Checkpoint Inhibitor Therapy In Patients Research Articles

CTIM-04. MODULATION OF THE INTRATUMORAL IMMUNE MICROENVIRONMENT BY LOCAL THERAPY WITH NATURAL KILLER CELLS ENGINEERED WITH A HER2-TARGETED CHIMERIC ANTIGEN RECEPTOR IN COMBINATION WITH SYSTEMIC ANTI-PD-1 CHECKPOINT INHIBITION IN PATIENTS WITH RECURRENT GLIOBLASTOMA

Abstract Glioblastoma (GB) is characterized by a marked immunosuppressive tumor microenvironment. In the multicenter CAR2BRAIN phase I first-in-human clinical trial, we investigated the modulation of the tumor microenvironment by repetitive local injection of clonal chimeric antigen receptor (CAR)-NK cells (NK-92/5.28.z) targeting HER2 alone and in combination with systemic anti-PD-1 checkpoint inhibitor therapy in patients with recurrent HER2-positive GB. 6 patients were treated with repetitive doses of CAR-NK cells as monotherapy and 12 patients received a combination therapy with the anti-PD-1 checkpoint inhibitor ezabenlimab. In three of those, we were able to implement a biopsy-treat-resect-treat strategy. After initial biopsy, combination treatment was initiated before planned tumor resection, enabling analysis of the transformation of the tumor immune microenvironment by highplex multispectral fluorescent analyses and cytokine quantification. None of the patients developed a cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. Profound alterations of the immune cell distribution in the cerebrospinal fluid (CSF) and in the tumor were observed. In CSF sampled from the resection cavity, combination immunotherapy induced a local immune response with elevated pro-inflammatory cytokines and cell counts. In post-treatment tissue samples, we observed an increase of CD4+ and CD8+ T cells, and a decrease of regulatory CD4+FoxP3+ T cells. The three patients treated following the biopsy-treat-resect-treat strategy achieved a median progression-free survival (PFS) of 24 weeks, compared to 10 weeks for patients with upfront resection. Local immunotherapy with HER2-targeted CAR-NK cells is feasible and safe both as monotherapy and in combination with the systemic checkpoint inhibitor ezabenlimab and induces local immune reactions in CSF and tumor tissue. Given the signal for possible clinical benefit provided by the increase in PFS in the patients of the biopsy-treat-resect-treat cohort, further trials are warranted.

P259 The impact of concomitant medication on the efficacy of immune checkpoint inhibitor therapy in patients with urothelial carcinoma

P259 The impact of concomitant medication on the efficacy of immune checkpoint inhibitor therapy in patients with urothelial carcinoma

1389P Safety and effectiveness of immune checkpoint inhibitor therapy in patients with lung cancer and pre-existing autoimmune disease

1389P Safety and effectiveness of immune checkpoint inhibitor therapy in patients with lung cancer and pre-existing autoimmune disease

DCE-CT parameters as new functional imaging biomarkers at baseline and during immune checkpoint inhibitor therapy in patients with lung cancer – a feasibility study

BackgroundWith the development of immune checkpoint inhibitors for the treatment of non-small cell lung cancer, the need for new functional imaging techniques and early response assessments has increased to account for new response patterns and the high cost of treatment. The present study was designed to assess the prognostic impact of dynamic contrast-enhanced computed tomography (DCE-CT) on survival outcomes in non-small cell lung cancer patients treated with immune checkpoint inhibitors.MethodsThirty-three patients with inoperable non-small-cell lung cancer treated with immune checkpoint inhibitors were prospectively enrolled for DCE-CT as part of their follow-up. A single target lesion at baseline and subsequent follow-up examinations were enclosed in the DCE-CT. Blood volume deconvolution (BVdecon), blood flow deconvolution (BFdecon), blood flow maximum slope (BFMax slope) and permeability were assessed using overall survival (OS) and progression-free survival (PFS) as endpoints in Kaplan Meier and Cox regression analyses.ResultsHigh baseline Blood Volume (BVdecon) (> 12.97 ml × 100 g−1) was associated with a favorable OS (26.7 vs 7.9 months; p = 0.050) and PFS (14.6 vs 2.5 months; p = 0.050). At early follow-up on day seven a higher relative increase in BFdecon (> 24.50% for OS and > 12.04% for PFS) was associated with an unfavorable OS (8.7 months vs 23.1 months; p < 0.025) and PFS (2.5 vs 13.7 months; p < 0.018). The relative change in BFdecon (categorical) on day seven was a predictor of OS (HR 0.26, CI95: 0.06 to 0.93 p = 0.039) and PFS (HR 0.27, CI95: 0.09 to 0.85 p = 0.026).ConclusionDCE-CT-identified parameters may serve as potential prognostic biomarkers at baseline and during early treatment in patients with NSCLC treated with immune checkpoint inhibitor therapy.

