Validation of a multiomic model of plasma extracellular vesicle PD-L1 and radiomics for prediction of response to immunotherapy in NSCLC.

BACKGROUND: Immune-checkpoint inhibitors (ICIs) have showed unprecedent efficacy in the treatment of patients with advanced non-small cell lung cancer (NSCLC). However, not all patients manifest clinical benefit due to the lack of reliable predictive biomarkers. We showed preliminary data on the predictive role of the combination of radiomics and plasma extracellular vesicle (EV) PD-L1 to predict durable response to ICIs. MAIN BODY: Here, we validated this model in a prospective cohort of patients receiving ICIs plus chemotherapy and compared it with patients undergoing chemotherapy alone. This multiparametric model showed high sensitivity and specificity at identifying non-responders to ICIs and outperformed tissue PD-L1, being directly correlated with tumor change. SHORT CONCLUSION: These findings indicate that the combination of radiomics and EV PD-L1 dynamics is a minimally invasive and promising biomarker for the stratification of patients to receive ICIs.

How to use anti-PD-1 therapy in gastric cancer: the approach in the United States.

Gastric cancer is a leading global cause of cancer-related mortality. In the past, survival achieved in metastatic disease with chemotherapy was less than 1 year. The advent of immune checkpoint inhibitors has changed the treatment of gastric cancer. With demonstration of single agent activity for anti-programmed cell death protein 1 (anti-PD-1) agents in gastric cancer with a particularly high degree of activity in microsatellite instability (MSI) high cancers, global clinical trials added nivolumab and pembrolizumab to first line chemotherapy. Improvements in progression free survival, overall survival and increased response rates led to regulatory approval of these agents in the U.S. The benefit in survival seems limited, however, to patients with programmed cell death ligand 1 (PD-L1) positive or MSI high cancers. Adjuvant therapy with nivolumab improved disease-free survival after chemoradiotherapy and surgery in esophageal and gastroesophageal junction adenocarcinoma in patients with residual disease resected at surgery, and is a new care standard. Results of ongoing trials adding immune checkpoint inhibitors to perioperative chemotherapy in gastric cancer are anxiously awaited. In locally advanced MSI high gastric cancer, immune checkpoint inhibitor therapy is being explored as preoperative therapy given the demonstration of a high degree of pathologic complete response to these agents. Some trials may offer patients nonoperative management if a complete response is achieved.

Development of Plant-Derived Bispecific Monoclonal Antibody Targeting PD-L1 and CTLA-4 against Mouse Colorectal Cancer.

Checkpoint blockade immunotherapy has revolutionized cancer treatment, with monoclonal antibodies targeting immune checkpoints, yielding promising clinical benefits. However, with the advent of resistance to immune checkpoint inhibitor treatment in clinical trials, developing next-generation antibodies with potentially increased efficacy is critical. Here, we aimed to generate a recombinant bispecific monoclonal antibody for dual inhibition of programmed cell death protein 1/programmed cell death ligand 1 and cytotoxic T-lymphocyte-associated protein 4 axes. The plant system was used as an alternative platform for bispecific monoclonal antibody production. Dual variable domain immunoglobulin atezolizumab × 2C8 is a plant-derived bispecific monoclonal antibody that combines both programmed cell death ligand 1 and cytotoxic T-lymphocyte-associated protein 4 blockade into a single molecule. Dual variable domain immunoglobulin atezolizumab × 2C8 was transiently expressed in Nicotiana benthamiana and the expression level was determined to be the highest after 4 days of infiltration. The size and assembly of the purified bispecific monoclonal antibody were determined, and its function was investigated in vitro and in vivo. The molecular structures of plant-produced dual variable domain immunoglobulin atezolizumab × 2C8 are as expected, and it was mostly present as a monomer. The plant-produced dual variable domain immunoglobulin atezolizumab × 2C8 showed in vitro binding to programmed cell death ligand 1 and cytotoxic T-lymphocyte-associated protein 4 proteins. The antitumor activity of plant-produced bispecific monoclonal antibody was tested in vivo by treating humanized Balb/c mice bearing a CT26 colorectal tumor. Plant-produced dual variable domain immunoglobulin atezolizumab × 2C8 significantly inhibited tumor growth by reducing tumor volume and weight. Body weight changes indicated that the plant-produced bispecific monoclonal antibody was safe and tolerable. Overall, this proof of concept study demonstrated the viability of plants to produce functional plant-based bispecific immunotherapy.

Impacts of hyperthermic chemotherapeutic agent on cytotoxicity, chemoresistance-related proteins and PD-L1 expression in human gastric cancer cells.

