Rate Of Immune-related Adverse Events Research Articles

Advanced Renal Cell Cancer Combination Immunotherapy Clinical Trial (ARCITECT; HCRN GU 22-587)

Abstract Background First-line treatment for patients with metastatic clear cell renal cell carcinoma (mccRCC) often includes an anti-PD1 inhibitor in combination with either an anti-CTLA inhibitor (IO/IO) or a VEGF receptor tyrosine kinase inhibitor (TKI) (IO/TKI). Although some patients treated with nivolumab/ipilimumab (Nivo/Ipi) (IO/IO) experience durable responses leading to treatment free intervals, over two-thirds experience disease progression. Resistance to Nivo (anti-PD1) monotherapy has been associated with increased presence of a subpopulation of Tregs in the tumor microenvironment. Botensilimab (Bot) is an IO agent that leverages novel FcyR-associated mechanisms of action to enhance T cell priming, deplete intratumoral Tregs and enhance myeloid activation. Combination botensilimab/balstilimab (Bot/Bal) (anti-CTLA/anti-PD1) has shown impressive anti-tumor activity in diseases where Nivo/Ipi has shown little to no efficacy. Methods ARCITECT is a phase II, multicenter study evaluating the efficacy and safety of Bot/Bal relative to Nivo/Ipi. Patients with mccRCC (favorable, intermediate, or poor risk), no prior systemic therapy (including adjuvant or neoadjuvant), and at least one measurable lesion as defined by RECIST 1.1 are eligible for enrollment. 120 patients will be randomized in a 2:1 fashion to Arm A (Bot/Bal induction followed by Bal maintenance) or Arm B (Nivo/Ipi induction followed by Nivo maintenance) each for a maximum of 2 years. Stratification factors include IMDC risk groups and sarcomatoid histology. The primary endpoint is overall response rate (ORR) per RECIST 1.1. We hypothesize that Bot/Bal will lead to a superior ORR (55%) relative to Nivo/Ipi (40%). This trial has > 90% power to detect the alternative hypothesis while maintaining a one-sided significance level of not more than 0.10 using the exact binomial. The study will be monitored for early stopping in favor of the null hypothesis based on a Simon’s two stage design. In the first stage, 69 patients will be enrolled (Arm A:46 and Arm B:23). If at the end of the first stage, Arm A has either at least 18/42 (42.8%) of eligible patients responding or an ORR at least numerically equivalent to that for eligible patients in Arm B, then the trial will progress to the second stage. The primary endpoint will be met if there are 38/80 responders (ORR > 47.5%) in Arm A. Key secondary endpoints include landmark progression-free survival, treatment-free survival and rates of immune-related adverse events. Correlative studies will explore immune and molecular predictors of response and resistance to IO/IO in tumor and blood. Clinical trial information: NCT05928806. Results

Cardiovascular toxicities of immune therapies for cancer-a scientific statement of the Heart Failure Association (HFA) of the ESC and the ESC Council of Cardio-Oncology.

The advent of immunological therapies has revolutionized the treatment of solid and haematological cancers over the last decade. Licensed therapies which activate the immune system to target cancer cells can be broadly divided into two classes. The first class are antibodies that inhibit immune checkpoint signalling, known as immune checkpoint inhibitors (ICIs). The second class are cell-based immune therapies including chimeric antigen receptor T lymphocyte (CAR-T) cell therapies, natural killer (NK) cell therapies, and tumour infiltrating lymphocyte (TIL) therapies. The clinical efficacy of all these treatments generally outweighs the risks, but there is a high rate of immune-related adverse events (irAEs), which are often unpredictable in timing with clinical sequalae ranging from mild (e.g. rash) to severe or even fatal (e.g. myocarditis, cytokine release syndrome) and reversible to permanent (e.g. endocrinopathies).The mechanisms underpinning irAE pathology vary across different irAE complications and syndromes, reflecting the broad clinical phenotypes observed and the variability of different individual immune responses, and are poorly understood overall. Immune-related cardiovascular toxicities have emerged, and our understanding has evolved from focussing initially on rare but fatal ICI-related myocarditis with cardiogenic shock to more common complications including less severe ICI-related myocarditis, pericarditis, arrhythmias, including conduction system disease and heart block, non-inflammatory heart failure, takotsubo syndrome and coronary artery disease. In this scientific statement on the cardiovascular toxicities of immune therapies for cancer, we summarize the pathophysiology, epidemiology, diagnosis, and management of ICI, CAR-T, NK, and TIL therapies. We also highlight gaps in the literature and where future research should focus.

Examination of irAE and treatment discontinuation irAE in patients with RCC with T effector phenotype.

4549 Background: The standard of care for renal cell carcinoma (RCC) is physician-choice of dual immunotherapy with ipilimumab/nivolumab (IO/IO) or a combination a VEGF inhibitor with immunotherapy (VEGF/IO). The IMmotion 151 trial identified gene expression signatures that differentiate likelihood of response to IO/IO (cluster 4 and 5 – T effector) versus VEGF/IO (cluster 1 and 2 - Angiogenic). Given that the T effector RNA-seq signature consists of higher expression of genes associated with inflammation, we hypothesized that patients with the T effector phenotype would have higher rates of immune-related adverse events (irAE) on IO-based therapy. Methods: Patients with metastatic RCC treated with systemic IO-based therapy had RNA sequencing completed on the primary tumor or metastatic site. Charts of patients who had a T effector RNA-seq signature were manually curated to identify development of irAE by reading the most recent clinic note and searching ‘steroids’, ‘irAE’, ‘rash’, ‘thyroid’. Hits from searches were investigated by manual chart review. Results: 118 patients underwent RNA sequencing and 105 passed quality control. Nineteen patients (18%) were assigned the T effector phenotype. Of the 17 metastatic patients, twelve of these patients received at least one dose of IO/IO in the first or second line of therapy, five were treated with VEGF/IO Among patients treated with IO/IO, 8 developed any grade irAE (66%; 41% grade 3+), 5 (41%) required steroid treatment, 5 (41%) required hospitalization, and 4 (33%) discontinued treatment due to irAE. Grade 3 toxicities in this group included colitis, adrenal insufficiency, and hypophysitis. Of the 5 patients treated with VEGF/IO, 3 developed any grade irAE (60%; 20% grade 3+), none were treated with steroids, and none were hospitalized. The grade 3 toxicity in this group was adrenal insufficiency. Conclusions: Patients with a T effector RNA-seq signature had higher rates ofirAE than historic controls when treated with IO/IO leading to high rates of steroid use and treatment discontinuation. VEGF/IO-treated patients with the T effector RNA-seq signature had similar rates of irAE to historic controls. The ongoing OPTIC clinical will expand on these results by studying treatment assignment in a prospective manner.

