First-line Immune Checkpoint Inhibitors Research Articles

Patterns of immune checkpoint inhibitor utilization and PD-L1 testing in advanced gastroesophageal cancers using real-world data.

370 Background: Globally, gastroesophageal cancer (GEC) is a leading cause of morbidity and mortality, with poor 5-year overall survival (OS). The addition of immune checkpoint inhibitors (ICIs) such as nivolumab and pembrolizumab to chemotherapy has resulted in significant improvement in OS of those patients (pts) with metastatic GEC (mGEC), most notably in those with tumors exhibiting high PD-L1 CPS scores. However, the pattern of ICI utilization in associated PD-L1 testing since the adoption of this treatment (tx) has yet to be elucidated. We evaluated the patterns of ICI utilization and PD-L1/CPS testing in the first-line tx of mGEC pre and post FDA approval of ICI use in this setting. Methods: Pts ≥ 18 years of age, with recurrent/metastatic squamous or adenocarcinoma GEC diagnosed after 2011 were included from the de-identified nationwide Flatiron Health, electronic health record-derived database. We presented the proportion of pts receiving ICI therapy, stratified by line of tx, as well as the proportion of patients who received PD-L1 testing at 6-month intervals. Pts demographics and clinical characteristics, including age, gender, race, ECOG score, documented insurance, and stage at diagnosis (dx) were described and compared using T or Wilcoxon rank-sum tests for continuous variables, and chi-square or Fisher’s exact tests for categorical data. We compared tx rates and PDL-1 testing across four time points: time 1: Jan-June 2020, prior to ASCO data presentation; time 2: July-Dec 2020, ASCO data presentation; time 3: Jan- June 2021, FDA label change; time 4: July 2021 to 6 m after FDA label change using Chi-square test. Results: A total of 9,573 pts were included with 1,593 (16.6%) receiving ICI-based tx. Among these, 62.3% were White, 7% Black. Descriptive statistics indicated that pts with ICI- tx tend to be younger (median age 65y vs. 66.7; (p <0.001). Within the total cohort, 74% pt were dx before FDA approval of ICI tx, while 26% pts were dx after FDA approval. PD-L1 testing was conducted in 4,065 (42.5%) pts. A total of 1,268 (13%) pts received first-line ICI-based tx. Of these, 154 pts (12.1%) were treated before FDA approval, while 1,114 pts (87.9%) received tx following FDA approval. The rate of first-line ICI tx significantly increased at each subsequent time point Time 2: 11.2% (p <0.0001), Time 3: 32.9% (p <0.0001), Time 4: 37.4% (p <0.0001). PD-L1 testing rates also increased over time, particularly after FDA label change. Testing rates at Time 1 was 68%. Comparatively, testing rates at subsequent time points were: Time 2 (67.2%; p 0.88), Time 3 (71.5%; p 0.324) and Time 4 (77.4%; p=0.004). Conclusions: The approval of ICIs for first-line tx of mGEC led to a significant increase in both ICI utilization and PD-L1/CPS testing rates. Despite these advancements, ongoing disparities in tx access and testing highlight the need for further research and efforts to ensure equitable care.

Dual-energy CT iodine concentration as a biomarker for immunotherapy treatment response in metastatic melanoma and renal cell carcinoma patients.