Objective: Gastric cancer with peritoneal metastasis is considered to be final stage gastric cancer. One current treatment approach for this condition is combined cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC). However, the therapeutic mechanisms of HIPEC remain largely undescribed. Method: In order to assess the cellular effects of HIPEC in vitro, we treated AGS human gastric adenocarcinoma cells with or without 5-fluorouracil (5-Fu) at 37 °C or at 43 °C (hyperthermic temperature) for 1 h followed by incubation at 37 °C for 23 h. The impacts of hyperthermia/5-Fu on apoptosis, cell survival signals, oxidative stress, chemoresistance-related proteins and programmed death-ligand 1 (PD-L1) expression were measured. Results: Our results showed that hyperthermia potentiates 5-Fu-mediated cytotoxicity in AGS cells. Furthermore, the combination of 5-Fu and hyperthermia reduces levels of both phosphorylated STAT3 and STAT3, while increasing the levels of phosphorylated Akt and ERK. In addition, 5-Fu/hyperthermia enhances reactive oxygen species and suppresses superoxide dismutase 1. Chemoresistance-related proteins, such as multidrug resistance 1 and thymidylate synthase, are also suppressed by 5-Fu/hyperthermia. Interestingly, hyperthermia enhances 5-Fu-mediated induction of glycosylated PD-L1, but 5-Fu-mediated upregulation of PD-L1 surface expression is prevented by hyperthermia. Conclusion: Taken together, our findings provide insights that may aid in the development of novel therapeutic strategies and enhanced therapeutic efficacy of HIPEC.

First-line treatment with camrelizumab plus famitinib in advanced or metastatic NSCLC patients with PD-L1 TPS ≥1%: results from a multicenter, open-label, phase 2 trial.

BACKGROUND: The combination of immune-checkpoint inhibitors and antiangiogenic agents can synergistically modulate the tumor microenvironment and represents a promising treatment option. Here, we evaluated the efficacy and safety of camrelizumab plus famitinib (a receptor tyrosine kinase inhibitor) as a first-line treatment for advanced or metastatic NSCLC patients with a programmed death ligand-1 (PD-L1) tumor proportion score (TPS) of ≥1%, in an open-label, multicenter, phase 2 basket trial. METHODS: Eligible patients received camrelizumab (200 mg once every 3 weeks via intravenous infusion) plus oral famitinib at an initial dose of 20 mg once daily. The primary endpoint was the objective response rate (ORR), as assessed by the investigator per Response Evaluation Criteria in Solid Tumors V.1.1. Key secondary endpoints included disease control rate (DCR), duration of respons, progression-free survival (PFS), overall survival (OS), 12-month OS rate, and safety profile. RESULTS: Of the enrolled 41 patients, 21 (51.2%) had a PD-L1 TPS of 1-49%. As of the cut-off date on June 22, 2022, the combination regimen of camrelizumab and famitinib achieved an ORR of 53.7% (95% CI 37.4% to 69.3%) and a DCR of 92.7% (95% CI 80.1% to 98.5%). The median PFS was 16.6 months (95% CI 8.3 to not reached), and OS data were not yet mature, with an estimated 12-month OS rate of 76.8% (95% CI 60.0% to 87.3%). The most common treatment-related adverse events of grade 3 or higher included hypertension (22.0%), increased alanine aminotransferase (12.2%), decreased neutrophil count (9.8%), proteinuria (7.3%), decrease platelet count (7.3%), and hypokalemia (7.3%). One (2.4%) patient died from grade 5 hemoptysis, which was considered possibly related to the study treatment by the investigator. CONCLUSION: Camrelizumab plus famitinib demonstrated promising antitumor activity in advanced or metastatic NSCLC patients and had an acceptable safety profile. These findings suggest that this combination regimen could be an alternative therapeutic option and warrant further investigation. TRIAL REGISTRATION NUMBER: NCT04346381.

Toripalimab plus nab-paclitaxel in metastatic or recurrent triple-negative breast cancer: a randomized phase 3 trial.

The combination of immune-checkpoint blockade with chemotherapy for the first-line treatment of advanced triple-negative breast cancer (TNBC) has generated mixed results. TORCHLIGHT is a randomized, double-blinded phase 3 trial evaluating the efficacy and safety of first-line toripalimab and nab-paclitaxel (nab-P) (n = 353; experimental arm) versus placebo and nab-P (n = 178; control arm) for the treatment of women with metastatic or recurrent TNBC. The primary end point was progression-free survival (PFS) assessed by a blinded independent central review in the PD-L1-positive and intention-to-treat populations. The secondary end points included overall survival and safety. Overall, 200 and 100 patients, in the toripalimab and placebo arm respectively had PD-L1-positive TNBC. At the prespecified interim analysis, a statistically significant improvement in PFS assessed by a blinded independent central review was demonstrated in the experimental arm in the PD-L1-positive population (median PFS 8.4 versus 5.6 months; hazard ratio (HR) = 0.65, 95% confidence interval (CI) 0.470-0.906, P = 0.0102). The median overall survival was 32.8 versus 19.5 months (HR = 0.62, 95% CI 0.414-0.914, P = 0.0148). Similar incidences of treatment-emergent adverse events (AEs) (99.2% versus 98.9%), grade ≥3 treatment-emergent AEs (56.4% versus 54.3%) and fatal AEs (0.6% versus 3.4%) occurred in the experimental and control arms. The addition of toripalimab to nab-P provided a significant improvement in PFS for PD-L1-positive patients with metastatic or recurrent TNBC with an acceptable safety profile. ClinicalTrial.gov identifier NCT03777579 .

