Background: ASTRUM-002 met the primary endpoint of progression-free survival (PFS) with the combination of serplulimab plus HLX04 (bevacizumab biosimilar) and chemotherapy at interim analysis. Here, we report the results of the final survival analysis. Methods: A total of 636 patients with treatment-naïve, locally advanced or metastatic nonsquamous non-small cell lung cancer (nsq-NSCLC) without epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK)/ROS proto-oncogene 1 receptor tyrosine kinase (ROS1) genetic alterations were randomized 1:1:1 to receive serplulimab plus HLX04 and chemotherapy (group A), serplulimab plus HLX04 placebo and chemotherapy (group B), or double placebo plus chemotherapy (group C). Patients and the investigators were blinded to the group assignments. The primary endpoint was blinded independent central review-assessed PFS. Overall survival (OS) was the key secondary endpoint. Results: At the final analysis, median OS was 23.7 (95% confidence interval [CI] 20.5 to 27.5) months, 26.8 (95% CI 21.2 to 30.9) months, and 20.3 (95% CI 16.2 to 24.6) months in groups A (n = 212), B (n = 214), and C (n = 210), respectively. A significant reduction in risk of death for group B compared to group C was observed (hazard ratio [HR] = 0.66, 95% CI 0.52 to 0.83; P < 0.001). A total of 79 (37.6%) patients in group C had crossed over to serplulimab plus HLX04 treatment. Median OS in group C adjusted by the 2-stage model was 14.2 months (95% CI 11.9 to 17.0), corresponding to an adjusted HR of 0.53 (95% CI 0.42 to 0.68; P < 0.001) for group B versus group C. Using the rank-preserving structural failure time model, the adjusted median OS in group C was 17.9 months (95% CI 14.2 to 20.3), with a corresponding adjusted HR of 0.65 (95% CI 0.51 to 0.83; P < 0.001). No statistical difference in median OS for group A compared to group B (HR = 1.12, 95% CI 0.88 to 1.42; P = 0.363) was found. Conclusions: Serplulimab plus chemotherapy significantly prolonged OS and maintained PFS benefit compared to chemotherapy; however, the addition of bevacizumab biosimilar HLX04 did not yield further improvement for the first-line treatment of nsq-NSCLC without EGFR or ALK/ROS1 genetic alterations. Trial registration: This trial was registered at ClinicalTrials.gov (NCT03952403, date of registration: 2019 May 14).

BACKGROUND:Immunotherapy targeting programmed cell death protein (death-ligand) 1 [PD-(L)1] have improved the survival of patients with non-small cell lung cancer (NSCLC), however, the subset of the population that responded remains limited. Combination therapy may broaden the benefit population and receptor tyrosine kinase inhibitor (RTKI) provides a promising approach. Previous research has demonstrated that RTKI can enhance the efficacy of immunotherapy in a dose-dependent manner. Here, we investigated the synergistic effects of different doses CX1003, a novel RTKI, and PD-L1 blockade in NSCLC using a mouse model with subcutaneous tumor. METHODS:The synergistic treatment response of CX1003 and PD-L1 blockade was evaluated in subcutaneous in NSCLC mouse models. To elucidate the underlying mechanisms, various techniques including immunofluorescence, spectral flow cytometry, transcriptomics were employed to analyze the tumor microenvironment. RESULTS:Both doses of CX1003 enhanced the efficacy of PD-L1 blockade, with the high-dose combination therapy exhibiting superior antitumor efficacy in subcutaneous tumors. Subsequent analysis of the tumor microenvironment(TME) indicated that both doses of CX1003 induced tumor vascular normalization, but only high-dose CX1003 promoted CD8 + T lymphocyte infiltration and cytotoxicity when combined with PD-L1 blockade, suggesting that different doses of CX1003 combined with immunotherapy may have different mechanisms. The transcriptional landscape revealed enhancement of cell death related signaling following low-dose CX1003 and immune signaling following high-dose CX1003 when combined with PD-L1 blockade. Subsequent experiments indicated that low-dose CX1003 triggered apoptosis through the mitochondrial pathway, and high-dose CX1003 enhanced TCR signaling and IL-2 secretion when combined with PD-L1 blockade. Moreover, IL-2 and MAP2K2, the genes upregulated in the TCR signaling pathway following high-dose CX1003 combined with PD-L1 blockade treatment, are correlated with the prognosis of NSCLC receiving immunotherapy. CONCLUSIONS:Both high and low doses of CX1003 enhance the efficacy of PD-L1 blockade in NSCLC, albeit through distinct mechanisms. High-dose CX1003 enhance the efficacy via inducing the T cell-mediated immune response, whereas low dose augment efficacy by promoting apoptosis. These findings provide rationale for treating NSCLC patients with the combination therapy.

