Long-term treatment results of pembrolizumab monotherapy: reconsideration of immune checkpoint inhibitor monotherapy.

Objective: The extended outcomes of the KEYNOTE-024 study demonstrated a favorable 5-year overall survival (OS) rate of 31.9%. The present study investigated the outcomes of pembrolizumab monotherapy for advanced or recurrent non-small cell lung cancer (NSCLC) at our institution. Patient: The long-term outcomes of 102 patients with advanced or recurrent NSCLC treated with pembrolizumab monotherapy between March 2017 and December 2022 were retrospectively assessed. Results: This study included a total of 102 patients [mean age: 72 ± 9.6 years (range: 41-91 years), male/female=77/25; performance status (PS; 0, 1, 2, 3, 4)=49/38/15/0/0; smokers=91 (89%), non-squamous cell carcinoma/squamous cell carcinoma=66/36, PD-L1 tumor proportion score (TPS) ≥50%/1-49%=80/22, positive for EGFR mutation=5, advanced/postoperative recurrence=51/51, treatment line: first/second or later=81/21, treatment courses: median 8 (range: 1-39), objective response rate/disease control rate=44%/55%, immune-related adverse events (irAEs): 47, 5-year OS=34%]. On univariate analysis, PS, PD-L1 TPS, and irAEs were significant prognostic factors. On multivariate analysis, histology, PD-L1 TPS, and irAEs were significant prognostic factors. Conclusion: Pembrolizumab monotherapy demonstrated promising treatment outcomes for advanced or recurrent NSCLC, as evidenced by the significant association of PD-L1 TPS with irAEs and prognosis, suggesting its potential as a beneficial therapeutic option.

An updated overview of K-RAS G12C inhibitors in advanced stage non-small cell lung cancer.

The discovery of KRAS mutations, particularly the KRASG12C variant, has been a milestone in understanding the molecular underpinnings of non-small cell lung cancer (NSCLC). These mutations are associated with aggressive tumor behavior and resistance to conventional therapies, highlighting the urgent need for targeted interventions. In this comprehensive review, we analyze the advancements in KRAS G12C inhibitors for the treatment of non-small cell lung cancer. Literature search is made from PubMed, Medline ASCO and ESMO Annual Meetings abstracts by using the following search keywords: "sotorasib", "adagrasib", "divarasib" and "KRAS G12C inhibitors." The last search was on 5 June 2024. This review highlights the importance of pharmacokinetics, pharmacodynamics and potential adverse effects for treating individual patients and ensuring the best outcomes. Additionally, the review discusses research identifying biomarkers that can predict therapy responses and mentions the combination strategies to overcome resistance. Results of the studies and ongoing clinical trials are also briefly summarized in this review. KRASG12C inhibitors sotorasib, adagrasib and the newer divarasib, has revolutionized treating patients harboring this mutation. Ongoing studies and future clinical trials will refine our understandings with the ultimate goal of improving survival and quality of life for patients with this challenging disease.

[Box: see text].

Case report: Emerging therapies for transformed small cell lung cancer: efficacy of serplulimab and a comprehensive case report.

This research reports a case of histological transformation from non-small cell lung cancer (NSCLC) to transformed small cell lung cancer (T-SCLC) in a patient undergoing EGFR-tyrosine kinase inhibitors (TKIs). The aggressive characteristics of the tumor diverged significantly from those commonly associated with lung adenocarcinomas, leading to further histological analysis. The subsequent histological examination confirmed the transformation to SCLC, consistent with established mechanisms of acquired resistance in NSCLC. Given the limited therapeutic options, the patient was administered a serplulimab-based immunochemotherapy regimen, achieving a progression-free survival (PFS) of 6 months post-transformation. The study underscores the potential of PD-1 inhibitors, particularly serplulimab, in the treatment landscape for T-SCLC and highlights the need for future comprehensive research.