Avelumab Versus Platinum-Based Doublet Chemotherapy as First-Line Treatment for Patients With High-Expression Programmed Death-Ligand 1-Positive Metastatic NSCLC: Primary Analysis From the Phase 3 JAVELIN Lung 100 Trial.

INTRODUCTION: We report the primary analysis from JAVELIN Lung 100, a phase 3 trial comparing avelumab (anti⁠-programmed death-ligand 1 [PD-L1]) versus platinum-based doublet chemotherapy as first-line treatment for PD-L1-positive (+) advanced NSCLC. METHODS: Adults with PD-L1+ (≥1% of tumor cells; PD-L1 immunohistochemistry 73-10 pharmDx), EGFR and ALK wild-type, previously untreated, stage IV NSCLC were randomized to avelumab 10 mg/kg every 2 weeks (Q2W), avelumab 10 mg/kg once weekly (QW) for 12 weeks and Q2W thereafter, or platinum-based doublet chemotherapy every 3 weeks. Primary end points were overall survival (OS) and progression-free survival (PFS) per independent review committee. The primary analysis population was patients with high-expression PD-L1+ tumors (≥80% of tumor cells). RESULTS: A total of 1214 patients were randomized to avelumab Q2W (n = 366), avelumab QW (n = 322), or chemotherapy (n = 526). In the primary analysis population, hazard ratios (HRs) for OS and PFS with avelumab Q2W (n = 151) versus chemotherapy (n = 216) were 0.85 (95% confidence interval [CI]: 0.67-1.09; one-sided p = 0.1032; median OS, 20.1 versus 14.9 mo) and 0.71 (95% CI: 0.54-0.93; one-sided p = 0.0070; median PFS, 8.4 versus 5.6 mo), respectively. With avelumab QW (n = 130) versus chemotherapy (n = 129), HRs were 0.79 (95% CI: 0.59-1.07; one-sided p = 0.0630; median OS, 19.3 versus 15.3 mo) and 0.72 (95% CI: 0.52-0.98; one-sided p = 0.0196; median PFS, 7.5 versus 5.6 mo), respectively. No new safety signals were observed. CONCLUSIONS: Longer median OS and PFS were observed with avelumab versus platinum-based doublet chemotherapy in advanced NSCLC, but differences in OS and PFS were not statistically significant, and the trial did not meet its primary objective. CLINICALTRIALS: gov Identifier: NCT02576574.

Perioperative Atezolizumab Plus Fluorouracil, Leucovorin, Oxaliplatin, and Docetaxel for Resectable Esophagogastric Cancer: Interim Results From the Randomized, Multicenter, Phase II/III DANTE/IKF-s633 Trial.

PURPOSE: This trial evaluates the addition of the PD-L1 antibody atezolizumab (ATZ) to standard-of-care fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) as a perioperative treatment for patients with resectable esophagogastric adenocarcinoma (EGA). METHODS: DANTE started as multicenter, randomized phase II trial, which was subsequently converted to a phase III trial. Here, we present the results of the phase II proportion, focusing on surgical pathology and safety outcomes on an exploratory basis. Patients with resectable EGA (≥cT2 or cN+) were assigned to either four preoperative and postoperative cycles of FLOT combined with ATZ, followed by eight cycles of ATZ maintenance (arm A) or FLOT alone (arm B). RESULTS: Two hundred ninety-five patients were randomly assigned (A, 146; B, 149) with balanced baseline characteristics between arms. Twenty-three patients (8%) had tumors with microsatellite instability (MSI), and 58% patients had tumors with a PD-L1 combined positive score (CPS) of ≥1. Surgical morbidity (A, 45%; B, 42%) and 60-day mortality (A, 3%; B, 2%) were comparable between arms. Downstaging favored arm A versus arm B (ypT0, 23% v 15% [one-sided P = .044]; ypT0-T2, 61% v 48% [one-sided P = .015]; ypN0, 68% v 54% [one-sided P = .012]). Histopathologic complete regression rates (pathologic complete response or TRG1a) were higher after FLOT plus ATZ (A, 24%; B, 15%; one-sided P = .032), and the difference was more pronounced in the PD-L1 CPS ≥10 (A, 33%; B, 12%) and MSI (A, 63%; B, 27%) subpopulations. Complete margin-free (R0) resection rates were relatively high in both arms (A, 96%; B, 95%). The incidence and severity of adverse events were similar in both groups. CONCLUSION: Within the limitations of the exploratory nature of the data, the addition of ATZ to perioperative FLOT is safe and improved postoperative stage and histopathologic regression.

Immunotherapy Guided by Immunohistochemistry PD-L1 Testing for Patients with NSCLC: A Microsimulation Model-Based Effectiveness and Cost-Effectiveness Analysis.

