Phase 1b trial of anti-HER2 antibody inetetamab and pan-HER inhibitor pyrotinib in HER2-positive advanced lung cancer.

There remains an unmet need for targeted therapies against advanced non-small-cell lung cancer (NSCLC) with HER2 mutations. To improve the antitumor activity of single anti-HER2 agent, this prospective, single-arm clinical trial (NCT05016544) examined the safety profile and efficacy of anti-HER2 antibody inetetamab and pan-HER TKI pyrotinib in HER2-posivite advanced NSCLC patients. Enrolled patients received inetetamab every 3 weeks and pyrotinib once per day (pyrotinib, dose-escalation part, 240 mg, 320 mg; dose-expansion part, 320 mg). Primary endpoints were dose-limiting toxicity (DLT) dosage and safety. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). A total of 48 patients were enrolled. During the dose-escalation period, no DLT occurred. Diarrhea was the most commonly reported treatment-related adverse event (TRAE). Grade 3 TRAEs occurred in seven patients. The median PFS (mPFS) was 5.5 months [95% confidence interval (CI): 4.4-8.6 months]. The confirmed ORR and DCR reached 25% (11/44) and 84.1% (37/44), respectively. Responses were shown in patients with distinct HER2 aberrations. In summary, inetetamab in combination with pyrotinib demonstrated acceptable safety and antitumor activity among patients with advanced HER2-mutant NSCLC.

Neoadjuvant-Adjuvant vs Neoadjuvant-Only PD-1 and PD-L1 Inhibitors for Patients With Resectable NSCLC: An Indirect Meta-Analysis.

Importance: Neoadjuvant therapy combining programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1) inhibitors with platinum-based chemotherapy has demonstrated significant improvement in pathologic response and survival rates among patients with resectable non-small cell lung cancer (NSCLC). However, it remains controversial whether PD-1 blockade therapy given before and after surgery (neoadjuvant-adjuvant treatment) is associated with better outcomes than when given only before surgery (neoadjuvant-only treatment). Objective: To compare the efficacy and safety associated with neoadjuvant-adjuvant anti-PD-1 and anti-PD-L1 therapy with neoadjuvant-only anti-PD-1 and anti-PD-L1 therapy for patients with resectable NSCLC. Data Sources: A systematic search was conducted across databases including PubMed, Embase, and the Cochrane Library, as well as major oncology conferences, through July 31, 2023. Study Selection: Randomized clinical trials comparing neoadjuvant-adjuvant or neoadjuvant-only PD-1 and PD-L1 inhibitor therapy vs chemotherapy alone for patients with resectable NSCLC were selected. Data Extraction and Synthesis: Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline, 2 authors independently extracted data. Hazard ratios (HRs) and 95% CIs for event-free survival (EFS) and overall survival (OS) were extracted and then pooled through the generic inverse-variance methods. Relative risks (RRs) for treatment-related adverse events (TRAEs) were derived via the Mantel-Haenszel method. Using chemotherapy as a common comparator, indirect comparisons between neoadjuvant-adjuvant immunotherapy and neoadjuvant-only immunotherapy were conducted using frequentist methods. A random or fixed model was used based on intertrial heterogeneity identified through the Cochran Q test. Main Outcomes and Measures: The primary outcome was EFS, with secondary outcomes including OS and TRAEs. Results: The study encompassed 4 trials of neoadjuvant-adjuvant immunotherapy and 1 trial of neoadjuvant-only immunotherapy, involving 2385 patients. Direct meta-analysis revealed significant improvements in EFS for both neoadjuvant-adjuvant and neoadjuvant-only immunotherapy compared with chemotherapy alone. In indirect meta-analysis, the addition of adjuvant immunotherapy to neoadjuvant immunotherapy was not associated with improved EFS (HR, 0.90; 95% CI, 0.63-1.30; P = .59) or OS (HR, 1.18; 95% CI, 0.73-1.90; P = .51) compared with neoadjuvant-only immunotherapy. Moreover, the incidence of any grade of TRAEs significantly increased with the addition of adjuvant immunotherapy (RR, 1.08; 95% CI, 1.00-1.17; P = .04). Conclusions and Relevance: This meta-analysis suggests that adding PD-1 or PD-L1 inhibitors in the adjuvant phase to neoadjuvant treatment with PD-1 or PD-L1 inhibitors and chemotherapy may not improve survival outcomes for patients with resectable NSCLC and may be associated with increased adverse events. Future validation of these findings is warranted through head-to-head randomized clinical trials.