Analysis of the association between immune-related adverse events and the effectiveness in patients with advanced non-small-cell-lung cancer.

PURPOSE: Immune checkpoint inhibitors (ICIs) have improved lung cancer treatment but are associated with immune-related adverse events (irAEs). This study analyzes the relationship between irAEs and treatment effectiveness in advanced non-small cell lung cancer (NSCLC) patients. METHODS: We conducted a retrospective study of NSCLC patients treated with ICIs from March 2019 to October 2022 at Zhongshan Hospital (Xiamen). Patients were divided into irAE and non-irAE groups, and treatment outcomes were compared. RESULTS: A total of 154 patients were included, with 36.4% in the irAE group and 63.6% in the non-irAE group. Most irAEs were Grade 1-2 (86.4%), with 13.6% being Grade 3 or higher. The irAE group had higher disease control rates (DCR: 94.6% vs. 76.5%, P = 0.004) and objective response rates (ORR: 42.9% vs. 26.5%, P = 0.037). Median progression-free survival (PFS) was longer in the irAE group (18 vs. 9 months, HR: 0.53, P = 0.001), as was overall survival (OS: 39.5 vs. 16 months, HR: 0.46, P = 0.001). Landmark analysis at 6 and 12 weeks confirmed that irAEs were associated with improved outcomes. Moreover, patients who experienced two or more adverse events during treatment had significantly longer OS compared to those who had only one or no adverse events (41.6 months vs. 34.0 vs. 23.6, P = 0.003). CONCLUSION: Patients with irAEs demonstrated better outcomes, including ORR, DCR, PFS, and OS. Further studies on biomarkers and irAE incidence are warranted to improve lung cancer management.

Tumor Cell Spatial Organization Directs EGFR/RAS/RAF Pathway Primary Therapy Resistance through YAP Signaling.

Non-small cell lung cancers (NSCLC) harboring common mutations in EGFR and KRAS characteristically respond transiently to targeted therapies against those mutations, but invariably, tumors recur and progress. Resistance often emerges through mutations in the therapeutic target or activation of alternative signaling pathways. Mechanisms of acute tumor cell resistance to initial EGFR (EGFRi) or KRASG12C (G12Ci) pathway inhibition remain poorly understood. Our study reveals that acute response to EGFR/RAS/RAF-pathway inhibition is spatial and culture context specific. In vivo, EGFR mutant tumor xenografts shrink by > 90% following acute EGFRi therapy, and residual tumor cells are associated with dense stroma and have increased nuclear YAP. Interestingly, in vitro EGFRi induced cell cycle arrest in NSCLC cells grown in monolayer, while 3D spheroids preferentially die upon inhibitor treatment. We find differential YAP nuclear localization and activity, driven by the distinct culture conditions, as a common resistance mechanism for selective EGFR/KRAS/BRAF pathway therapies. Forced expression of the YAPS127A mutant partially protects cells from EGFR-mediated cell death in spheroid culture. These studies identify YAP activation in monolayer culture as a non-genetic mechanism of acute EGFR/KRAS/BRAF therapy resistance, highlighting that monolayer vs spheroid cell culture systems can model distinct stages of patient cancer progression.

TIL Therapy in Lung Cancer: Current Progress and Perspectives.

Lung cancer remains the most prevalent malignant tumor worldwide and is the leading cause of cancer-related mortality. Although immune checkpoint blockade has revolutionized the treatment of advanced lung cancer, many patients still do not respond well, often due to the lack of functional T cell infiltration. Adoptive cell therapy (ACT) using expanded immune cells has emerged as an important therapeutic modality. Tumor-infiltrating lymphocytes (TIL) therapy is one form of ACT involving the administration of expanded and activated autologous T cells derived from surgically resected cancer tissues and reinfusion into patients and holds great therapeutic potential for lung cancer. In this review, TIL therapy is introduced and its suitability for lung cancer is discussed. Then its historical and clinical developments are summarized, and the methods developed up-to-date to identify tumor-recognizing TILs and optimize TIL composition. Some perspectives toward future TIL therapy for lung cancer are also provided.

