First-line Immune Checkpoint Inhibitors Research Articles

Phase Ib study of anti-PD-L1 monoclonal antibody socazolimab in combination with nab-paclitaxel as first-line therapy for advanced urothelial carcinoma.

PD-1/PD-L1 immune checkpoint inhibitors (ICIs) have demonstrated activity in the post-platinum and platinum-ineligible settings for advanced urothelial carcinoma (aUC). As only around 50% of patients with aUC can tolerate platinum-containing treatment, treatments combining first-line ICIs with non-platinum drugs are urgently needed. Therefore, we assessed the safety and efficacy of the anti-PD-L1 monoclonal antibody Socazolimab in combination with nab-paclitaxel as first-line therapy in aUC (NCT04603846). This was a multi-center, single-arm, phase Ib study that enrolled patients with treatment-naive aUC. Patients received Socazolimab (5mg/kg) and nab-paclitaxel (260mg/m2) Q3w. The primary endpoint was safety and tolerability of the combination regimen. Second endpoints were the objective response rate (ORR) and progression-free survival. Between September, 2020 and September, 2021, 20 patients with urothelial carcinoma were enrolled, arising from renal pelvis (5), bladder (8), and ureter (7). After a median follow-up of 17 months, the median number of treatment cycles was 12. No patients had dose limiting toxicity. All patients had treatment-related adverse events (TRAEs), most of which were grade 1 or 2. The common TRAEs (≥20%) were peripheral neurotoxicity, alopecia, rash, increased ALT, weight loss, weakness, pruritus, increased AST, increased γGT, increased ALP, neutropenia, emesis, and anorexia. Nine patients (45%) developed grade 3 TRAEs including peripheral neurotoxicity (30.0%), increased ALT (10.0%), and increased γGT (5.0%). Two patients (10%) discontinued treatment because of grade 3 mouth ulcer (n = 1) and grade 2 lung fibrosis (n = 1). No grade 4-5 TRAEs were observed. Among the 17 patients who had received at least one tumor assessment, ORR was 58.8% (95% CI, 32.9%-81.6%) and the median progression-free survival was 8.3 months (95% CI, 5.2-19.5). The median duration of response was 13.3 months (95% CI, 2.0-20.1), and the overall survival was 19.5 months (95% CI, 11.2-not reached). Socazolimab combined with nab-paclitaxel has shown good safety and promising antitumor activity as first-line therapy in patients with advanced urothelial carcinoma.

Progression of vertebral fractures in metastatic melanoma and non-small cell lung cancer patients given immune checkpoint inhibitors

IntroductionThe immune system mediates important effects on bone metabolism, but little has been done to understand immunotherapy’s role in this interaction. This study aims to describe and identify risk factors for the occurrence and/or exacerbation of vertebral fractures (vertebral fracture progression) during immune checkpoint inhibitors (ICIs). MethodsWe conducted an observational, retrospective, monocentric study. We collected data on melanoma and NSCLC patients, treated with first-line ICIs at the Medical Oncology Department ASST Spedali Civili of Brescia, between January 2015 and November 2021, and with a median follow-up of 20.1 (6–36) months. We collected data on patients, diseases, immune-related adverse events, and cortico-steroid therapy initiated on concomitant ICIs. ResultsWe identified 135 patients, 65 (48.2 %) with locally advanced/metastatic melanoma and 70 (51.8 %) with locally advanced/metastatic non-small cell lung cancer (NSCLC). Twenty-one (15.6 %) patients already had an asymptomatic vertebral fracture at baseline before starting ICIs in monotherapy. A total of ten patients, or 7.4 %, had a vertebra fracture progression defined as a new vertebral fracture or a worsening of a previous fracture. There was a strong relation between the steroid therapy and irAEs with vertebra fracture progression [OR (95 % CI) 8.1 (3.7–17.8) p-value < 0.001] in univariable analysis. However, only steroid therapy resulted to be an independent risk factor [8.260 (95 % CI 0.909–75.095); p-value 0.061] at the multivariable analysis. ConclusionConcurrent steroid therapy in patients receiving immunotherapy exposes them to a high risk of fractures due to skeletal fragility. The use of bone resorption inhibitors should be considered in these patients to prevent these adverse events.

EP.13D.03 Prognostic Factors of First-Line Immune Checkpoint Inhibitors in Combination with Chemotherapy in Extensive-Stage Small Cell Lung Cancer

EP.13D.03 Prognostic Factors of First-Line Immune Checkpoint Inhibitors in Combination with Chemotherapy in Extensive-Stage Small Cell Lung Cancer

Patients with Extensive-Stage Small Cell Lung Cancer Harboring Less Than 4 Metastatic Sites May Benefit from Immune Checkpoint Inhibitor Rechallenge by Reshaping Tumor Microenvironment.