Rechallenge of immune checkpoint inhibitors in advanced non-small cell lung cancer.

Immune checkpoint inhibitor (ICI) rechallenge in non-small cell lung cancer (NSCLC) is a promising therapeutic strategy. The situation for ICI rechallenge can be divided into three categories: adverse events (AEs); resistance to ICIs, and rechallenge becomes compulsive because of tumor relapse while the patients had completed a 2 year course of immunotherapy. However, these categories are still controversial and should be explored further. Through voting at the 6th Straits Summit Forum on Lung Cancer, in this study we summarize the consensus of 147 experts in ICI rechallenges. A total of 97.74% experts agreed to rechallenge; 48.87% experts rechallenge with the original drug, and the others rechallenge with a different drug; 40.3% agreed to rechallenge directly after progression; 88.06% experts agreed to ICI rechallenge with a combination regimen; and factors such as previous performance status score, PD-1 expression, and age should also be considered. Understanding the the clinical studies in ICI rechallenge could bring us one step closer to understanding the consensus. In patients with advanced NSCLC who have suffered recurrent or distant metastasis after immunotherapy, the option of rechallenge with ICIs is a promising treatment option.

Impact of prophylactic dexamethasone on the efficacy of immune checkpoint inhibitors plus platinum-based chemotherapy in patients with advanced Non-Squamous Non-Small-Cell lung cancer.

BACKGROUND: Baseline corticosteroids exposure is associated with inferior clinical outcomes in patients with non-small-cell lung cancer (NSCLC) treated with programmed cell death-1 (PD-1) axis blockade. Dexamethasone is a potent corticosteroid used in the prevention of chemotherapy-associated adverse events (CAAEs). OBJECTIVE: Since dexamethasone has immunosuppressive properties, this study attempted to elucidate its effects on the efficacy of immunotherapy plus chemotherapy in patients with non-squamous NSCLC. METHODS: The study retrospectively analyzed the medical records of 254 advanced non-squamous NSCLC patients who received front-line treatment with a PD-1 pathway inhibitor and platinum-based chemotherapy at three academic institutions. The average dosage of prophylactic dexamethasone per chemotherapy cycle was calculated. Patients were divided into three groups based on the dose of dexamethasone: High-d (≥24 mg), Moderate-d (12-24 mg), and Low-d (<12 mg). Spearman's rank correlation was used to assess the correlation between the dosage of dexamethasone and progression-free survival (PFS). Logistic regression was used to assess the correlation between dexamethasone dosage and the occurrence of immune related adverse effects (irAE). Univariate and multivariate Cox proportional hazards regression models were used to analyze the differences in survival among the different dexamethasone dosage groups. RESULT: The dosage of prophylactic dexamethasone was not significantly correlated with PFS (Spearman's rho = -0.103, P = 0.098). Results from the univariate [hazard ratio (HR)Low-d/High-d, 1.00; P = 0.997; HRModerate-d/High-d, 0.85; P = 0.438] and multivariate (HRLow-d/High-d, 0.71; P = 0.174; HRModerate-d/High-d, 0.87; P = 0.512) analyses showed no significant association between dexamethasone and PFS. Dexamethasone did not have significant effect on the objective response rate, disease control rate or overall survival. The toxicity profiles of irAE were similar across all three groups. CONCLUSION: The results of this study suggest that the use of prophylactic dexamethasone does not have an adverse effect on the clinical outcomes of non-squamous NSCLC patients treated with PD-1 blockade therapy and chemotherapy. Routine use of dexamethasone for preventing CAAEs should be recommended for patients undergoing combined immunotherapy and chemotherapy.

Clinical definition of secondary resistance to immunotherapy in non-small cell lung cancer.