To investigate the predictive value of tumor iodine concentration obtained with dual-energy CT (DECT) for treatment response in patients treated with immune checkpoint inhibitors (ICI). Retrospective single-center study of consecutive metastatic melanoma and renal cell carcinoma (RCC) patients undergoing first-line ICI treatment. The iodine concentration measurement time points include prior to initiation of therapy (baseline [BL]), after initiation (follow-up [FU1]), and either time point nearest to 12 months or at time of progression (final follow-up [FFU]). Target lesion DECT-based whole-volume tumor normalized iodine concentration average (NICave) and size measurements were obtained. Reference standard was individual lesion FFU status categorized as responders or nonresponders per RECIST 1.1. Logistic regression model assessed NICave change and FU1 lesion response as predictors of FFU lesion outcome. Model's performance was summarized with AUC. Intraclass correlation coefficient (ICC) summarized inter-rater agreement of NICave. Forty-six patients were included (mean age 61 ± 11 years, 12 women; 16 melanoma). Sixty-four of 175 target lesions were confirmed nonresponders at FFU. In a multivariable model, lesion status at FU1 (odds ratio [OR]: 27.4, p < 0.001) and changes in NICave from BL to FU1 (OR: 2.42 per 1-SD increase, p = 0.019) were significant predictors of lesion status at FFU. The model's AUC was 0.86 (95% CI: 0.76-0.93). Inter-rater reliability of NICave was 0.98 (95% CI: 0.97-0.99). Changes in iodine concentration from baseline to first follow-up improve identification of delayed responding metastatic melanoma and RCC lesions treated with immune checkpoint inhibitor, initially classified as nonresponders by size change. Question How can pseudoprogression/delayed treatment response in metastatic renal cell carcinoma (RCC) and melanoma patients on first-line immune checkpoint inhibitors be accurately identified? Findings Combining iodine concentration change from Dual-energy CT (baseline to first follow-up) with RECIST-based lesion size change improved prediction of final lesion outcome. Clinical relevance DECT-based whole-volume tumor iodine concentration for target lesions is useful as a predictive imaging biomarker for distinguishing delayed response from true progression in patients with metastatic RCC and melanoma treated with first-line immune checkpoint inhibitors.

High‑intensity focused ultrasound thermal ablation boosts the efficacy of immune checkpoint inhibitors in advanced cancers with liver metastases: A single‑center retrospective cohort study.

High-intensity focused ultrasound thermal ablation (HIFU) is a novel non-invasive technique in the treatment of liver metastases (LIM) that allows focal destruction and is not affected by dose limits. This retrospective study aimed to explore the efficacy of HIFU in improving survival and the safety of the method in newly diagnosed patients with cancer with LIM who received first-line immune checkpoint inhibitor (ICI) therapy. Between January 2018 and December 2023, data from 438 newly diagnosed patients with cancer and LIM who were treated at Mianyang Central Hospital (Mianyang, China) were reviewed. A total of 94 patients were enrolled in this study, of whom 28 were diagnosed with lung carcinoma, 36 with gastric carcinoma, 11 with esophageal carcinoma, 7 with cholangiocarcinoma and 12 with other malignancies. The patients were divided into groups depending on whether they underwent HIFU. Progression-free survival (PFS), overall survival (OS) and adverse events (AEs) were compared. Clinicopathological features were analyzed using the chi-squared test. Of the 94 patients, 28 received ICI + HIFU as first-line treatment. After a median follow-up of 13.8 months, the median PFS and OS in the HIFU group were 2.38 times [10.95 vs. 4.60 months, 95% confidence interval (CI): 1.087-3.106, P<0.0001] and 1.84 times (19.6 vs. 10.67 months, 95% CI: 1.087-3.106, P=0.0418), respectively, higher than in the group without HIFU. All-cause AEs and immune-mediated AEs were similar between the groups with and without HIFU. However, the incidence of grade 1-2 immune-mediated AEs, troponin elevation, hepatotoxicity and renal dysfunction were more common in the current patients with LIM than those reported previously for the entire population. No immune-mediated AEs of grade ≥3 occurred in either group. HIFU prolonged the PFS and OS of first-line ICI in newly diagnosed patients with advanced cancer with LIM, with manageable safety and tolerability. The efficacy of HIFU in patients with LIM who plan to undergo ICI treatment warrants further prospective clinical investigation.

Predicting the tumor microenvironment composition and immunotherapy response in non-small cell lung cancer from digital histopathology images

Immune checkpoint inhibitors (ICI) have become integral to treatment of non-small cell lung cancer (NSCLC). However, reliable biomarkers predictive of immunotherapy efficacy are limited. Here, we introduce HistoTME, a novel weakly supervised deep learning approach to infer the tumor microenvironment (TME) composition directly from histopathology images of NSCLC patients. We show that HistoTME accurately predicts the expression of 30 distinct cell type-specific molecular signatures directly from whole slide images, achieving an average Pearson correlation of 0.5 with the ground truth on independent tumor cohorts. Furthermore, we find that HistoTME-predicted microenvironment signatures and their underlying interactions improve prognostication of lung cancer patients receiving immunotherapy, achieving an AUROC of 0.75 [95% CI: 0.61-0.88] for predicting treatment responses following first-line ICI treatment, utilizing an external clinical cohort of 652 patients. Collectively, HistoTME presents an effective approach for interrogating the TME and predicting ICI response, complementing PD-L1 expression, and bringing us closer to personalized immuno-oncology.