BACKGROUND:Limertinib is a new third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. This study aimed to prospectively assess the efficacy and safety of limertinib versus gefitinib as a first-line treatment for locally advanced or metastatic non-small-cell lung cancer (NSCLC) with EGFR-sensitising mutation. METHODS:This multicentre, randomised, double-blind, double-dummy, phase 3 trial was done at 56 hospitals in China. Eligible patients were aged ≥18 years with locally advanced or metastatic NSCLC with EGFR-sensitising mutation (exon 19 deletion or exon 21 L858R mutation) detected in tumour tissue samples using the Cobas EGFR Mutation Test at a central laboratory. Patients were randomly assigned (1:1) to receive oral limertinib 80 mg twice a day and gefitinib-matching placebo 250 mg once a day or oral gefitinib 250 mg once a day plus limertinib-matching placebo 80 mg twice a day in 21-day cycles, until disease progression or other discontinuation criteria was met. Random assignment was stratified according to EGFR mutation type (exon 19 deletion or exon 21 L858R mutation) and CNS metastasis (yes or no) using permuted blocks (block size four) through an interactive web-based response system. The primary endpoint was independent central review (ICR)-assessed progression-free survival. All enrolled patients who received at least one dose of study treatment were included in the full analysis set for efficacy analysis. All enrolled patients who received at least one dose of study treatment and one safety assessment were included in the safety set. This study is registered with ClinicalTrials.gov, NCT04143607, and follow-up is ongoing. FINDINGS:Between June 30, 2021, and Sept 22, 2022, 337 patients were enrolled and 168 were randomly assigned to the limertinib group and 169 to the gefitinib group. Patients' median age was 63 years (34-82). 214 (64%) of 337 patients were female and 123 (36%) were male. The median masked ICR-assessed progression-free survival was 20·7 months (95% CI 15·2-22·1) in the limertinib group and 9·7 months (95% CI 8·3-11·1) in the gefitinib group (hazard ratio [HR] 0·44 [95% CI 0·34-0·58]; p<0·0001). Treatment-related adverse events of grade 3 or worse occurred in 42 (25%) of 168 patients in the limertinib group and 42 (25%) of 169 patients in the gefitinib group. Treatment-related serious adverse events occurred in nine (5%) patients and 17 (10%) patients in each group, respectively. Six (4%) patients in the limertinib group died due to adverse events, all of which were considered possibly unrelated to the study drug by investigators. In the gefitinib group, seven (4%) patients died due to adverse events, with three (2%) of those deaths judged as possibly related to the study drug by investigators. Three treatment-related deaths in the gefitinib group were recorded (one case related to pneumonia and two with cause of death unknown). INTERPRETATION:Limertinib showed superior efficacy compared with gefitinib and a manageable safety profile for locally advanced or metastatic NSCLC patients with EGFR-sensitising mutation and should be considered as another first-line treatment option for this patient population. FUNDING:Jiangsu Aosaikang Pharmaceutical. TRANSLATION:For the Chinese translation of the abstract see Supplementary Materials section.

BACKGROUND:Whether the addition of bevacizumab to a programmed cell death protein-1 (PD-1) inhibitor plus chemotherapy can provide further survival benefits as first-line treatment in non-squamous non-small-cell lung cancer (NSCLC) without EGFR sensitising mutations, or ALK/ROS1 rearrangements, is unknown. We evaluated serplulimab (an anti-PD-1 antibody) plus HLX04 (a bevacizumab biosimilar) and chemotherapy in non-squamous NSCLC. METHODS:ASTRUM-002 is a randomised, double-blind, multicentre, phase 3 trial with a three-arm design. Patients (aged ≥18 years and ≤75 years) with locally advanced or metastatic non-squamous NSCLC without EGFR sensitising mutations or ALK/ROS1 rearrangements and previous systemic therapy were randomly assigned (1:1:1; stratified by PD-L1 expression, smoking history, and brain metastasis) to receive serplulimab (4·5 mg/kg intravenously) plus HLX04 (15 mg/kg intravenously) and chemotherapy (pemetrexed and carboplatin; group A), serplulimab plus chemotherapy plus HLX04 placebo (group B), or chemotherapy plus serplulimab placebo plus HLX04 placebo (group C). The primary endpoint was the blinded independent central review assessed progression-free survival per the Response Evaluation Criteria in Solid Tumors version 1.1, assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03952403, and is complete. FINDINGS:Between Nov 25, 2019, and June 15, 2022, 642 patients were enrolled across 72 hospitals in China; six in the safety run-in phase and the remaining 636 patients were randomised to group A (212 patients), B (214), or C (210). 465 (73%) were male, 171 (27%) were female, and 599 (94%) were of Han ethnicity. By the data cutoff date of June 15, 2023, the median follow-up duration was 23·4 months (95% CI 21·6-24·9) in group A, 23·1 (21·4-25·6) in group B, and 23·0 (20·7-25·6) in group C. Median progression-free survival was 12·6 months (95% CI 8·7-14·0; 123 events) in group A, 11·0 months (95% CI 8·4-12·7; 130 events) in group B, and 5·6 months (95% CI 4·8-6·8; 156 events) in group C. A significant reduction was seen in risk of progressive disease or death for patients in group B compared with group C (hazard ratio [HR] 0·55, 95% CI 0·43-0·69; p<0·0001). No significant improvement in progression-free survival was seen for group A compared with group B (HR 0·86, 0·67-1·11; p=0·25). Treatment-related serious adverse events occurred in 82 (39%) patients in group A, 79 (37%) in group B, and 51 (24%) in group C. Grade 3 or worse treatment-related adverse events occurred in 149 (71%) patients in group A, 142 (66%) in group B, and 119 (57%) in group C. Treatment-related adverse events leading to death occurred in ten (5%) patients in group A, five (2%) in group B, and seven (3%) in group C. INTERPRETATION:The addition of serplulimab to chemotherapy led to significantly longer progression-free survival in patients with locally advanced or metastatic non-squamous NSCLC compared with chemotherapy alone and represents an alternative first-line treatment option for this patient population. HLX04 plus serplulimab and chemotherapy did not confer further statistical benefit compared with serplulimab plus chemotherapy. FUNDING:Shanghai Henlius Biotech.