Immune checkpoint inhibitors (ICIs) has prolonged survival in patients with extensive-stage small cell lung cancer (ES-SCLC) as first-line treatment. However, whether ICI rechallenge could bring survival benefit to patients with ES-SCLC following its failure as first-line treatment remains unknown. Therefore, we aim to address the issue and identify the cohort of patients that may derive such benefit. Patients with ES-SCLC from both the IMpower133 study and Shandong Cancer Hospital and Institute (shanzhong cohort) who failed first-line ICI were included. Kaplan Meier analysis was performed to compare overall survival (OS). Both univariate and multivariate Cox regression analyses were conducted to identify factors affecting survival. Tumor immune cell infiltration was evaluated by the CIBERSORT algorithm and detected by multiplex immunofluorescence (mIF). A total of 125 ES-SCLC patients undergoing atezolizumab and 161 patients undergoing ICI as first-line treatment were recruited from IMpower133 and shanzhong cohort. Those receiving ICI rechallenge had a longer OS than those without in IMpower133 (P = 0.08) and shanzhong cohort (P = 0.013). In IMpower133 cohort, subgroup analyses found that patients with <4 metastatic sites derived more survival benefit from atezolizumab (P = 0.008). For patients with ES-SCLC harboring <4 metastatic sites, there was significant OS difference between atezolizumab versus non-atezolizumab as retreatment (P = 0.036). Moreover, for ES-SCLC patients with <4 metastatic sites, atezolizumab improved survival compared with non-atezolizumab (hazard ratio [HR]: 0.457; 95% CI: 0.256-0.817; P = 0.008). These findings were confirmed in shanzhong cohort. Those harboring <4 metastatic sites had fewer M2 macrophage and more CD4 naïve T cells infiltration, which was further confirmed by mIF of ES-SCLC samples from shanzhong cohort. Our study provides rationale for ICI rechallenge among ES-SCLC patients with <4 metastatic sites, suggesting beneficial outcome by reshaping TME.

Brain Metastases as Inaugural Sign of Non-Small Cell Lung Carcinoma: Case Series and Review of Literature.

In the era of immune checkpoint inhibitors (ICI), managing non-oncogene driven non-small cell lung cancer (NSCLC) with brain metastases (BM) is challenging, especially when brain involvement is the initial sign. Patients with newly diagnosed brain metastatic NSCLC without epidermal growth factor receptor (EFGR) nor anaplastic lymphoma kinase (ALK) alterations were retrospectively included. Twenty-five patients were analyzed; 15 (60%) had symptomatic BM as the first sign (group 1), while 10 (40%) had BM discovered during complementary examinations (group 2). Fourteen patients (56%) had concomitant extracerebral metastases, primarily in group 2. Eight (32%) had oligometastatic disease, with seven in group 1. Over half received chemotherapy and pembrolizumab as first-line treatment. BM surgical resection occurred in twelve (80%) patients in group 1 and one in group 2. Median cerebral progression-free survival was 10 months: 12 in group 1 and 5 in group 2. Median overall survival was 25 months: not reached in group 1 and 6 months in group 2. This case series highlights survival outcomes for patients with inaugural BM, a demographic underrepresented in pivotal trials. Oligometastatic disease and symptomatic BM as initial signs seem associated with better prognosis due to increased use of multimodal local approaches. Combining local approaches with first-line ICI+/- chemotherapy appears to improve survival in brain metastatic NSCLC. A literature review was conducted to explore key questions regarding upfront ICI alone or in combination with systemic drugs or local approaches in brain metastatic NSCLC.

1330P Phase II study of pembrolizumab (pemb) plus plinabulin (plin) and docetaxel (doc) for patients (pts) with metastatic NSCLC after failure on first-line immune checkpoint inhibitor alone or combination therapy: Initial efficacy and safety results on Immune Re-sensitization

1330P Phase II study of pembrolizumab (pemb) plus plinabulin (plin) and docetaxel (doc) for patients (pts) with metastatic NSCLC after failure on first-line immune checkpoint inhibitor alone or combination therapy: Initial efficacy and safety results on Immune Re-sensitization

Impact of pretreatment body mass index on clinical outcomes in patients with metastatic renal cell carcinoma receiving first-line immune checkpoint inhibitor-based therapy: A systematic review and meta-analysis.