Advanced renal cell cancer combination immunotherapy clinical trial (ARCITECT; HCRN GU 22-587).

TPS4614 Background: First-line treatment for patients with metastatic clear cell renal cell carcinoma (mccRCC) often includes an anti-PD1 inhibitor in combination with either an anti-CTLA inhibitor (IO/IO) or a VEGF receptor tyrosine kinase inhibitor (TKI) (IO/TKI). Although some patients treated with nivolumab/ipilimumab (Nivo/Ipi) (IO/IO) experience durable responses leading to treatment free intervals, over two-thirds experience disease progression. Resistance to Nivo (anti-PD1) monotherapy has been associated with increased presence of a subpopulation of Tregs in the tumor microenvironment. Botensilimab (Bot) is an IO agent that leverages novel FcyR-associated mechanisms of action to enhance T cell priming, deplete intratumoral Tregs and enhance myeloid activation. Combination botensilimab/balstilimab (Bot/Bal) (anti-CTLA/anti-PD1) has shown impressive anti-tumor activity in diseases where Nivo/Ipi has shown little to no efficacy. Methods: ARCITECT is a phase II, multicenter investigator initiated trial evaluating the efficacy and safety of Bot/Bal relative to Nivo/Ipi. Patients with mccRCC (favorable, intermediate, or poor risk), no prior systemic therapy (including adjuvant or neoadjuvant), and at least one measurable lesion as defined by RECIST 1.1 are eligible for enrollment. 120 patients will be randomized in a 2:1 fashion to Arm A (Bot/Bal induction followed by Bal maintenance) or Arm B (Nivo/Ipi induction followed by Nivo maintenance) each for a maximum of 2 years. Stratification factors include IMDC risk groups and sarcomatoid histology. The primary endpoint is overall response rate (ORR) per RECIST 1.1. We hypothesize that Bot/Bal will lead to a superior ORR (55%) relative to Nivo/Ipi (40%). This trial has > 90% power to detect the alternative hypothesis while maintaining a one-sided significance level of not more than 0.10 using the exact binomial. The study will be monitored for early stopping in favor of the null hypothesis based on a Simon’s two stage design. In the first stage, 69 patients will be enrolled (Arm A:46 and Arm B:23). If at the end of the first stage, Arm A has either at least 18/42 (42.8%) of eligible patients responding or an ORR at least numerically equivalent to that for eligible patients in Arm B, then the trial will progress to the second stage. The primary endpoint will be met if there are 38/80 responders (ORR > 47.5%) in Arm A. Key secondary endpoints include landmark progression-free survival, treatment-free survival and rates of immune-related adverse events. Correlative studies will explore immune and molecular predictors of response and resistance to IO/IO in tumor and blood. Clinical trial information: NCT05928806 .

Progression-Free Survival (PFS) and Toxicity with Nivolumab-AVD Compared to Brentuximab Vedotin-AVD in Pediatric Advanced Stage (AS) Classic Hodgkin Lymphoma (cHL), Results of SWOG S1826

Background: Approaches to therapy in pediatric and adult cHL have differed historically. Brentuximab vedotin (BV) is efficacious in pediatric patients (pts) with high-risk cHL when combined with chemotherapy and response based involved site radiation therapy (RT) ( Castellino. NEJM 2022). Inhibition of the PD-1 pathway, central to the pathogenesis of cHL, is safe and effective in children with relapsed HL but has not been evaluated in the frontline setting. Led by SWOG, the National Clinical Trials Network (NCTN) conducted the randomized, phase 3 trial S1826 to evaluate nivolumab (N)-AVD vs BV-AVD in pts ages ≥12 years (y) with newly diagnosed Stage 3-4 cHL. Methods: Eligible pts were randomized 1:1 to either 6 cycles of N-AVD or BV-AVD. At randomization enrollment was stratified by age, International Prognostic Score (IPS), and intent to use RT. Treating site of pts 12-17y, the subject of this subgroup analysis, declared intent to use RT for residual metabolically active lesions on the end of treatment PET per protocol. Recipients of BV-AVD were required to receive G-CSF prophylaxis vs optional with N-AVD. Dexrazoxane was permitted, but not mandated. Response and disease progression was assessed by investigators using the 2014 Lugano Classification. The primary endpoint was PFS; secondary endpoints included overall survival (OS), event-free survival (EFS), and safety. Results: Of 976 eligible pts enrolled (from 7/9/2019 to 10/5/2022): 24.3% (n=237) were 12-17 y and randomized to N-AVD (n=120) or BV-AVD (n=117). Median age was 15.6 y (range, 12-17.9 y), 50% of pts were male, 69% were white, 15% were black, and 18% were Hispanic. 27% had an IPS score 4-7. At the 2nd interim analysis (50% of total PFS events) the SWOG Data and Safety Monitoring Committee recommended reporting the primary results as the primary PFS endpoint crossed the protocol-specified conservative statistical boundary for the full trial. In the pediatric cohort, 6 PFS events were observed after N-AVD compared to 12 events after BV-AVD. At a median follow-up of 12.1 months, the PFS was compared between arms [HR 0.48, 95% CI 0.18-1.28, stratified one-sided logrank p=0.067) in the pediatric cohort; 1 y PFS: N-AVD, 94%, BV-AVD, 88% (Fig.1). There have been no deaths in this age group. Overall use of RT was 0.8% (2/237) and 79% of pediatric pts received dexrazoxane. The rate of grade (gr) ≥ 3 hematologic adverse events (AE) was 45% after N-AVD compared to 41% after BV-AVD, with 3% gr ≥ 3 febrile neutropenia and 1% with sepsis after either regimen, despite differences in GCSF use (59.2% N, 93.2% BV). Overall rates of immune related AEs (irAEs) (any gr) were low: pneumonitis (3.0% N vs 1% BV), and colitis (0% N vs 1% BV). Rash (any gr) was more common in BV-AVD (2% N vs 14% BV). Hypo/hyperthyroidism (any gr) was higher after N-AVD (2% N vs 0% BV). Rates of transaminitis were similar (ALT elevation: 42% N vs 54% BV). While sensory peripheral neuropathy was more frequent after BV-AVD (sensory: 18% N vs 29% BV; motor: 8% N vs 5% BV), only 1% was > grade 3. Discontinuation of N vs BV therapy occurred in 8.3% vs 2.6% of pediatric pts respectively, compared to 7.9% vs 21.1% of adults. Conclusions: In early follow-up, N-AVD and BV-AVD are well tolerated and associated with low rates of irAEs in pts ages 12-17 y. With 12.1 mos median follow-up the PFS benefit observed for N-AVD in pediatric pts mirrors that observed in the overall study. RT usage is lower, and cumulative doxorubicin dose is higher than historical pediatric cHL trials. The difference in rate of discontinuation between study arms and by age group needs further evaluation. Longer follow-up is needed to better define the roles of N-AVD and Bv-AVD for AS cHL. S1826 is a model NCTN trial, providing earlier access to novel agents and harmonization of treatment for adolescents and young adults with AS cHL. Funding: NIH/NCI/NCTN grants U10CA180888 and U10CA180819, U10CA180820, U10CA180821, U10CA180863, U10 CA180886; and Bristol-Myers Squibb. Bv provided by Seagen (Canada Only). Clinical Trial NCT03907488.