Background: Although the approval of immunotherapy in patients with extensive-stage small-cell lung cancer (ES-SCLC) has significantly improved the patient’s prognosis, synchronous chemoradiotherapy has always been the standard treatment for limited-stage small-cell lung cancer (LS-SCLC). Objectives: Immuno-combined and radio-combined therapy in LS-SCLC has been applied in clinical practice, but what is the best for LS-SCLC? Design: This was a retrospective cohort study. Methods: Patients with LS-SCLC from January 2019 to December 2023 were retrospectively screened and divided into three groups according to the initial treatment regimen whether included immune-combined and radio-combined treatment. Univariate and multivariate Cox regression were used to analyze the predictors affecting the survival of LS-SCLC, and the progression pattern of patients and the occurrence of adverse events (AEs) were also recorded. Results: In this study, the median overall survival (OS) was 15.8 months, not yet reached (NR) and NR, and the median progression-free survival (PFS) was 11.7, 20.9, and 18.9 months in the immunotherapy combined chemotherapy ( N = 34), immune combined chemoradiotherapy ( N = 26), and chemoradiotherapy ( N = 53) groups, respectively. OS and PFS were significantly prolonged in the radio-combined groups compared with the non-radio-combined group, and there was no significant difference between the radio-combined groups, namely immunotherapy combined chemoradiotherapy and chemoradiotherapy groups. In this study, we also constructed some indexes to predict prognosis for LS-SCLC, derived neutrophil and lymphocyte ratios were significantly associated with worse survival, and systemic inflammatory index and neuron-specific enolase (NSE) levels were significantly associated with shorter PFS. The primary organs of progression remained the lung and brain, the main immune-related AE was hypothyroidism, and the radiation-related AE was pneumonia. Conclusion: Radiation-combined therapy still plays an important role in LS-SCLC in the era of immunotherapy, and clinicians cannot abandon the use of radiation therapy in the initial treatment plan for LS-SCLC.

Immune checkpoint inhibitors (ICIs) had modest advances in the treatment of extensive-stage small cell lung cancer (ES-SCLC) in clinical trials, but there is a lack of biomarkers for prognosis in clinical practice. We retrospectively collected data from ES-SCLC patients who received ICIs combined chemotherapy from two centers in China, integrated clinical and blood parameters, and constructed risk prognostication for immunochemotherapy. The population was divided into high- and low-risk groups, and the performance of the model was assessed separately in the training and validation cohorts. Two hundred and twenty and 43 patients were included in the training and validation groups, respectively. The important predictors were screened including body mass index, liver metastases, coefficient variation of red blood cell distribution width, lactate dehydrogenase, albumin, and C-reactive protein. Predicting 1-year overall survival (OS), the AUC values under ROC for the model under training, internal validation, and external validation were 0.760, 0.732, and 0.722, respectively, and the calibration curve and clinical decision curve performed well. Applied the model to divide patients into low-risk and high-risk groups, and the median OS was 23.7 months and 9.1 months, and the median progression-free survival was 8.2 months and 4.8 months, respectively; furthermore, this ability to discriminate survival was also observed in the validation cohort. We constructed a novel prognostic model for ES-SCLC to predict survival employing baseline tumor burden, nutritional and inflammatory parameters, it is easily measured to screen high-risk patient populations.

BACKGROUND:The initial randomized, double-blinded, actively controlled, phase III ANEAS study (NCT03849768) demonstrated that aumolertinib showed superior efficacy relative to gefitinib as first-line therapy in epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC). Metastatic disease in the central nervous system (CNS) remains a challenge in the management of NSCLC. This study aimed to compare the efficacy of aumolertinib versus gefitinib among patients with baseline CNS metastases in the ANEAS study. METHODS:Eligible patients were enrolled and randomly assigned in a 1:1 ratio to orally receive either aumolertinib or gefitinib in a double-blinded fashion. Patients with asymptomatic, stable CNS metastases were included. Follow-up imaging of the same modality as the initial CNS imaging was performed every 6 weeks for 15 months, then every 12 weeks. CNS response was assessed by a neuroradiological blinded, independent central review (neuroradiological-BICR). The primary endpoint for this subgroup analysis was CNS progression-free survival (PFS). RESULTS:Of the 429 patients enrolled and randomized in the ANEAS study, 106 patients were found to have CNS metastases (CNS Full Analysis Set, cFAS) at baseline by neuroradiological-BICR, and 60 of them had CNS target lesions (CNS Evaluable for Response, cEFR). Treatment with aumolertinib significantly prolonged median CNS PFS compared with gefitinib in both cFAS (29.0 vs. 8.3 months; hazard ratio [HR] = 0.31; 95% confidence interval [CI], 0.17-0.56; P < 0.001) and cEFR (29.0 vs. 8.3 months; HR = 0.26; 95% CI, 0.11-0.57; P < 0.001). The confirmed CNS overall response rate in cEFR was 85.7% and 75.0% in patients treated with aumolertinib and gefitinib, respectively. Competing risk analysis showed that the estimated probability of CNS progression without prior non-CNS progression or death was consistently lower with aumolertinib than with gefitinib in patients with and without CNS metastases at baseline. No new safety findings were observed. CONCLUSIONS:These results indicate a potential advantage of aumolertinib over gefitinib in terms of CNS PFS and the risk of CNS progression in patients with EGFR-mutated advanced NSCLC with baseline CNS metastases. TRIAL REGISTRATION:ClinicalTrials.gov number, NCT03849768.