BACKGROUND: On the basis of immunohistochemistry PD-L1 testing results, patients with advanced non-small cell lung cancer (NSCLC) are treated differently. Theoretically, patients with high PD-L1 expression (50% or 1%) should receive PD-1 monotherapy for fewer adverse reactions and cost savings from avoiding chemotherapy; however, there is controversy surrounding the cut-off criteria (1% or 50%) for immunohistochemistry testing and threshold for PD-1 monotherapy. OBJECTIVE: This study aims to predict the effectiveness and cost-effectiveness of different immunotherapy strategies for patients with NSCLC in China from the healthcare system perspective. PATIENTS AND METHODS: A microsimulation model was developed to evaluate the effectiveness and cost-effectiveness of three treatment strategies: PD-L1 testing (1%) (PD-1 monotherapy for those with PD-L1 expression at 1% threshold, and combination with chemotherapy for others with immunohistochemistry testing), PD-L1 testing (50%) (PD-1 monotherapy for those with PD-L1 expression at 50% threshold, and combination with chemotherapy for others with immunohistochemistry testing), and No PD-L1 testing (PD-1 combined with chemotherapy without immunohistochemistry testing). The model assumed 1000 patients per strategy, with each patient entering a unique clinical path prior to receiving treatment on the basis of PD-L1 test results. Clinical inputs were derived from clinical trials. Cost and utility parameters were obtained from the database and literature. One-way probabilistic sensitivity analyses (PSA) and six scenario analyses were used to test the model's robustness. RESULTS: The study revealed a hierarchy of survival benefits across three strategies, with No PD-L1 testing demonstrating the most survival advantage, followed by PD-L1 testing (50%), and finally, PD-L1 testing (1%). The comparative analysis demonstrated that No PD-L1 testing significantly enhanced overall survival (OS) (HR 0.85, 95% CI 0.78-0.93), progression-free survival (HR 0.82, 95% CI 0.75-0.90), and progression-free2 survival (PFS2) (HR 0.91, 95% CI 0.83-0.99) when juxtaposed against PD-L1 testing (1%). However, these improvements were not as pronounced when compared with PD-L1 testing (50%), particularly in relation to PFS, PFS2, and OS. The cost-effectiveness analysis further unveiled incremental cost-utility ratios (ICUR), with No PD-L1 testing versus PD-L1 testing (50%) at $34,003 per quality-adjusted life year (QALY) and No PD-L1 testing versus PD-L1 testing (1%) at $34,804 per QALY. In parallel, the ICUR for PD-L1 testing (50%) versus PD-L1 testing (1%) stood at $35,713 per QALY. Remarkably, the PSA result under a willingness-to-pay (WTP) threshold of $10,144 per QALY, with a 100% probability, demonstrated PD-L1 testing (1%) as the most cost-effective option. CONCLUSIONS: The survival benefits of PD-1 monotherapy for high expression with PD-L1 immunohistochemistry testing are inferior to those of PD-1 combined with chemotherapy without testing, but it is found to be more cost-effective at the WTP thresholds in China and holds great potential in increasing affordability and reducing the economic burden.

Bromodomain-containing protein 4 inhibition improves the efficacy of cisplatin and radiotherapy in oral squamous cell carcinoma by suppressing programmed cell death-ligand 1 expression.

The bromodomain-containing protein 4 (BRD4) is highly expressed in oral squamous cell carcinoma (OSCC) and plays a crucial role in tumour progression. However, the impact of BRD4 on the efficacy of chemotherapy and radiotherapy by regulating the expression of programmed cell death-ligand 1 (PD-L1) in OSCC remains unclear. In this study, we found that the BRD4 inhibitor JQ1 effectively enhanced the inhibitory effects of cisplatin and radiotherapy on cell proliferation and promoted the apoptosis of OSCC cells by cisplatin and radiotherapy. Furthermore, treatment with JQ1 reversed the increase of the expression of PD-L1 by cisplatin and radiotherapy, whereas the overexpression of PD-L1 partially countered the beneficial effects of JQ1 on the anticancer efficacy of cisplatin and radiotherapy. These results demonstrate that the inhibition of BRD4 improves the anticancer effect of chemotherapy and radiotherapy by suppressing the expression of PD-L1 in OSCC, suggesting that targeting BRD4 could be a promising therapeutic approach for chemo/radioresistant OSCC.

Phase III, Randomized Study of Atezolizumab Plus Bevacizumab and Chemotherapy in Patients With EGFR- or ALK-Mutated Non-Small-Cell Lung Cancer (ATTLAS, KCSG-LU19-04).

