steroids, plasmapheresis, immunosuppressive medications, respiratory support, and cessation of causative medications. ICI-related diaphragmatic dysfunction should be suspected in those patients at risk with hypoxia, hypercapnia, or prolonged invasive or noninvasive ventilation without a distinct etiology. This case report exemplifies the importance of multidisciplinary workup and management of respiratory symptoms and insufficiency to identify and ameliorate irAEs. Diaphragmatic involvement can be associated with significant morbidity and mortality despite early aggressive multimodal therapy.

Dual immune checkpoint inhibition with nivolumab and ipilimumab (N+I) in patients with advanced anaplastic thyroid carcinoma (ATC).

e18075 Background: There are no standard of care therapies in advanced incurable setting for BRAF wild type (WT) ATC, &amp; after dabrafenib and trametinib (D+T) for BRAF V600E mutant ATC. We previously showed promising clinical activity of dual inhibition with N+I in exploratory cohort of 10 patients (pts) with advanced ATC in a single arm phase II clinical trial, with objective response rate (ORR) of 30% (NCT03246958, Lorch ASCO 2020). Here, we present efficacy and safety outcomes from a real-world cohort of pts with advanced ATC treated with N+I regimen. Methods: We conducted a retrospective cohort study of pts with advanced ATC (unresectable or with distant metastases, DM) who were seen at the Dana-Farber Cancer Institute (DFCI) thyroid cancer center from July 2021 to Jan 2024, received at least one dose of N+I with palliative intent &amp; completed at least one response assessment (data cutoff, 1/31/24). Pts on the DFCI clinical trial were not included. Investigator-assessed ORR (for the first N+I based treatment regimen) and immune-related adverse events (irAEs, collected till cutoff regardless of ongoing treatment) were evaluated. Results: 19 pts with advanced ATC (5: unresectable disease, 14: DM) were included, BRAF WT 12/19 (63%). Median age was 70y (range, 34-81), 68% female. ECOG PS at start was 0-1 in 14/19 (74%), 2 in 4 (21%) &amp; 3 in 1 (5%) pts. 5/19 (26%) pts received N+I concurrently with D+T; 4/5 (80%) in 2nd line after either mixed response or progressive disease (PD) on D+T. Best overall response (BOR) in N+I+D+T group was partial response (PR, 1/5, 20%) &amp; stable disease (SD, 4/5, 80%); ORR 20%. 14/19 (74%) pts received N+I, 12/14 (86%) as 1st line palliative therapy. 5 pts in N+I group (all with DM) received local therapies concurrently (1: debulking thyroid surgery, 3: radiation therapy (RT) to thyroid, &amp; 1: palliative RT to bone DM). BOR in N+I group were: complete response, CR (4/14, 28.6%); PR (3, 21.4%); SD (4, 28.6%); &amp; PD (3, 21.4%); ORR 50%. Excluding 5 pts with concurrent local therapies, ORR was 33.3% (1/9 CR, 2/9 PR).PD-L1 TPS was available for 12/19 pts (4: N+I+D+T, 8: N+I) and ≥1 in all tumors (range, 1-100). In 8 pts in N+I group, ORR stratified by PD-L1 TPS: TPS &lt;50 (range, 1-30): 0% (0/2: 1 SD, 1 PD), &amp; TPS ≥50 (range, 80-100): 83.3% (5/6: 3 CR, 2 PR, 1 PD). Any grade irAEs were observed in 16/19 (84.2%) pts. ≥Grade 3 irAEs occurred in 11/19 (57.9%) pts, most frequent were colitis (5, 26.3%), dermatitis/pruritus (3, 15.8%), myocarditis (2, 10.5%), &amp; adrenal insufficiency (2, 10.5%). There were no treatment-related deaths. Conclusions: In this largest real-world cohort study of pts with advanced ATC, N+I therapy showed high ORR of 50% (congruent with DFCI trial), albeit with high rates of iRAEs. High ORR was seen with PD-L1 TPS ≥50. Survival outcomes and genomic biomarkers, currently under investigation, will be presented at the meeting. N+I merit further investigation in an ATC focused clinical trial.