Efficacy, safety, and biomarker analysis of first-line immune checkpoint inhibitors with chemotherapy versus chemotherapy for advanced gastric cancer: a multicenter, retrospective cohort study

BackgroundRecent phase III randomized controlled trials have demonstrated that first-line immune checkpoint inhibitors (ICIs) improve prognosis in advanced HER-2-negative gastric cancer patients with programmed death ligand 1 (PD-L1) combined positive score (CPS) higher than 5. However, these findings are not confirmed in real-world settings, and the benefits in PD-L1 CPS < 5 patients remain controversial.MethodsIn this multicenter, retrospective cohort study, data from across thirteen medical centers were analyzed by inverse probability of treatment weighting for matching, alongside univariate and multivariate COX proportional hazard regression models. Genomic and transcriptomic analyses were conducted to identify efficacy prognostic models and resistance mechanisms.ResultsThis study included 573 patients with advanced gastric cancer, 265 treated with chemotherapy and 308 with ICIs plus chemotherapy. In the overall cohort and HER-2-negative patients, the combination therapy significantly improved progression-free survival and overall survival, without marked increases in severe adverse events. Notably, patients with PD-L1 CPS 1–4 showed significant overall survival prolongation and a trend towards improved progression-free survival with combination therapy. Patients with unknown PD-L1 status also benefitted from ICIs. SMARCA4 and BRCA2 mutations were more frequent in patients with responses, while CCNE1 and ZFHX3 alternation, alongside high “ABC transporters” signatures, were more common in non-responsive patients. A novel risk model, PGFIC, outperformed traditional biomarkers in predicting treatment outcomes.ConclusionsAdding ICIs to first-line treatment significantly prolongs survival in overall patients and in those with PD-L1 CPS 1–4 or unknown. This study also provides valuable insights into prognostic markers and resistance mechanisms, potentially guiding immunotherapy strategies.

Precision targeting of β-catenin induces tumor reprogramming and immunity in hepatocellular cancers.

First-line immune checkpoint inhibitor (ICI) combinations show responses in subsets of hepatocellular carcinoma (HCC) patients. Nearly half of HCCs are Wnt-active with mutations in CTNNB1 (encoding for β-catenin), AXIN1/2 , or APC , and demonstrate limited benefit to ICI due to an immune excluded tumor microenvironment. We show significant tumor responses in multiple β-catenin-mutated immunocompetent HCC models to a novel siRNA encapsulated in lipid nanoparticle targeting CTNNB1 (LNP-CTNNB1). Both single-cell and spatial transcriptomics revealed cellular and zonal reprogramming of CTNNB1 -mutated tumors, along with activation of immune regulatory transcription factors IRF2 and POU2F1, re-engaged type I/II interferon signaling, and alterations in both innate and adaptive immune responses upon β-catenin suppression with LNP-CTNNB1. Moreover, LNP-CTNNB1 synergized with ICI in advanced-stage disease through orchestrating enhanced recruitment of cytotoxic T cell aggregates. Lastly, CTNNB1 -mutated patients treated with atezolizumab plus bevacizumab combination had decreased presence of lymphoid aggregates, which were prognostic for response and survival. In conclusion, LNP-CTNNB1 is efficacious as monotherapy and in combination with ICI in CTNNB1 -mutated HCCs through impacting tumor cell intrinsic signaling and remodeling global immune surveillance, providing rationale for clinical investigations.

Real-World and Clinical Trial Validation of a Deep Learning Radiomic Biomarker for PD-(L)1 Immune Checkpoint Inhibitor Response in Advanced Non-Small Cell Lung Cancer.