OPtimal Treatment by Invoking biologic clusters in renal cell carcinoma (OPTIC RCC)

Abstract Background The first-line treatment for metastatic clear cell renal cell carcinoma (mccRCC) includes immune oncology (IO) based combination therapy. The current standard includes a PD-1 inhibitor plus either an anti-CTLA-4 inhibitor (IO/IO) or an anti-vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGF TKI) (IO/TKI). Currently, there is no evidence to guide a physician’s choice between an IO/IO versus an IO/TKI combination. The phase III IMmotion 151 trial performed RNA-seq from 823 ccRCC tumors and established seven biologically distinct gene expression clusters of ccRCC (Motzer and Rini et al., Cancer Cell 2020). The seven clusters showed differential responses to immune checkpoint inhibitor and may serve as a predictive biomarker to select clusters to assign patients with mccRCC to either an IO/IO (ipilimumab/ nivolumab) or an IO/TKI (nivolumab/cabozantinib) regimen. Methods Patients diagnosed with mccRCC without prior systemic therapy (including in the neoadjuvant or adjuvant setting) and at least one measurable lesion as defined by RECIST 1.1 are eligible for enrollment. RNA-seq will be performed on metastatic tumor specimens and used to assign tumor clusters. Patients with cluster 1/2 tumors will be assigned to the nivolumab/cabozantinib arm. Patients with cluster 4/5 tumors will be assigned to the ipilimumab/nivolumab arm. Cluster 3/6/7 will be excluded. The primary endpoint is overall response rate (ORR) per RECIST 1.1. Key secondary endpoints include progression-free survival, depth of response >80%, and rate of immune-related adverse events (irAEs). The hypothesis is that use of tumor clusters to assign front-line therapy to either nivolumab/cabozantinib or ipilimumab/nivolumab will lead to a 20% greater ORR compared to unselected historical controls in CheckMate 9ER (ORR 55%) or CheckMate 214 (ORR: 40%). This trial adopts Simon’s MiniMax two-stage design (power: 80%, one-sided alpha: 0.1). For the nivolumab/cabozantinib arm, stage I will enroll 12 eligible patients. If there are 7 or more responders in the first 12 patients, stage II will enroll an additional 14 patients (n=26). For the ipilimumab/ nivolumab arm, stage I will enroll 16 eligible patients. If there are 7 or more responders in the first 16, stage II will enroll an additional 12 patients (n=28). The primary endpoint will be met if there are 15 or more responders (ORR>60%). This trial is open and enrolling with 12 patients on study at Vanderbilt University Medical Center and additional sites to open including UT Southwestern, City of Hope, University Hospitals Seidman Cancer Center, and Cleveland Clinic. This trial is funded by the Department of Defense Kidney Cancer Research Program Clinical Trial Award (W81XWH-22-1-1033) (NCT05361720). CDMRP DOD Funding: yes

JK5G postbiotics attenuate immune-related adverse events in NSCLC patients by regulating gut microbiota: a randomized controlled trial in China.

This study aimed to evaluate the effects of JK5G postbiotics to regulate imbalanced gut microbiota and its impacts on the efficacy and incidence rate of immune-related adverse events (irAEs) in non-small-cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs). This randomized, double-blind, placebo-controlled trial was conducted in China and included non-squamous or squamous NSCLC patients without EGFR, ROS1, and ALK alteration, treatment-naive, and stage IIIb-IV. Patients were randomly (1:1) divided into two groups to receive four cycles (three weeks for each cycle) of programmed cell death-1 (PD-1) plus chemotherapy plus placebo (control group, n = 30) or to receive PD-1 plus chemotherapy plus JK5G postbiotics (JK5G group, n = 30). The primary endpoint was objective response rate. The secondary endpoints were quality of life (QoL), adverse effects, and the 16S DNA sequencing of gut microbiota, blood inflammatory cytokines, and lymphocyte subsets. This study was registered at www.chictr.org.cn (ChiCTR2200064690). Sixty patients were enrolled. The objective response rate was 36.67% (11/30) in the control group and 50.00% (15/30) in the JK5G group (p = 0.297). The JK5G group had better QoL and nutritional levels, as well as lower depression symptoms than the control group (all p < 0.05). Moreover, the JK5G group had a lower incidence of anemia (63.33% vs. 13.33%, p < 0.001), decreased lymphocyte count (20.00% vs. 0%, p = 0.010), decreased appetite (53.33% vs. 16.67%, p = 0.003), nausea (33.33% vs. 6.67%, p = 0.010), and asthenia (30.00% vs. 6.67%, p = 0.017) than the control group. Moreover, JK5G attenuated gut microbiota imbalance, accompanied by increased Faecalibacterium, Ruminococcaceae, and fecal butyrate concentration, and diminished Escherichia-Shigella. Furthermore, JK5G administration significantly decreased the levels of pro-inflammatory markers, including TNF-α, IL-2, and C-reactive protein (CRP) (all p < 0.05). Significant increases in CD3+CD4+ T cells and CD4/CD8 ratio were observed in the peripheral blood of JK5G group patients (all p < 0.05). The enterotype data showed that patients were clustered into Blautia (E1) and Escherichia-Shigella (E2) enterotypes, and JK5G postbiotics intervention might be related to enterotype modulations. Our current findings indicated that JK5G postbiotics might attenuate irAEs, and enhance the QoL and nutrition levels of advanced NSCLC patients who received ICIs. JK5G postbiotics could also improve the gut microbiota structures and ameliorate the tumor microenvironment andinflammation. www.chictr.org.cn, identifier ChiCTR2200064690.