This study aimed to assess the prognostic role of body mass index (BMI) in patients with metastatic renal cell carcinoma (mRCC) treated with first-line immune checkpoint inhibitor (ICI)-based therapy. We searched for relevant studies in the MEDLINE, Embase, and Cochrane Library databases. The initial search yielded 599 records, of which seven articles (2,517 patients) were selected for analysis. Patients with a high BMI had a favorable overall survival (OS) based on hazard ratio (HR) (crude HR 0.69, 95% confidence interval [CI] 0.57-0.83, p<0.0001; adjusted (a)HR 0.75, 95% CI 0.59-0.95, p=0.02), but not relative risk (RR 0.88, 95% CI 0.67-1.16, p=0.37). In the subgroup analysis, patients with a high BMI had better OS in the ICI with tyrosine kinase inhibitor (TKI) subgroup (aHR 0.71, 95% CI 0.55-0.92, p=0.01), while no significant difference was found in the ICI-only subgroup (aHR 1.02, 95% CI 0.56-1.87, p=0.95). Adjusted statistics for progression-free survival (PFS) were assessable in predominantly ICI-only studies and demonstrated a favorable outcome for patients with a low BMI (aHR 1.67, 95% CI 1.14-2.45, p=0.01). In conclusion, the impact of high BMI varies depending on the treatment type, exhibiting a favorable correlation with OS within ICI with TKI subgroup, but indicating an adverse association with PFS in the ICI-only subgroup. Further research is needed to clarify the influence of BMI by stratifying patients into ICI-only and ICI with TKI treatment to provide more insights.

535P Safety and efficacy of first-line immune checkpoint inhibitors in elderly colorectal cancer patients: An Italian real-world multicenter experience

535P Safety and efficacy of first-line immune checkpoint inhibitors in elderly colorectal cancer patients: An Italian real-world multicenter experience

The prognosis and metabolite changes of NSCLC patients receiving first-line immunotherapy combined chemotherapy in different M1c categories according to 9th edition of TNM classification.

The 9th edition of the TNM Classification for lung cancer delineates M1c into two subcategories: M1c1 (Multiple extrathoracic lesions within a single organ system) and M1c2 (Multiple extrathoracic lesions involving multiple organ systems). Existing research indicates that patients with lung cancer in stage M1c1 exhibit superior overall survival compared to those in stage M1c2. The primary frontline therapy for patients with advanced non-small cell lung cancer (NSCLC), lacking driver gene mutations, involves the use of immune checkpoint inhibitors (ICIs) combined with chemotherapy. Nevertheless, a dearth of evidence exists regarding potential survival disparities between NSCLC patients with M1c1 and M1c2 undergoing first-line immune-chemotherapy, and reliable biomarkers for predicting treatment outcomes are elusive. Serum metabolic profiles may elucidate distinct prognostic mechanisms, necessitating the identification of divergent metabolites in M1c1 and M1c2 undergoing combination therapy. This study seeks to scrutinize survival discrepancies between various metastatic patterns (M1c1 and M1c2) and pinpoint metabolites associated with treatment outcomes in NSCLC patients undergoing first-line ICIs combined with chemotherapy. In this study, 33 NSCLC patients lacking driver gene mutations diagnosed with M1c1, and 22 similarly diagnosed with M1c2 according to the 9th edition of TNM Classification, were enrolled. These patients received first-line PD-1 inhibitor plus chemotherapy. The relationship between metastatic patterns and progression-free survival (PFS) in patients undergoing combination therapy was analyzed using univariate and multivariate Cox regression models. Serum samples were obtained from all patients before treatment initiation for untargeted metabolomics analysis, aiming to identify differential metabolites. In the univariate analysis of PFS, NSCLC patients in M1c1 receiving first-line PD-1 inhibitor plus chemotherapy exhibited an extended PFS (HR = 0.49, 95% CI, 0.27-0.88, p = 0.017). In multivariate PFS analyses, these M1c1 patients receiving first-line PD-1 inhibitor plus chemotherapy also demonstrated prolonged PFS (HR = 0.45, 95% CI, 0.22-0.92, p = 0.028). The serum metabolic profiles of M1c1 and M1c2 undergoing first-line PD-1 inhibitors plus chemotherapy displayed notable distinctions. In comparison to M1c1 patients, M1c2 patients exhibited alterations in various pathways pretreatment, including platelet activation, linoleic acid metabolism, and the VEGF signaling pathway. Diminished levels of lipid-associated metabolites (diacylglycerol, sphingomyelin) were correlated with adverse outcomes. NSCLC patients in M1c1, devoid of driver gene mutations, receiving first-line PD-1 inhibitors combined with chemotherapy, experienced superior outcomes compared to M1c2 patients. Moreover, metabolomic profiles strongly correlated with the prognosis of these patients, and M1c2 patients with unfavorable outcomes manifested distinct changes in metabolic pathways before treatment. These changes predominantly involved alterations in lipid metabolism, such as decreased diacylglycerol and sphingomyelin, which may impact tumor migration and invasion.