A randomized double-blind phase 3 trial (CHOICE-01, NCT03856411) demonstrated that combining toripalimab with chemotherapy substantially improves progression-free survival (PFS) in advanced non-small cell lung cancer (NSCLC) patients without pretreatment. This study presents the prespecified final analysis of overall survival (OS) and biomarkers utilizing circulating tumor DNA (ctDNA) and tissue-based sequencing. Additionally, the analysis revealed a higher median overall survival (OS, 23.8 months) in the toripalimab group than that in the control group (17.0 months). (HR = 0.69, 95%CI: 0.57-0.93, nominal P = 0.01). This survival benefit was particularly notable in the non-squamous subgroup. As the first phase 3 study to perform both baseline tissue whole-exome sequencing (WES) and peripheral blood ctDNA testing, we investigated efficacy predictive biomarkers based on both tissue and ctDNA, Genomic sequencing of ctDNA showed high concordance with tumor tissue independently confirmed that individuals exhibiting a high tumor mutational burden, as well as mutations in the FA-PI3K-Akt and IL-7 signaling pathways benefited more from the toripalimab treatment. Furthermore, a ctDNA response observed on cycle 3 day 1, was associated with improved clinical outcomes for patients treated with the combination therapy. In conclusion, Toripalimab plus chemotherapy yields significant improvements in OS as a first-line treatment. The study highlights the utility of ctDNA as a proxy for tumor tissue, providing novel prospects for predicting efficacy of immuno-chemotherapy through continuous ctDNA monitoring.

Stratification strategies for chemotherapy plus PD-1 inhibitors in advanced non-small-cell lung cancer (NSCLC) are critically demanded. We performed high-throughput panel-based deep next-generation sequencing and low-pass whole genome sequencing on prospectively collected circulating tumor DNA (ctDNA) specimens from 460 patients in the phase 3 CHOICE-01 study at different time points. We identified predictive markers for chemotherapy plus PD-1 inhibitor, including ctDNA status and genomic features such as blood-based tumor mutational burden, intratumor heterogeneity, and chromosomal instability. Furthermore, we established an integrated ctDNA-based stratification strategy, blood-based genomic immune subtypes (bGIS) scheme, to distinguish patients who benefit from the addition of PD-1 inhibitor to first-line chemotherapy. Moreover, we demonstrated potential applications for the dynamic monitoring of ctDNA. Overall, we proposed a potential therapeutic algorithm based on the ctDNA-based stratification strategy, shedding light on the individualized management of immune-chemotherapies for patients with advanced NSCLC.

Immunochemotherapy is the first-line standard for extensive-stage small-cell lung cancer (ES-SCLC). Combining the regimen with anti-angiogenesis may improve efficacy. ETER701 was a multicenter, double-blind, randomized, placebo-controlled phase 3 trial that investigated the efficacy and safety of benmelstobart (a novel programmed death-ligand 1 (PD-L1) inhibitor) with anlotinib (a multi-target anti-angiogenic small molecule) and standard chemotherapy in treatment-naive ES-SCLC. The ETER701 trial assessed two primary endpoints: Independent Review Committee-assessed progression-free survival per RECIST 1.1 and overall survival (OS). Here the prespecified final progression-free survival and interim OS analysis is reported. Patients randomly received benmelstobart and anlotinib plus etoposide/carboplatin (EC; n = 246), placebo and anlotinib plus EC (n = 245) or double placebo plus EC ('EC alone'; n = 247), followed by matching maintenance therapy. Compared with EC alone, median OS was prolonged with benmelstobart and anlotinib plus EC (19.3 versus 11.9 months; hazard ratio 0.61; P = 0.0002), while improvement of OS was not statistically significant with anlotinib plus EC (13.3 versus 11.9 months; hazard ratio 0.86; P = 0.1723). The incidence of grade 3 or higher treatment-related adverse events was 93.1%, 94.3% and 87.0% in the benmelstobart and anlotinib plus EC, anlotinib plus EC, and EC alone groups, respectively. This study of immunochemotherapy plus multi-target anti-angiogenesis as first-line treatment achieved a median OS greater than recorded in prior randomized studies in patients with ES-SCLC. The safety profile was assessed as tolerable and manageable. Our findings suggest that the addition of anti-angiogenesis therapy to immunochemotherapy may represent an efficacious and safe approach to the management of ES-SCLC. ClinicalTrials.gov identifier: NCT04234607. In this triple-arm, placebo-controlled phase 3 trial, first-line treatment of patients with extensive-stage small-cell lung cancer with the anti-PD-L1 benmelstobart, tyrosine kinase inhibitor anlotinib and chemotherapy (CT) showed improved survival outcomes compared with anlotinib and CT or CT alone.

