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PURPOSE The CHOICE-01 study investigated the efficacy and safety of toripalimab in combination with chemotherapy as a first-line treatment for advanced non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS Patients (N = 465) with treatment-naive, advanced NSCLC without EGFR/ALK mutations were randomly assigned 2:1 to receive toripalimab 240 mg (n = 309) or placebo (n = 156) once every 3 weeks in combination with chemotherapy for 4-6 cycles, followed by the maintenance of toripalimab or placebo once every 3 weeks plus standard care. Stratification factors included programmed death ligand-1 expression status, histology, and smoking status. The primary end point was progression-free survival (PFS) by investigator per RECIST v1.1. Secondary end points included overall survival and safety. RESULTS At the final PFS analysis, PFS was significantly longer in the toripalimab arm than in the placebo arm (median PFS, 8.4 v 5.6 months, hazard ratio = 0.49; 95% CI, 0.39 to 0.61; two-sided P < .0001). At the interim OS analysis, the toripalimab arm had a significantly longer OS than the placebo arm (median OS not reached v 17.1 months, hazard ratio = 0.69; 95% CI, 0.53 to 0.92; two-sided P = .0099). The incidence of grade ≥ 3 adverse events was similar between the two arms. Treatment effects were similar regardless of programmed death ligand-1 status. Genomic analysis using whole-exome sequencing from 394 available tumor samples revealed that patients with high tumor mutational burden were associated with significantly better PFS in the toripalimab arm (median PFS 13.1 v 5.5 months, interaction P = .026). Notably, patients with mutations in the focal adhesion-PI3K-Akt signaling pathway achieved significantly better PFS and OS in the toripalimab arm (interaction P values ≤ .001). CONCLUSION Toripalimab plus chemotherapy significantly improves PFS and OS in patients with treatment-naive advanced NSCLC while having a manageable safety profile. Subgroup analysis showed the OS benefit was mainly driven by the nonsquamous subpopulation.

Aim: Report the final analysis from ASTRIS, the largest real-world study of second-/later-line osimertinib in advanced/metastatic EGFR T790M non-small-cell lung cancer (NSCLC). Methods: Patients with advanced/metastatic EGFR T790M NSCLC and prior EGFR-TKI treatment, received once-daily osimertinib 80 mg. Primary end point: overall survival (OS); secondary end points: progression-free survival (PFS), time-to-treatment discontinuation (TTD) and response rate. Safety was also recorded. Results: In 3014 patients, median OS: 22.8 months (21.6–23.8), median PFS: 11.1 months (11.0–12.0), median TTD: 13.5 months (12.6–13.9), and response rate: 57.3% (55.5–59.2). All end points reported with 95% CIs. Numerically longer median OS was observed in patients with baseline WHO performance status Clinical Trial Registration: NCT02474355 ( ClinicalTrials.gov )

Treatment options for Chinese patients with locally advanced or metastatic squamous-cell non-small-cell lung cancer (sqNSCLC) after failure of first-line chemotherapy are limited. This study (ORIENT-3) aimed to evaluate the efficacy and safety of sintilimab versus docetaxel as second-line treatment in patients with locally advanced or metastatic sqNSCLC.ORIENT-3 was an open-label, multicenter, randomized controlled phase 3 trial that recruited patients with stage IIIB/IIIC/IV sqNSCLC after failure with first-line platinum-based chemotherapy. Patients were randomized in a 1:1 ratio to receive either 200 mg of sintilimab or 75 mg/mBetween August 25, 2017, and November 7, 2018, 290 patients were randomized. For FAS, 10 patients from the docetaxel arm were excluded. The median OS was 11.79 (n = 145; 95% confidence interval [CI], 10.28-15.57) months with sintilimab versus 8.25 (n = 135; 95% CI, 6.47-9.82) months with docetaxel (hazard ratio [HR]: 0.74; 95% CI, 0.56-0.96; P = 0.025). Sintilimab treatment significantly prolonged PFS (median 4.30 vs. 2.79 months; HR: 0.52; 95% CI, 0.39-0.68; P0.001) and showed higher ORR (25.50% vs. 2.20%, P0.001) and DCR (65.50% vs. 37.80%, P0.001) than the docetaxel arm. The median DoR was 12.45 (95% CI, 4.86-25.33) months in the sintilimab arm and 4.14 (95% CI, 1.41-7.23) months in the docetaxel arm (P = 0.045). Treatment-related adverse events of grade ≥ 3 were reported in 26 (18.1%) patients in the sintilimab arm and 47 (36.2%) patients in the docetaxel arm. Exploratory biomarker analysis showed potential predictive values of expression levels of two transcription factors, including OVOL2 (HR: 0.35; P0.001) and CTCF (HR: 3.50; P0.001)，for sintilimab treatment.Compared with docetaxel, sintilimab significantly improved the OS, PFS, and ORR of Chinese patients with previously treated locally advanced or metastatic sqNSCLC.