Immune checkpoint inhibitors (PD-1/PD-L1 and CTLA-4 blockade) have revolutionized the treatment landscape in non-small cell lung cancer (NSCLC). Secondary resistance to immunotherapy (IO), which poses a substantial challenge in clinical settings, occurs in several initial responders. Currently, new treatment approaches have been extensively evaluated in investigational studies for these patients to tackle this difficult problem; however, the lack of consistency in clinical definition, uniform criteria for enrollment in clinical trials, and interpretation of results remain significant hurdles to progress. Thus, our expert panel comprehensively synthesized data from current studies to propose a practical clinical definition of secondary resistance to immunotherapy in NSCLC in metastatic and neoadjuvant settings. In addition to patients who received IO alone (including IO-IO combinations), we also generated a definition for patients treated with chemotherapy plus IO. This consensus aimed to provide guidance for clinical trial design and facilitate future discussions with investigators. It should be noted that additional updates in this consensus are required when new data is available.

Tumor response assessment by measuring the single largest lesion per organ in advanced non-small cell lung cancer patients treated with PD-1/PD-L1 inhibitor.

Background: For Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST1.1), measuring up to two target lesions per organ is an arbitrary criterion. Objectives: We sought to compare response assessment using RECIST1.1 and modified RECIST1.1 (mRECIST1.1, measuring the single largest lesion per organ) in advanced non-small cell lung cancer (aNSCLC) patients undergoing anti-PD-1/PD-L1 monotherapy. Methods: Concordance of radiologic response categorization between RECIST1.1 and mRECIST1.1 was compared using the Kappa statistics. C-index was calculated to evaluate prognostic accuracy of radiologic response by the two criteria. The Kaplan-Meier method and Cox regression analysis were conducted for progression-free survival (PFS) and overall survival (OS). Results: Eighty-seven patients who had at least two target lesions in any organ per the RECIST1.1 were eligible for comparison analysis. Tumor response showed excellent concordance when measured using the RECIST1.1 and mRECIST1.1 (Kappa = 0.961). C-index by these two criteria was similar for PFS (0.784 versus 0.785) and OS (0.649 versus 0.652). Responders had significantly longer PFS and OS versus non-responders (p < 0.05), whichever criterion adopted. Radiologic response remained a significant predictor of PFS and OS in multivariate analysis (p < 0.05). Conclusion: The mRECIST1.1 was comparable to RECIST1.1 in response assessment among aNSCLC patients who received single-agent PD-1/PD-L1 inhibitor. The mRECIST1.1, with reduced number of lesions to be measured, may be sufficient and more convenient to assess antitumor activity in clinical practice.

Adjuvant therapy in completely resected, EGFR-mutant non-small cell lung cancer: a comparative analysis of treatment efficacy between EGFR-TKI and anti-PD-1/PD-L1 immunotherapy.

The IMpower010 and KEYNOTE-091 trials have demonstrated the benefit of adjuvant immunotherapy (IO) after chemotherapy (C+IO) in resected non-small cell lung cancer (NSCLC), including those with epidermal growth factor receptor gene (EGFR) mutation. Meanwhile, several studies have reported that EGFR-tyrosine kinase inhibitor (EGFR-TKI) may prolong disease-free survival (DFS) in these patients. However, there is currently a lack of head-to-head comparison between these two adjuvant therapy strategies. Therefore, we designed a comparative analysis of their efficacy to inform clinical decision-making by assessing DFS as the primary outcome. The results of direct meta-analysis indicated that EGFR-TKI reduced the risk of recurrence and/or death in completely resected NSCLC (HREGFR-TKI/chemo = 0.41, 95% CI: 0.23 to 0.74, p=0.003), while C+IO did not significantly improve DFS compared with chemotherapy alone (HRC+IO/chemo=0.68, 95% CI: 0.31 to 1.50, p=0.338). Indirect comparison suggested that EGFR-TKI has a trend to prolong DFS compared with C+IO (HR EGFR-TKI/C+IO = 0.60, 95% CI: 0.23 to 1.61, p=0.312), while the third-generation TKI (3rd-TKI) osimertinib significantly outperformed C+IO (HR3rd-TKI/C+IO = 0.29, 95% CI: 0.12 to 0.70, p=0.006). In conclusion, osimertinib rather than immunotherapy should be regarded as the preferred adjuvant therapy in completely resected, EGFR-mutant NSCLC.

Deciphering transcriptomic determinants of the divergent link between PD-L1 and immunotherapy efficacy.