Mitochondrial Pyruvate Carrier 1 as a Novel Prognostic Biomarker in Non-Small Cell Lung Cancer.

BACKGROUND: Abnormal mitochondrial pyruvate carrier 1 (MPC1) expression plays a key role in tumor metabolic reprogramming and progression. Understanding its significance in non-small cell lung cancer (NSCLC) is crucial for identifying therapeutic targets. METHODS: TIMER 2.0 was utilized to assess the expression of MPC1 in both normal and cancer tissues in pan-cancer. Overall survival (OS) differences between high and low MPC1 expression were analyzed in NSCLC using the Cancer Genome Atlas (TCGA) datasets. We also examined the expression of MPC1 in NSCLC cell lines using western blotting and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). In addition, the tissue samples and clinical information of 80 patients with NSCLC from our hospital were collected. Immunohistochemistry (IHC) was used to assess MPC1 expression, and OS was evaluated using Kaplan-Meier curves and the log-rank test. Univariate and multivariate Cox regression analyses were conducted to evaluate the prognostic values of the clinical characteristics and MPC1expression. RESULTS: Analysis of public databases suggested that MPC1 was downregulated in NSCLC compared to that in normal lung tissue and predicted poor prognosis. In addition, the expression of MPC1 in NSCLC cell lines was lower than that in human bronchial epithelial (HBE) cells at both protein and mRNA levels. Further clinical analysis suggested that MPC1 expression was correlated with age, tumor T stage, and TNM stage. Kaplan-Meier analysis revealed that NSCLC patients with high MPC1 expression had a better prognosis, particularly in lung adenocarcinoma (LUAD), whereas no survival benefit was observed in lung squamous cell carcinoma (LUSC). Univariate and multivariate analyses suggested that MPC1 was an independent prognostic factor for patients with NSCLC. CONCLUSIONS: MPC1 is poorly expressed in NSCLC, particularly in LUAD, which predicts a poor prognosis and may serve as an independent prognostic factor. Further studies on MPC1 may reveal new targets for the treatment of NSCLC.

ALKBH5-Mediated m6A Modification of XBP1 Facilitates NSCLC Progression Through the IL-6-JAK-STAT3 Pathway.

The X-box-binding protein 1 (XBP1) is an important transcription factor during endoplasmic reticulum stress response, which was reported as an oncogene in non-small cell lung cancer (NSCLC) tumorigenesis and development. However, the regulatory mechanism of XBP1 expression in NSCLC progression was less reported. N6-methyladenosine (m6A) RNA modification is an emerging epigenetic regulatory mechanism for gene expression. This study aimed to investigate the regulatory role of the m6A modification in XBP1 expression in NSCLC. We identified XBP1 as a downstream target of ALKBH5-mediated m6A modification in A549 and PC9 cells. Knockdown of ALKBH5 increased the m6A modification and the stability of XBP1 mRNA, while overexpression of ALKBH5 had the opposite effect. Furthermore, IGF2BP3 was confirmed to be a reader of XBP1 m6A methylation and to enhance the stability of XBP1 mRNA. Additionally, IGF2BP3 knockdown significantly reversed the increase in XBP1 stability mediated by ALKBH5 depletion. In vivo and in vitro experiments demonstrated that ALKBH5/IGF2BP3 promotes the proliferation, migration, and invasion of NSCLC cells by upregulating XBP1 expression. In addition, we also showed that XBP1 promoted NSCLC cell proliferation, migration, and invasion by activating IL-6-JAK-STAT3 signaling. Our research suggested that ALKBH5-mediated m6A modification of XBP1 facilitates NSCLC progression through the IL-6-JAK-STAT3 pathway.