PURPOSE Aumolertinib (formerly almonertinib; HS-10296) is a novel third-generation epidermal growth factor receptor tyrosine kinase inhibitor approved in China. This double-blind phase III trial evaluated the efficacy and safety of aumolertinib compared with gefitinib as a first-line treatment for locally advanced or metastatic EGFR-mutated non–small-cell lung cancer (NSCLC; ClinicalTrials.gov identifier: NCT03849768 ). METHODS Patients at 53 sites in China were randomly assigned 1:1 to receive either aumolertinib (110 mg) or gefitinib (250 mg) once daily. The primary end point was progression-free survival (PFS) per investigator assessment. RESULTS A total of 429 patients who were naïve to treatment for locally advanced or metastatic NSCLC were enrolled. PFS was significantly longer with aumolertinib compared with gefitinib (hazard ratio, 0.46; 95% CI, 0.36 to 0.60; P < .0001). The median PFS with aumolertinib was 19.3 months (95% CI, 17.8 to 20.8) versus 9.9 months with gefitinib (95% CI, 8.3 to 12.6). Objective response rate and disease control rate were similar in the aumolertinib and gefitinib groups (objective response rate, 73.8% and 72.1%, respectively; disease control rate, 93.0% and 96.7%, respectively). The median duration of response was 18.1 months (95% CI, 15.2 to not applicable) with aumolertinib versus 8.3 months (95% CI, 6.9 to 11.1) with gefitinib. Adverse events of grade ≥ 3 severity (any cause) were observed in 36.4% and 35.8% of patients in the aumolertinib and gefitinib groups, respectively. Rash and diarrhea (any grade) were observed in 23.4% and 16.4% of patients who received aumolertinib compared with 41.4% and 35.8% of those who received gefitinib, respectively. CONCLUSION Aumolertinib is a well-tolerated third-generation epidermal growth factor receptor tyrosine kinase inhibitor that could serve as a treatment option for EGFR-mutant NSCLC in the first-line setting.

The global Phase III IMpower132 study evaluating atezolizumab plus pemetrexed and carboplatin or cisplatin (APP) versus pemetrexed plus carboplatin or cisplatin (PP) for first-line treatment of non-squamous advanced non-small cell lung cancer (NSCLC) met its co-primary progression-free survival (PFS) endpoint at the primary analysis in the intention-to-treat (ITT) population. Although the co-primary overall survival (OS) endpoint was not met, numerical OS improvement favoring APP over PP was observed at the final analysis. We report primary results for Chinese patients in IMpower132.Treatment-naive Chinese patients with non-squamous stage IV EGFR/ALK mutation-negative NSCLC were randomized 1:1 to receive 4 or 6 cycles of APP or PP, followed by maintenance atezolizumab plus pemetrexed or pemetrexed. Co-primary endpoints were investigator-assessed PFS and OS.The ITT population included 163 Chinese patients (82 in the APP arm and 81 in the PP arm). At data cutoff (median follow-up, 11.7 months), the median PFS in the APP and PP arms was 8.3 and 5.8 months, respectively; the unstratified hazard ratio (HR) was 0.73 (95% CI: 0.50, 1.08). At the interim OS analysis, median OS was not estimable in either arm; the unstratified HR was 0.70 (95% CI: 0.40, 1.24). No new safety signals were observed.Among Chinese patients in IMpower132, PFS benefit was seen with APP versus PP. Though interim OS data were immature, there was a trend toward OS benefit favoring APP versus PP. The safety profile of the APP was consistent with the known risks of the individual treatment components.gov: NCT02657434.

Background As a potential target receptor tyrosine kinase, mesenchymal-epithelial transition factor (MET) exhibits high aberrant expression across various tumors. This study aimed to evaluated the safety, tolerability, efficacy and pharmacokinetics (PK) of BPI-9016M, a novel tyrosine kinase inhibitor (TKI) targeting c-MET, in c-MET overexpression or MET exon 14 skipping mutation patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC). Methods/design In this two-part multicenter phase Ib study, eligible patients with locally advanced or metastatic NSCLC harboring c-MET overexpression or MET exon 14 skipping mutation were enrolled into Part A (tested positive for c-MET overexpression [immunohistochemical staining score ≥ 2+]; 300 mg quaque die [QD], 450 mg QD and 600 mg QD cohorts) or Part B (tested positive for MET exon 14 skipping mutation; 400 mg bis in die [BID] cohort), respectively. The primary endpoints were safety, objective response rate (ORR) and disease control rate (DCR), the second endpoints were PK parameters, progression-free survival (PFS) and overall survival (OS). Results Between March 15, 2017 and September 18, 2021, 38 patients were enrolled (Part A, n = 34; Part B, n = 4). Of 38 patients, 32 (84.2%) patients completed the treatment protocol. As of the data cut-off date on January 27, 2022, all patients reported at least one treatment-emergent adverse event (TEAE). Ninety-two point one percent (35/38) of patients experienced treatment-related adverse events (TRAEs), and grade ≥ 3 TRAEs were observed in 11 (28.9%) patients. The most common TRAEs were elevated alanine aminotransferase (ALT, 14/38, 36.8%) and elevated aspartate aminotransferase (AST, 11/38, 28.9%). Only one (2.6%) patient had treatment-related serious adverse event (SAE) in 600 mg QD cohort due to thrombocytopenia. PK analysis showed BPI-9016M and its main metabolites (M1 and M2-2) reached steady state after seven days of continuous administration. At the dose of 300 mg QD and 450 mg QD, the exposure of BPI-9016M increased with increasing dose. Exposure of BPI-9016M was similar at 450 mg QD and 600 mg QD, which may exhibit a saturation trend. In all patients, ORR and DCR were 2.6% (1/38, 95% confidence interval [CI] 0.1–13.8%) and 42.1% (16/38, 95% CI 26.3–59.2%), respectively. Only one partial response (PR) patient was observed at a dose of 600 mg QD in Part A. In Part B, DCR was 75.0% (3/4, 95% CI 19.4–99.4%). The median PFS and OS in all 38 patients were 1.9 months (95% CI 1.9–3.7) and 10.3 months (95% CI 7.3–not evaluable [NE]), respectively. Conclusion BPI-9016M showed manageable safety profile in c-MET overexpression or MET exon 14 skipping mutation patients with locally advanced or metastatic NSCLC, but showed limited efficacy. Trial registration Clinicaltrials.gov NCT02929290 (11/10/2016).