Programmed cell death ligand 1 (PD-L1) expression remains the most widely used biomarker for predicting response to immune checkpoint inhibitors (ICI), but its predictiveness varies considerably. Identification of factors accounting for the varying PD-L1 performance is urgently needed. Here, using data from three independent trials comprising 1239 patients, we have identified subsets of cancer with distinct PD-L1 predictiveness based on tumor transcriptome. In the Predictiveness-High (PH) group, PD-L1+ tumors show better overall survival, progression-free survival, and objective response rate with ICI than PD-L1- tumors across three trials. However, the Predictiveness-Low (PL) group demonstrates an opposite trend towards better outcomes for PD-L1- tumors. PD-L1+ tumors from the PH group demonstrate the superiority of ICI over chemotherapy, whereas PD-L1+ tumors from the PL group show comparable efficacy between two treatments or exhibit an opposite trend favoring chemotherapy. This observation of context-dependent predictiveness remains strong regardless of immune subtype (Immune-Enriched or Non-Immune), PD-L1 regulation mechanism (adaptative or constitutive), tumor mutation burden, or neoantigen load. This work illuminates avenues for optimizing the use of PD-L1 expression in clinical decision-making and trial design, although this exploratory concept should be further confirmed in large trials.

STK11/LKB1-Deficient Phenotype Rather Than Mutation Diminishes Immunotherapy Efficacy and Represents STING/Type I Interferon/CD8+ T-Cell Dysfunction in NSCLC.

INTRODUCTION: Conflicting findings have been reported regarding the association between STK11/LKB1 mutations and immune checkpoint inhibitor (ICB) efficacy in NSCLC. It has been reported that tumors could exhibit impaired STK11/LKB1 function even without STK11 mutations. We hypothesized that STK11 phenotype rather than mutation may better stratify ICB outcomes. METHODS: Selected functional STK11 events and LKB1 protein data were leveraged to establish a transcriptomics-based classifier of STK11 phenotype (STK11-deficient [-def] or -proficient [-prof]). We analyzed in-house and Genentech/Roche's data of three randomized trials of programmed cell death protein-1 or programmed death-ligand 1 (PD-L1) inhibition in NSCLC (ORIENT-11, n = 171; OAK, n = 699; POPLAR, n = 192) and The Cancer Genome Atlas-NSCLC cohort. RESULTS: Tissue STK11 mutation did not affect ICB outcomes. However, the survival benefit of ICB versus chemotherapy were lost or reversed in STK11-def tumors (hazard ratios for death, 95% confidence interval: OAK [0.97, 0.69-1.35]; POPLAR [1.61, 0.88-2.97]; ORIENT-11 [1.07, 0.50-2.29]), while remaining in STK11-prof tumors (hazard ratios for death, 95% confidence interval: OAK [0.81, 0.66-0.99]; POPLAR [0.66, 0.46-0.95]; ORIENT-11 [0.59, 0.37-0.92]). In tumors differentially classified by phenotype and mutation status, STK11-wild-type/def tumors had significantly worse ICB outcomes than STK11-mutated (STK11-MUT)/prof tumors (p < 0.05). The deleterious impact of STK11 deficiency was independent of STK11/KRAS/KEAP1 status or PD-L1 expression. The STING/interferon-I signaling, which was previously shown to be suppressed in STK11-MUT models, was perturbed in patients with STK11-def tumors rather than those with STK11-MUT tumors. Surprisingly, whereas high CD8+ T-cell infiltration was significantly associated with prolonged survival with ICB in STK11-prof tumors (p < 0.05 for 3 trials), it predicted an opposite trend toward worse ICB outcomes in STK11-def tumors across three trials. This suggested an association between STK11 deficiency and CD8+ T-cell dysfunction, which might not be reversed by programmed cell death protein 1 or PD-L1 blockade. CONCLUSIONS: STK11 phenotype rather than mutation status can accurately identify patients with ICB-refractory NSCLC and reflect immune suppression. It can help refine stratification algorithms for future clinical research and also provide a reliable resource aiding basic and translational studies in identifying therapeutic targets.

Machine learning-based risk model incorporating tumor immune and stromal contexture predicts cancer prognosis and immunotherapy efficacy.