Multiple immune-related adverse events secondary to checkpoint inhibitor therapy in patients with advanced cancer: association with treatment effectiveness.

Checkpoint inhibitors (CPI) are widely used in cancer treatment with a potential of causing immune-related adverse events (IRAEs). Several studies have reported a positive correlation between development of IRAEs and improved survival outcome. However, few studies have focused on the potential role of multiple IRAEs on treatment effectiveness. This study aimed at investigating the association between multiple IRAEs and treatment effectiveness in terms of progression-free survival (PFS) and overall survival (OS) in advanced cancer patients. We performed a retrospective cohort study at three Swedish centers. All patients (n=600) treated with PD-L1 or PD-1 inhibitor, in monotherapy or in combination for advanced cancer between January 2017 and December 2021 were included. Multiple IRAEs were defined as IRAEs involving more than one organ system either simultaneously or sequentially. Time-depending Cox-regression model to mitigate the risk for immortal time bias (ITB) was applied. The major tumor types were non-small cell lung cancer (205 patients; 34.2%) and malignant melanoma (196 patients; 32.7%). Of all patients,32.8% developed single IRAE and 16.2% multiple IRAEs. Patients with multiple IRAEs showed significantly improved PFS (Hazard Ratio, HR=0.78 95% Confidence Interval, CI: 0.57-0.98) and OS (HR=0.65 95% CI: 0.44-0.95) compared to patients with single IRAE or no IRAE (HR=0.46 95% CI:0.34-0.62 for PFS vs HR=0.41 95% CI: 0.28-0.60 for OS). In conclusion, our data supports a stronger association between development of multiple as opposed to single IRAEs and clinical effectiveness in advanced cancer patients treated with CPIs.

Intrapatient variation in PD-L1 expression and tumor mutational burden and the impact on outcomes to immune checkpoint inhibitor therapy in patients with non-small-cell lung cancer

Programmed death receptor ligand 1 (PD-L1) tumor proportion score (TPS) and tumor mutational burden (TMB) are key predictive biomarkers for immune checkpoint inhibitor (ICI) efficacy in non-small-cell lung cancer (NSCLC). Data on their variation across multiple samples are limited. Patients with NSCLC and multiple PD-L1 TPS and/or TMB assessments were included. Clinicopathologic and genomic data were analyzed according to PD-L1 and TMB variation. In total, 402 PD-L1 sample pairs and 413 TMB sample pairs were included. Concordance between pairs was moderate for PD-L1 (ρ= 0.53, P < 0.0001) and high for TMB (ρ= 0.80, P < 0.0001). Shorter time between biopsies correlated with higher concordance in PD-L1, but not in TMB. Major increases (ΔTPS ≥+50%) and decreases (ΔTPS ≤-50%) in PD-L1 were observed in 9.7% and 8.0% of cases, respectively. PD-L1, but not TMB, decreased with intervening ICI (P= 0.02). Acquired copy number loss of CD274, PDCD1LG2, and JAK2 were associated with major decrease in PD-L1 (q < 0.05). Among patients with multiple PD-L1 assessments before ICI, cases where all samples had a PD-L1 ≥1%, compared to cases with at least one sample with PD-L1 <1% and another with PD-L1 ≥1%, achieved improved objective response rate and progression-free survival (PFS). Among patients with at least one PD-L1 <1% and one ≥1% before ICI, cases where the most proximal sample was PD-L1 ≥1% had longer median PFS compared to cases where the most proximal PD-L1 was <1%. Among patients with multiple TMB assessments before ICI, patients with a TMB ≥10 mut/Mb based on the most recent assessment, as compared to those with a TMB <10 mut/Mb, achieved improved PFS and overall survival to ICI; instead, no differences were observed when patients were categorized using the oldest TMB assessment. Despite intrapatient concordance in PD-L1 and TMB, variation in these biomarkers can influence ICI outcomes, warranting consideration for reassessment before ICI initiation when feasible.

Immune checkpoint inhibitor therapy in patients with cancer and pre-existing systemic sclerosis