Background Lipusu is the first commercialized liposomal formulation of paclitaxel and has demonstrated promising efficacy against locally advanced lung squamous cell carcinoma (LSCC) in a small‐scale study. Here, we conducted a multicenter, randomized, phase 3 study to compare the efficacy and safety of cisplatin plus Lipusu (LP) versus cisplatin plus gemcitabine (GP) as first‐line treatment in locally advanced or metastatic LSCC. Methods Patients enrolled were aged between 18 to 75 years, had locally advanced (clinical stage IIIB, ineligible for concurrent chemoradiation or surgery) or metastatic (Stage IV) LSCC, had no previous systemic chemotherapy and at least one measurable lesion as per the Response Evaluation Criteria in Solid Tumors (version 1.1) before administration of the trial drug. The primary endpoint was progression‐free survival (PFS). The secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety profiles. To explore the possible predictive value of plasma cytokines for LP treatment, plasma samples were collected from the LP group at baseline and first efficacy evaluation time and were then subjected to analysis by 45‐Plex ProcartaPlex Panel 1 to detect the presence of 45 cytokines using the Luminex xMAP technology. The correlation between treatment outcomes and dynamic changes in the levels of cytokines were evaluated in preliminary analyses. Results The median duration of follow‐up was 15.4 months. 237 patients in the LP group and 253 patients in the GP group were included in the per protocol set (PPS). In the PPS, the median PFS was 5.2 months versus 5.5 months in the LP and GP group (hazard ratio [HR]: 1.03, P = 0.742) respectively. The median OS was 14.6 months versus 12.5 months in the LP and GP group (HR: 0.83, P = 0.215). The ORR (41.8% versus 45.9%, P = 0.412) and DCR (90.3% versus 88.1%, P = 0.443) were also similar between the LP and GP group. A significantly lower proportion of patients in the LP group experienced adverse events (AEs) leading to treatment interruptions (10.9% versus 26.4%, P < 0.001) or treatment termination (14.3% versus 23.1%, P = 0.011). The analysis of cytokine levels in the LP group showed that low baseline levels of 27 cytokines were associated with an increased ORR, and 15 cytokines were associated with improved PFS, with 14 cytokines, including TNF‐α, IFN‐γ, IL‐6, and IL‐8, demonstrating an overlapping trend. Conclusion The LP regimen demonstrated similar PFS, OS, ORR and DCR as the GP regimen for patients with locally advanced or metastatic LSCC but had more favorable toxicity profiles. The study also identified a spectrum of different cytokines that could be potentially associated with the clinical benefit in patients who received the LP regimen., Cisplatin plus Lipusu (LP) regimen has comparable efficacy and more favorable toxicity profiles compared with cisplatin plus gemcitabine (GP) regimen for patients with advanced LSCC. The study also demonstrated that LP had a significant impact on the levels of plasma cytokines and a spectrum of cytokines were associated with clinical benefit in patients who received LP. Thus, our results provided a new option for patients with advanced LSCC.

Objective Small cell lung cancer (SCLC) transformation had previously been reported mainly in epidermal growth factor receptor (EGFR) mutant adenocarcinoma. However, the underlying genomic profile remains unclear. Our study aim to find the evolution and genotypic characteristic of SCLC transformation. Patients and methods Thirty-one SCLC transformation patients who were initially diagnosed as Non-Small Cell Lung Cancer (NSCLC) patients were included. Whole exome sequencing (WES) of both primary and transformed re-biopsy lesions was conducted on 12 patients. Clinical characteristics were analyzed using R software (v.3.6.1). Results Our study included 31 patients, of whom, three had lung squamous cell carcinoma. Six patients did not carry EGFR mutations. Thirty patients received chemotherapy for SCLCs. The disease control rate (DCR) was 96.7%, and the median progression-free survival (PFS) was 4.03 months. The median time to transformation was 33.07 months, and the median overall survival (OS) was 62.08 months. Somatic mutation analysis showed that besides TP53, RB1, and EGFR, there was a high occurrence of mutations to CSMD3 and ADAMTS19, especially in the EGFR-wild type (EGFR-wt) group. Concerning mutational signature, the EGFR-mutant (EFFR-mut) transformed group favored an APOBEC (apolipoprotein B mRNA editing catalytic polypeptide-like)-associated mutation pattern (P = 0.16). DNA Damage Repair (DDR)-related signatures were significantly enriched in the EGFR-wt transformed group (P = 0.034). Additionally, clonal evolution analysis revealed that all patients had the same main trunk genes in the phylogenetic tree. Transformed SCLCs are not sensitive to immunotherapy, possibly due to increased tumor heterogeneity. Conclusion Our results indicated that the EGFR-wt patients could also transform to SCLCs, but they have different genetic features with EGFR-mut patients. SCLC-transformed patients respond to classical chemotherapy and have a better prognosis than those with classical SCLCs.