Nivolumab plus ipilimumab with chemotherapy for non-small cell lung cancer with untreated brain metastases: A multicenter single-arm phase 2 trial (NIke, LOGiK 2004).

BACKGROUND: The effect of dual immunotherapy combined with platinum-based chemotherapy on untreated brain metastases derived from non-small cell lung cancer (NSCLC) has remained unclear. METHODS: This multicenter single-arm phase 2 study enrolled patients with chemotherapy-naïve advanced NSCLC and at least one brain metastasis ≥ 5 mm in size that had not been previously treated. Patients received nivolumab plus ipilimumab combined with platinum-doublet chemotherapy (two cycles), followed by nivolumab-ipilimumab alone. The primary endpoint of the study was intracranial response rate as determined by modified Response Evaluation Criteria in Solid Tumors (RECIST) for brain metastases of ≥ 5 mm as target lesions. RESULTS: A total of 30 patients from 18 institutions was enrolled in this study. The median age was 66.5 years (range, 47-83 years), and 26 patients (87 %) had a non-squamous cell carcinoma histology. The median size of all target brain lesions was 8.4 mm, with a range of 5-39 mm. The intracranial response rate assessed by modified RECIST was 50.0 % (95 % CI, 33.2-66.8 %), with the rate of complete response being 20.0 %, and the study met its primary endpoint. The systemic response rate was 53.3 % (95 % CI, 36.1-69.8 %), and responses for intracranial and extracranial lesions were generally consistent. The median intracranial progression-free survival was 8.1 months, and both the median intracranial duration of response and time to brain radiotherapy were not reached. CONCLUSION: Nivolumab plus ipilimumab combined with platinum-based chemotherapy showed promising intracranial activity in NSCLC patients with untreated brain metastases. TRIAL REGISTRATION: jRCT071210019.

Cost-effectiveness of multigene sequencing test and treatment for metastatic non-small cell lung cancer: A unique setting in the initial adoption phase in Japan allowing testing only after standard treatment.

Objective: To clarify the cost-effectiveness of comprehensive diagnosis and treatment of metastatic non-small cell lung cancer in Japan, from initial diagnosis to post-standard treatment, using three different strategies. Methods: A decision tree was created using three diagnostic and treatment strategies, assuming that Foundation One CDx (F1CDx), a comprehensive genome panel, was introduced in Japan in June 2019. This comprehensive decision tree includes Markov models, cost-effectiveness analyses (CEA), and cost-utility analyses (CUA) of the three strategies from the perspective of Japanese payers. Specifically, Strategy1 involves single-gene testing at the initial diagnosis and F1CDx after standard treatment; Strategy2 involves only single-gene testing at the initial diagnosis; Strategy3 involves F1CDx at the initial diagnosis. The incremental cost-effectiveness ratios (ICERs) of the three strategies are estimated. Sensitivity analyses were performed to assess the uncertainty of the parameter settings. Results: Strategy3 was dominated for both CUA and CEA. The ICER/quality-adjusted life year (QALY) for Strategy2 versus Strategy1 was USD 13,734 (JPY 2,080,923, USD 1 = JPY 151.39 on April 1st, 2024), which is less than the willingness to pay of USD 45,900 (JPY 7,500,000), and Strategy2 was more cost-effective than Strategy1. F1CDx was not cost-effective compared to multiple simultaneous single tests at the initial diagnosis, either after standard treatment or at the initial diagnosis. Sensitivity analysis also showed that the most influential factor on the ICER for both CEA and CUA was treatment cost. Conclusions: From both patient benefit and health economic perspectives, introducing F1CDx after standard treatment in June 2019 was not as cost-effective as multiple simultaneous single tests at the initial diagnosis but was more realistic from a health economic perspective than introducing F1CDx at the time of initial diagnosis. Therefore, the policy at the time of F1CDx introduction in Japan was appropriate from a short-term health-economic perspective.