This study developed and validated a novel deep learning radiomic biomarker to estimate response to immune checkpoint inhibitor (ICI) therapy in advanced non-small cell lung cancer (NSCLC) using real-world data (RWD) and clinical trial data. Retrospective RWD of 1,829 patients with advanced NSCLC treated with PD-(L)1 ICIs were collected from 10 academic and community institutions in the United States and Europe. The RWD included data sets for discovery (Data Set A-Discovery, n = 1,173) and independent test (Data Set B, n = 458). A radiomic pipeline, containing a deep learning feature extractor and a survival model, generated the computed tomography (CT) response score (CTRS) applied to the pretreatment routine CT/positron emission tomography (PET)-CT scan. An enhanced CTRS (eCTRS) also incorporated age, sex, treatment line, and lesion annotations. Performance was evaluated against progression-free survival (PFS) and overall survival (OS). Biomarker generalizability was further evaluated using a secondary analysis of a prospective clinical trial (ClinicalTrials.gov identifier: NCT02573259) evaluating the PD-1 inhibitor sasanlimab in second or later line of treatment (Data Set C, n = 54). In RWD Test Data Set B, the CTRS identified patients with a high probability of response to ICI with a PFS hazard ratio (HR) of 0.46 (95% CI, 0.26 to 0.82) and an OS HR of 0.50 (95% CI, 0.28 to 0.92) in the first-line ICI monotherapy cohort, after adjustment for baseline covariates including the PD-L1 tumor proportion score. In Clinical Trial Data Set C, the CTRS demonstrated an adjusted PFS HR of 1.03 (95% CI, 0.43 to 2.47) and an OS HR of 0.33 (95% CI, 0.14 to 0.91). The CTRS and eCTRS outperformed traditional imaging biomarkers of lesion size in PFS and OS for RWD Test Data Set B and in OS for the Clinical Trial Data Set. The study developed and validated a deep learning radiomic biomarker using pretreatment routine CT/PET-CT scans to identify ICI benefit in advanced NSCLC.

Efficacy and Safety Evaluation of Immune Checkpoint Inhibitors in Combination With Chemotherapy for Extensive Small Cell Lung Cancer: Real-World Evidence.

Extensive small cell lung cancer (ES-SCLC) are currently managed using first-line chemotherapy options, including atezolizumab (Atezo) plus etoposide and carboplatin (CE) or durvalumab (Durva) plus etoposide with either cisplatin (PE) or carboplatin (CE). However, a definitive distinction in therapeutic effects between Atezo and Durva in these regimens remains unestablished. We analyzed data from 100 patients diagnosed with ES-SCLC who received immune checkpoint inhibitors (ICIs) as first-line chemotherapy. Among them, 70 were administered Atezo + CE, 12 received Durva + PE, and 18 received Durva + CE. We assessed the efficacy of the two ICIs across various factors. The progression-free survival (PFS) and overall survival (OS) did not significantly differ between Atezo + CE and Durva + CE/PE as first-line chemotherapy treatments for SCLC. We observed no significant differences in age, sex, performance status (PS), liver metastasis, bone metastasis, or platinum-based agent usage between the treatment cohorts. However, a marked improvement in PFS and OS was observed in the solitary patient with brain metastasis treated with Atezo + CE. The primary distinction between these treatments was observed in the management of patients with brain metastasis. The literature lacks comparative studies on the effects of first-line ICI treatment on the central nervous system, rendering our findings significant in clinical practice. Despite the retrospective nature of this study and the potential for various biases, we recommend the preferential use of Atezo + CE in patients with brain metastasis to potentially enhance prognosis.

Prognostic Role of Inflammatory and Nutritional Biomarkers in Non-Small-Cell Lung Cancer Patients Treated with Immune Checkpoint Inhibitors Alone or in Combination with Chemotherapy as First-Line.