Background Early diagnosis of lung adenocarcinoma (LUAD), one of the most common types of lung cancer, is very important to improve the prognosis of patients. The current methods can’t meet the requirements of early diagnosis. There is a pressing need to identify novel diagnostic biomarkers. Secretory proteins are the richest source for biomarker research. This study aimed to identify candidate secretory protein biomarkers for early diagnosis of LUAD by integrated bioinformatics analysis and clinical validation. Methods Differentially expressed genes (DEGs) of GSE31210, gene expression data of early stage of LUAD, were analyzed by GEO2R. Upregulated DEGs predicted to encode secreted proteins were obtained by taking the intersection of the DEGs list with the list of genes encoding secreted proteins predicted by the majority decision-based method (MDSEC). The expressions of the identified secreted proteins in the lung tissues of early-stage LUAD patients were further compared with the healthy control group in mRNA and protein levels by using the UALCAN database (TCGA and CPTAC). The selected proteins expressed in plasma were further validated by using Luminex technology. The diagnostic value of the screened proteins was evaluated by receiver operating characteristic (ROC) analysis. Cell counting kit-8 assay was carried out to investigate the proliferative effects of these screened proteins. Results A total of 2183 DEGs, including 1240 downregulated genes and 943 upregulated genes, were identified in the GSE31210. Of the upregulated genes, 199 genes were predicted to encode secreted proteins. After analysis using the UALCAN database, 16 molecules were selected for further clinical validation. Plasma concentrations of three proteins, Midkine (MDK), WAP four-disulfide core domain 2 (WFDC2), and C-X-C motif chemokine ligand 14 (CXCL14), were significantly higher in LUAD patients than in healthy donors. The area under the curve values was 0.944, 0.881, and 0.809 for MDK, WFDC2, and CXCL14, 0.962 when combined them. Overexpression of the three proteins enhanced the proliferation activity of A549 cells. Conclusions MDK, WFDC2, and CXCL14 were identified as candidate diagnostic biomarkers for early-stage LUAD and might also play vital roles in tumorigenesis.

Background Although advanced non-squamous non-small cell lung cancer (NSCLC) patients have significantly better survival outcomes after pemetrexed based treatment, a subset of patients still show intrinsic resistance and progress rapidly. Therefore we aimed to use a blood-based protein signature (VeriStrat, VS) to analyze whether VS could identify the subset of patients who had poor efficacy on pemetrexed therapy. Methods This study retrospectively analysed 72 advanced lung adenocarcinoma patients who received first-line pemetrexed/platinum or combined with bevacizumab treatment. Results Plasma samples from these patients were analysed using VS and classified into the Good (VS-G) or Poor (VS-P) group. The relationship between efficacy and VS status was further investigated. Of the 72 patients included in this study, 35 (48.6%) were treated with pemetrexed plus platinum and 37 (51.4%) were treated with pemetrexed/platinum combined with bevacizumab. Among all patients, 60 (83.3%) and 12 (16.7%) patients were classified as VS-G and VS-P, respectively. VS-G patients had significantly better median progression-free survival (PFS) (Unreached vs. 4.2 months; P Conclusions Our study indicated that VS might be considered as a novel and valid method to predict the efficacy of pemetrexed-based therapy and identify a subset of advanced lung adenocarcinoma patients who had intrinsic resistance to pemetrexed based regimens. However, larger sample studies are still needed to further confirm this result.

Background: Hepatocellular Carcinoma (HCC), the second leading cause of cancer-related mortality with over half a million new cases diagnosed annually in the world, accounts for nearly 70% of cancer deaths in parts of Asia and Africa. Podophyllum, one of the important members of the lignane class of natural products derived from plants in Podophyllum peltatum L., has been shown to suppress tumor growth in various cancers. However, the effects of Podophyllum compounds on HCC and the mechanisms for its tumor-suppressive function remain unknown. Methods: A molecular docking study was employed to the analysis of the interaction between compounds and their targeted proteins. Cell proliferation was measured by MTT assay. Western blot analysis was used to evaluate protein expression. qRT-PCR was performed to assess RNA expression. Results: Molecular docking analysis was consistent with the beneficial effect of fluorine atom substituent in the 3-position of 2-aminopyridine in our previous study. Also, P-3F and D-3F displayed the most potent cytotoxicities against PLC/PRF/5 with p53-R249S and weakest inhibition of L02 (normal liver cell) growth. However, these derivatives had no effect on the suppression of HepG2 (wild-type p53) and Hep3B (p53-null) proliferation significantly. Further study showed that both compounds increase γ-H2AX expression in PLC/PRF/5 cell, along with repression of the c-Myc activation, purportedly by induction of p53 level and transcriptional activation. Conclusion: The results suggested that podophyllum derivatives containing fluorine atom in the 3-position of 2- aminopyridine could inhibit the growth of HCC harboring p53-R249S by restoring the activity of p53 with decreasing the level of c-Myc.