The immune and stromal contexture within the tumor microenvironment (TME) interact with cancer cells and jointly determine disease process and therapeutic response. We aimed at developing a risk scoring model based on TME-related genes of squamous cell lung cancer to predict patient prognosis and immunotherapeutic response. TME-related genes were identified through exploring genes that correlated with immune scores and stromal scores. LASSO-Cox regression model was used to establish the TME-related risk scoring (TMErisk) model. A TMErisk model containing six genes was established. High TMErisk correlated with unfavorable OS in LUSC patients and this association was validated in multiple NSCLC datasets. Genes involved in pathways associated with immunosuppressive microenvironment were enriched in the high TMErisk group. Tumors with high TMErisk showed elevated infiltration of immunosuppressive cells. High TMErisk predicted worse immunotherapeutic response and prognosis across multiple carcinomas. TMErisk model could serve as a robust biomarker for predicting OS and immunotherapeutic response.

Continuation of anti-PD-1 therapy plus physician-choice treatment beyond first progression is not associated with clinical benefit in patients with advanced non-small cell lung cancer.

Objective: Few data are available on the optimal treatment options after disease progression from first-line treatment of immune checkpoint inhibitors (ICIs) plus chemotherapy. This study aimed to describe the safety and efficacy of continuing ICIs beyond first progress disease (PD) in non-small cell lung cancer (NSCLC). Methods: Patients with NSCLC previously treated with first-line anti-PD-1 antibody plus platinum-doublet chemotherapy and hence had PD as per Response Evaluation Criteria in Solid Tumors v1.1 were enrolled. For the subsequent line, patients received physician's choice (PsC) with or without an anti-PD-1 antibody. The primary outcome was progression-free survival after second-line treatment (PFS2). Secondary outcomes included overall survival (OS) from the initiation of first-line treatment, post-second-progression survival (P2PS), overall response rate (ORR), disease control rate (DCR), and safety during second-line treatment. Results: Between July 2018 and January 2021, 59 patients were included. A total of 33 patients received a physician-decided second-line regimen plus ICIs (PsC plus ICIs group), and 26 patients did not continue ICIs (PsC group). There was no significant difference in PFS2 between the PsC plus ICIs group and the PsC group (median, 6.5 vs. 5.7 months, p = 0.46). median OS (28.8 vs. 29.2 months), P2PS (13.4 vs. 18.7 months), ORR (18.2% vs. 19.2%), and DCR (78.8% vs, 84.6%) were also similar between the two groups. No new safety signals were observed. Conclusion: In this real-world setting, patients treated with continued ICIs beyond their first disease progression did not experience clinical benefit but without compromising safety.

LRRC3B and its promoter hypomethylation status predicts response to anti-PD-1 based immunotherapy.

Background: The leucine rich repeat containing 3B (LRRC3B) gene is a tumor suppressor gene involved in the anti-tumor immune microenvironment. Expression of LRRC3B and DNA methylation at the LRRC3B promoter region may serve as a useful marker to predict response to anti-PD-1 therapy. However, no studies have yet systematically explored the protective role of LRRC3B methylation in tumor progression and immunity. Methods: Expression of LRRC3B of 33 cancer types in The Cancer Genome Atlas (TCGA) was downloaded from UCSC Xena (http://xena.ucsc.edu/). And, we evaluated the differential expression of LRRC3B according to tumor stage, overall survival, and characteristics of the tumor microenvironment. The immunotherapeutic cohorts included IMvigor21, GSE119144, and GSE72308 which were obtained from the Gene Expression Omnibus database. We conducted pearson correlation analysis of LRRC3B and tumor microenvironment (TME) in pan-cancer. Also, six immune cell types (B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells) and tumor purity were analyzed using the Tumor IMmune Estimation Resource (TIMER1.0) (Tumor IMmune Estimation Resource (TIMER2.0). And, a "silencing score" model base on LRRC3B promoter methylation to predict overall survival (OS) by multivariate Cox regression analysis was constructed. Finally, the model was applied to predict anti-PD-1 therapy in non-small cell lung cancer (NSCLC) and breast cancer (BRCA). Results: LRRC3B expression associated with less tumor invasion, less severe tumor stage, and decreased metastasis. The inactivation of LRRC3B promoted the enrichment of immuneosuppressive cells, including myeloid-derived suppressor cells (MDSCs), cancer-associated fibroblasts (CAFs), M2 subtype of tumor-associated macrophages (M2-TAMs), M1 subtype of tumor-associated macrophages (M1-TAMs), and regulatory T (Treg) cells. A high silencing score was significantly associated with immune inhibition, low expression of LRRC3B, poor patient survival, and activation of cancer-related pathways. Conclusion: Our comprehensive analysis demonstrated the potential role of LRRC3B in the anti-tumor microenvironment, clinicopathological features of cancer, and disease prognosis. It suggested that LRRC3B methylation could be used as a powerful biomarker to predict immunotherapy responses in NSCLC and BRCA.