Long-Term Survival in Patients With Advanced Melanoma

Long-term survival data from clinical trials show that survival curves of patients with advanced melanoma treated with immune checkpoint inhibitors (ICIs) gradually reach a plateau, suggesting that patients have a chance of achieving long-term survival. To investigate long-term survival in patients with advanced melanoma treated with ICIs outside clinical trials. Cohort study using prospectively collected data from the nationwide Dutch Melanoma Treatment Registry, including patients in the Netherlands with advanced melanoma treated with first-line ICIs from 2012 to 2019. Data were analyzed from January to September 2023. Patients were treated with first-line ipilimumab-nivolumab, antibodies that target programmed cell death (anti-PD-1), or ipilimumab. Progression-free survival (PFS) and melanoma-specific survival were analyzed, and a Cox proportional hazards model was used to investigate factors associated with PFS after reaching partial response (PR) or complete response (CR). A total of 2490 patients treated with first-line ICIs were included (median [IQR] age, 65.0 [55.3-73.0] years; 1561 male patients [62.7%]). Most patients had an Eastern Cooperative Oncology Group Performance Status of 1 or lower (2202 patients [88.5%]) and normal lactate dehydrogenase levels (1715 patients [68.9%]). PFS for all patients was 23.4% (95% CI, 21.7%-25.2%) after 3 years and 19.7% (95% CI, 18.0%-21.4%) after 5 years. Overall survival for all patients was 44.0% (95% CI, 42.1%-46.1%) after 3 years and 35.9% (95% CI, 33.9%-38.0%) after 5 years. Patients with metastases in 3 or more organ sites had a significantly higher hazard of progression after reaching PR or CR (adjusted hazard ratio, 1.37; 95% CI, 1.11-1.69). This cohort study of patients with advanced melanoma treated with ICIs in clinical practice showed that their survival reached a plateau, comparable with patients participating in clinical trials. These findings can be used in daily clinical practice to guide long-term surveillance strategies and inform both physicians and patients regarding long-term treatment outcomes.

Development of mutated β-catenin gene signature to identify CTNNB1 mutations from whole and spatial transcriptomic data in patients with HCC

Background & AimsPatients with β-catenin (encoded by CTNNB1)-mutated hepatocellular carcinoma (HCC) demonstrate heterogenous responses to first-line immune checkpoint inhibitors (ICIs). Precision-medicine based treatments for this subclass are currently in clinical development. Here, we report derivation of Mutated β-catenin Gene Signature (MBGS) to predict CTNNB1-mutational status in patients for future personalized medicine. MethodsCo-expression of mutant-Nrf2 and hMet ± mutant-β-catenin in murine livers in mice led to HCC development. Using bulk RNA-seq and intersectional transcriptomic analysis of various β-catenin-mutated and non-mutated HCC models, MBGS was derived. Integrated RNA/whole-exome-sequencing and spatial transcriptomic data from multiple HCC patient cohorts was assessed to address ability of MBGS to detect CTNNB1 mutation, tumor immune microenvironment and/or predict therapeutic responses. ResultsBulk RNA-seq comparing HCCs in mutant β-catenin-Nrf2, β-catenin-Met and β-catenin-Nrf2-Met to Nrf2-Met HCC model yielded 95 common upregulated genes. In TCGA-LIHC, differential gene expression analysis with FDR=0.05 and log2FC>1.5 on the 95 common genes comparing CTNNB1-mutated vs wild-type patients narrowed the gene panel to 13-genes MBGS. MBGS predicted CTNNB1-mutations in TCGA (n=374) and French (n=398) patient cohorts with ROC AUC of 0.90 and 0.94, respectively. Additionally, increased MBGS expression score was associated with lack of significant overall survival or progression-free survival effects in the atezolizumab-bevacizumab arm versus sorafenib arm in IMbrave150 cohort. MBGS performed comparable or superior to other CTNNB1-mutant classifiers. MBGS overlapped with Hoshida S3, Boyault G5/G6, and Chiang CTNNB1 subclass tumors in TCGA and in HCC spatial transcriptomic datasets visually depicting these tumors to be situated in an immune excluded tumor microenvironment. ConclusionsMBGS will aid in patient stratification to guide precision medicine therapeutics for CTNNB1-mutated HCC subclass as a companion diagnostic, as anti-β-catenin therapies become available.