PURPOSE: In the treatment of non-small-cell lung cancer (NSCLC) with a driver mutation, the role of anti-PD-(L)1 antibody after tyrosine kinase inhibitor (TKI) remains unclear. This randomized, open-label, multicenter, phase III study evaluates the efficacy of atezolizumab plus bevacizumab, paclitaxel, and carboplatin (ABCP ) in EGFR- or ALK-mutated NSCLC that progressed before TKI therapy. MATERIALS AND METHODS: We compared the clinical efficacy of ABCP followed by maintenance therapy with atezolizumab plus bevacizumab with pemetrexed plus carboplatin or cisplatin (PC) followed by pemetrexed maintenance. The primary end point was progression-free survival (PFS). RESULTS: A total of 228 patients with activating EGFR mutation (n = 215) or ALK translocation (n = 13) were enrolled from 16 sites in the Republic of Korea and randomly assigned at 2:1 ratio to either ABCP (n = 154) or PC arm (n = 74). The median follow-up duration was 26.1 months (95% CI, 24.7 to 28.2). Objective response rates (69.5% v 41.9%, P < .001) and median PFS (8.48 v 5.62 months, hazard ratio [HR], 0.62 [95% CI, 0.45 to 0.86]; P = .004) were significantly better in the ABCP than PC arm. PFS benefit increased as PD-L1 expression increased, with an HR of 0.47, 0.41, and 0.24 for PD-L1 ≥1%, ≥10%, and ≥50%, respectively. Overall survival was similar between ABCP and PC arm (20.63 v 20.27 months, HR, 1.01 [95% CI, 0.69 to 1.46]; P = .975). The safety profile of the ABCP arm was comparable with that previously reported, with no additional safety signals, but higher rates of treatment-related adverse events were observed compared with the PC arm. CONCLUSION: To our knowledge, this study is the first randomized phase III study to demonstrate the clinical benefit of anti-PD-L1 antibody in combination with bevacizumab and chemotherapy in patients with EGFR- or ALK-mutated NSCLC who have progressed on relevant targeted therapy.

Dual-drug controllable co-assembly nanosystem for targeted and synergistic treatment of hepatocellular carcinoma.

The effectiveness of chemotherapeutic agents for hepatocellular carcinoma (HCC) is unsatisfactory because of tumor heterogeneity, multidrug resistance, and poor target accumulation. Therefore, multimodality-treatment with accurate drug delivery has become increasingly popular. Herein, a cell penetrating peptide-aptamer dual modified-nanocomposite (USILA NPs) was successfully constructed by coating a cell penetrating peptide and aptamer onto the surface of sorafenib (Sora), ursolic acid (UA) and indocyanine green (ICG) condensed nanodrug (USI NPs) via one-pot assembly for targeted and synergistic HCC treatment. USILA NPs showed higher cellular uptake and cytotoxicity in HepG2 and H22 cells, with a high expression of epithelial cell adhesion molecule (EpCAM). Furthermore, these NPs caused more significant mitochondrial membrane potential reduction and cell apoptosis. These NPs could selectively accumulate at the tumor site of H22 tumor-bearing mice and were detected with the help of ICG fluorescence; moreover, they retarded tumor growth better than monotherapy. Thus, USILA NPs can realize the targeted delivery of dual drugs and the integration of diagnosis and treatment. Moreover, the effects were more significant after co-administration of iRGD peptide, a tumor-penetrating peptide with better penetration promoting ability or programmed cell death ligand 1 (PD-L1) antibody for the reversal of the immunosuppressive state in the tumor microenvironment. The tumor inhibition rates of USILA NPs + iRGD peptide or USILA NPs + PD-L1 antibody with good therapeutic safety were 72.38 % and 67.91 % compared with control, respectively. Overall, this composite nanosystem could act as a promising targeted tool and provide an effective intervention strategy for enhanced HCC synergistic treatment.

Integrin α2 promotes immune escape in non-small-cell lung cancer by enhancing PD-L1 expression in exosomes to inhibit CD8 + T-cell activity.

This study intended to delineate the mechanism and functional role of integrin α2 (ITGA2) in non-small-cell lung cancer (NSCLC) cell immune escape. Bioinformatics analysis was utilized to analyze ITGA2 expression in NSCLC tissues, and correlations between ITGA2 expression and patient survival time, ITGA2 expression and programmed cell death ligand 1 (PD-L1; CD274) expression, and ITGA2 expression and CD8+ T-cell infiltration. Quantitative real-time polymerase chain reaction detected ITGA2 expression. Transmission electron microscopy was applied to examine the morphology of exosomes, and western blot measured CD9, CD63, and PD-L1 levels. CCK-8 measured cell viability. Cell toxicity experiment measured the killing effect of CD8+ T cells on cancer cells. Enzyme-linked immunosorbent assay assessed secretion levels of interleukin-2, interferon-gamma, tumor necrosis factor-alpha, and PD-L1 expression in exosomes. Immunohistochemistry detected ITGA2, CD8, and PD-L1 expression in patient tissue samples. ITGA2 was highly expressed in NSCLC, and Pearson correlation analysis showed a negative correlation of ITGA2 with CD8+ T-cell infiltration and a positive correlation of ITGA2 with PD-L1 expression. Cell experiments showed that silencing ITGA2 hindered NSCLC cell progression and increased levels of CD8+ T-cell secretory factors. Further mechanism studies found that ITGA2 reduced CD8+ T-cell-mediated antitumor immunity via the increase in PD-L1 expression. Clinical sample testing unveiled that ITGA2 was upregulated in NSCLC tissues. PD-L1 upregulation was seen in exosomes separated from patient blood, and correlation analysis showed a positive correlation of exosomal PD-L1 expression in blood with ITGA2 expression in tissues. This study displays a novel mechanism and role of ITGA2 in NSCLC immune escape, providing directions for the clinical therapy of NSCLC patients.