Pretreatment Serum Lactate Dehydrogenase and Metastases Numbers as Potential Determinants of Anti-PD-1 Therapy Outcome in Nasopharyngeal Carcinoma.

BACKGROUND: We aimed to investigate the determinant factors of anti-PD-1 therapy outcome in nasopharyngeal carcinoma (NPC). METHODS: In this retrospective study, we included 64 patients with recurrent/metastatic NPC. The association of patients' characteristics, C-reactive protein (CRP), neutrophil to lymphocyte ratio (NLR), and lactate dehydrogenase (LDH) with survival benefit of anti-PD-1 therapy were analyzed using Cox regression models and Kaplan-Meier analyses. Patients were divided based on the median value of CRP, NLR or LDH into different subgroups. RESULTS: At a median follow-up time of 11.4 months (range: 1-28 months), median progression-free survival (PFS) and overall survival (OS) were 1.9 months (95% CI, .18-3.6) and 15 months (95% CI, 10.9-19.1) months, respectively. Pretreatment metastases numbers was significant predictor of PFS (HR = 1.99; 95% CI 1.10-3.63; P = .024) and OS (HR = 2.77; 95% CI 1.36-5.61; P = .005). Baseline LDH level was independent predictor of OS (HR = 7.01; 95% CI 3.09-15.88; P < .001). Patients with LDH level >435 U/L at the baseline had significantly shorter PFS and OS compared to patients with LDH level ≤435 U/L (median PFS: 1.7 vs 3.5 months, P = .040; median OS: 3.7 vs 18.5 months, P < .001). Patients with non-durable clinical benefit (NDB) had significantly higher LDH level at the baseline compared to patients who achieved durable clinical benefit (DCB) (P = .025). Post-treatment levels of CRP, LDH, and NLR were decreased compared to baseline in patients with DCB (P = .030, P = .088, and P = .066, respectively), whereas, there was a significant increase in post-treatment level of LDH compared with baseline in patients with NDB (P = .024). CONCLUSIONS: LDH level at the baseline was an independent predictor of OS and pretreatment metastases numbers was a significant predictor of PFS and OS.

Role of antiangiogenic agents in first-line treatment for advanced NSCLC in the era of immunotherapy.