Ultrasound-responsive nanocarriers with siRNA and Fe3O4 regulate macrophage polarization and phagocytosis for augmented non-small cell lung cancer immunotherapy.

The immunosuppressive tumor microenvironment (TME) significantly inhibits the effective anti-tumor immune response, greatly affecting the efficacy of immunotherapy. Most tumor-associated macrophages (TAMs) belong to the M2 phenotype, which contributes significantly to the immunosuppressive effects in non-small cell lung cancer (NSCLC) TME. The interaction between signal regulatory protein α (SIRPα) expressed on macrophages and CD47, a transmembrane protein overexpressed on cancer cells, activates the "eat-me-not" signaling pathway, inhibiting phagocytosis. In this study, a folic acid (FA)-modified ultrasound responsive gene/drugs delivery system, named FA@ PFP @ Fe3O4 @LNB-SIRPα siRNA (FA-PFNB-SIRPα siRNA), was developed using 1,2-dioleoacyl-3-trimethylammonium-propane (DOTAP), FA-1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N- [amino (polyethylene glycol)2000] (DSPE-PEG2000-FA), cholesterol, and perfluoropentane (PFP), for the delivery of siRNA encoding SIRPα mRNA and immune adjuvant Fe3O4 nanoparticles. Under ultrasound conditions, the nanobubbles effectively transfected macrophages, inhibiting SIRPα mRNA and protein expression, promoting the phagocytosis of TAMs, and synergistically reversing M2 polarization. This system promotes the infiltration of T cells, enhances the proliferation and activation of cytotoxic T cells, and inhibits the infiltration of immunosuppressive cells in tumor tissues. Administration of FA-PFNB-SIRPα siRNA combined with ultrasound significantly inhibits NSCLC progression. The study highlights the potential of ultrasound nanotechnology-enabled delivery of SIRPα siRNA and Fe3O4 as an effective strategy for macrophage-based immunotherapy to reshape the immunosuppressive TME for cancer therapy.

Safety and efficacy of consolidative stereotactic radiotherapy for oligo-residual EGFR-mutant non-small cell lung cancer after first-line third-generation EGFR-tyrosine kinase inhibitors: a single-arm, phase 2 trial.

Background: Prospective data is limited on the efficacy and safety of consolidative stereotactic radiotherapy (SRT) in metastatic epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) patients harboring oligo-residual disease (ORD) after first-line third-generation EGFR-tyrosine kinase inhibitors (TKIs). Methods: In this single-arm, phase II trial, 61 patients from two academic centers were enrolled from March 2021 to March 2023. All these patients had metastatic EGFR-mutant NSCLC and harbored ORD after first-line third-generation EGFR-TKIs. Consolidative SRT was performed and EGFR-TKIs were not held during SRT. The primary endpoint was progression-free survival (PFS) and the secondary endpoints included overall survival and treatment-related adverse events (TRAEs). A prespecified propensity score matched (PSM) comparison was conducted with a contemporary cohort of patients who developed ORD but received EGFR-TKIs alone. This trial was registered with ClinicalTrails.gov, NCT04764214. Findings: All patients received consolidative SRT. With a median follow-up of 21.1 months, the median PFS was 29.9 (80% CI 22.4-32.4) months and the lower boundary exceeded the predefined threshold, meeting the primary endpoint. TRAEs occurred in 43 (70%) patients, with pneumonitis (27.9%) and esophagitis (26.2%) being the most common toxicities. Four patients (6.6%) reported grade ≥3 TRAEs, each for pneumonitis, esophagitis, leukopenia, and cranial radiation necrosis. PSM analysis showed significantly prolonged PFS in EGFR-TKI + SRT group compared to EGFR-TKI group (HR 0.46, 80% CI 0.20-0.61; p = 0.002). Interpretation: Consolidative SRT is associated with an encouraging PFS in first-line third-generation EGFR-TKI-treated metastatic NSCLC patients harboring ORD, with generally acceptable toxicities. Further confirmatory studies are warranted. Funding: Hui Lan Public Welfare and the Chinese Society of Clinical Oncology Foundation.