Prognostic Role of Pre-Treatment Body Composition Parameters in Patients Undergoing First-Line Immunotherapy for Metastatic Renal Cell Carcinoma.

We investigated the relationship between body mass index (BMI), radiological body composition, and survival outcomes in patients with metastatic renal cell carcinoma (mRCC) underwent first-line immune checkpoint inhibitor (ICI)-based therapy. Analyzing data from 102 patients treated between November 2019 and March 2023, pre-treatment computed tomography (CT) scans assessed fat and muscle areas. BMI and body composition indices were examined, including skeletal muscle index, subcutaneous fat index (SFI), visceral fat index, and total fat index. Kaplan-Meier curves and Log rank tests compared progression-free survival (PFS) and overall survival (OS), while multivariable Cox proportional regression analysis was performed to identify the variables significantly associated with survival outcomes. 54 patients (52.9%) experienced disease progression, and 26 (25.5%) died during a median follow-up of 17.4 months. High SFI was significantly associated with improved OS (p = 0.018) but not PFS (p = 0.090). Multivariable analysis confirmed the positive impact of high SFI on OS (adjusted HR: 0.37, p = 0.029) and suggested a trend towards improved PFS (adjusted HR: 0.61, p = 0.088). Notably, in the ipilimumab + nivolumab subgroup, high SFI significantly correlated with both PFS and OS (p = 0.047 and p = 0.012, respectively). High SFI predicts favorable OS in patients with mRCC receiving first-line ICI-based therapy, especially patients treated with ipilimumab + nivolumab displayed a significant association between high SFI and favorable PFS and OS.

Timing of stereotactic radiosurgery within the first-line systemic treatment in non-small cell lung cancer brain metastases: a retrospective single-center cohort study.

Stereotactic radiosurgery/radiotherapy (SRS/SRT) and novel systemic treatments, such as tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs), have demonstrated to be effective in managing brain metastases in non-small cell lung cancer (NSCLC). However, the optimal treatment sequence of SRS/SRT and TKI/ICI remains uncertain. This retrospective monocentric analysis addresses this question by comparing the outcomes of patients with NSCLC brain metastases who received upfront SRS/SRT versus those who were initially treated with TKI/ICI. All patients treated with SRS/SRT and TKI/ICI for NSCLC brain metastases were collected from a clinical database. The patients who received first-line TKI or ICI for the treatment of brain metastases were then selected for further analysis. Within this cohort, a comparative analysis between upfront SRS/SRT and patients initially treated with TKI/ICI was conducted, assessing key parameters such as overall survival (OS), intracranial progression-free survival (iPFS) and treatment-related toxicity. Both OS and iPFS were defined as the time from SRS/SRT to either death or disease progression, respectively. The analysis encompassed 54 patients, of which 34 (63.0%) patients received SRS/SRT and TKI/ICI as their first-line therapy. Of the latter, 17 (50.0%) patients received upfront SRS/SRT and 17 (50.0%) were initially treated with TKI/ICI; 24 (70.6%) received SRS/SRT and ICI, and 10 (29.4%) received SRS/SRT and TKI. The cohorts did not significantly differ in the univariable analyses for the following parameters: sex, age, histology, molecular genetics, disease stage at study treatment, performance status, number of brain metastases, treatment technique, tumor volume, target volume, disease progression, radiation necrosis, dosimetry. While no significant differences were found in terms of iPFS and OS between patients treated with upfront SRS/SRT and patients initially treated with TKI, upfront SRS/SRT demonstrated significantly superior OS when compared to patients initially treated with ICI (median OS not reached vs. 17.5 months; mean 37.8 vs. 23.6 months; P=0.03) with no difference in iPFS. No significant differences in treatment-related toxicity were observed among the cohorts. In this retrospective, single-center cohort study, patients treated with upfront SRS/SRT demonstrated significantly longer OS compared to patients initially treated with ICI in the cohort receiving first-line therapy for brain metastases. However, given the retrospective design and the limited cohort size, definitive conclusions cannot be drawn from these findings. Nevertheless, the results suggest that the timing of SRS/SRT may play an important role in treatment outcomes. Further investigation, preferably through prospective randomized trials, is warranted to provide more conclusive answers to this important question.