Purpose This study aimed to investigate the clinical utility of diverse aneuploid circulating tumor cell (CTC) subtypes and particularly CTC-associated white blood cell (CTC-WBC) clusters in predicting treatment response, prognosis and real-time monitoring disease progression in advanced driver gene-negative non-small lung cancer (NSCLC) patients. Materials and methods A total of 74 eligible patients were prospectively enrolled and serial blood samples were collected at pre-treatment(t 0 ), after two cycles of therapy (t 1 ) and at post-four-to-six treatment cycles (t 2 ). Co-detection of diverse subtypes of aneuploid CTCs and CTC-WBC clusters was conducted in advanced NSCLC patients receiving first-line treatment. Results At baseline, CTCs were detected in 69 (93.24%) patients and CTC-WBC clusters were detected in 23 (31.08%) patients. Patients with CTCs < 5/6ml or with CTC-WBC clusters undetectable exhibited a better treatment response than patients with pre-therapeutic aneuploid CTCs ≥ 5/6ml or harboring CTC-WBC clusters ( p = 0.034 and p = 0.012, respectively). Before treatment, patients bearing tetraploid CTCs ≥ 1/6ml showed significantly inferior progression-free survival (PFS) [hazard ratio (HR):2.420, 95% confidence interval (CI): 1.426–4.106; p = 0.001] and overall survival (OS) compared to patients with tetraploid CTCs < 1/6ml (HR:1.907, 95%CI: 1.119–3.251; p = 0.018). A longitudinal study demonstrated that post-therapeutic patients harboring CTC-WBC clusters displayed the reduced PFS and OS compared with those without CTC-WBC clusters, and subgroup analysis showed that the presence of CTC-WBC clusters indicated a worse prognosis in both lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) patients. After adjusting for multiple significant factors, post-therapeutic CTC-WBC clusters were the only independent predictor of both PFS (HR:2.872, 95% CI: 1.539–5.368; p = 0.001) and OS (HR:2.162, 95% CI: 1.168–4.003; p = 0.014). Conclusions In addition to CTCs, longitudinal detection of CTC-WBC clusters provided a feasible tool to indicate initial treatment response, dynamically monitor disease progression and predict survival in driver gene-negative advanced NSCLC patients.

The objective of the present study was to investigate the role of postoperative radiotherapy (PORT) after radical resection of stage IIIA-N2 non-small cell lung cancer (NSCLC). Subgroups of patients who benefited from PORT were evaluated. A retrospective review of 288 consecutive patients with resected pIIIA-N2 NSCLC at Beijing Chest Hospital (Beijing, China) was performed. Of these patients, 61 received PORT. The 288 patients were divided into PORT and non-PORT groups according to the treatment received. The baseline characteristics of the two patient groups were balanced using propensity score-matching (PSM; 1:1 matching). In total, 60 patients in the PORT group and 60 patients in the non-PORT group were matched. After PSM, the median survival time of the matched patients was 53 months. The 1-, 3- and 5-year overall survival (OS) rates of the PORT patient group were 95.0, 63.2 and 48.2%, respectively, while those of the non-PORT group were 86.7, 58.3 and 34.5%, respectively, and there was no significant difference between the two groups (P=0.056). The 5-year local recurrence-free survival (LRFS) rate in the PORT group was significantly improved (P=0.001). The effects of PORT on OS and LRFS rates were analysed in patients with different clinicopathological features. For subgroups with multiple N2 stations, N2 positive lymph nodes ≥4 and squamous cell carcinoma, PORT significantly increased the OS and LRFS rates (P<0.05). In conclusion, there was no statistically significant improvement in the 5-year OS rate with PORT overall, but there may be subgroups, such as patients with multiple N2 stations, N2 positive nodes ≥4 and squamous cell carcinoma histology, that could be explored as potentially benefitting from improved 5-year OS and LRFS rates with PORT.