Effect on Non-Small Cell Lung Cancer after Combination of Driver Gene Mutations and Anti-PD-1/PD-L1 Immunotherapy as Well as Chemotherapy.

Background: We aimed to reveal the correlation between pathological indicators and PD-L1, between gene mutation status in lung cancer through clinico-pathological data and lung cancer-related gene mutation and PD-L1 expression analysis. Methods: The study was conducted in Jinhua Municipal Central Hospital, Zhejiang, China from 2017 to 2022. PD-L1 testing and targeted gene mutations detection were evaluated. The clinical characteristics of these non-small cell lung cancer (NSCLC) samples have been obtained. The groups (LUAD, n=142; LUSC, n=143) were grouped according to clinico-pathological features and PD-L1 expression (Yes/No or High/Low), and the clinico-pathological and genetic and molecular features and correlation with PD-L1 expression were compared across the above groups. Comparisons and analyses were made between different treatment schemes. Results: Lung adenocarcinoma (LUAD, n=142) and lung squamous carcinoma (LUSC, n=143) samples were enrolled (median age: 64 years old). Pleural invasion and M staging were significantly different from PD-L1 alterations (P<0.05). The percentage of patients with PD-L1 tumor proportion score (TPS)≥50% was 36.24% and the percentage of patients with PD-L1 TPS<50% was 29.53%. The percentage of patients with PD-L1 high-expressed and treated by immunotherapy was 75.93% and 63.41% experienced Partial Response/Complete Response. The mutations ratio of EGFR, ALK, KRAS, MET, RET and TP53 were 28.86%, 1.34%, 6.04%, 0.67%, 1.34% and 0.67%, respectively. KRAS mutation was significantly different from PD-L1 alterations (P<0.01). Conclusion: There are individual differences in PD-L1 expression, which can also vary depending on the different clinical features. Specific molecular features correlate with differential PD-L1 expression and may influence the response to therapy.

The peripheral CD4+ T cells predict efficacy in non-small cell lung cancer (NSCLC) patients with the anti-PD-1 treatment.

Background: Programmed cell death protein 1 (PD-1) inhibitor therapy has become a routine treatment for advanced non-small cell lung cancer (NSCLC). However, only some NSCLC patients would benefit from anti-PD-1 therapy. We urgently need to identify biomarkers associated with clinical response to change treatment strategies promptly for patients who fail to benefit from anti-PD-1 treatment. This study was aimed to explore whether circulating CD4+ T cells and CD8+ T cells could be biomarkers for predicting anti-PD-1 efficacy. Methods: In this study, 118 NSCLC patients who received anti-PD-1 therapy were enrolled. The percentages of circulating CD4+ T cells and CD8+ T cells before and after anti-PD-1 treatment were determined by flow cytometry. The programmed cell death ligand 1 (PD-L1) expression of tumor tissues was detected by immunocytochemistry. The anti-PD-1 treatment efficacy was assessed by immune response evaluation criteria in solid tumors (iRECIST). Results: The percentage of CD4+ T cells and CD4+/CD8+ ratio in the peripheral blood (PB) was significantly elevated after anti-PD-1 treatment. In contrast, the percentage of CD8+ T cells in the PB was significantly decreased after anti-PD-1 treatment. Furthermore, we found that the percentages of CD4+ T cells and CD4+/CD8+ ratios considerably increased, and the percentages of CD8+ T cells significantly reduced in the effective group. On the contrary, the patients in the ineffective group showed no significant differences in the biomarkers. Multivariate logistic revealed that the percentage of CD4+ T cells at baseline was an independent predictor of anti-PD-1 treatment. The area under the curve (AUC) of the CD4+ T cells percentage was 0.7834 with a cut-off value of 28.53% (sensitivity =82.5%, specificity =66.23%). Conclusions: The percentage of CD4+ T cells at baseline could predict anti-PD-1 efficacy in NSCLC patients.