In recent years, several inflammation-related factors and nutritional parameters have been evaluated to develop prognostic scores as potential biomarkers in non-small-cell lung cancer (NSCLC) patients receiving immune checkpoint inhibitors (ICIs). The aim of this study was to retrospectively investigate the prognostic role of the advanced lung cancer inflammation (ALI) index, lung immune prognostic index (LIPI), prognostic nutritional index (PNI) and systemic inflammation score (SIS) in metastatic NSCLC patients receiving ICI alone or in combination with chemotherapy. We retrospectively included 191 patients with advanced NSCLC who received first-line ICI with or without chemotherapy from 2017 to 2024. The association between pretreatment ALI, LIPI, PNI, and SIS and overall survival (OS) was evaluated using the Kaplan-Meier method and Cox regression models. After a median follow-up of 27.7 months, significantly longer OS was associated with an ALI score > 18 vs. ≤18 (18.0 vs. 7.3 months; p = 0.00111), LIPI score 0 vs. 1 and 2 [18.9 vs. 8.2 and 4.2 months; (p = 0.001)], PNI ≥ 45 vs. <45 (22.7 vs. 9.6 months; p = 0.002), and SIS score 0 vs. 1 and 2 (27.4 vs. 7.1 and 8.6 months, respectively; p < 0.001). The OS benefit was independent of treatment (ICI vs. ICI + chemotherapy). At multivariate analysis, pretreatment albumin was positively associated with OS, while ECOG PS 1 and liver metastases were negatively associated with OS. Inflammatory and nutritional biomarkers such as the ALI, LIPI, PNI, and SIS represent useful tools to prognosticate survival in metastatic lung cancer patients treated with ICI alone or in combination with chemotherapy as first-line.

Tertiary lymphoid structures potentially promote immune checkpoint inhibitor response in SMARCB1-deficient medullary renal cell carcinoma

The WHO’s classification of renal cell carcinoma (RCC) has identified loss of SMARCB1 as one of the driven mutations. Despite intensive postoperative interventions, the prognosis for SMARCB1-deficient medullary RCC remains poor, indicating insufficiency in current therapy. Herein, we reported the treatment outcomes of five patients with metastatic SMARCB1-deficient medullary RCC and molecular correlates. Four patients were treated with first-line immune checkpoint inhibitors (ICI) plus tyrosine kinase inhibitors (TKI) combination therapy with a median PFS (mPFS) of 12.3 months. Transcriptomic analysis revealed enrichment of immune-related pathways in SMARCB1-deficient medullary RCC compared to clear-cell and papillary RCC. Multiple immunofluorescence (mIF) revealed the association between the formation of mature tertiary lymphoid structures (TLSs) and the favorable response to ICI-based combination therapy. In conclusion, ICI-based combination therapy showed promising anti-tumor activity in SMARCB1-deficient medullary RCC patients. The presence of mature tertiary TLSs may partially elucidate the mechanism underlying treatment response.

Efficacy and safety of first-line immune checkpoint inhibitor combination therapies in patients with advanced esophageal squamous cell carcinoma: a network meta-analysis.

We performed a network meta-analysis of phase III trials to compare the efficacy and safety of first-line regimens for patients with advanced esophageal squamous cell carcinoma (ESCC). A systematic review and Bayesian network meta-analysis were conducted by retrieving relevant literature from PubMed, Embase, the Cochrane Library, and the Web of Science. We included published sources of randomized clinical trials comparing immunotherapy combinations for treating advanced ESCC. We analyzed seven studies involving eight immunotherapy combinations and 4688 patients. For patients without programmed death-ligand 1 (PD-L1) selection, it was found that the combination of toripalimab and chemotherapy provided better overall survival than chemotherapy alone (hazard ratio = 0.58, 95% confidence interval (CI) 0.43-0.78). Compared with chemotherapy alone, Sintilimab or camrelizumab plus chemotherapy seemed to achieve the best progression-free survival (hazard ratio = 0.56, 95% CI 0.46-0.68). Nivolumab plus chemotherapy appeared to provide the best objective response rate, with significant differences versus chemotherapy alone (odds ratio = 0.49, 95% CI 0.38-0.64). Nivolumab plus ipilimumab resulted in a relatively lower incidence of adverse events of grade ≥3 than other regimens. The combination of immune checkpoint inhibitors (ICIs) with chemotherapy provided a high probability of more effective treatment in comparison with chemotherapy alone for patients with advanced ESCC. Toripalimab and sintilimab plus chemotherapy were ranked as providing the highest OS and PFS benefit in the first-line setting, respectively.