Management of Metastatic Renal Cell Carcinoma Following First-Line Immune Checkpoint Therapy Failure: A Systematic Review.

There is a significant gap in the literature concerning the effective management of second-line therapy for patients with metastatic renal cell carcinoma (RCC) who have received immune checkpoint inhibitors (ICIs). Most of the published articles were small multicenter series or phase 2 studies. To our knowledge, a systematic review that comprehensively outlines the range of treatment options available for patients with metastatic RCC who do not respond to first-line ICIs has not yet been conducted. Our aim was to synthesize evidence on second-line therapies for patients with metastatic RCC after initial treatment with ICIs and to offer recommendations on the best treatment regimens based on the current literature. We conducted a search in PubMed, Embase, and the Cochrane Library on 29 February 2024, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We selected articles that met the predetermined inclusion criteria (written in English, retrospective observational studies, prospective series, and randomized trials reporting second-line therapy for metastatic RCC after failure of ICI-based therapy). Relevant articles were identified in the reference lists. The main endpoint was the overall response rate (ORR), with the median progression-free survival (PFS) and overall survival (OS) as secondary endpoints. We included 27 studies reporting the outcomes of 1970 patients. Salvage therapies were classified as targeted therapy (VEGFR TKIs) in 18 studies and ICIs in 8 studies. In studies where TKIs were the second line of choice, the pooled ORR was 34% (95% CI: 30.2-38%). In studies where ICIs, alone or in combination with TKIs, were used as second-line therapies, the ORR was 25.7% (95% CI: 15.7-39.2%). In studies where TKIs and ICIs were the second-line choices, the pooled median PFS values were 11.4 months (95% CI: 9.5-13.6 months) and 9.8 months (95% CI: 7.5-12.7 months), respectively. This systematic review shows that VEGFR TKIs and ICIs are effective second-line therapies following an initial treatment with anti-PD(L)1 alone or in combination. The treatment choice should be personalized, taking into account the patient's response to first-line ICIs, the site of the disease, the type of first-line combination (with or without VEGFR TKIs), and the patient's overall condition.

The performance status gap in immunotherapy for frail patients with advanced non-small cell lung cancer

PurposeIn advanced non-small cell lung cancer (NSCLC), immune checkpoint inhibitor (ICI) monotherapy is often preferred over intensive ICI treatment for frail patients and those with poor performance status (PS). Among those with poor PS, the additional effect of frailty on treatment selection and mortality is unknown.MethodsPatients in the veterans affairs national precision oncology program from 1/2019–12/2021 who received first-line ICI for advanced NSCLC were followed until death or study end 6/2022. Association of an electronic frailty index with treatment selection was examined using logistic regression stratified by PS. We also examined overall survival (OS) on intensive treatment using Cox regression stratified by PS. Intensive treatment was defined as concurrent use of platinum-doublet chemotherapy and/or dual checkpoint blockade and non-intensive as ICI monotherapy.ResultsOf 1547 patients receiving any ICI, 66.2% were frail, 33.8% had poor PS (≥ 2), and 25.8% were both. Frail patients received less intensive treatment than non-frail patients in both PS subgroups (Good PS: odds ratio [OR] 0.67, 95% confidence interval [CI] 0.51 − 0.88; Poor PS: OR 0.69, 95% CI 0.44 − 1.10). Among 731 patients receiving intensive treatment, frailty was associated with lower OS for those with good PS (hazard ratio [HR] 1.53, 95% CI 1.2 − 1.96), but no association was observed with poor PS (HR 1.03, 95% CI 0.67 − 1.58).ConclusionFrail patients with both good and poor PS received less intensive treatment. However, frailty has a limited effect on survival among those with poor PS. These findings suggest that PS, not frailty, drives survival on intensive treatment.

Prognostic Impact of the Administration of Antibiotics and Proton Pump Inhibitors in Immune Checkpoint Inhibitor Combination Therapy for Advanced Renal Cell Carcinoma.