Similar Efficacy Observed for First-Line Immunotherapy in Racial/Ethnic Minority Patients With Metastatic NSCLC.

BACKGROUND: Limited data exist on the impact of immunotherapy use in ethnic minority patients with non-small cell lung cancer (NSCLC), because they have been underrepresented in immunotherapy trials. This study aims to evaluate race/ethnicity and other demographic, socioeconomic, and clinical factors of patients with metastatic NSCLC treated with first-line immunotherapy. METHODS: A retrospective cohort study of 5,920 patients diagnosed with lung cancer treated at Montefiore Einstein Cancer Center from January 1, 2013, to June 1, 2022, was used to identify patients with metastatic NSCLC without EGFR, ALK, or ROS1 alterations who underwent first-line immunotherapy (n=248). The primary endpoint was overall survival (OS), with secondary endpoints of progression-free survival (PFS) and time to discontinuation (TTD) from the start of immunotherapy. RESULTS: Among the 248 patients, median follow-up time was 12.0 months, median age at start of treatment was 66 years, and 39.1% were non-Hispanic Black, 30.2% were Hispanic, and 30.7% were non-Hispanic White. OS (P=.39), PFS (P=.29), and TTD (P=.98) were similar among racial/ethnic groups. Patients with an ECOG performance status (PS) of <2 at the start of immunotherapy had longer OS compared with those with ECOG PS of ≥2 (P<.0001). PD-L1 expression (<50% vs ≥50%; P=.03) and body mass index (BMI) (P=.01) were also found to be associated with PFS, and ECOG PS (P<.0001) and BMI (P=.02) were associated with TTD. In a multivariate analysis of OS and PFS, ECOG PS was the only variable found to be significant. CONCLUSIONS: Our study observed similar benefits of immunotherapy in patients with metastatic NSCLC in different racial and ethnic groups. Furthermore, ECOG PS was associated with OS, and PD-L1 expression and BMI were associated with PFS and TTD. These findings help identify potential factors associated with outcomes and care while patients are undergoing immunotherapy.

First-in-human study of SBRT and adenosine pathway blockade to potentiate the benefit of immunochemotherapy in early-stage luminal B breast cancer: results of the safety run-in phase of the Neo-CheckRay trial.

BACKGROUND: Luminal B breast cancer (BC) presents a worse prognosis when compared with luminal A BC and exhibits a lower sensitivity to chemotherapy and a lower immunogenicity in contrast to non-luminal BC subtypes. The Neo-CheckRay clinical trial investigates the use of stereotactic body radiation therapy (SBRT) directed to the primary tumor in combination with the adenosine pathway inhibitor oleclumab to improve the response to neo-adjuvant immuno-chemotherapy in luminal B BC. The trial consists of a safety run-in followed by a randomized phase II trial. Here, we present the results of the first-in-human safety run-in. METHODS: The safety run-in was an open-label, single-arm trial in which six patients with early-stage luminal B BC received the following neo-adjuvant regimen: paclitaxel q1w×12 → doxorubicin/cyclophosphamide q2w×4; durvalumab (anti-programmed cell death receptor ligand 1 (PD-L1)) q4w×5; oleclumab (anti-CD73) q2w×4 → q4w×3 and 3×8 Gy SBRT to the primary tumor at week 5. Surgery must be performed 2-6 weeks after primary systemic treatment and adjuvant therapy was given per local guidelines, RT boost to the tumor bed was not allowed. Key inclusion criteria were: luminal BC, Ki67≥15% or histological grade 3, MammaPrint high risk, tumor size≥1.5 cm. Primary tumor tissue samples were collected at three timepoints: baseline, 1 week after SBRT and at surgery. Tumor-infiltrating lymphocytes, PD-L1 and CD73 were evaluated at each timepoint, and residual cancer burden (RCB) was calculated at surgery. RESULTS: Six patients were included between November 2019 and March 2020. Median age was 53 years, range 37-69. All patients received SBRT and underwent surgery 2-4 weeks after the last treatment. After a median follow-up time of 2 years after surgery, one grade 3 adverse event (AE) was reported: pericarditis with rapid resolution under corticosteroids. No grade 4-5 AE were documented. Overall cosmetical breast evaluation after surgery was 'excellent' in four patients and 'good' in two patients. RCB results were 2/6 RCB 0; 2/6 RCB 1; 1/6 RCB 2 and 1/6 RCB 3. CONCLUSIONS: This novel treatment combination was considered safe and is worth further investigation in a randomized phase II trial. TRIAL REGISTRATION NUMBER: NCT03875573.

Anti-tumor effect of PD-L1-targeting antagonistic aptamer-ASO delivery system with dual inhibitory function in immunotherapy.