Investigation of cardiotoxicity with concomitant use of anthracyclines and checkpoint inhibitors.

e24022 Background: Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment and currently are the standard of care for early stage triple negative breast cancer in combination with anthracyclines (AC). It is known that both ICI and AC carry risk of cardiotoxicity. Studies have also shown that there is increased risk of cardiotoxicity with dual ICI. However no studies have evaluated the risk with concomitant use of ICI and AC. Here we investigated if there is increased cardiotoxicity risk with this combination regimen in a retrospective study. Methods: We did a retrospective analysis of patients with stage II and stage III triple negative breast cancer treated with combined AC and ICI at University of South Alabama Mitchell Cancer Institute Mobile, AL from January 2020 until June 2023. Data included demographics, cardiovascular (CV) risk factors and treatment. CV risk factors were detailed from 2022 ASCO guidelines. Echocardiograms were used to evaluate left ventricular ejection (LVEF). Therapy related cardiovascular toxicity was defined by ESC guidelines 2022 as any new decrease in LVEF to &lt; 40% or any decrease in LVEF &lt; 50% and 10 percentage points decrease from baseline. Adverse events (AE) and risk analysis were calculated. Results: Of the total 49 patients, all were female with a mean age of 53 years old (30-82). 55% of patients had less than 2 CV risk factors (n = 27) and 45% had more than 2 (n = 22). 84% completed all 4 cycles of neoadjuvant AC course without dose adjustment. The median number of cycles of Pembrolizumab was 12 with a range of 7 to 17 cycles including adjuvant Pembrolizumab. All patients had a baseline echo with LVEF &gt; 55%. Two patients (0.04%) developed cardiotoxicity. One patient had LVEF that decreased to EF 45-50% while on surveillance. Another patient developed myocarditis during treatment with EF 25-30% and died from cardiogenic shock. Both patients had 2 CV risk factors and were African American. Only 24% (n = 12) had surveillance echocardiograms completed one year post treatment. Conclusions: Our study results showed that cardiotoxicity risk was lower compared to that in the Keynote-522 trial. The outcomes are limited as a majority (76%) of the patients did not have surveillance echos completed. While the risk of cardiotoxicity with ICI and AC have been studied independently, there have been mouse models that showed that AC therapy may make heart vulnerable to toxicity from ICI therapy. To our knowledge, this is the first study to evaluate cardiotoxicity in patients who received concomitant AC and ICI treatment. Our study highlights the importance of prospective studies and long term follow up to monitor cardiotoxicity in these patients as early detection is key to prevent future morbidity. [Table: see text]

Predictive Impact of Tumor Mutational Burden on Real-World Outcomes of First-Line Immune Checkpoint Inhibition in Metastatic Melanoma.

The choice of threshold and reliability of high tumor mutational burden (TMB) to predict outcomes and guide treatment choice for patients with metastatic melanoma receiving first-line immune checkpoint inhibitor (ICI) therapy in the real world is not well known. Using a deidentified nationwide (US-based) melanoma clinicogenomic database, we identified a real-world cohort of patients with metastatic melanoma (N = 497) who received first-line monotherapy anti-PD-1 (n = 240) or dual anti-PD-1 and anti-CTLA-4 ICI (n = 257) and had a tissue-based comprehensive genomic profiling test TMB score. TMB-high (TMB-H; ≥10 mutations per megabase [muts/Mb], n = 352, 71%) was independently predictive of superior real-world progression-free survival and overall survival versus TMB-low (<10 mut/Mb, n = 145, 29%) in both mono ICI (hazard ratio [HR], 0.45 [95% CI, 0.32 to 0.63]; P < .001; HR, 0.61 [95% CI, 0.41 to 0.90]; P = .01, respectively) and dual ICI (HR, 0.67 [95% CI, 0.49 to 0.90]; P = .009; HR, 0.61 [95% CI, 0.42 to 0.88]; P = .007, respectively) patients. Dual ICI offered no significant advantage in BRAFwt patients and unexpectedly demonstrated greatest benefit in the TMB 10-19 mut/Mb group, identifying a TMB-very high (≥20 mut/Mb, n = 247, 50%) BRAFmut patient subgroup for whom mono ICI may be preferable. TMB-H predicts superior outcomes on ICI while coassessment of BRAF status and TMB may inform first-line regimen choice.