Kirsten rat sarcoma viral oncogene homolog (KRAS) is an important driver gene of non-small cell lung cancer (NSCLC). Despite a rapid progress achieved in the targeted therapy, chemotherapy remains the standard treatment option for patients with KRAS-mutant NSCLC. This study aimed to assess real-world data of Chinese patients with KRAS-mutant NSCLC undergoing chemotherapy and/or immunotherapy.KRAS mutational status was analyzed using next-generation sequencing of 150,327 NSCLC patients from the Lung Cancer Big Data Precise Treatment Collaboration Group (LANDSCAPE) project (Cohort I). Treatment data were collected and analyzed retrospectively from 4348 NSCLC patients who were admitted to the Peking University Cancer Hospital and Institute between January 2009 and October 2020 (Cohort II).In Cohort I, 18,224 patients were detected with KRAS mutations (12.1%) of whom G12C (29.6%) was the most frequent subtype, followed by G12D (18.1%) and G12V (17.5%). In case of concomitant mutations, TP53 had the highest incidence of 33.6%, followed by EGFR (11.6%), STK11 (10.4%), KEAP1(6.2%), and CDKN2A (6.0%). Cohort II included 497 patients (11.4%) with KRAS mutations. In the first-line chemotherapeutic analysis of Cohort II, patients benefited more from the pemetrexed/platinum (PP) regimen than the gemcitabine/platinum (GP) or taxanes/platinum (TP) regimen (median progression-free survival [PFS], 6.4 vs. 4.9 vs. 5.6 months, hazard ratio [HR] = 0.65, 95% confidence interval [CI] 0.48-0.88, p = 0.033 and HR = 0.69, 95% CI 0.47-1.00, p = 0.05, respectively), with no significant difference when combined with bevacizumab. Regarding patients who received immune checkpoint inhibitors (ICIs), the objective response rate was 26% for a median PFS of 9.6 months (95% CI 6.16-13.03). Patients who received ICIs combined with chemotherapy had a significantly longer survival than monotherapy (median PFS, 13.9 vs. 5.2 months, HR = 0.59, 95% CI 0.35-0.99, p = 0.049).KRAS is an important driver gene in NSCLC, compromising 12.1% in this study, and G12C was noted as the most common subtype. Patients with KRAS-mutant NSCLC could benefit from pemetrexed-based chemotherapy and ICIs.

Background High concordance has been observed between Ventana D5F3 ALK immunohistochemistry (IHC) and fluorescence in-situ hybridization (FISH) in lung adenocarcinoma (LADC). However, whether a similar conclusion can be applied to lung squamous-cell carcinoma (LSCC) has remained unclear. We therefore evaluated the ALK (anaplastic lymphoma kinase) status and the therapeutic effect of an ALK tyrosine kinase inhibitor (TKI) in IHC- or FISH-positive LSCC. Materials and methods A total of 2403 LSCC patients from three institutions were screened for ALK aberration by IHC. All IHC-positive cases were subjected to FISH (with an approximately equal number of negative cases as a control group) and next-generation sequencing (NGS). Clinical efficacy was evaluated for the patients who received TKI therapy. Results In 2403 cases of LSCC, 37 cases were identified as ALK-positive by IHC. After quality control, 28 cases were succeeded by FISH (six with insufficient tissue, three with lack of signals) and 13 by NGS (24 failed due to insufficient samples or poor DNA quality); the percentage of non-diagnostic tests was 24.3% (9/37) and 64.9% (24/37), respectively. Four cases (4/2394, 0.17%) analyzed by FISH were determined as ALK-positive. For the control group (40 ALK IHC), FISH demonstrated no samples with ALK gene fusion. The concordance between ALK IHC- and ALK FISH-positive results was 14.3% (4/28). In the 13 cases studied by NGS, two cases showed ALK-EML4 fusion (consistent with two FISH-positive results), and two cases were interpreted as harboring an ALK-association gene mutation. Among four patients (two FISH-positive and two IHC-positive only cases) receiving TKI therapy, two patients had stable disease and the other two had progressive disease. Conclusions The positive concordance rate of ALK IHC and FISH in LSCC is far less than that reported for LADC. Therefore, ALK IHC detection in LSCC cannot be used as a diagnostic method for ALK rearrangement.

Background: At a predefined interim analysis (IA), RATIONALE-303 (NCT03358875) demonstrated improved overall survival (OS) for TIS vs D in the intent-to-treat (ITT) population with a manageable safety profile. Given disease characteristics, standard of care treatment/prognosis differ between histologic types of NSCLC. Here we report the data on the sq population. Methods: 805 patients (pts) with histologically confirmed, advanced NSCLC with progressive disease during or after ≥ 1 platinum (Pt)-containing chemotherapy regimen were randomized (2:1) to TIS 200 mg IV or D 75 mg/m2 IV every 3 weeks until disease progression, intolerable toxicity, or withdrawal. Histology (sq vs non-sq), was a stratification factor for randomization. Dual primary endpoints were OS in the ITT and PD-L1 ≥ 25% populations. The IA was conducted after ~426 deaths (76% of planned events). Efficacy and safety were assessed in 370 randomized pts with sq histology. Results: Baseline characteristics of sq pts were balanced between treatment arms and similar to the ITT population. As of August 10, 2020, at median follow-up of 19.0 and 19.3 months (mo), respectively, median (95% CI) OS was longer with TIS (16.0 mo [13.8, 18.9]) vs D (11.3 mo [8.7, 12.7]) in the sq ITT population, and progression free survival (PFS), objective response rate (ORR) and duration of response (DoR) were also improved for TIS vs D (Table). 95.1% (TIS) and 99.1% (D) of pts had ≥ 1 treatment-emergent adverse event (TEAE) and 38.1% (TIS) and 79.5% (D) of pts had ≥ Grade 3 TEAEs. The most common TEAEs were anemia, cough and alanine amino transferase increased (TIS arm), and anemia, alopecia, and neutrophil count decreased (D arm). Conclusions: TIS prolonged OS with a favorable safety profile in pts with advanced sq NSCLC who progressed after a Pt-containing regimen. The data are consistent with the overall ITT population. Efficacy* TIS (n=248) D (n=122) Median OS, mo (95% CI) 16.0 (13.80, 18.86) 11.3 (8.67, 12.68) OS HR (95% CI)† 0.58 (0.436, 0.761) P < 0.0001‡§ Median PFS, mo (95% CI) 6.2 (4.21, 6.37) 2.3 (2.10, 3.38) PFS HR (95% CI)† 0.45 (0.343, 0.577) P < 0.0001‡§ ORR, n (%) 57 (23.0) 5 (4.1) Median DoR, mo (95% CI) 16.7 (8.31, NE) 6.2 (2.10, 8.31) Safety** TIS (n=247) D (n=117) TEAEs ≥ 20% of patients in either arm, n (%) All grades ≥ Grade 3 All grades ≥ Grade 3 Anemia 76 (30.8) 7 (2.8) 56 (47.9) 10 (8.5) Decreased appetite 41 (16.6) 2 (0.8) 33 (28.2) 3 (2.6) Asthenia 38 (15.4) 5 (2.0) 27 (23.1) 6 (5.1) White blood cell count decreased 12 (4.9) 1 (0.4) 32 (27.4) 21 (17.9) Leukopenia 9 (3.6) 1 (0.4) 31 (26.5) 19 (16.2) Neutrophil count decreased 7 (2.8) 2 (0.8) 42 (35.9) 35 (29.9) Alopecia 5 (2.0) 0 (0.0) 52 (44.4) 0 (0.0) Neutropenia 2 (0.8) 0 (0.0) 37 (31.6) 34 (29.1) *Efficacy analysis set - Sq patients; †Stratified; ‡One-sided stratified log-rank test; §Descriptive P-value; **Safety analysis set - Sq patients CI; confidence interval; D, docetaxel; DoR, duration of response; HR, hazard ratio; mo, months; NE, not evaluable; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; sq, squamous; TEAE, treatment-emergent adverse event; TIS, tislelizumab Data cut-off: August 10, 2020 Citation Format: Jie Wang, Zhiyong Ma, Dingzhi Huang, Yun Fan, Xinmin Yu, Sheng Hu, Ziping Wang, Zhihua Liu, Devrim Cabuk, Mahmut Gumus, Yiyuan Ma, Yan Wang, Yan Ma, Caicun Zhou. Tislelizumab (TIS) versus docetaxel (D) in patients with previously treated advanced squamous (sq) non-small-cell lung cancer (NSCLC): Sub-analysis from phase 3 RATIONALE-303 randomized clinical study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT554.