Pembrolizumab Alone or With Chemotherapy for 70+ Year-Old Lung Cancer Patients: A Retrospective Study

ObjectiveFirst-line pembrolizumab alone, as approved for PD-L1 ≥50%, or with chemotherapy was analyzed in older non–small-cell lung cancer (NSCLC) patients, for whom evidence is scarce. Materials and MethodsA total of 156 consecutive ≥70 year-old patients treated between January 2016 and May 2021 were retrospectively analyzed. Tumor progression was verified through radiologic review, while toxicity was captured from records. ResultsPembrolizumab plus chemotherapy (n = 95) caused higher rates of adverse events (91% vs. 51%, P < .001), treatment discontinuation (37% vs. 21%, P = .034), and hospitalization (56% vs. 23%, P < .001), but similar rates of immune-related adverse events (irAEs, mean 35%, P = .998) compared to pembrolizumab monotherapy (n = 61). Progression-free (PFS) and overall survival (OS) were similar between the 2 groups (7 vs. 8 months, and 16 vs. 14 months in median, P > .25). Occurrence of irAEs was associated with longer survival in a 12-week landmark analysis (median PFS 11 vs. 5 months, hazard ratio [HR] 0.51, P = .001; median OS 33 vs. 10 months, HR 0.46, P < .001), but occurrence of other AEs not (both P > .35). A worse ECOG performance status (PS) ≥2, presence of brain metastases at diagnosis, squamous histology and lack of tumor PD-L1 expression were independent predictors of shorter PFS and OS in multivariable analysis (HR 1.6-3.9 for PFS and OS, all P < .05). ConclusionChemoimmunotherapy increases the rate of adverse events and hospitalization without prolonging PFS or OS in newly diagnosed NSCLC patients aged 70 years or older compared to pembrolizumab monotherapy. ECOG PS 2, presence of brain metastases at diagnosis, squamous histology and PD-L1 negativity are associated with poor outcome.

#5974 CLINICAL AND HISTOPATHOLOGICAL CHARACTERISTICS OF THE ONCONEPHROLOGICAL POPULATION: A MULTICENTRE PROSPECTIVE OBSERVATIONAL STUDY

Abstract Background and Aims Onconephrology is a recently developed discipline aimed at diagnosing and managing renal disease in cancer patients. Few data are available regarding clinical and histological aspects concerning the whole population referred to an onconephrology clinic. Our study aimed to describe the clinical and histopathological characteristics of these patients and to evaluate indices of renal function recovery, renal damage progression, and mortality; a specific aim was to determine in our cohort the prevalence of acute kidney injury (AKI), chronic kidney disease (CKD) and acute kidney disease (AKD) which included all patients meeting KDIGO criteria for AKD but not for AKI. Secondary aims were the analysis of the immunotherapy subgroup and to determine the rate of immune-related adverse events (IRAEs). Method In this prospective observational study, we consecutively enrolled 84 patients for the clinical analysis and 10 patients in two centres for the histopathological study. Clinical assessment in the former group were performed at the first visit (T0), 1 month (T1), 3 months (T2) and 1 year (T3) and compared with a pre-determined baseline. Complete oncological and nephrological assessments were performed. For kidney biopsies, histopathological findings were expressed with quantitative and semi-quantitative parameters. Outcomes were: AKI or AKD complete or partial recovery of renal function (respectively defined as: return to baseline; sCr reduction ≥ 0.3 mg/dl or ≥ 25% or improvement to a lower stage of AKI); a composite of events (MAKE) based on CKD development or progression or death (only at T3). Results Our population was predominantly elderly, hypertensive, in metastatic phase (64.2%), M&amp;gt;F; other factors associated with increased cardiovascular risk were: previous AKI (18.8%), diagnosis of type 2 diabetes (25.9%), history of former/current smoker (55.4% and 19.6%), hyperuricemia (mean uric acid 7 mg/dl), previous/current cisplatin treatment (15.5% and 3.6%). The estimated prevalence in our cohort was: AKI 30.1%; CKD 27.7%; AKI on CKD 25.7%; AKD 9.6%. Regarding AKI, 68.4% were stage 1; for CKD, most patients were stage 3A and 3B (28.2% and 46.2%). More than 1/3 of the patients presented with suspended anticancer treatment; complete therapy resume rates were modest. Complete and partial AKI recovery rates at T2 were both ∼33%. Renal function was fully recovered in 50% of the AKD patients. During the follow-up, a new episode of AKI was observed in 15.5% of the patients, more frequently in the first 3 months. Patients receiving immunotherapy showed worse renal function (sCr 2.02 vs 1.51 mg/dl at T0, p&amp;lt;.001) and higher mortality (4 vs 0, p&amp;lt;.05); patients with IRAEs (25.8%) presented more frequently with discontinued therapy (Table 1). Of 36 patients with data available at 1 year, 21 (58.3%) presented the outcome MAKE; 11 patients died, 4 in the first three months. No nephrological conditions were found to predict MAKEs; presence of metastasis and female sex were the only predictors with Cox regression. Patients who underwent renal biopsy showed marked heterogeneity in the diagnoses (4 Membranous nephropathy, 1 drug-induced podocyte damage, 1 extracapillary GN after SARSCoV2 vaccination, 1 Light/Heavy Chain Deposition Disease, 1 Chronic Tubulointerstitial Nephritis, 1 sclerohyalinosis, 1 nonspecific); histopathological data was unremarkable. Conclusion AKI and CKD occur frequently in the onconephrological population. These patients are susceptible to new AKI episodes. The absence of AKI recovery and anticancer therapy withdrawal are common, potentially holding negative prognostic value. Particular attention should be paid to patients undergoing immunotherapy, especially when associated with IRAE. A larger number of patients is needed to estimate the impact of nephrological factors in the extended follow-up.