Checkpoint inhibitor antibody therapy by blocking the interaction of surface programmed death-ligand 1(PD-L1) and programmed cell death protein 1(PD-1) has promising advantages in cancer immunotherapy. However, the response of many patients remains unsatisfactorily, suspected to be relevant to PD-L1 located in other cellular compartments and antibodies do not have access to the intracellular compartments. Herein, we identify a PD-L1-targeting DNA aptamer (PA9-1) with dual roles, including an antagonist and a delivery agent dependent on PD-L1 internalization. And we design the PD-L1-targeting antagonistic aptamer-ASO delivery system (PA9-1-ASO), with synergistic inhibitory PD-L1 activity involving the combination of blockade and silencing mechanisms. This chimera not only blocks PD-L1/PD-1 but also achieves targeted delivery of the conjugated ASO to reduce both surface PD-L1 and total PD-L1 expression. Compared with the single blockade, this chimera with the dual inhibitory function synergistically inhibits PD-L1 to amplify immunotherapeutic efficacy, providing a promising synergistic strategy for immunotherapy.

Randomized, open-label, phase II, biomarker study of immune-mediated mechanism of action of neoadjuvant subcutaneous trastuzumab in patients with locally advanced, inflammatory, or early HER2-positive breast cancer-Immun-HER trial (GOIRC-01-2016).

BACKGROUND: It is possible to induce immunomodulation in HER2-positive breast cancer (BC) by modifying the route of administration of trastuzumab. METHODS: In this multicenter randomized phase II trial, all enrolled patients (pts) with T2-T4d HER2-positive BC received 3 cycles of neoadjuvant treatment (NAT) with fluorouracil, epirubicin and cyclophosphamide every 3 weeks (q21), followed by docetaxel/pertuzumab plus intravenous trastuzumab (arm A) or, docetaxel/pertuzumab plus subcutaneous (SC) trastuzumab (arm B) q21x4 cycles. After surgical operation, each pt was treated with trastuzumab q21x14 cycles using the same SC or intravenous formulation of NAT. Primary endpoint was the proportion of subjects with high stromal tumor-infiltrating lymphocytes (sTILs) in postneoadjuvant residual disease (RD). RESULTS: Sixty-three pts (31 (arm A) and 32 (arm B)) were enrolled. Pathological complete response was obtained by 20/31 pts (64.5%; 95% CI 45.4% to 80.1%) in arm A and 19/32 pts (59.4%; 95% CI 40.1% to 76.3%) in arm B. High sTILs were observed in 27% and 46% of postneoadjuvant residual tumors in arms A and B, respectively. CD8+ T cells increased significantly in RDs of both arms (p=0.014 and 0.002 for arm A and B, respectively), whereas a significant decline in the level of CD4+ FoxP3+ regulatory T cells was observed only in arm B (p=0.016). A significant upregulation of PD-1 on sTILs was found in RD of pts enrolled in arm B (p=0.012), while programmed death-ligand 1 (PD-L1) was significantly overexpressed in residual tumors of arm A (p=0.02). A strong negative correlation was reported in arm B between expression of PD-L1 on pretreatment sTILs and CD3 expression on sTILs in RD (τ: -0.73). Grade≥3 AE incidence rates were similar between the two arms. CONCLUSIONS: SC trastuzumab induced relevant sTILs enrichment, with favorable variations of immune parameters in HER2-positive BC pts with RD after NAT. Novel immunotherapy strategies should be tested to achieve SC-specific, antitumor immune response. TRIAL REGISTRATION NUMBER: NCT03144947, and EudraCT number: 2016-000435-41.

Immunotherapy in combination with chemotherapy vs. immunotherapy alone for advanced non-small cell lung cancer and programmed death ligand 1 score <50.

INTRODUCTION: Little is known about the effectiveness of immunotherapy alone or with chemotherapy for patients with non-small cell lung cancer (NSCLC) and programmed death ligand 1 (PD-L1) expression <50 %. We examined the outcomes of PD-L1 therapy vs. PD-L1 therapy in combination with chemotherapy as first-line treatment among NSCLC patients with PD-L1 score <50 %. METHODS: We used administrative claims and prior authorization data of a national insurer from November 2015 to July 2021. We selected patients with Stage IIIb/IV NSCLC and PD-L1 expression <50 %. Each patient was required to have ≥1 claim of a PD-L1 or PD-1 inhibitor. Treatment groups were propensity-score matched 1:1 on baseline characteristics. We measured PD-L1 therapy duration, incident immune-related adverse events (irAEs), healthcare utilization, costs, and overall survival (OS). RESULTS: In the matched sample totaling 176 patients, mean duration of PD-L1 therapy was similar (4.1 [SD 3.3] months combination vs. 4.0 [SD 4.9] months monotherapy, p = 0.800). IrAEs were similar, both for FDA-recognized irAEs (48.9 % combination, 48.9 % monotherapy, p = 0.710) and other types (34.1 % combination, 39.8 % monotherapy, p = 0.473). The combination group had more all-cause inpatient stays, ER visits, and outpatient visits (all p < 0.001). Total adjusted all-cause medical cost was $112,833 (95 % CI $5,548-$251,973) higher for combination therapy. We saw no difference in OS (adjusted hazard ratio 1.09 [95 % CI 0.72-1.65]). CONCLUSION: This study found no difference in adverse drug effects or survival between PD-L1 monotherapy compared to combination therapy for patients with Stage IIIb/IV NSCLC and PD-L1 expression <50 %, though the combination therapy cohort had higher healthcare utilization and costs. MICROABSTRACT: Use of immunotherapy alone or combined with chemotherapy for patients with non-small cell lung cancer and programmed death ligand 1 expression <50 % is understudied. Our observational study using claims and authorization data from a matched sample of 176 patients found no difference in survival or the rate of adverse drug effects between groups, although the chemo-immunotherapy cohort generated higher overall healthcare costs.