Real-world analysis of the incidence and risk factors of pneumonitis in non-small cell lung cancer patients treated with combined thoracic radiotherapy and immunotherapy

Abstract Objectives Combining radiotherapy with immune checkpoint inhibitor (ICI) treatment has emerged as an important therapeutic regimen. However, this combined treatment may increase the risk of pneumonitis. The aim of this study is to analyze the incidence and risk factors for pneumonitis in non-small cell lung cancer (NSCLC) patients receiving combined thoracic radiotherapy and ICI (RT + ICI) treatment in the real-world clinical setting, offering a reference and guidance for clinical physicians. Methods This study identified 447 patients with pathologically confirmed NSCLC at West China Hospital of Sichuan University from 2016 to 2021. Clinical characteristics, treatment regimens, immune-related adverse events (irAEs), and hematological data were collected and analyzed. Results Patients receiving combined RT + ICI treatment had a higher risk of developing pneumonitis than those receiving ICI treatment alone (26.9 vs. 6.7 %, p&lt;0.001). The multivariate logistic analysis identified the following independent risk factors for pneumonitis in patients undergoing combined RT + ICI treatment: history of lung disease (p=0.032), first-line ICI treatment (p=0.001), anti-PD-L1 instead of anti-PD-1 treatment (p=0.035), and the development of immunotherapy-related thyroid dysfunction (p=0.019). The independent risk factors were incorporated into a nomogram to predict the incidence of pneumonitis. The area under the receiver operating characteristic curve is 0.727, suggesting an acceptable predictive efficacy. Conclusions Compared to ICI monotherapy, NSCLC patients receiving the combination of thoracic radiotherapy and ICI treatment are at higher risk of developing pneumonitis. The nomogram holds promise for facilitating the risk assessment and early identification of pneumonitis in NSCLC patients receiving combined RT + ICI treatment.

Abstract 4117414: Risk Factors Associated with Cardiac Hospital Admissions in Cancer Patients Treated with Immune Checkpoint Inhibitors

Background: Immune checkpoint inhibitors (ICIs) are highly effective anti-cancer treatments for several cancers. However, treatment with ICIs is associated with metabolic perturbations, accelerated atherosclerosis, and increased risks of adverse cardiovascular events. In this study, we aimed to determine risk factors associated with cardiac hospital admissions in patients treated with ICIs for their cancer. Methods: Retrospective data was collected for all patients treated with ICIs between 1 January 2010 and 1 January 2020 through the Hunter New England Local Health District (HNELHD), Australia. Patient medical history and demographics were collected through electronic medical records. Outcome data was obtained from the HNELHD Institutional Cardiac and Stroke Outcomes Unit database. Cardiac admission was defined as cardiac disease based on hospital administration ICD-10 codes. Binary logistic regression was used for multivariate analysis and performed through SPSS version 28. Results: A total of 1,080 patients were included in the final analysis. Mean age of patients was 66.9 ± 11.7 years, with the majority male sex ( n =685; 63.4%). Primary cancer diagnosis of patients treated with ICIs included melanoma ( n =417; 38.7%), and cancer of the lung ( n =327; 30.3%). Nivolumab monotherapy was the most used first-line ICI treatment ( n =475; 44.0%) followed by pembrolizumab monotherapy ( n =428; 39.6%). A total of 266 (24.6%) patients had at least one cardiac hospital admission. On univariate analysis, pre-existing cardiovascular disease (CVD) ( p &lt;0.001), diabetes mellitus ( p &lt;0.001), chronic kidney disease ( p &lt;0.001), and prior CVD medications ( p &lt;0.001) were associated with cardiac hospitalisation. On multivariate analysis, prior history of heart failure ( p &lt;0.001), hypertension ( p =0.003), ischaemia, and peripheral vascular disease ( p =0.049) were independently associated with an increased risk of cardiac hospital admission. Conclusions: In cancer patients treated with ICIs, pre-existing CVD risk factors increases the risk of cardiac-associated hospitalisations. Adequate CVD risk modification and monitoring during treatment with ICIs may be necessary to reduce cardiac hospitalisations.