ObjectiveImmune checkpoint inhibitor (ICI) therapies have dramatically improved outcomes in multiple cancers. ICI's mechanism of action involves immune system activation to augment anti-tumor immunity. Patients with pre-existing autoimmune diseases, such as systemic sclerosis (SSc), were excluded from initial ICI clinical trials due to concern that such immune system activation could precipitate an autoimmune disease flare or new, severe immune related adverse events (irAE). In the present study, we report our experience with ICIs in patients with pre-existing SSc. MethodsPatients with SSc who received ICI therapy for cancer were identified from the Johns Hopkins Scleroderma Center Research Registry. Through chart review and prespecified definitions, we identified whether patients experienced worsening SSc activity or new irAEs. SSc disease activity worsening was pre-defined as an increase in modified Rodnan skin score (mRSS), new scleroderma renal crisis, progression of interstitial lung disease (ILD) on CT scan, increased Raynaud's phenomenon frequency or severity, new pulmonary hypertension, or myositis flare. IrAEs also included active inflammatory arthritis and dermatitis. ResultsEight patients with SSc who received ICI therapy for cancer were included. Overall, SSc symptoms remained stable during and after ICI therapy. None of the patients with long-standing sine or limited cutaneous SSc (lcSSc) had progressive skin thickening after ICI therapy. One patient, who was early in his diffuse cutaneous SSc (dcSSc) disease course, experienced worsening skin thickening and renal crisis. Three patients (38 %) experienced a total of five irAEs (grade 2: diarrhea, mucositis and dermatitis; grade 3: pneumonitis, and grade 4: nephritis). The patient with grade 4 nephritis developed scleroderma renal crisis and immune checkpoint related nephritis simultaneously. There were no deaths due to irAEs. ConclusionIn this study, ICI therapy was well tolerated in patients with longstanding, sine or lcSSc. IrAE were common but generally manageable. Patients with early, active SSc may be at greater risk from ICI therapy, but more research is needed.

Abstract CT245: Circulating tumor DNA and nivolumab maintenance: A pilot study in diffuse large B cell lymphoma

Abstract Introduction: Molecular minimal residual disease (MRD) status correlates with disease relapse in patients (pts) with diffuse large B cell lymphoma (DLBCL). However, the clinical impact of early treatment intervention a time of detectable MRD (dMRD) prior to clinical relapse is unknown. Checkpoint inhibitor (CPI) therapy has activity in some pts with DLBCL. We hypothesized that early CPI therapy in patients with dMRD without clinical relapse may lower relapse rate. We conducted a pilot study in high risk pts in remission after most recent line of therapy (LOT) in whom maintenance nivolumab (MN) was offered at time of dMRD to assess effect on MRD clearance and relapse rate. Methods: Pts &amp;gt;18 years (yrs) with high-risk DLBCL (ABC-subtype, high grade B cell lymphoma (HGBCL), MYC translocation, relapsed/refractory disease, or Ki67 &amp;gt;90%) who had achieved CR on most recent LOT were eligible. Patients were monitored for detectable MRD (dMRD) based on the clonoSEQ assay for circulating tumor DNA (ctDNA). Pts had monthly MRD assessment and every 4 month imaging for 2 yrs. If conversion from uMRD to dMRD without clinical relapse, pts received MN (240 mg IV q2 weeks) for up 2 yrs. Pts with overt relapse at time of dMRD or dMRD at initial MRD assessment were ineligible for MN. The primary endpoint was rate of conversion from dMRD to undetectable MRD (uMRD). Results: 20 pts were screened and 15 pts enrolled between June 2018 and March 2022. 4 had transformed DLBCL (2 from FL, 1 from MZL, and 1 Richter’s transformation from CLL), 2 pts had HGBCL (one of which was also transformed). All pts with dMRD had radiographic relapse within 4 months of molecular relapse. No pts with uMRD by ctDNA had clinical relapse on study during 2 yrs follow up. Of the 8 pts who enrolled after first LOT, none had molecular or clinical relapse. Of the 7 pts with 2+ prior LOT, 3 had dMRD: two had clinical relapse at same time as dMRD and were taken off study (one had dMRD at baseline MRD assessment and the other 135 days post enrollment after initial period of uMRD). In the single patient eligible for MN, dMRD preceded radiographic relapse by 105 days, 410 days after enrollment. The pt received 2 cycles of MN before clinical progression and was taken off study. This pt failed to achieve conversion of dMRD to uMRD. Conclusion: Due to small sample size and lower than expected relapse, we were unable to demonstrate conversion of dMRD to uMRD using MN. However, this pilot study did confirm high correlation of uMRD and dMRD status with disease free survival and clinical relapse within 4 months, respectively. If strong negative predictive value is confirmed in a larger study, ctDNA MRD testing may be used to spare pts from imaging or to guide additional work up in pts with inconclusive findings on scans. Citation Format: Shazia Nakhoda, Tamarrah Sklarz, Cheyenne Pagan, Matthew Matasar, Zachary A. Frosch, Marcus Messmer, Asya Varshavsky Yanovsky, Rashmi Khanal, Carlyn Tan, Eli Mikkelsen, Henry Fung, Eric Ross, Mark Roschewski, Allison Jacob, Nadia Khan. Circulating tumor DNA and nivolumab maintenance: A pilot study in diffuse large B cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT245.