Clinical features and prognostic biomarkers in patients with SMARCA4-mutated non-small cell lung cancer.

Background: Patients with non-small cell lung cancer (NSCLC) carrying SMARCA4 mutations (SMARCA4-Mut) tend to have more advanced disease and a poor prognosis. However, due to the rarity of this mutation and the lack of related studies, the characteristics of SMARCA4-Mut NSCLC patients remains poorly determined. To clarify the clinical characteristics and prognostic factors of SMARCA4-Mut NSCLC, we initiated the present study to provide a clinical reference. Methods: We used data from two cohorts of NSCLC-SMARCA4-mutated samples: The Cancer Genome Atlas (TCGA) database and our center's clinical data. The TCGA database was used to obtain 481 NSCLC-SMARCA4-Mut samples for clinical characterization. The center collected data on 224 consecutive NSCLC patients treated between December 2020 to July 2022. Among them, 26 harbored SMARCA4 mutations, and 20 were eligible for inclusion in the study. Clinical, pathological, and molecular features, as well as prognostic role of SMARCA4 mutations were analyzed. Additionally, we analyzed the prognostic impact of Napsin A expression in SMARCA4-Mut patients. Results: The TCGA database included 480 patients with SMARCA4-Mut NSCLC, 311 males (64.8%) and 169 females (35.2%), with a median age of 67 years. Among the 20 SMARCA4-Mut patients in our center series, 12 (60%) were males and 8 (40%) females, with a median age of 63. The intergroup prognostic correlation analysis showed that SMARCA4-Mut patients had significantly worse prognosis than those the wild-type SMARCA4 (SMARCA4-WT) (P=0.04). Within the SMARCA4-Mut group, patients with Napsin A expression had longer overall survival (OS) (P=0.03) than those without expression. Median survival in the Napsin A-positive and negative groups was 32 and 15 months, respectively. According to time-dependent receiver operating curve analysis, patients with Napsin A expression had significantly longer first-line treatment progression-free survival (PFS1) [area under the curve (AUC) =0.748] and OS (AUC =0.586). No prognostic value of Napsin A was found in patients SMARCA4-WT patients. Conclusions: SMARCA4-Mut is an adverse prognostic feature in NSCLC patients. Napsin A expression in SMARCA4-Mut patients is associated with prolonged OS.

Prognostic and predictive significance of soluble programmed death ligand 1 in bronchoalveolar lavage fluid in stage IV non-small cell lung cancer.

Background: Patients with non-small cell lung cancer (NSCLC) have been shown to exhibit elevated levels of soluble programmed death-ligand 1 (sPD-L1) in the blood, associated with poor survival in NSCLC. The bronchoalveolar lavage fluid (BALF) composition reflects the tumor microenvironment of lung cancer. In this study, we investigated sPD-L1 levels in BALF and its role as a prognostic and predictive marker in patients with stage IV NSCLC. Methods: We prospectively obtained BALF from lung cancer patients who underwent bronchoscopy between January 2020 and September 2022 at Chungnam National University Hospital (CNUH). Finally, 94 NSCLC stage IV patients were included in this study. Soluble PD-L1 levels in BALF were measured using a human PD-L1 Quantikine ELISA kit. Results: The correlation between PD-L1 expression in tumor cells and sPD-L1 in BALF was weakly positive (rho =0.314, P=0.002). The median overall survival (OS) of the low sPD-L1 in BALF group was 16.47 months [95% confidence interval (CI): 11.15-21.79 months], which is significantly longer than 8.87 months (95% CI: 0.0-19.88 months, P=0.001) in the high sPD-L1 in BALF group. In 64 patients treated with or without immune checkpoint inhibitors (ICIs), sPD-L1 in BALF was significantly associated with progression-free survival (PFS) and OS. In the subgroup analysis of 31 patients treated with ICI, the objective response rate (ORR) in the low sPD-L1 BALF group was significantly higher than in high sPD-L1 in BALF group (ORR: 60.9% vs. 12.5%, P=0.02). Conclusions: Soluble PD-L1 in BALF is a potential prognostic indicator for patients with stage IV NSCLC and a predictive marker for ICI treatment response.