9003 Background: Toripalimab in combination with chemotherapy showed significant improvement over chemotherapy alone in progression-free survival (PFS) and overall survival (OS) as first-line treatment of advanced NSCLC at the final PFS analysis of the CHOICE-01 study (NCT03856411). Here we report the final OS analysis. Methods: Patients (n=465) with treatment-naïve, advanced NSCLC without EGFR/ALK mutations were randomized 2:1 to receive toripalimab 240 mg (n=309) or placebo (n=156) in combination with chemotherapy for 4-6 cycles, followed by maintenance toripalimab or placebo plus standard care until disease progression, intolerable toxicity, or completion of 2 years of treatment. Patients from the placebo arm were actively crossed-over to receive toripalimab upon disease progression. The primary endpoint was PFS. The secondary endpoints included OS and safety. Results: By the cutoff date of August 31, 2022, when 283 events triggered the final OS analysis, the median survival follow up was 19.4 months. A significant improvement in OS was observed for the toripalimab arm over the placebo arm: HR=0.73 (95% CI: 0.57-0.93), two-sided p=0.0108, median OS 23.8 vs 17.0 months. A consistent effect on OS, favoring the toripalimab arm, was observed all PD-L1 expression subgroups. The OS benefit is greater in non-squamous NSCLC, HR=0.50 (95% CI: 0.36-0.70), median OS 27.8 vs 15.9 months, whereas no significant difference was found in the squamous subgroup (mOS 19.6 vs 18.1 months) despite a significant PFS improvement. The squamous subgroup had a high 70% crossover rate. No new safety signal was identified since the interim report. The incidence of Grade ≥3 adverse events (AEs) (78.9% vs 82.1%) was similar between the two arms. AEs leading to discontinuation of toripalimab/placebo (14.3% vs 3.2%), fatal AEs (5.5% vs 2.6%), and immune-related (irAEs) (50.6% vs. 21.2%) were more frequent in the toripalimab arm. Whole exome sequencing results indicated patients with mutations in the FAK-PI3K-Akt pathway achieved significantly better OS from the toripalimab arm. Conclusions: The addition of toripalimab to chemotherapy in patients with advanced NSCLC provided significant OS benefit than chemotherapy alone with a manageable safety profile. These results support the use of toripalimab with chemotherapy as 1st line therapy for advanced NSCLC patients without EGFR/ALK mutations. Clinical trial information: NCT03856411 .

Background:Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have limited or no response in some certain patients of non-small-cell lung cancer (NSCLC). However, real-world survival analyses comparing clinical data and EGFR-plasma mutation are still lacking.Methods:In total, 159 patients with advanced NSCLC resistant to first-generation EGFR-TKIs were included for consecutive blood sampling in this study. Super-amplification refractory mutation system (Super-ARMS) was used to detect EGFR-plasma mutations and correlations between survival and circulating tumor DNA (ctDNA) were analyzed.Results:Among 159 eligible patients, the T790M mutation was detected in 27.0% (43/159) of patients. The median progression-free survival (mPFS) was 10.7 months in all patients. Survival analysis revealed that patients with the T790M mutation had shorter progression-free survival (PFS) than those with the T790M wild-type (10.6 months vs 10.8 months, P = .038). Patients who cleared EGFR-plasma mutation had prolonged PFS compared with those with nonclearing EGFR-plasma mutation (11.6 months vs 9.0 months, P = .001). Cox multivariate analysis showed that the nonclearance of EGFR-plasma mutations was an independent risk factor for PFS (RR = 1.745, 95% CI: [1.184, 2.571], P = .005). The T790M mutation was associated with nonclearance of the EGFR-plasma mutation (χ2 = 10.407, P = .001).Conclusion:Patients with advanced NSCLC who were resistant to the first-generation EGFR-TKI had a prolonged PFS with clearance of EGFR-plasma mutation. Those nonclearers were more likely to harbor T790M mutations in plasma.

Abstract Background Hepatocyte growth factor (HGF) is a peptide-containing multifunctional cytokine, which is overexpressed and/or activated in multiple malignancies and is reported to be associated with tumor development and inferior survival. At present, the role of HGF in small cell lung cancer (SCLC) has not been fully explored yet. Materials and methods The expression of HGF and its value in predicting survival in SCLC were explored from GEO database and in pan-cancer analysis. Furthermore, we detected the expression of HGF using tumor tissue and paired plasma samples from a validation cohort of 71 SCLC patients at our institute. Correlation between tumor and plasma HGF expression and the prognostic values were analyzed. Results GEO database analysis revealed that tumor tissue had lower HGF expression than paired normal tissue in SCLC. At our institute, immunohistochemical staining showed negative expression of HGF in tumor tissue of SCLC at our institute (47/47, 100%). The average baseline plasma HGF was 1.28 (range,0.42–4.35) ng/ml. However, plasma HGF was higher in SCLC patients with patients with N3, M1, liver metastasis (LM) and bone metastasis (BM) disease compared with those N0 − 2 (1.25 vs. 1.75 ng/mL, P = 0.000), M0 (1.26 vs. 1.63 ng/mL, P = 0.003), non-LM (1.32 vs. 2.06 ng/mL, P = 0.009), and non-BM (1.35 vs. 1.77 ng/mL, P = 0.047), respectively. Multivariate analysis revealed plasma HGF was an independent predictor for LM and prognostic factor of OS. Conclusion Our results revealed that plasma HGF rather than tumor HGF exhibited a potential role in predicting metastasis and survival in SCLC. Plasma HGF might be used as a non-invasive detecting and monitoring tool for SCLC.