Atrial and ventricular arrhythmias with immune checkpoint inhibitor therapy in patients without evidence of myocarditis

Abstract Background Immune checkpoint inhibitor (ICI) therapy has improved the prognosis of many cancer types. Immune-related adverse events (irAEs) are common and recent studies suggest ICI therapy may be associated with an increased risk of arrhythmias. However, data on arrhythmias after ICI therapy has been limited by small sample sizes, the inclusion of patients with ICI myocarditis, or an incomplete characterization of the factors that drive arrhythmias with an ICI. Purpose This study aimed to characterize the association between ICIs and arrhythmias in patients without evidence of myocarditis. Methods We conducted a hospital network-wide retrospective cohort study on all patients treated with ICI who were free from arrhythmias at the start of ICI therapy, and had no evidence of immune-related myocarditis. We used a historical pre-ICI therapy era cohort of cancer patients of similar age and tumor types, diagnosed between 2008-2012. The main study outcome was the incidence of atrial fibrillation, atrial flutter, supraventricular tachycardia, and ventricular tachycardia after ICI therapy. International Classification of Diseases 9th and 10th edition codes were used to ascertain baseline characteristics and to detect the study outcomes. Myocarditis cases were identified through the application of natural language processing techniques to electronic health records. Patients on ICI therapy and controls were followed from the start of ICI therapy, and from the first visit after 2008, respectively, up to three years after the index date. Results The study population consisted of 7441 patients on ICI therapy and 2311 controls. Patients on ICI therapy were older (65±13 vs. 63±13 years, p&amp;lt;0.001) and more frequently had arterial hypertension (52% vs. 47%, p&amp;lt;0.001), but had lower rates of prior congestive heart failure (6% vs. 11%, p&amp;lt;0.001). Over a median follow-up period of 36 months, 9.8% on ICI therapy were diagnosed with any incident atrial or ventricular arrhythmia, compared to 7.1% in the control group (p&amp;lt;0.001) with corresponding incidence rates of 4.4 and 2.3 cases per 100 person-years, respectively (Fig. 1). When correcting for age, sex, cancer type, prior congestive heart failure, and cardiovascular risk factors, patients on ICI therapy had a higher risk of a composite outcome of any arrhythmia (hazard ratio [HR] 1.68, 95% confidence interval [CI]: 1.39-2.04, p&amp;lt;0.001), atrial fibrillation (HR 1.29, 95%CI: 1.02-1.63, p=0.034) and ventricular tachycardia (HR 2.01, 95%CI: 1.34-3.04, p&amp;lt;0.001). In a multivariable logistic regression model, the occurrence of a non-cardiovascular irAE was a predictor of an incident arrhythmia (odds ratio 1.81, 95%CI: 1.56-2.23, p&amp;lt;0.001). Conclusion This study, to the best of our knowledge, is the largest to report on ICI therapy-related arrhythmias and the first to show the occurrence of non-cardiovascular irAEs as a predictor of arrhythmia risk in patients on ICI therapy without evidence of myocarditis.Fig. 1

FRI553 ICI-induced Thyroid Ophthalmopathy With De Novo Graves’ Disease

Abstract Disclosure: S.I. Moctezuma: None. J. Perlman: None. J.S. Mammen: None. Background: Immune checkpoint inhibitors frequently target the thyroid gland. However, immune checkpoint inhibitor (ICI)-induced Graves’ disease (GD) is rare. To our knowledge, there are no reported cases of thyroid eye disease after immune checkpoint inhibitor therapy in patients with newly positive anti-thyroid antibodies. Clinical Case: An 81-year-old man developed thyroiditis within three weeks of a single dose of ipilimumab/nivolumab for the treatment of metastatic cholangiocarcinoma. ICI therapy was discontinued for cardiotoxicity. He presented one year later with onset of periorbital edema, pain with downgaze, redness, irritation and progressive proptosis with diplopia. He did not have a prior history of thyroid disease. Thyroid function tests before the start of ICI therapy revealed euthyroidism [TSH 2.982 uIU/mL (0.55 - 4.78)]. Symptoms of palpitations, weight loss, and hyper-defecation that characterized his initial presentation with thyroiditis were absent at the time of onset of eye disease. At presentation of thyrotoxicosis his TSH was &amp;lt;0.01 uIU/mL, free T4 3.6 ng/dL (0.89 - 1.76) total T3 190 ng/dL (60-180) Thyroid-peroxidase autoantibodies (TPOAb) and thyroid-stimulating immunoglobulin (TSI) were negative. When his visual symptoms appeared, TPOAb remained negative while a repeat TSI antibody was positive [0.64 IU/L (0.00 - 0.55)]. Thyroid ultrasound at the time of thyroiditis revealed a heterogeneous gland without discrete nodules and a normal vascular flow. Most cases of ICI-induced GD have been reported at the start of therapy, particularly in the first 6 weeks, although thyrotoxicosis has been described to occur as late as 224 days after starting PD-1 inhibitor. GD is more frequently reported with combination anti-CTLA-4 and anti-PD-1 therapy. Patients with thyroid ICI-induced adverse events experience either isolated hypothyroidism or thyroiditis spontaneously evolving towards hypothyroidism. However, ICI-induced GD is more likely to have a relapsing-remitting disease. In 2021, Peiffert et al. described the antibody profile for 243 patients with ICI-induced thyrotoxicosis. In this case series, 5 patients developed thyrotoxicosis with positive thyrotropin-receptor antibodies (TRAb). Only 2 patients had a typical clinical presentation of GD. TSI antibodies were not reported. Furthermore, none of the patients with positive TRAb had Graves’ ophthalmopathy. Conclusion: Our case demonstrates the acquisition of auto-antibodies capable of mediating Graves’ disease, and raises the possibility that thyroid eye disease-like orbital inflammation may occur as a side effect of immune checkpoint inhibitor therapy. These symptoms developed as late as one year after initiation of therapy. As with sporadic cases, this can occur in the absence of clinically significant hyperthyroidism. Presentation: Friday, June 16, 2023