Efficacy of ALK inhibitors in Asian patients with ALK inhibitor-naïve advanced ALK-positive non-small cell lung cancer: a systematic review and network meta-analysis.

Background: A previous network meta-analysis (NMA) compared the efficacy of anaplastic lymphoma kinase (ALK) inhibitors in ALK-positive non-small cell lung cancer (NSCLC). The phase III INSPIRE study of iruplinalkib was published recently. The present study aimed to add the results related to iruplinalkib to the NMA. Methods: A systematic literature search was performed in PubMed, Embase, Cochrane Library, Google, and Baidu. Randomized controlled trials (RCTs) reporting the independent review committee-assessed progression-free survival (PFS), objective response rate (ORR), or disease control rate (DCR) results of Asian patients with ALK inhibitor-naïve advanced ALK-positive NSCLC were eligible for inclusion in the NMA. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool. Bayesian fixed-effect models were used for the direct and indirect pairwise comparisons. This study was registered with PROSPERO (CRD42024555299). Results: Eight studies, involving 1,477 Asian patients and seven treatments (crizotinib, alectinib, brigatinib, ensartinib, envonalkib, iruplinalkib, and lorlatinib), were included in the NMA. In terms of the overall risks of bias, all of the studies had "some concerns". All the next-generation ALK inhibitors were statistically superior to crizotinib in terms of PFS. Iruplinalkib had the best surface under the cumulative ranking curve (74.0%), followed by brigatinib (69.1%) and ensartinib (63.7%). Most of the pairwise comparisons did not reveal significant differences in the ORR and DCR. In terms of both the ORR and DCR, alectinib ranked first, followed by lorlatinib. Conclusions: Next-generation ALK inhibitors had better efficacy than crizotinib in the treatment of Asian patients with ALK inhibitor-naïve advanced ALK-positive NSCLC. Iruplinalkib may have more favorable PFS benefit than other ALK inhibitors for Asians.

Safety and efficacy of immunotherapy using a double-dose regimen in advanced non-small cell lung cancer (NSCLC): results of IDEE study.

Background: Pembrolizumab 400 mg every six weeks (Q6W) and nivolumab 480 mg every four weeks (Q4W) are used since 2020 and the coronavirus disease 2019 (COVID-19) pandemic. This recommendation relied on pharmacokinetic and pharmacodynamic models. The objective of the IDEE (Immunothérapie Double dose Etendue: Experience bretonne) study is to determine the safety and efficacy of this treatment regimen in real life conditions. Methods: We conducted an observational, retrospective, multicentric study including 117 patients with advanced non-small cell lung cancer (NSCLC) who received pembrolizumab Q6W or nivolumab Q4W between March 2020 and March 2021. Results: The median age was 67 years, 68% were men with predominantly lung adenocarcinoma. The median time to double-dose regimen failure (TDDF) was 9.2 months. The survival rate at 12 months was 79%. TDDF was not influenced by sex, line of treatment, pathologic subtypes or anti-programmed cell death protein 1 (PD-1) antibody. There was no correlation between TDDF and duration of prior exposition to immunotherapy before switching. Sixty-eight patients experienced double-dose treatment failure, 28% because of toxicity including five definitive discontinuations. Five grade ≥3 immune-adverse events were reported included two cases of pneumonitis, all responding to corticosteroid therapy. Conclusions: Our multicentric cohort supports the feasibility of pembrolizumab Q6W and nivolumab Q4W for patients with advanced NSCLC. There is no warning signal regarding safety neither efficacy in our real-life data.