BACKGROUND & OBJECTIVE: "Anti-angiogenetic drugs plus chemotherapy" (anti-angio-chemo) and "immune checkpoint inhibitors plus chemotherapy" (ICI-chemo) are superior to traditional chemotherapy in the first-line treatment of patients with advanced non-small-cell lung cancer (NSCLC). However, in the absence of a direct comparison of ICI-chemo with anti-angio-chemo, the superior one between them has not been decided, and the benefit of adding anti-angiogenetic agents to ICI-chemo remains controversial. This study aimed to investigate the role of antiangiogenic agents for advanced NSCLC in the era of immunotherapy. METHODS: Eligible randomized controlled trials (RCTs) comparing chemotherapy versus therapeutic regimens involving ICIs or anti-angiogenetic drugs were included. Outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and rate of grade 3-4 toxicity assessment. R-4.3.1 was utilized to perform the analysis. RESULTS: A total of 54 studies with a sample size of 25,046 were finally enrolled. "Atezolizumab + Bevacizumab + Chemotherapy" significantly improved the ORR compared with "Atezolizumab + Chemotherapy" (Odds ratio (OR) = 2.73, 95% confidence interval (CI): 1.27-5.87). The trend also favored "Atezolizumab + Bevacizumab + Chemotherapy" in PFS and OS (hazard ratio (HR) = 0.71, 95% CI: 0.39-1.31; HR = 0.94, 95% CI: 0.77-1.16, respectively). In addition, "Pembrolizumab + Chemotherapy" and "Camrelizumab + Chemotherapy" significantly prolonged the PFS compared to "Bevacizumab + Chemotherapy" (HR = 0.65, 95% CI: 0.46-0.92; HR = 0.63, 95% CI: 0.41-0.97; respectively). Meanwhile, "Pembrolizumab + Chemotherapy" and "Sintilimab + Chemotherapy" yielded more OS benefits than "Bevacizumab + Chemotherapy" (HR = 0.69, 95% CI: 0.56-0.83; HR = 0.64, 95%CI: 0.46-0.91; respectively). Scheme between "Atezolizumab + Bevacizumab + Chemotherapy" and "Atezolizumab + Chemotherapy" made no significant difference (OR = 1.18, 95%CI: 0.56-2.42) concerning the rate of grade 3-4 toxicity. It seemed that ICI-chemo yielded more improvement in quality-adjusted life-year (QALY) than "Bevacizumab + Chemotherapy" in cost-effectiveness analysis. CONCLUSION: Our results suggest that ICI-chemo is associated with potentially longer survival, better cost-effectiveness outcomes, and comparable safety profiles than anti-angio-chemo. Also, adding bevacizumab to ICI-chemo seemed to provide additional therapeutic benefits without adding treatment burden. Our findings would supplement the current standard of care and help the design of future clinical trials for the first-line treatment of patients with advanced NSCLC.

Optimizing the tumor shrinkage threshold for evaluating immunotherapy efficacy for advanced non-small-cell lung cancer.

PURPOSE: The rise of immune checkpoint inhibitors (ICIs) in recent years has coincided with unusual clinical response patterns. Modification of the sum of longest diameters (SLD)-based threshold that reflecting dynamic change of the tumor burden and predicting response to ICIs, may markedly improve current treatment regimens. METHODS: The baseline and post-treatment SLD of target lesion was recorded and the maximum percent change of the SLD from baseline was designated as SLD-change score. The optimal cut-off value was obtained using the X-tile program. The relationship between SLD-change score and survival outcome (PFS, OS) was evaluated. RESULTS: 10% cut-off value of SLD-change score was found to be most distinctive for PFS. Responders defined according to this cut-off value showed a significant improvement for PFS and OS. Bone metastasis and brain metastasis were also two independent prognostic factors of PFS and OS, respectively. CONCLUSIONS: 10% SLD change score could discriminate for ICIs treatment response, which holds great promise in promoting the development of precise immunotherapeutic strategy.

[Cuproptosis-related immune gene signature predicts clinical benefits from anti-PD-1/PD-L1 therapy in non-small-cell lung cancer.

Non-small-cell lung cancer (NSCLC) remains the major cause of cancer-related death. Immune checkpoint inhibition has become the cornerstone treatment for NSCLC. Cuproptosis is a newly identified form of cell death relying on mitochondrial respiration that might play a role in shaping tumor immune microenvironment (TIME). The clinical significance of cuproptosis-related genes (CRGs) remains unclear and warrant investigation. The current study extracted RNA sequencing profiles and corresponding clinical information from six aggregated datasets from the Gene Expression Omnibus (GEO) repository as the training set, and from The Cancer Genome Atlas (TCGA) database as the testing set. Cuproptosis-related immune genes (CRIMGs) were obtained through coexpression analysis, univariate Cox regression analysis, and LASSO analysis for overall survival (OS) association analysis. Consensus clustering was employed to divide the subjects into clusters. Stepwise multivariate Cox regression was used to establish the prognostic CRIMG_score from the CRIMGs. A 17-gene prediction signature was established that informed patients' OS both in the training and testing datasets (p < 0.001). The predictive value of the signature in terms of immunotherapeutic responses was assessed in two publicly available NSCLC immunotherapy datasets (POPLAR and OAK studies) and an internal dataset from Sun Yat-sen University Cancer Center (ORIENT-11 study). Patients in the high-risk group displayed worse survival, a characteristic suppressive tumor immune microenvironment, and low immunotherapeutic benefits compared to those in the low-risk group. Collectively, the CRIMG_score established herein could serve as a promising indicator of prognosis and immunotherapeutic response in patients with NSCLC.