362936 Background: Toripalimab (anti–PD-1) in combination with chemotherapy showed significant improvement in progression-free survival (PFS) and overall survival (OS) in the first-line treatment of advanced non–small cell lung cancer (NSCLC) regardless of tumor PD-L1 expression. Whole-exome sequencing (WES) was performed to identify correlative biomarkers for survival. Methods: Patients (465 patients) with treatment-naïve, advanced NSCLC without EGFR/ALK mutations were randomly assigned 2:1 to receive toripalimab 240 mg (309 patients) or placebo (156 patients) in combination with chemotherapy for 4-6 cycles, followed by maintenance of toripalimab or placebo plus standard care until disease progression, intolerable toxicity, or completion of 2 years of treatment. Stratification factors included PD-L1 expression status, histology, and smoking status. The primary endpoint was PFS by investigator per RECIST v1.1. Secondary endpoints included PFS by a blinded independent review committee (BIRC), OS, and safety. Results: At the prespecified final PFS analysis (cutoff date Oct 31, 2021), a significant improvement in PFS as assessed by investigator was observed for the toripalimab arm over the placebo arm: HR, 0.49 (95% CI, 0.39-0.61); two-sided p < .0001; and median PFS 8.4 vs. 5.6 months. The 1-year PFS rates were 36.7% vs. 17.2%. PFS as assessed by BIRC was also significantly longer in the toripalimab arm. The improvements of PFS were observed across key subgroups, including histology and PD-L1 expression. At the interim OS analysis, the toripalimab arm had a significantly longer OS than the placebo arm: HR, 0.69 (95% CI, 0.52-0.92); two-sided p = .0099; median OS not reached vs. 17.1 months. The incidence of grade ≥ 3 adverse events (AEs; 78.6% vs. 82.1%) was similar between the two arms. AEs leading to discontinuation of toripalimab/placebo (14.3% vs. 3.2%) and fatal AEs (5.5% vs. 2.6%) were more frequent in the toripalimab arm. WES results from 394 available patients revealed that patients with high tumor mutational burden (TMB; ≥ 10 mutations per million base pairs) were associated with significantly better PFS in the toripalimab arm over the placebo arm (median PFS 13.1 vs. 5.5 months; interaction p = .026). In addition, patients with mutations in the FAK-PI3K-Akt pathway or IL-7 signaling pathways achieved significantly better PFS and OS from the toripalimab chemotherapy combination (interaction p values ≤ .01). Conclusions: The addition of toripalimab to chemotherapy in patients with advanced NSCLC provided superior PFS and OS when compared to chemotherapy alone with a manageable safety profile. These results support the use of toripalimab with chemotherapy as first-line therapy for patients with advanced NSCLC without EGFR/ALK mutations. Clinical trial information: NCT03856411.

Current management of small cell lung cancer (SCLC) remains challenging. Effective biomarkers are needed to subdivide patients presenting distinct treatment response and clinical outcomes. An understanding of heterogeneous phenotypes of aneuploid CD31- circulating tumor cells (CTCs) and CD31+ circulating tumor endothelial cells (CTECs) may provide novel insights in the clinical management of SCLC. In the present translational and prospective study, increased cancer metastasis-related cell proliferation and motility, accompanied with upregulated mesenchymal marker vimentin but down-regulated epithelial marker E-cadherin, were observed in both lentivirus infected SCLC and NSCLC cells overexpressing the stemness marker CD44v6. Aneuploid CTCs and CTECs expressing CD44v6 were longitudinally detected by SE-iFISH in 120 SCLC patients. Positive detection of baseline CD44v6+ CTCs and CD44v6+ CTECs was significantly associated with enhanced hepatic metastasis. Karyotype analysis revealed that chromosome 8 (Chr8) in CD44v6+ CTCs shifted from trisomy 8 towards multiploidy in post-therapeutic patients compared to pre-treatment subjects. Furthermore, the burden of baseline CD44v6+ CTCs (t0) or amid the therapy (t1-2), the ratio of baseline CD31+ CTEC/CD31- CTC (t0), and CTC-WBC clusters (t0) were correlated with treatment response and distant metastases, particularly brain metastasis, in subjects with limited disease (LD-SCLC) but not in those with extensive disease (ED-SCLC). Multivariate survival analysis validated that longitudinally detected CD44v6+/CD31- CTCs was an independent prognostic factor for inferior survival in SCLC patients. Our study provides evidence for the first time that comprehensive analyses of CTCs, CTECs, and their respective CD44v6+ subtypes enable clinical stratification and improve prognostic prediction of SCLC, particularly for potentially curable LD-SCLC.