Background: METex14 mutations was reported in 3~4% of NSCLC patients and became a new target in the treatment of NSCLC. SCC244 is a highly selective and potent oral MET inhibitor. This is the first report of data from an ongoing single-arm phase II study of SCC244 in NSCLC patients with METex14 mutations (GLORY study). Methods: GLORY study is an open label, international, multi-center, single-arm phase II study to evaluate the efficacy and safety of SCC244 in patients with locally advanced or metastatic NSCLC harboring METex14 mutations which was confirmed by central laboratory. The enrolled patients have either failed one or two prior lines of systemic therapies or been not eligible/refused chemotherapy after being well-informed. SCC244 was taken orally at a dose of 300 mg once daily in 21-day treatment cycles until disease progression or intolerable toxicity. Tumor was evaluated every 6 weeks for the first 8 treatment cycles and every 9 weeks thereafter. The primary endpoint was objective response rate (ORR) assessed by blinded independent review committee (BIRC) per RECIST 1.1, secondary endpoints include ORR by investigator assessment (INV), duration of response (DoR), time to response (TTR) and safety etc. Post-hoc analysis was done to explore the intracranial anti-tumor activity. Results: At data cut-off on May 6th, 2021, a total 73 patients screened from 163 patients in 42 sites were treated at 300 mg QD dose and had ≥2 post-baseline tumor assessments or discontinued for any reason. 69 of them were with METex14 mutation confirmed by central laboratory. In the 69 patients, ORR by BIRC was 60.9% (95% CI: 48.4%, 72.4%) overall, 66.7% (95% CI: 50.5, 80.4) and 51.9% (95% CI: 31.9, 71.3) in treatment naïve and previously treated patients respectively. Median DoR was 8.2 months (95% CI: 4.8, NE) and median PFS was 7.6 months (95% CI: 4.2, NE), tumor response from 30 of 42 responders was still ongoing. The response occurred fast with a median TTR of 1.4 months (range: 1.2, 4.2). Partial response was observed in 8 of 10 patients with brain metastasis. 5 patients who had brain metastasis selected as targeted lesion had intracranial response by INV with a median intracranial tumor shrinkage of 57% (range: 34%, 71%). The most common (≥20%) treatment-related adverse events (TRAEs) of any grade were peripheral edema, headache, nausea, loss of appetite, hypoalbuminemia, ALT increase and vomiting. The incidence of ≥ grade 3 TRAEs was 43.8%. TRAEs leading to treatment discontinuation occurred in 6.8% patients, among which peripheral edema was the most common (4.1%). Conclusions: The data shows high and robust efficacy of SCC244 in NSCLC patients with METex14 mutations across treatment lines and encouraging intracranial anti-tumor activity. The safety profile was favorable with manageable toxicity. The data supports SCC244 as a valuable targeted treatment option for METex14 NSCLC patients. Citation Format: Shun Lu, Yongfeng Yu, Jianya Zhou, Koichi Goto, Xingya Li, Jun Sakakibara-Konishi, Kazumi Nishino, Tanaka Kentaro, Lin Wu, Xuhong Min, Wei Zhang, Dingzhi Huang, Yongqian Shu, Chengzhi Zhou, Min Li, Xiaorong Dong, Chong Bai, Lu Li, Jiuwei Cui, Li Zhang, Lejie Cao, Xiaoling Li, AiMin Zang, Haruki Kobayashi, Yiping Zhang, Yan Yu, Xiuwen Wang, Terufumi Kato, Shoichiro Yamamoto, Yuki Shinno, Xiaoyan Lin, Yanqiu Zhao, Yanping Hu, Qitao Yu, Ziping Wang, Masahiro Kodani, Jian Fang, Jialei Wang, Meiqi Shi, Diansheng Zhong, Wen Dong, Hiroshi Tanaka, Yasuto Yoneshima, Minghui Sun, Jun Zhou, Qiuxia Wu, Meng Li. Phase II study of SCC244 in NSCLC patients harboring MET exon 14 skipping (METex14) mutations (GLORY study) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT034.