Effective treatment strategies and key factors influencing therapeutic efficacy in advanced SMARCA4-deficient non-small cell lung cancer

IntroductionSMARCA4/BRG1-deficient non-small cell lung cancer (SD-NSCLC) with high invasiveness and poor prognosis is associated with primary resistance to standard treatment, especially in late-stage patients. This study aimed to explore effective treatments and identify critical factors impacting therapeutic efficacy to enhance outcomes for SD-NSCLC patients. Methods103 SD-NSCLC patients in stage III/IV diagnosed by immunohistochemistry from May 2019 to March 2024 were included in this study. We assessed the patients’ clinical and genetic features, analyzed the clinical outcomes of local treatment and immunotherapy according to the TNM stage, and further evaluated the factors impacting therapeutic efficacy. ResultsIn stage III patients, no significant differences in the median progression-free survival (mPFS) and median overall survival (mOS) were observed between patients receiving local treatment at the primary site and those who did not (p > 0.05), while adding ICIs (immune checkpoint inhibitors) to local treatment significantly improved mPFS compared with non-ICIs (15.0 vs. 7.7 months, p = 0.033), though not mOS (p > 0.05). For stage IV patients, ICIs significantly improved mPFS (8.9 vs. 4.2 months, p = 0.006) and mOS (19.7 vs. 13.1 months, p = 0.007) compared to non-ICIs treatments. However, among ICIs-treated patients, the addition of local treatment to the primary lesion did not significantly affect mPFS and mOS (p > 0.05). Patients with STK11/KEAP1 mutations had significantly shorter mPFS (3.6 vs. 16.2 months, p = 0.001) and mOS (17.7 vs. 31.3 months, p = 0.002), while no significant difference was observed in mPFS and mOS in patients with different tumor mutation burden (TMB) and PD-L1 expression levels. ConclusionThe addition of ICIs to local treatment shows promising results for locally advanced patients with SD-NSCLC, and first-line ICIs are associated with improved survival in metastatic SD-NSCLC. STK11/KEAP1 mutations may be linked to reduced efficacy of immunotherapy.

Durvalumab Versus Chemotherapy as First-line Treatment for Metastatic NSCLC With Tumor PD-L1 Expression of 25% or Higher: Results From the Randomized Phase 3 PEARL Study

IntroductionPEARL (NCT03003962) is an open-label, phase 3 study comparing first-line durvalumab monotherapy with chemotherapy in patients with metastatic NSCLC (mNSCLC [EGFR/ALK wild type]) with programmed cell death ligand 1 (PD-L1) tumor cell (TC) membrane expression status of 25% or higher. We report the final analysis of PEARL. MethodsAdults (N = 669) with previously untreated stage IV mNSCLC were randomized (1:1) to durvalumab 20 mg/kg every four weeks or chemotherapy every three weeks for four to six cycles. Dual primary endpoints were overall survival (OS) in the PD-L1 TC of 25% and higher and the PD-L1 TC of 25% and higher low risk of early mortality populations. ResultsDurvalumab was associated with a numerical reduction in the risk of death versus chemotherapy in the 25% and higher PD-L1 TC population (OS hazard ratio [HR] = 0.84, 95% confidence interval [CI]: 0.71–0.99, p = 0.037; median OS 14.6 months, 95% CI: 12.2–16.9 versus 12.8 months, 95% CI: 10.1–14.7, respectively). In the 25% and higher PD-L1 TC low risk of early mortality population the OS hazard ratio for durvalumab versus chemotherapy was 0.96 (95% CI: 0.79–1.15, p = 0.628); median OS 14.6 months (95% CI: 12.6–17.2) versus 15.0 months (95% CI: 13.1–16.8), respectively. In the safety population, the incidence of grade 3/4 treatment-related adverse events was 15.5% (durvalumab) and 45.9% (chemotherapy). ConclusionsDurvalumab did not statistically significantly improve OS versus chemotherapy as first-line treatment in patients with mNSCLC and 25% and higher PD-L1 TC. The numerical improvement in OS was consistent with previous studies of first-line immune checkpoint inhibitor monotherapy in patients with mNSCLC.

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.