2198P Clinicopathologic characteristics and outcomes to immune checkpoint inhibitor therapy in patients with HER2-altered metastatic non-small cell lung cancer

2198P Clinicopathologic characteristics and outcomes to immune checkpoint inhibitor therapy in patients with HER2-altered metastatic non-small cell lung cancer

Supervised clustering of peripheral immune cells associated with clinical response to checkpoint inhibitor therapy in patients with advanced melanoma

Immune therapy with checkpoint inhibitors (CPIs) is a highly successful therapy in many cancers including metastatic melanoma. Still, many patients do not respond well to therapy and there are no blood-borne biomarkers available to assess the clinical outcome. To investigate cellular changes after CPI therapy, we carried out flow cytometry-based immune monitoring in a cohort of 90 metastatic melanoma patients before and after CPI therapy using the FlowSOM algorithm. To evaluate associations to the clinical outcome with therapy, we divided the patients based on progression-free survival. We found significant associations with CPI therapy in both peripheral blood mononuclear cell and T-cell subsets, but with the most pronounced effects in the latter. Particularly CD4+ effector memory T-cell subsets were associated with response with a positive correlation between CD27+HLA-DR+CD4+ effector memory T cells in a univariate (odds ratio: 1.07 [95% confidence interval 1.02-1.12]) and multivariate regression model (odds ratio: 1.08 [95% confidence interval 1.03-1.14]). We also found a trend towards stronger accumulation of CD57+CD8+ T cells in non-responding patients. Our results show significant associations between immune monitoring and clinical outcome of therapy that could be evaluated as biomarkers in a clinical setting.

Peripheral CD4 memory T cells predict the efficacy of immune checkpoint inhibitor therapy in patients with non-small cell lung cancer

Immune checkpoint inhibitors have significantly improved the prognosis in patients with non-small cell lung cancer, compared with cytotoxic agents. However, the prediction of treatment response is often difficult, even after assessing the tumor programmed death-ligand 1 expression. We conducted this observational study to analyze the association between the differentiation of peripheral CD4 + T cells and the efficacy of immune checkpoint inhibitor therapy. We enrolled patients who were diagnosed with non-small cell lung cancer and received immune checkpoint inhibitor therapy between 2020 and 2022. Blood samples were collected at the start of immune checkpoint inhibitor therapy, and the expressions of PD-1, CCR7, and CD45RA in peripheral CD4 + T cells were analyzed by flow cytometry. The association between the findings of flow cytometry and survival after the initiation of the immune checkpoint inhibitor therapy was evaluated. Forty patients with non-small cell lung cancer were enrolled. The Cox proportional hazards model showed that an increased proportion of CD45RA-CD4 + T cells was associated with a reduced risk of progression after adjustment for performance status, tumor programmed death-ligand 1 expression level, mutation status of the epidermal growth factor receptor gene, and combined therapy with cytotoxic agents. The present study showed that the proportion of peripheral CD45RA- CD4 + T cells was associated with progression-free survival after the initiation of immune checkpoint inhibitor therapy, independent of several clinical factors.