9096 Background: We previously reported (Lu, ASCO 2021, abstract # 9013) that treatment with aumolertinib (Au), a 3rd generation EGFR TKI, led to robust improvement in progression free survival (PFS) (median PFS 19.3 to 9.9 months, HR = 0.46, p < 0.0001) when compared to gefitinib (G) with a predictable and encouraging safety profile. This benefit was maintained across all prespecified stratification factors including the subset of ̃ 27% of patients (pts) with CNS metastases (HR = 0.38). Here we undertook this analysis to more fully characterize the activity and benefit of Au as compared to G in this clinically important subset of EGFR mutant NSCLC pts. Methods: Pts with previously untreated metastatic or locally advanced NSCLC with EGFR sensitizing mutations were enrolled and randomly assigned in a 1:1 ratio to receive either Au (110 mg QD) or G (250 mg QD). Predefined stratification factors were EGFR-mutated status (Ex19del vs L858R) and CNS metastases (yes vs no). Patients with stable, asymptomatic CNS metastases were eligible for enrollment. All pts had baseline brain imaging by magnetic resonance imaging or computed tomography. The primary endpoint was PFS assessed by investigator per RECIST v1.1 in full analysis set (systemic analysis). Independent CNS efficacy was performed both in pts with baseline CNS metastases (CNS full analysis set, cFAS) and in pts with baseline CNS target lesions (CNS evaluable-for-response set, cEFS) by blinded independent central neuroradiology review (BICR) per RECIST v1.1. Results: Of 429 pts, 106 pts (Au, n = 51; G, n = 55) were found to have CNS metastases (cFAS) and 61 pts (Au, n = 29; G, n = 32) had CNS target lesions as defined by RECIST 1.1 (cEFS) at baseline by BICR. At the cutoff date (Aug 6, 2021), based on cEFS, CNS PFS events were observed in 11 pts (38%) treated with Au versus 20 pts (63%) who were randomized to receive G. Treatment with Au significantly prolonged CNS median PFS compared with G (29.0 vs 8.3 months; HR = 0.300; 95% CI, 0.137-0.657; P = 0.0015). Estimated CNS PFS rate at 12 and 18 months were 71% and 62% in Au arm compared with 23% and 0% in G arm. The confirmed CNS ORR were 82.8% and 75.0% in pts treated with Au and G, respectively (odds ratio = 1.600; 95% CI, 0.457-5.597; P = 0.4621). Au also achieved longer CNS median PFS over G in cFAS (29.0 vs 8.3 months; HR = 0.323; 95% CI, 0.181-0.576; P < 0.0001). No new safety findings were observed. Conclusions: Au demonstrated superior clinical efficacy against CNS metastases over G as first-line therapy in EGFR-mutated advanced NSCLC, and the safety profile was consistent with that reported previously. Additional randomized studies of Au in pts with CNS metastases are ongoing (NCT04870190). Clinical trial information: NCT03849768.

8572 Background: Taletrectinib (AB-106 / DS-6051b) is a next-generation, potent, CNS- penetrant, selective ROS1 tyrosine kinase inhibitor. The ongoing TRUST study (NCT04395677) is a multicenter, open-label, single-arm, Phase 2 study of taletrectinib in Chinese ROS1-positive NSCLC patients who are TKI -naïve or crizotinib-pretreated. Here we present the updated efficacy and safety results of the study. Methods: The eligible ROS1-positive NSCLC patients were enrolled into either TKI-naïve or crizotinib-pretreated cohorts, and treated with taletrectinib 600mg once daily. The study endpoints included overall response rate (ORR), duration of response (DOR), disease control rate (DCR), overall intracranial response rate (IC-ORR), progression-free survival (PFS), and safety profile. Results: As of the data cutoff date of September 7, 2021, 61 of the 86 stage IV patients enrolled in the study have at least three postbaseline tumor assessment of which 40 patients in the TKI-naïve cohort, and 21 patients in the crizotinib-pretreated cohort (50% patients having at least one prior chemotherapy). In the TKI -naïve cohort, the confirmed ORR by investigators per RECIST 1.1 was 90.0%: [95%CI: 76.3%; 97.2%] (36/40); and the DCR was 95% [95%CI: 83.1%; 99.4%] (38/40). In the crizotinib-pretreated cohort, the confirmed ORR by investigators was 47.6% [95%CI: 25.7%; 70.2%] (10/21); and DCR was 76.2%: [52.8%; 91.8%] (16/21). The mDOR and mPFS are not reached yet for both cohorts. Of 6 patients having brain metastasis and measurable target brain lesions at baseline, the intracranial ORR and IC-DCR were 83.3% and 100%, respectively. Of 4 patients with ROS1 G2032R mutation, 3 patients achieved partial response (PR), and 1 patient achieved stable disease (SD). The most common treatment-related adverse events (TRAEs) include diarrhea, nausea, vomiting, transaminase elevation, anemia, neutrophil count decrease, etc. were Grade 1 or 2, and the most common AEs (below 10%) were ALT/AST increased but reversible. Conclusions: Taletrectinib demonstrated meaningful clinical efficacy in both TKI-naïve and crizotinib-pretreated ROS1 positive NSCLC patients. In particular, taletrectinib showed clinical effectiveness in patients with ROS1 secondary G2032 mutations and patients with brain metastasis. Taletrectinib was well tolerated in this patient population. Clinical trial information: NCT04395677.