BACKGROUND:In the first interim analysis of the ORIENT-31 trial, compared with chemotherapy alone, sintilimab plus bevacizumab biosimilar IBI305 plus chemotherapy (pemetrexed and cisplatin) significantly improved progression-free survival in patients with EGFR-mutated non-squamous non-small-cell lung cancer (NSCLC) who progressed on EGFR tyrosine-kinase inhibitor treatment. However, the benefit of anti-PD-1 or PD-L1 antibody added to chemotherapy in this patient population remains unclear, with no prospective evidence from phase 3 trials globally. We report the results from the prespecified second interim analysis of progression-free survival between sintilimab plus chemotherapy and chemotherapy alone, the updated results of sintilimab plus IBI305 plus chemotherapy, and preliminary overall survival results. METHODS:This double-blind, randomised, placebo-controlled, phase 3 trial was done at 52 centres across China and included patients aged 18-75 years with locally advanced or metastatic (stage IIIB, IIIC, or IV according to the American Joint Committee on Cancer, eighth edition) EGFR-mutated non-squamous NSCLC, disease progression after EGFR tyrosine-kinase inhibitor treatment (according to the Response Evaluation Criteria in Solid Tumours version 1.1 [RECIST 1.1]), and at least one measurable lesion (according to RECIST 1.1). Patients were randomly assigned (1:1:1), using an interactive web response system, to receive sintilimab (200 mg) plus IBI305 (15 mg/kg) plus pemetrexed (500 mg/m2) and cisplatin (75 mg/m2), sintilimab plus chemotherapy, or chemotherapy alone on day 1 of each 3-week cycle for four cycles, followed by maintenance therapy of sintilimab, IBI305, and pemetrexed. All study drugs were administered intravenously. The primary endpoint was progression-free survival in the intention-to-treat population assessed by an independent radiographic review committee. Data cutoff was March 31, 2022, unless otherwise specified. The study is registered at ClinicalTrials.gov, NCT03802240 (ongoing). FINDINGS:Between July 11, 2019, and March 31, 2022, 1011 patients were screened and 476 were randomly assigned (158 to the sintilimab plus IBI305 plus chemotherapy group, 158 to the sintilimab plus chemotherapy group, and 160 to the chemotherapy alone group). The median follow-up duration for progression-free survival was 12·9 months (IQR 8·2-17·8) in the sintilimab plus IBI305 plus chemotherapy group, 15·1 months (8·0-19·5) in the sintilimab plus chemotherapy group, and 14·4 months (9·8-23·8) in the chemotherapy alone group. Sintilimab plus chemotherapy significantly improved progression-free survival compared with chemotherapy alone (median 5·5 months [95% CI 4·5-6·1] vs 4·3 months [4·1-5·3]; hazard ratio [HR] 0·72 [95% CI 0·55-0·94]; two-sided p=0·016). Significant progression-free survival benefit was sustained with sintilimab plus IBI305 plus chemotherapy compared with chemotherapy alone (median 7·2 months [95% CI 6·6-9·3]; HR: 0·51 [0·39-0·67]; two-sided p<0·0001). As of data cutoff (July 4, 2022), the median overall survival was 21·1 months (95% CI 17·5-23·9) for sintilimab plus IBI305 plus chemotherapy (HR 0·98 [0·72-1·34]) and 20·5 months (15·8-25·3) for sintilimab plus chemotherapy group (HR 0·97 [0·71-1·32]) versus 19·2 months (15·8-22·4) for chemotherapy alone; after adjusting for crossover, the HR for sintilimab plus IBI305 plus chemotherapy to chemotherapy alone ranged from 0·79 (0·57-1·09) to 0·84 (0·61-1·15) and the HR for sintilimab plus chemotherapy to chemotherapy alone ranged from 0·78 (0·57-1·08) to 0·84 (0·61-1·16). The safety results were generally consistent with those in the first interim analysis; in particular, treatment-related adverse events of grade 3 or worse occurred in 88 (56%) of 158 patients in the sintilimab plus IBI305 plus chemotherapy group, 64 (41%) of 156 patients in the sintilimab plus chemotherapy group, and 79 (49%) of 160 patients in the chemotherapy alone group. INTERPRETATION:This is the first prospective phase 3 trial to show the benefit of anti-PD-1 antibody plus chemotherapy in patients with EGFR-mutated NSCLC who progressed on treatment with tyrosine-kinase inhibitors. Compared with chemotherapy alone, sintilimab combined with pemetrexed and cisplatin showed significant and clinically meaningful improvement of progression-free survival with an optimal safety profile. Sintilimab plus IBI305 plus chemotherapy continued to show progression-free survival benefit compared with chemotherapy alone in this second interim analysis with an additional 8-month follow-up. FUNDING:National Natural Science Foundation of China, Shanghai Municipal Science & Technology Commission Research Project, and Innovent Biologics. TRANSLATION:For the Chinese translation of the abstract see Supplementary Materials section.

Objective To retrospectively analyze the clinical data of 47 young NSCLC patients mutation style of EGFR and PD-L1 expression in tumor cells, to understand their clinicopathological and molecular characteristics. Methods We enrolled 47 young (≤40 years old) patients confirmed as NSCLC who underwent surgical resection, and 94 old patients (≥60 years old) were matched as 1:2 by R language. EGFR mutation status was detected by ARMS-PCR, and the expression of PD-L1 was detected by immunohistochemistry. Results The median age of 47 young patients with NSCLC was 37 years old. The disease was more common in women and the majority type was adenocarcinoma. In youth group, the 19del and 20ins were more frequent, but the exon 21 L858R point mutation proportion was higher in elder group. The expression of PD-L1 was significantly increased in the solid predominant histological subtype. The PD-L1 expression in 19del patients was higher than that in the patients with L858R mutation in youth group. Conclusion The majority of young NSCLC patients are female, nonsmokers and suffered from adenocarcinoma cancer. The proportion of EGFR alteration in 19del and 20ins in youth group is higher than that in elder group. The positive rate of PD-L1 expression in solid predominant histological subtype is higher than that with other subtypes. The expression of PD-L1 in young patients with EGFR 19del is higher than that with L858R.