Safety and tolerability of immune checkpoint inhibitor (CPI) use in advanced hepatocellular carcinoma (aHCC) with Child-Pugh (CP) class B and C.

e14676 Background: The vast majority of HCC cases occur in the setting of liver cirrhosis. Patients with decompensated cirrhosis CHILD-Pugh Class B and C (CPB and CPC) are usually excluded from clinical trials. Here we report the safety and tolerability of CPI in patients with CPB/CPC. Methods: A retrospective chart review was performed of all patients with aHCC who received therapy with CPI from 1/2019 to 12/2022 at our institution. Patients with CP class B and C were included in this study. Safety endpoints included rates of immune-related adverse events (irAEs), grade ≥3 adverse events (graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 5.0]), duration of treatment with CPI and overall survival (OS) were reported. Results: We performed this retrospective chart review of 60 patients with aHCC who were treated with CPI at our institution. A total of 22 patients with CPB and CPC at the time of CPI initiation were included, 86.4% with CPB (n=19) and 13.6% with CPC (n=3). Median age was 68 (range 40-82). Amongst patients with CPB, 10 patients (45.4%) had CP score 7 (CP7) and 9 patients (40.9%) had CP score 8 or 9. Single agent nivolumab was the most common CPI used, followed by pembrolizumab and combination of ipilimumab and nivolumab, 38.4%, 27.3% and 13.6% respectively. Any grade irAEs were reported in 54.5% of patients (n=12).9% of patients (n=2) had grade ≥3 irAEs. In the CP7 subgroup, the rate of irAEs reported was 40% and no grade ≥3 irAEs were observed. In contrast, 55.5% of patients with CP 8 and 9 experienced irAEs and of those, 11.1% had grade ≥3 irAEs (n=1). In the CPC subgroup, 2 out of 3 patients reported irAEs (75%), one with a grade 4 irAE. GI complications(n=5) were the most common irAEs reported, followed by endocrine (n=4) and dermatologic complications (n=3). The median time on treatment was 1.63 months (95% CI,1.08-2.99). The median overall survival from the time of CPI initiation was 3.7 months (95% CI, 1.97-9.79). Conclusions: Immunotherapy has an acceptable safety and toxicity profile in aHCC patients with CP7. Higher rate of irAEs were observed in patients with CP ≥8. Further studies are warranted to evaluate the safety of CPI in patients with CP ≥8. We reported shorter duration of treatment with CPI and shorter OS in real world practice compared with those reported in the CheckMate 040 trial.[Table: see text]

Neoadjuvant tislelizumab plus nab-paclitaxel and carboplatin followed by adjuvant tislelizumab in patients with early triple-negative breast cancer.

602 Background: Triple-negative breast cancer (TNBC) is the subtype with the least favorable outcomes. However, TNBC is associated with higher immune cell abundance than other subtypes, making it a good candidate for immunotherapy. Neoadjuvant chemotherapy is the preferred treatment approach for early TNBC. Emerging evidence shows that additional immune checkpoint inhibitors (ICI) in neoadjuvant therapy significantly increases pathological complete response (pCR) and event-free survival in early TNBC. Treatment regimens of paclitaxel and carboplatin (TP) is class I recommendation for TNBC neoadjuvant therapy, the application of ICI with TP regimens is worth exploring. Methods: In this multicenter, open-label, phase II study, patients with untreated, histologically confirmed TNBC in stage II-III (per AJCC 8th edition) were enrolled. Patients received six cycles of neoadjuvant therapy with tislelizumab at 200 mg once every 3 weeks plus nab-paclitaxel (125 mg/m2 on days 1 and 8) and carboplatin (at a dose based on an area under the concentration 2 on days 1 and 8) every 3 weeks. Patients who either completed or discontinued the neoadjuvant treatment would undergo definitive surgery. After surgery, the patients received adjuvant tislelizumab every 3 weeks for up to 12 cycles. The primary endpoint was the rate of pCR (ypT0/Tis ypN0). The secondary endpoints included 1-, 2-, 3-year event free survival rates and overall survival rates. Based on the Simon’s Two-Stage design, if &gt; 13 of 32 patients achieved pCR, the enrollment would proceed to full accrual of 62 patients as planned. If &gt; 29 of 62 patients achieved pCR, we would deem the study to have met the primary endpoint. Results: From Mar 2021 to Jan 2022, 32 patients were enrolled; 18 of them achieved pCR, and therefore the study proceeded to complete the enrollment of 62 patients. At the data cut-off of Oct 13, 2022, 62 patients were enrolled, among which 50 patients received neoadjuvant treatment and underwent definitive surgery. The median age was 50 years. 36 (72.0%) patients had stage II breast cancer at diagnosis. 31 of the 50 patients achieved pCR (ypT0/Tis ypN0), and the pCR rate was 62.0% (95% CI, 47.2-75.4). Patients with immune cell PD-L1 expression ≥10% had numerically higher pCR rate (81.8% vs 53.6%) than those with PD-L1 expression ≥1%. All 50 (100%) patients reported any grade of neoadjuvant treatment-related adverse events (TRAEs). Grade ≥3 TRAEs occurred in 27 (54%) patients. The rate of immune-related adverse events (irAEs) was 34% (17/50), with the common occurring (10%) irAE of hypothyroidism (n = 8, 16%). 2 (4.9%) patients experienced grade ≥3 irAEs. Severe adverse events were reported in 5 (10%) patients. Conclusions: The study has met its primary endpoint. Tislelizumab plus nab-paclitaxel and carboplatin achieved a higher pCR and was generally well tolerated in the neoadjuvant treatment of early TNBC. Clinical trial information: ChiCTR2100041675 .