Microbiome, socioeconomic status (SES), fiber intake, and response to checkpoint inhibitor therapy in patients with non-small cell lung cancer (NSCLC): A pilot study.

e14710 Background: Lung cancer affects a disproportional number of socioeconomically disadvantaged patients (pts). Responses to checkpoint inhibitor therapy (CIT) vary. Microbiome diversity may correlate with benefit from CIT. High fiber diets lead to microbiome diversity. We hypothesize that unexplained lung cancer disparities may be in part due to differences in microbiome diversity determined by unhealthy dietary patterns dictated by lower SES. Methods: Following IRB review, 25 pts with metastatic NSCLC starting CIT-based treatment were enrolled. Pre-treatment oral and fecal samples were collected. 24-hour dietary recalls were obtained. SES index was calculated based on education, employment, housing and annual income. High fiber intake was defined as &gt; 20 g/day. Best treatment response per RECIST 1.1 was assessed. Microbial 16s rRNA were sequenced with Illumina MiSeq platform. Sequence analyses utilized QIIME 2 with DADA2 plugin. Taxonomic assignments used the Greengenes database. Microbiome composition was analyzed by calculating alpha diversity (Chao1, Shannon diversity and Simpson index), beta diversity and differential abundance of microbial compositions. Hierarchical linear model was constructed for each SES variable with and without biological covariates. Results: Pts with samples &gt;1000 operational taxonomic unit (OTU) levels were included (N = 22) in the analysis. 50% were male, median age was 71, 36% (8/22) were of Black race and 23% (5/22) were of low SES. Median fiber intake was 11.9 grams. Males had higher alpha diversity than females (p=.038). Pts with high fiber intake had greater fecal Proteobacteria compared to low fiber intake pts (p&lt;0.05). Bacteroides and Firmicutes fecal levels were significantly different for all pts compared to Human Microbiome Project (HMP) reported normal levels (p&lt;0.01). Actinobacteria and Proteobacteria levels for low-fiber intake pts were also significantly elevated compared to HMP normal levels (p&lt;0.05). There were no differences observed in microbiome when comparing SES index. However, high SES index patients had elevated fecal levels of Actinobacteria, Firmicutes and Proteobacteria and lower levels of Bacteroides compared to HMP levels. There was a trend towards higher alpha diversity of oral samples in partial responders pts compared to those with stable or progression of the disease (p=0.08). Conclusions: Pts with metastatic NSCLC exhibited different microbial composition compared to HMP normal levels. Associations between SES and microbial distribution in such pts warrant further investigation. Increased sample size is needed to better determine differences in oral microbiome in responders to immunotherapy and better evaluate the role of sex in this setting.

Treatment outcomes and prognosis of immune checkpoint inhibitors therapy in patients with advanced thymic carcinoma: A multicentre retrospective study

BackgroundImmunotherapy has demonstrated good efficacy and survival outcomes in solid tumours. However, efficacy data for immune checkpoint inhibitors (ICIs) in advanced thymic carcinoma are lacking. The present study aimed to assess the activity of ICIs in advanced thymic carcinoma. MethodsA multicentre retrospective study was conducted to explore the efficacy and safety of ICIs for advanced thymic carcinoma. Objective response rate (ORR), progression-free survival (PFS), overall survival, and immune-related adverse events (irAEs) were analysed. In addition, factors independently associated with treatment efficacy and survival outcomes were evaluated. ResultsA total of 77 patients with advanced thymic carcinoma were enrolled between March 2016 and September 2021. The ORR was existing the difference between ICIs monotherapy (n = 23) and ICIs combined with chemotherapy (n = 54) (17.4% versus 44.4%, P = 0.024). The ICIs combination treatments were associated with better median PFS (mPFS) compared to ICIs monotherapy (12.7 months versus 2.1 months, P < 0.001). Notably, liver or brain metastasis was a poor prognostic factor of mPFS (1.8 months versus 3.5 months, P = 0.012) in the ICIs monotherapy group. In addition, mPFS for the first-line treatment (n = 27) was longer than that for ICIs as the second- or posterior-line treatment (n = 50) (P < 0.001). The incidence of irAEs was 54.5% (42/77) in the 77 enrolled patients. The incidence of grade 3–4 irAE was 15.6% (12/77). ConclusionsImmunotherapy is effective in advanced thymic carcinoma, especially for combination with chemotherapy showed promising antitumour activity, which indicates worthy of combination treatment strategy for further study. IrAEs also require close monitoring and management.

Prognostic value of the lung immune prognostic index in patients with untreated advanced renal cell carcinoma (aRCC) receiving nivolumab plus ipilimumab (N+I) or sunitinib (SUN) in the CheckMate 214 trial.