[Prevention, Diagnosis, Therapy, and Follow-up of Lung Cancer - Interdisciplinary Guideline of the German Respiratory Society and the German Cancer Society - Abridged Version]. / Prävention, Diagnostik, Therapie und Nachsorge des Lungenkarzinoms.

The current S3 Lung Cancer Guidelines are edited with fundamental changes to the previous edition based on the dynamic influx of information to this field:The recommendations include de novo a mandatory case presentation for all patients with lung cancer in a multidisciplinary tumor board before initiation of treatment, furthermore CT-Screening for asymptomatic patients at risk (after federal approval), recommendations for incidental lung nodule management , molecular testing of all NSCLC independent of subtypes, EGFR-mutations in resectable early stage lung cancer in relapsed or recurrent disease, adjuvant TKI-therapy in the presence of common EGFR-mutations, adjuvant consolidation treatment with checkpoint inhibitors in resected lung cancer with PD-L1 ≥ 50%, obligatory evaluation of PD-L1-status, consolidation treatment with checkpoint inhibition after radiochemotherapy in patients with PD-L1-pos. tumor, adjuvant consolidation treatment with checkpoint inhibition in patients withPD-L1 ≥ 50% stage IIIA and treatment options in PD-L1 ≥ 50% tumors independent of PD-L1status and targeted therapy and treatment option immune chemotherapy in first line SCLC patients.Based on the current dynamic status of information in this field and the turnaround time required to implement new options, a transformation to a "living guideline" was proposed.

Perioperative Durvalumab for Resectable Non-Small-Cell Lung Cancer.

BACKGROUND: Neoadjuvant or adjuvant immunotherapy can improve outcomes in patients with resectable non-small-cell lung cancer (NSCLC). Perioperative regimens may combine benefits of both to improve long-term outcomes. METHODS: We randomly assigned patients with resectable NSCLC (stage II to IIIB [N2 node stage] according to the eighth edition of the AJCC Cancer Staging Manual) to receive platinum-based chemotherapy plus durvalumab or placebo administered intravenously every 3 weeks for 4 cycles before surgery, followed by adjuvant durvalumab or placebo intravenously every 4 weeks for 12 cycles. Randomization was stratified according to disease stage (II or III) and programmed death ligand 1 (PD-L1) expression (≥1% or <1%). Primary end points were event-free survival (defined as the time to the earliest occurrence of progressive disease that precluded surgery or prevented completion of surgery, disease recurrence [assessed in a blinded fashion by independent central review], or death from any cause) and pathological complete response (evaluated centrally). RESULTS: A total of 802 patients were randomly assigned to receive durvalumab (400 patients) or placebo (402 patients). The duration of event-free survival was significantly longer with durvalumab than with placebo; the stratified hazard ratio for disease progression, recurrence, or death was 0.68 (95% confidence interval [CI], 0.53 to 0.88; P = 0.004) at the first interim analysis. At the 12-month landmark analysis, event-free survival was observed in 73.4% of the patients who received durvalumab (95% CI, 67.9 to 78.1), as compared with 64.5% of the patients who received placebo (95% CI, 58.8 to 69.6). The incidence of pathological complete response was significantly greater with durvalumab than with placebo (17.2% vs. 4.3% at the final analysis; difference, 13.0 percentage points; 95% CI, 8.7 to 17.6; P<0.001 at interim analysis of data from 402 patients). Event-free survival and pathological complete response benefit were observed regardless of stage and PD-L1 expression. Adverse events of maximum grade 3 or 4 occurred in 42.4% of patients with durvalumab and in 43.2% with placebo. Data from 62 patients with documented EGFR or ALK alterations were excluded from the efficacy analyses in the modified intention-to-treat population. CONCLUSIONS: In patients with resectable NSCLC, perioperative durvalumab plus neoadjuvant chemotherapy was associated with significantly greater event-free survival and pathological complete response than neoadjuvant chemotherapy alone, with a safety profile that was consistent with the individual agents. (Funded by AstraZeneca; AEGEAN ClinicalTrials.gov number, NCT03800134.).