The prognostic impact of the administration of antibiotics and proton pump inhibitors (PPIs) in immune checkpoint inhibitor (ICI) therapy for advanced cancer has recently been documented. However, how these drugs affect the outcomes of first-line ICI combination therapy for advanced renal cell carcinoma (RCC) remains unclear. We retrospectively evaluated the data of 128 patients with RCC who received first-line ICI combination therapy. The patients were grouped according to their history of antibiotics and PPIs use one month before the initiation of ICI combination therapy. Progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) after ICI combination therapy were compared between patients treated with and without antibiotics or PPIs. Of the 128 patients, 30 (23%) and 44 (34%) received antibiotics and PPIs, respectively. Patients treated with antibiotics exhibited shorter PFS and OS compared to those who did not receive antibiotics (median PFS: 4.9 vs. 16.1 months, p<0.0001; OS: 20.8 vs. 49.0 months, p=0.0034). Multivariate analyses showed that antibiotic administration was an independent predictor of shorter PFS (hazard ratio: 2.54: p=0.0002) and OS (hazard ratio: 2.56: p=0.0067) after adjusting for other covariates. In contrast, there were no significant differences in either PFS or OS between patients who received PPIs and those who did not. (PFS: p=0.828; OS: p=0.105). Antibiotics administration before ICI combination therapy was negatively associated with outcomes of first-line ICI combination therapy for advanced RCC. Therefore, careful monitoring is required for potentially high-risk patients undergoing ICI combination therapy.

Immune checkpoint inhibitor combined with chemotherapy versus chemotherapy alone in the first-line treatment for recurrent or metastatic nasopharyngeal carcinoma: a meta-analysis of random controlled trials.

Immune checkpoint inhibitor (ICI) monotherapy and chemotherapy (CT) have been used to treat recurrent or metastatic nasopharyngeal carcinoma (R/M-NPC), with demonstrated survival benefits and good safety. However, whether combination therapy is superior to CT alone remains unclear. We summarized the existing evidence comparing the effectiveness and toxicities of ICI combined with CT versus CT alone. Online databases was conducted for eligible randomized controlled trials (RCTs) published up to November 1, 2023. Progression-free survival (PFS) and overall survival (OS) were the primary endpoint. Objective response rates (ORRs) and adverse events (AEs) were the secondary endpoint. Three randomized controlled trials (Capture-1st, JUPITER-02, and RATIONALE-309) were included. First-line ICI therapy combined with CT showed significant improvement in PFS (hazard ratio[HR], 0.53; 95% confidence interval[CI]: 0.44-0.64), OS (HR, 0.63;95%CI: 0.49-0.81) and ORRs (odds ratio[OR], 1.79;95%CI: 1.30-2.46), when compared with CT alone. AEs ≥ grade 3 during treatment and treatment-related deaths were not significantly different between the two groups. In patients with R/M-NPC, ICI therapy combined with CT showed improved ORRs, PFS, and OS, with similar safety as CT alone.

Women patients with small-cell lung cancer using immunotherapy in a real-world cohort achieved long-term survival.

Usage of immune checkpoint inhibitors (ICIs) has prolonged the overall survival (OS) of patients with extensive-stage small-cell lung cancer (ES-SCLC). In clinical trials, males accounted for a large proportion, leading to the uncertainty of its efficacy in female patients. We therefore conducted this study to explore the efficacy and safety of using ICIs in female patients with ES-SCLC. We retrospectively enrolled female SCLC patients and subdivided them into two groups. Group A (n = 40) was defined as ES-SCLC patients who received first-line standard chemotherapy with or without ICIs. Group B (n = 47) included relapsed SCLC patients who were administered with second-line therapies. Kaplan-Meier methodology was used to calculate survival analysis. Chi-squared tests were used to analyze the incidence of adverse events (AEs). Median progression-free survival (PFS) and median OS favored the ICI-contained cohorts (Group A PFS: 8.3 vs. 6.1 months; OS: not reached vs. 11.3 months; Group B PFS: 15.1 vs. 3.3 months; OS: 35.3 vs. 8.3 months), especially in those patients who received second-line immunotherapies. Patients who received immunotherapy had a slightly higher incidence rate of grade ≥3 AEs (Group A: 71.4% vs. 46.2%; Group B: 44.5% vs. 13.2%). Those who developed grade ≥3 AEs in first-line ICIs cohort had a more favorable survival (PFS: 8.3 vs. 3.2 months; OS: not reached vs. 5.1 months). Our study suggested that female ES-SCLC patients treated with immunotherapy tended to achieve a relatively longer survival. The incidence of AEs (grade ≥3) was higher in women patients receiving ICIs, which requires monitoring more closely.