4538 Background: The Lung Immune Prognostic Index (LIPI), defined by lactate dehydrogenase (LDH) and derived neutrophil to lymphocyte ratio (dNLR), has been shown to correlate with outcomes of immune checkpoint inhibitor therapy in patients (pts) with lung and other cancers, including pts with previously treated aRCC receiving nivolumab in the phase 2 NIVOREN GETUG-AFU 26 trial. We report an analysis of LIPI in pts with previously untreated aRCC receiving N+I or SUN in the randomized phase 3 CheckMate 214 trial with 5 years minimum follow-up. Methods: Data were used from CheckMate 214 comparing N+I (N 3 mg/kg + I 1 mg/kg) vs SUN (50 mg) for untreated aRCC (N = 1096). Pts with available LIPI data were categorized into 3 LIPI groups (good [LG], dNLR ≤ 3 and LDH ≤ upper limit of normal [ULN]); intermediate [LI], dNLR &gt; 3 or LDH &gt; ULN; and poor [LP], dNLR &gt; 3 and LDH &gt; ULN). This analysis focused on the prognostic value of LIPI using overall survival (OS) outcomes. Univariable analyses (UVAs) were conducted to evaluate LIPI groups alongside known risk factors including age, sex, IMDC risk, baseline PD-L1 status, prior nephrectomy, and baseline tumor burden. Variables that were statistically significant in UVAs ( P &lt; 0.1) were included in the full multivariable analyses (MVAs), from which a reduced model was generated. Results: A total of 1085 pts were evaluable for LIPI (N+I, n = 542; SUN, n = 543). Pts were distributed evenly between treatment arms for all 3 LIPI groups, but distribution between LIPI groups was unbalanced, with most pts grouped as LG (Table). OS outcomes were improved with N+I over SUN across all LIPI groups. Moreover, pts in the LG group had better OS outcomes vs pts in the LI or LP groups regardless of treatment, but with more distinct differences between LIPI groups in the SUN arm (Table). Final MVA results showed the LIPI correlated with OS for LI vs LG in the N+I arm and for LI vs LG and LP vs LG in the SUN arm (Table). Conclusions: These results from CheckMate 214 indicate the potential prognostic value of the LIPI in pts with untreated aRCC receiving N+I or SUN. Additional analyses are ongoing to further investigate the prognostic value of LIPI in this pt population and its impact on other clinical outcomes. Clinical trial information: NCT02231749. [Table: see text]

Joint-Predominant Rheumatic Complications of Immune Checkpoint Inhibitor Therapy in Patients with Thymic Epithelial Tumors.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced cancers. However, activation of the immune system can occasionally cause life-threatening toxicity involving critical organs. Induction of immune-mediated toxicity is a significant concern for patients with thymic epithelial tumors (TETs) due to defects in immune tolerance. An increased risk of skeletal and cardiac muscle inflammation following treatment with ICIs is well recognized in patients with advanced TETs. However, uncommon musculoskeletal and rheumatic complications can also occur. The cases presented in this report highlight the spectrum of presentation of immune-mediated, joint-predominant musculoskeletal adverse events in patients with advanced TETs treated with ICIs, including polymyalgia rheumatica-like illness and inflammatory arthritis.

Hypersensitivity Reactions to Selpercatinib Treatment With or Without Prior Immune Checkpoint Inhibitor Therapy in Patients With NSCLC in LIBRETTO-001

IntroductionImmune checkpoint inhibitor (ICI) therapy has been found to increase the risk/severity of immune-mediated adverse events with subsequent kinase inhibitor treatment in oncogenically driven cancers. We explored the risk for hypersensitivity with selpercatinib, a first-in-class highly selective and potent, central nervous system-active RET inhibitor, in prior ICI-treated patients with RET fusion-positive NSCLC compared with their ICI-naive counterparts. MethodsData from patients enrolled by December 16, 2019, in the ongoing phase 1/2 LIBRETTO-001 (NCT03157128) trial were analyzed for hypersensitivity reactions reported using preferred terms of hypersensitivity/drug hypersensitivity and defined as a constellation of symptoms/findings characterized by maculopapular rash, often preceded by fever with arthralgias/myalgias, followed by greater than or equal to 1 of the following signs/symptoms: thrombocytopenia, increased aspartate aminotransferase or alanine aminotransferase, hypotension, tachycardia, or increased creatinine. ResultsOf 329 patients, 22 (7%) who experienced a grade 1 to 3 hypersensitivity reaction that met the defined constellation of events were attributed to selpercatinib by investigators, and more often in prior ICI-treated (n = 17, 77%) than ICI-naive (n = 5, 23%) patients. There were 19 patients with selpercatinib-related hypersensitivity who resumed selpercatinib post-hypersensitivity with dose modification/supportive care. Furthermore, 17 patients, of whom 14 received prior ICI therapy, were still on treatment at twice daily doses of 40 mg (n = 5), 80 mg (n = 4), 120 mg (n = 4), and 160 mg (n = 4). ConclusionsRates of selpercatinib-related hypersensitivity were low overall and, as with other kinase inhibitors, occurred predominantly in prior ICI-treated patients. Hypersensitivity to selpercatinib can be managed with supportive care measures regardless of prior ICI status and is reversible.