Clinical outcomes in patients with metastatic non-small cell lung cancer and head and neck squamous cell cancer treated with immune checkpoint inhibitors according to COVID-19 vaccination status.

e14696 Background: Immune checkpoint inhibitor (ICI) constitute the mainstay of therapy in metastatic non-small cell lung cancer (NSCLC) and head and neck squamous cell cancer (HNSCC). Infectious vaccines administered intratumorally or systemically have been suggested to enhance response to ICI and improve outcomes. No data is available on the effect of COVID-19 vaccines on clinical outcomes in patients treated with ICI. The aim of the study is to investigate overall survival (OS), progression-free survival (PFS), and immune related adverse events (IRAEs) according to mRNA COVID-19 vaccination status in patients with metastatic NSCLC and HNSCC who were treated with ICI. Methods: We performed retrospective analysis of clinical outcomes between a cohort of patients treated with ICI who received at least one dose of COVID-19 vaccine, and a historic control group of patients who did not receive COVID-19 vaccine and did not have documented COVID-19 infection. We included patients with metastatic NSCLC and HNSCC who had received at least one dose of ICI, either as monotherapy or in combination with chemotherapy or targeted therapy. Patients were stratified by age, gender, ethnicity, COVID-19 vaccination status, number of vaccinations, treatment type (monotherapy versus combined), treatment line, and PD-L1 status. Endpoints included IRAEs, PFS and OS. Results: A total of 151 patients met inclusion criteria (94 vaccinated and 57 control). Mean age at diagnosis was 62 years, the majority were female (51%), African American (58.3%), and received ICI monotherapy (57.6%). There was prolonged OS in patients who received COVID-19 vaccination versus control group ( p-value=0.04). In a multivariate analysis, patients in the COVID-19 vaccine arm had significantly reduced hazard of dying (HR:0.49, p =0.0446) when controlled for all of the above variables, and each additional received vaccine was associated with significant reduced hazard (HR=0.701, p-value = 0.0099). Race and type of cancer were statistically associated with PFS. Controlled for these factors, COVID arm patients had reduced hazard of disease progression (HR = 0.58, p-value = 0.0506), and each additional received mRNA vaccine was associated with a significantly reduced hazard of progression (HR = 0.74, p-value = 0.0046). There was no significant difference in the rate of IRAEs between vaccinated and non-vaccinated patients ( p=0.71). Conclusions: In this sample of patients with metastatic NSCLC and HNSCC who received ICI, there was significant improvement in OS between patients who received a COVID-19 vaccine compared patients who did not receive vaccination and did not have COVID-19 infection. There were no significant differences in IRAEs. Further studies are required to assess whether there is a synergistic effect between COVID-19 vaccination and ICI efficacy.

CO-induced TTP improves efficacy through resetting tumor-associated macrophages toward M1 phenotype in combined CTLA-4 and PD-1 blockade immunotherapy

Abstract Combined immune checkpoint blockade (CICB) targeting CTLA-4 and PD-1 has improved the prognosis for many malignancies, but also occurred a high rate of immune-related adverse events (irAEs). The manifestation of these toxicities is an important limiting factor for the successful implementation of CICB, restraining its anti-tumor efficacy. Carbon monoxide (CO), a pivotal endogenous signaling molecule, is able to maintain cell and tissue homeostasis and could be used as a therapeutic regimen. In our previous reports, CO could be useful therapeutics for the regulation of various inflammatory diseases through the increase of tristetraprolin (TTP) that binds to the AU-rich elements in target mRNA. In this study, we observed that CO-induced TTP activation ameliorated colitis and hepatitis, and improved anti-tumor efficacy in CICB treatment. We found that the colitis and hepatitis in TTP deficient mice were further exacerbated by CICB treatment. Moreover, CO increases CICB efficacy through TAM to M1 polarization together with diminishes irAEs through TTP enhancement in several irAEs target organ. Thus, we suggest that CO might be efficiently decouples anti-tumor efficacy and toxicity of CICB through TTP enhancement.

Nivolumab plus ipilimumab combination therapy in cancer: Current evidence to date.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer immunotherapy, yielding significant antitumor responses across multiple cancer types. Combination ICI therapy with anti-CTLA-4 and anti-PD-1 antibodies outperforms either antibody alone in terms of clinical efficacy. As a consequence, the U.S. Food and Drug Administration (FDA) approved ipilimumab (anti-CTLA-4) plus nivolumab (anti-PD-1) as the first-ever approved therapies for combined ICI in patients with metastatic melanoma. Despite the success of ICIs, treatment with checkpoint inhibitor combinations poses significant clinical challenges, such as increased rates of immune-related adverse events (irAEs) and drug resistance. Thus, identifying optimal prognostic biomarkers could help to monitor the safety and efficacy of ICIs and identify patients who may benefit the most from these treatments. In this review, we will first go over the fundamentals of the CTLA-4 and PD-1 pathways, as well as the mechanisms of ICI resistance. The results of clinical findings that evaluated the combination of ipilimumab and nivolumab are then summarized to support future research in the field of combination therapy. Finally, the irAEs associated with combined ICI therapy, as well as the underlying biomarkers involved in their management, are discussed.

Outcome comparison of pyrotinib with current standard of care in the second/third line setting in advanced non-small cell lung cancer patients with HER2 mutation.

Outcome comparison of pyrotinib with current standard of care in the second/third line setting in advanced non-small cell lung cancer patients with HER2 mutation.