PD-1 inhibition plus platinum-based chemotherapy (PBC) or PBC alone in the first-line treatment of locally advanced or metastatic pulmonary lymphoepithelioma-like carcinoma.

Background: Pulmonary lymphoepithelioma-like carcinoma (PLELC) is a distinctive subtype of non-small cell lung carcinoma that was not well presented in clinical studies. The management of advanced PLELC remains an important, unmet need due to the paucity of high-grade evidence. Herein, we carried out a multicenter, retrospective study to assess the effectiveness and tolerability of PD-1/PD-L1 inhibitor plus chemotherapy versus chemotherapy alone for patients with advanced PLELC in the first-line setting. Patients and Methods: This retrospective study enrolled patients with advanced PLELC receiving first-line treatment with PD-1 inhibition plus chemotherapy (IO-Chemo group) or chemotherapy alone (Chemo group) in three medical centers in China. The survival outcomes, efficacy, and safety profile were investigated. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), overall survival (OS), and adverse events (AEs). Results: A total of 133 patients were enrolled. PFS was significantly longer in the IO-Chemo group (median 12.8 months [95% CI 5.2-20.4]) than that in the Chemo group (median 7.7 months [95% CI 6.8-8.6]; hazard ratio [HR] 0.48 [95% CI 0.31-0.74]; P=0.001). ORR was 74.5% (95% CI, 63.0-86.1) in the IO-Chemo group and 34.6% (95% CI, 24.1-45.2) in the Chemo group (P<0.001). The median OS was not reached in the IO-Chemo group versus 35.7 months (95% CI 26.7-44.8) in the Chemo group (HR 0.47 [95% CI 0.20-1.07]; P=0.065). Multivariate analysis revealed that PD-1/PD-L1 inhibitor combination was independently associated with longer PFS (HR 0.40 [95% CI 0.25-0.63]; P<0.001). Grade 3 or higher AEs occurred in 36 (65.5%) patients in the IO-Chemo group and 56 (71.8%) patients in the Chemo group, respectively. Conclusions: In patients with advanced PLELC, adding PD-1/PD-L1 inhibitor to platinum-based chemotherapy significantly increased PFS and ORR with a tolerable safety profile.

Paclitaxel exposure-toxicity analysis reveals a pharmacokinetic determinant for dose-limiting neutropenia in East-Asian solid tumor patients: results from two prospective, phase II studies.

PURPOSE: The time of a paclitaxel (PTX) concentration remains above 0.05 µM (Tc > 0.05) has been associated with PTX-induced adverse effects in Caucasians, while limited studies were reported in Asians. This study was aimed to explore the characteristics of Tc > 0.05 and the relationship between PTX exposure and toxicity in East-Asian patients. METHODS: This study was based on two prospective phase II clinical trials and patients with advanced nasopharyngeal cancer (NPC) and non-small cell lung cancer (NSCLC) who were naïve to PTX were included independently. Eligible patients receive PTX (175 mg/m2) and carboplatin (AUC = 5) treatment every 3 weeks. PTX pharmacokinetic analysis was accessed. The relationship between PTX exposure and toxicities after first cycle as well as clinical efficacy was evaluated. RESULTS: A total of 93 NPC and 40 NSCLC patients were enrolled. PTX exposure was consistent in two trials with average Tc > 0.05 duration of 38.8 h and 38.4 h, respectively. Average Tc > 0.05 in patients with grade 3/4 neutropenia was significantly higher than those without severe neutropenia in NPC patients (P = 0.003) and NSCLC patients (P = 0.007). Cut-off value of Tc > 0.05 were identified from the NPC cohort and then verified in the NSCLC cohort, dividing patients into high exposure Tc > 0.05 group (> 39 h) and low exposure group (≤ 39 h). Incidence of grade 3/4 neutropenia were significantly higher in the high exposure group in NPC cohort (43.3% vs 10.0%, P < 0.001) and NSCLC cohort (42.1% vs 9.5%, P = 0.028). No significant relationship between Tc > 0.05 and efficacy were observed. CONCLUSION: Patients with PTX Tc > 0.05 duration above 39 h experience more severe neutropenia than those under 39 h. Prospective studies are needed to verify this threshold.