Real-world Treatment Sequencing and Outcomes With Cabozantinib After First-line Immune Checkpoint Inhibitor-based Combination Therapy For Patients With Advanced Renal Cell Carcinoma: CARINA Study Results

IntroductionReal-world data are limited on treatment sequencing and outcomes after first-line (1L) immune checkpoint inhibitor (CPI)-based combination treatment of advanced renal cell carcinoma (aRCC). Patients and MethodsIn this real-world, UK-based, retrospective study (CARINA; NCT04957160), data were obtained from hospital and electronic prescribing records. Patients were aged ≥ 18 years at aRCC diagnosis and had received 1L CPI–CPI or tyrosine kinase inhibitor (TKI)–CPI combination therapy before second-line (2L) therapy including cabozantinib. We describe treatment outcomes including 1L and 2L durations of treatment (DoT) and overall survival (OS). ResultsData from April 2015 to June 2022 were collected on 281 patients from nine UK centres. Median 1L DoT was 2.3 months for CPI–CPI therapy (n = 171) and 5.0 months for TKI–CPI therapy (n = 58). After 1L CPI–CPI or TKI–CPI therapy, median 2L DoT was 5.8 versus 4.2 months, respectively, for cabozantinib (n = 163), and 3.8 versus 2.4 months for other therapies (n = 118); median 2L OS was 15.2 and 15.3 months, respectively, for cabozantinib, and 14.6 and 24.2 months for other therapies. ConclusionDoT for 2L treatment was numerically better for cabozantinib than for other therapies, and after 1L CPI–CPI therapy than after 1L TKI–CPI therapy. Median OS was similar for 2L cabozantinib and other 2L therapies, and median OS for 2L cabozantinib was similar after both 1L therapy types. These results demonstrate the antitumour effect of 2L therapies, including cabozantinib, after 1L CPI-based combination treatment, regardless of whether 1L CPI–CPI or TKI–CPI therapy is used.

International, open-label phase 2 study of regorafenib plus pembrolizumab in patients with advanced hepatocellular carcinoma (HCC) previously treated with immune checkpoint inhibitors (ICI).

4007 Background: The optimal second-line treatment for HCC after ICI is not established. Regorafenib is approved for treatment of advanced HCC after sorafenib. The primary aim of this study was to evaluate the activity of regorafenib plus pembrolizumab in patients with advanced HCC who progressed on only one prior ICI regimen. Methods: Patients aged ≥18 years, CP Class A, BCLC stage B or C, and ECOG PS of 0 or 1 received oral regorafenib 90 mg once daily 3 weeks (wk) on/1 wk off plus i.v. pembrolizumab 400 mg every 6 wk. The daily regorafenib dose could be escalated to 120 mg after the first 4-wk cycle of regorafenib if tolerated. Pembrolizumab dose reductions were not allowed. Cohorts were defined by prior treatment: Cohort 1 = atezolizumab + bevacizumab; Cohort 2 = any other ICI regimen (alone or combination). Primary endpoint was overall response rate (ORR) by independent central review (RECIST 1.1). Results: 95 patients were treated in 8 countries; Cohort 2 appeared to have more favorable disease characteristics (Table). Most common prior ICIs in Cohort 2 were durvalumab (30%), nivolumab (30%), ipilimumab (22%), and pembrolizumab (19%). Overall, median follow up was 7.1 months (mo). Median duration of regorafenib/pembrolizumab treatment (including interruptions, delays) was shorter in Cohort 1 vs Cohort 2 (11.0/9.4 wk vs 21.4/24.1 wk). ORR was 5.9% in Cohort 1 and 11.1% in Cohort 2; stable disease rates were 48.5% and 63.0%, respectively. Median PFS was 2.8 mo in Cohort 1 and 4.2 mo in Cohort 2. Overall, treatment-emergent adverse events (TEAE) were grade 3 in 56% of patients and grade 4 in 5%; drug-related grade 3 and 4 TEAE occurred in 37% and 3%, respectively. One patient (Cohort 1) had a grade 5 drug-related TEAE (cardiac arrest). Most common drug-related TEAE were palmar-plantar erythrodysesthesia syndrome (39%), asthenia (33%), decreased appetite (32%), diarrhea (28%), and hypertension (20%). Biomarkers assessed in paired biopsies (baseline and wk 6/day 1) showed on-treatment reductions in macrophages and angiogenesis RNA signatures. Conclusions: To our knowledge, this is the first prospective evaluation of a kinase inhibitor plus an ICI following first-line ICI therapy for HCC. Regorafenib plus pembrolizumab had modest activity in second line after first-line ICI regimens. The safety profile of the combination was consistent with those of either drug. Optimal treatment for patients with advanced HCC who progress after an ICI regimen remains an unmet need. Biomarker findings will be detailed in presentation. Clinical trial information: NCT04696055 . [Table: see text]