Brief Report: High Levels of CD47 Expression in Thymic Epithelial Tumors

IntroductionCD47 is a tumor antigen that inhibits phagocytosis leading to immune evasion. Anti-CD47 therapy is a promising new immunotherapy across numerous tumor types, but it has not been tested in thymic epithelial tumors (TETs): thymomas and thymic carcinomas. TETs are rare tumors that are difficult to treat, especially with programmed cell death protein 1/programmed death-ligand 1 checkpoint inhibitors, owing to the excessive rates of immune-related adverse events. This study investigated the levels of CD47 expression in TETs to explore the possibility of anti-CD47 therapy. MethodsA total of 67 thymic tumors (63 thymomas and 4 thymic carcinomas) and 14 benign thymus controls and their clinical data were included. Samples were stained for CD47 expression (rabbit monoclonal antibody SP279, Abcam, Waltham, MA) and scored for both intensity and H-score (intensity multiplied by the percentage of tumor involved). Intensity was defined as follows: 0 = none, 1 = weak, 2 = moderate, and 3 = strong. H-scores ranged from 0 to 300. Samples with an intensity score below 2 or an H-score below 150 were considered CD47low, whereas the rest were CD47high. ResultsCompared with normal thymic tissues, TETs were more frequently CD47 positive and had significantly higher levels of CD47 expression. CD47 was positive in 79.1% of TETs compared with 57.1% of normal thymus. The level of CD47 expression was 16-fold higher in TETs (mean H-score 75.0 versus 4.6, p = 0.003). Multivariate analysis adjusted for age, sex, stage, resection status, and performance status revealed that CD47-high tumors were highly correlated with WHO histology type (p = 0.028). The most frequent CD47high tumors, in contrast to CD47low tumors, were types A (28.6% versus 7.5%) and AB (57.1% versus 13.2%), and the least frequent were B1 (7.1% versus 24.5%), B2 (0% versus 35.8%), B3 (7.1% versus 11.3%), and C (0% versus 7.5%). ConclusionsIn contrast to normal thymus, TETs had significantly higher levels of CD47 expression. Tumor samples with high CD47 expression were mostly WHO types A and AB. This is the first study to explore CD47 expression in thymic cancers and lends support for ongoing investigation of anti-CD47 macrophage checkpoint inhibitor therapy in these tumors.

Clinical outcomes of immune checkpoint inhibitor therapy for advanced lung adenosquamous carcinoma.

Primary adenosquamous carcinoma (ASC) of the lung is a rare and aggressive disease and limited information is available on the efficacy of immune checkpoint inhibitors (ICIs) for this disease. Here, we evaluated the expression status of programmed death-1 ligand 1 (PD-L1) and efficacy of ICIs in patients with pulmonary ASC. The efficacy and toxicity of ICIs were examined in 38 patients with previously treated lung ASC from November 2017 to October 2021 in Zhejiang Cancer Hospital (Hangzhou, China). Survival curves were plotted using the Kaplan-Meier method and the Cox proportional hazards model applied for univariate and multivariate analyses. A total of 38 patients with ASC were included in this retrospective study. ICI treatment induced an objective response rate (ORR) of 23.7% and a disease control rate (DCR) of 86.8%. The median progression-free survival (PFS) and median overall survival (OS) were 5.47 and 24.10 months, respectively. Seventeen patients were successfully evaluated for PD-L1 expression status, with 11 (64.7%) identified as PD-L1-positive. ORR and DCR for PD-L1-positive patients were 36.4% (4/11) and 100% (11/11) and the corresponding values for PD-L1-negative patients were 0 (0/6) and 50% (3/6), respectively. The median PFS of PD-L1-positive and PD-L1-negative patient groups was 5.00 and 1.90 months (P=0.166) while the median OS was 11.30 months and not reached, respectively (P=0.966). The incidence rate of immune-related adverse events (irAEs) was 52.6%, with 13.2% grade 3-4 irAEs. The most common irAEs were malaise and pneumonitis. One patient died of pneumonitis during the study. ICIs show considerable potential as a treatment option for lung ASC. PFS and OS rates are similar for PD-L1-positive and PD-L1-negative patients. Further large-scale studies are required to establish the relationship between PD-L1 expression and response to ICIs in ASC.

Abstract 4177: Th17 inhibition with interleukin 6 blockade decouples immunotoxicity from tumor immunity

Abstract Durable remission rates with immune checkpoint inhibitor (ICI) monotherapy remain low. Combination ICI therapies could overcome immune resistance but are associated with higher rates of immune-related adverse events (irAEs). To elucidate the underlying irAE immunobiology, we profiled human intestinal tissue, enterocolitis (irEC), and tumor tissue from ICI-treated patients using NanoString PanCancer Immune Panel (NanoPCIP) and multiplex immunohistochemistry (mIHC); hypotheses generated from these translational results for potential irAE treatments were tested in parallel preclinical mouse model studies. In 23 patients identified with both normal intestinal and irEC tissue, we found genes encoding interleukin-6 (IL-6), Th17 differentiating cytokine, and neutrophil and monocyte chemotactic molecules were the highest significantly upregulated in irEC compared to patient-matched normal intestine. Using NanoPCIP cell scoring (23 patients) and mIHC (27 patients), Th17 cells were significantly higher in irEC than Th1 cells. T-cell subsets were similar between anti-CTLA-4 based regimen versus anti-PD-1monotherapy induced irEC, except Th17 memory cells were significantly higher CTLA-4i-induced irEC. We compared the degree of differential gene expression in irEC (normal intestine versus irEC) to the differential expression in tumors (baseline versus on-treatment tumors). The genes highest upregulated in irEC (including Th17 differentiating cytokines IL-6 and IL-1B) were not upregulated in responding tumors from patients receiving ICI. NanoPCIP Th17 cell score was significantly more upregulated than Th1 cells and neutrophils more upregulated than CD8 T cells in the irEC analysis, but not in the responding tumor analysis where IL-12 and CD8 cell score was significantly upregualted . Based on these discoveries, we used C57BL/6 and Balb/c mouse strains to address whether the antitumor effect of ICIs can be enhanced by IL-6 blockade while also improving irAEs. We found that IL-6 blockade + ICI was associated with improved tumor control and a higher density of CD4/CD8 effector T-cells, with reduced Th17, macrophages, and MDSCs compared to ICI alone. Furthermore, in the experimental autoimmune encephalomyelitis (EAE) mouse model, the pathogenesis of which is well documented to be Th17 mediated (Robinson et al., 2014), we demonstrated that combined IL-6 blockade and ICI enhanced tumor rejection while simultaneously mitigating EAE symptoms versus ICI alone. Based on the totality of the basic science, translational, and clinical data we hypothesize that IL-6 blockade combined with ICIs could de-couple autoimmunity from antitumor immunity. We are currently conducting a prospective phase 2 trials of combination ipilimumab (3mg/kg) + Nivolumab (1mg/kg) + Tocilizumab in patients with metastatic melanoma, EGFR mutant NSCLC, and urothelial carcinoma ( NCT04940299). Citation Format: Daniel H. Johnson, Yared Hailemichael, Salah-Eddine Bentebibel, Noha Abdel-Wahab, Sungnam Cho, Wai C. Foo, Khalida Wani, Stephanie S. Watowich, Suhendan Ekmekcioglu, Adi Diab. Th17 inhibition with interleukin 6 blockade decouples immunotoxicity from tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4177.