Representativeness of the Index Lymph Node for Total Nodal Basin in Pathologic Response Assessment After Neoadjuvant Checkpoint Inhibitor Therapy in Patients With Stage III Melanoma

Neoadjuvant checkpoint inhibition in patients with high-risk stage III melanoma shows high pathologic response rates associated with a durable relapse-free survival. Whether a therapeutic lymph node dissection (TLND) can be safely omitted when a major pathologic response in the largest lymph node metastasis at baseline (index lymph node; ILN) is obtained is currently being investigated. A previous small pilot study (n = 12) showed that the response in the ILN may be representative of the pathologic response in the entire TLND specimen. To assess the concordance of response between the ILN and the total lymph node bed in a larger clinical trial population. Retrospective pathologic response analysis of a multicenter clinical trial population of patients from the randomized Study to Identify the Optimal Adjuvant Combination Scheme of Ipilimumab and Nivolumab in Melanoma Patients (OpACIN) and Optimal Neo-Adjuvant Combination Scheme of Ipilimumab and Nivolumab (OpACIN-neo) trials. Included patients were treated with 6 weeks neoadjuvant ipilimumab plus nivolumab. Patient inclusion into the trials was conducted from August 12, 2015, to October 24, 2016 (OpACIN), and November 24, 2016, and June 28, 2018 (OpACIN-neo). Data were analyzed from April 1, 2020, to August 31, 2021. Concordance of the pathologic response between the ILN and the TLND tumor bed. The pathologic response of the ILN was retrospectively assessed according to the International Neoadjuvant Melanoma Consortium criteria and compared with the pathologic response of the entire TLND specimen. A total of 82 patients treated with neoadjuvant ipilimumab and nivolumab followed by TLND (48 [59%] were male; median age, 58.5 [range, 18-80] years) were included. The pathologic response in the ILN was concordant with the entire TLND specimen response in 81 of 82 patients (99%) and in 79 of 82 patients (96%) concordant when comparing the ILN response with the response in every individual lymph node. In the single patient with a discordant response, the ILN response (20% viable tumor, partial pathologic response) underestimated the entire TLND specimen response (5% viable, near-complete pathologic response). Two other patients each had 1 small nonindex node that contained 80% viable tumor (pathologic nonresponse) whereas all other lymph nodes (including the ILN) showed a partial pathologic response. In these 2 patients, the risk of regional relapse might potentially have been increased if TLND had been omitted. The results of this study suggest that the pathologic response of the ILN may be considered a reliable indicator of the entire TLND specimen response and may support the ILN response-directed omission of TLND in a prospective trial.

Clinical Outcomes of Immune Checkpoint Inhibitor Therapy in Patients With Advanced Non-small Cell Lung Cancer and Preexisting Interstitial Lung Diseases: A Systematic Review and Meta-analysis

Patients with non-small cell lung cancer (NSCLC) and preexisting interstitial lung disease (ILD) are often excluded from clinical trials of immune checkpoint inhibitors (ICIs), leaving a gap in knowledge. What are the clinical outcomes of ICIs in patients with NSCLC and preexisting ILD? Systematic searches were conducted of PubMed, EMBASE, and Cochrane Library through April 2021 with no language or study design restrictions. Studies reporting the safety and efficacy data among patients with cancer and ILD receiving ICI therapy were collected. The primary end points were clinical efficacy to immunotherapy and the incidence of immune-related adverse events, especially for checkpoint inhibitor pneumonitis (CIP). A total of 179 patients in 10 studies were included. The pooled overall response rate (ORR) and pooled disease control rate (DCR) were 34%(95%CI, 20-47) and 66%(95%CI, 56-75), respectively. The ORR in patients with preexisting ILD was significantly higher than that in patients without ILD (OR, 1.99; 95%CI, 1.31-3.00). The DCR and progression-free survival in patients with preexisting ILD were not inferior to those without ILD (pooled OR, 1.46; 95%CI, 0.94-2.25 for DCR). The pooled incidences of any grade and grade 3 or higher CIP were 27%(95%CI, 17-37) and 15%(95%CI, 9-22) in patients with preexisting ILD, and 10%(95%CI, 6-13) and 4%(95%CI, 2-6) in patients without ILD. Meta-analysis found a significantly higher incidence rate of any grade and grade 3 or higher CIP in patients with NSCLC and preexisting ILD than in those patients without ILD (OR, 3.23 [95%CI, 2.06-5.06]; OR, 2.91 [95%CI, 1.47-5.74]). Programmed cell death protein 1/programmed cell death ligand 1 inhibitors had favorable efficacy in NSCLC with preexisting ILD. CIP is frequent in patients with preexisting ILD who receive ICI therapy but is often mild and easily manageable. Clinicians should be cautious when using ICIs in patients with preexisting ILD.