Impact of ethnicity and immune-related adverse events (IRAE) on outcomes for non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors.

e21115 Background: Immune checkpoint inhibitors (ICI) have become the standard systemic therapy for the treatment of non-small cell lung cancers (NSCLC). With increased ICI use, the presence of immune related adverse events (IRAE) has increased and become associated with improved outcomes. However, minority populations are often underrepresented in clinical trials and the impact of ethnic variance on outcomes on ICI is not well defined. Methods: A retrospective analysis was performed on all NSCLC patients treated with ICI from 2014-2020 at Norris Cancer Center, Keck Medical Center, and Los Angeles County hospital. Presence of IRAE were determined by primary Oncology notes and graded per CTCAE v 5.5. Patients were divided by ethnicity/race below. All statistical analysis was performed with R. Results: In total, 186 NSCLC patients were treated with ICIs. The mean age was 66.3 years old (range 35-89) and average BMI was 25.1. Among the 186 patients, 65 (34.9%) were Asian/Pacific Islander (API), 60 (32.2%) non-Hispanic white (NHW), 33 (17.7%) Hispanic/Latino (HIS), 18 (9.7%) Black/African American (AA), and 10 (5.4%) Other. The median PFS and OS for the entire cohort was 7.1 mo and 17.3 mo, respectively. The median PFS and OS for API, NHW, HIS, and AA, were 18.7 and 20.3 mo, 7.37 and 25.3 mo, 4.1 and 11.0 mo, and 7.2 and 24.4 mo, respectively. The Hispanic group had significantly worse PFS (p = 0.01) and OS (p = 0.002), compared to all other groups. The rate of IRAE by patients was (36.0%), among which 46 (68.7%) were CTCAE grades 1-2 and 21 (31.3%) were grade 3 and above. Sixteen (23.9%) of the IRAE patients received steroids. The organ systems most affected by IRAE were Endocrine (28.4%) followed by Dermatologic (19.4%) and GI (17.9%). Among HIS, 24.2% experienced IRAE, compared to 41.5% for API, 41.7% for NHW, and 22.2% for AA. There was no significant difference in presence of IRAE (p = 0.1624) or the use of steroids (p = 0.3844) by ethnicity. Among the entire cohort, the presence of IRAE was significantly associated with improved median PFS (21.9 mo v 5.06 mo, p = 3e^-04) and median OS (47.7 mo v 12.7 mo, p = 4e^-05) when compared to no IRAE. The degree of improvement in OS with IRAE differed by ethnic/racial group and this difference between groups was statistically significant (p = 6e^-04). Comparisons of median OS with IRAE v without by ethnic/racial group, including hazard ratios: HIS (13.8 mo v 10.8 mo, -0.412), API (59.8 v 15.8 mo, -0.769), AA (41.1 mo v 12.5 mo, -0.924), NHW (47.7 mo v 19.3 mo, -0.958). Conclusions: Our data supports growing evidence that ICI outcomes differ by ethnic/racial background. Specifically, worse outcomes have been noted in the Hispanic population. While all groups show improved clinical outcomes from ICI when experiencing IRAE, this benefit appears to be less among the Hispanic population.

Extended duration of anti-PD-1 therapy, using reduced frequency dosing, in patients with advanced melanoma and Merkel cell carcinoma.

2588 Background: Optimal duration of treatment (DoT) with immune checkpoint inhibitors (ICI) in patients with metastatic melanoma (Mel) and Merkel cell carcinoma (MCC) is unclear. ICI discontinuation in Mel patients, especially those without CR, may be associated with a higher rate of progression over time, as compared to ICI continuation. Thus, extending DoT could improve outcomes. However, indefinite continuation at standard frequency doses (SFD) is not logistically or financially viable. Based on data from phase I studies suggesting sustained PD-1 receptor occupancy beyond 3 months after a single dose of nivolumab, we employed reduced frequency dosing (RFD) of anti-PD-1 antibodies every 2-3 months, to extend ICI duration beyond 2 years. Methods: This retrospective study analyzes patients in our skin cancer clinic with metastatic Mel and MCC who experienced initial clinical benefit with anti-PD-1 administered at SFD and then transitioned to RFD. We analyzed safety and efficacy endpoints including progression free survival (PFS) and rates of immune-related adverse events (irAE) with RFD. We also compared the pharmaceutical costs and patient-centered costs between 2 years of treatment at SFD versus extended DoT at RFD. Results: From 2014 – 2021, 23 patients with either metastatic Mel (N = 18) or MCC (N = 5) received anti-PD-1 therapy at RFD. Median DoT at SFD in this cohort was 1.1 years (range 0.2 – 2.2) with best objective tumor responses of CR (N =6), PR (N = 11), SD (N = 6). Median DoT at RFD was 1.2 years (range 0.2 – 3.5). The median follow-up for the entire cohort is 3.7 years (range 0.7 – 6.3) after ICI initiation. The 3-year PFS in Mel patients was 100% in those with CR (3/3), 89% with PR (8/9), and 50% with SD (3/6). The 3-year PFS in MCC was 100% in all 5 patients, including patients with CR (3/3) and with PR (2/2). Any-grade irAEs occurred in 43% of patients by 3 years on RFD, and grade 3/4 irAEs presented in 15%. Among the subset of 15 patients with DoT &gt;2 years (median 3.4 yr, range 2.0 – 5.0), total savings amounted to $1.1 million in drugs costs and 384 hours of clinic and travel time despite the increased DoT, as compared to the calculated values for 2-year DoT at SFD. Conclusions: RFD may provide an alternative approach to extending DoT in patients receiving ICI without additional logistical and financial burden, while preserving outcomes. Efficacy and safety data suggest sustained biologic activity of ICI with RFD administration. PK/PD analyses on patient samples are ongoing to further characterize the RFD approach. The RFD approach could be utilized to expand ICI access to communities with limited healthcare resources, thereby impacting cancer outcomes at a global scale.