9019 Background: Based on IMPOWER 150, atezolizumab in combination with bevacizumab and platinum-based chemotherapy has been the first-line treatment for advanced non-squamous NSCLC with negative driver genes. AK112 is a global first-in-class anti-PD-1/VEGF bi-specific antibody developed by Akesobio. Preclinical and clinical studies have indicated that AK112 possess potential anti-tumor efficacy in solid tumors. Therefore, we aimed to assess the efficacy and safety of AK112 in combination with chemotherapy for patients with advanced NSCLC. Methods: This was an open-label, multi-center phase II study evaluating the efficacy and safety of AK112 in combination with chemotherapy in pts with advanced NSCLC. Enrolled pts were divided into three cohorts: Previously untreated advanced NSCLC pts with wide-type EGFR/ALK (Cohort 1), pts with EGFR mutations who had failed prior EGFR-TKI therapies without T790M mutation or failed osimertinib treatment (Cohort 2), and pts who progressed after anti-PD-1/L1 and platinum-based chemotherapy (Cohort 3). Pts were treated with 10mg/kg or 20mg/kg AK112 once every 3 weeks in combination with carboplatin and pemetrexed or carboplatin and paclitaxel for Cohort 1/2, and docetaxel for Cohort 3. Primary endpoint was ORR as assessed by investigator per RECIST v1.1. Results: 133 pts were enrolled from Feb 03, 2021 to Dec 31, 2021 and received AK112 plus chemotherapy (44 received AK112 10 mg/kg and 89 received AK112 20 mg/kg). As of Dec 31, 2021, in cohort-1, among 26 evaluable pts with squamous cell carcinoma, 20 partial response and 6 stable disease were observed for a 76.9% ORR and a 100.0% DCR, median DOR and median PFS was not reached while 6-month PFS rate was 86.2%. In Cohort-2, among 19 evaluable pts, 13 partial response and 5 stable disease were observed for a 68.4% ORR and a 94.7% DCR while median DOR was 5.5 months, and median PFS was 8.3 months. In Cohort-3, among 20 evaluable pts, 8 partial response and 8 stable disease were observed for a 40.0% ORR and a 80.0% DCR, median DOR and median PFS was not reached while 6-month PFS rate was 71.1%. Treatment emergent adverse events (TEAE) occurred in 86.5% (115/133) of the pts, and grade ≥3 AEs occurred in 28.6% (38/133) of pts including two deaths. Most common AE (incidence ≥ 5%) included alanine/aspartate aminotransferase increased, epistaxis, anemia, vomiting, nausea, rash, leukopenia, thrombocytopenia, and neutropenia. Treatment discontinuation due to AE occurred in 3.0% (4/133) of the pts. Conclusions: AK112 plus chemotherapy has shown a promising anti-tumor efficacy in each cohort and warrants potentially superior safety in comparison to anti-PD-(L)1 and anti-VEGF combination therapies in advanced NSCLC. PFS and ORR were also significantly improved with AK112 plus chemotherapy. Therefore, phase III registration studies of AK112 plus chemotherapy in advanced NSCLC will be initiated in 2022. Clinical trial information: NCT04736823.

Background The five-year cumulative incidence rate in patients diagnosed with stage I small-cell lung cancer (SCLC) who were instructed to undergo surgery was from 40 to 60%.The death competition influence the accuracy of the classical survival analyses. The aim of the study is to investigate the mortality of stage I small-cell lung cancer (SCLC) patients in the presence of competing risks according to a proportional hazards model, and to establish a competing risk nomogram to predict probabilities of both cause-specific death and death resulting from other causes. Methods The study subjects were patients diagnosed with stage I SCLC according to ICD-O-3. First, the cumulative incidence functions (CIFs) of cause-specific death, as well as of death resulting from other causes, were calculated. Then, a proportional hazards model for the sub-distribution of competing risks and a monogram were constructed to evaluate the probability of mortality in stage I SCLC patients. Results 1811 patients were included in this study. The five-year probabilities of death due to specific causes and other causes were 61.5 and 13.6%, respectively. Tumor size, extent of tumor, surgery, and radiotherapy were identified as the predictors of death resulting from specific causes in stage I SCLC. The results showed that surgery could effectively reduce the cancer-specific death, and the one-year cumulative incidence dropped from 34.5 to 11.2%. Like surgery, chemotherapy and radiotherapy improved the one-year survival rate. Conclusions We constructed a predictive model for stage I SCLC using the data from the SEER database. The proportional sub-distribution models of competing risks revealed the predictors of death resulting from both specific causes and other causes. The competing risk nomogram that we built to predict the prognosis showed good reliability and could provide beneficial and individualized predictive information for stage I SCLC patients.

Purpose: Primary mediastinal germ cell tumors (PMGCTs) are rare. The natural history and optimal treatment strategies still need to be defined. The aim of the study was to summarize the clinical characteristics, treatment outcomes, and prognostic factors of PMGCTs. Methods: Twenty-four patients with PMGCTs who were treated from December 2008 to January 2019 were evaluated retrospectively. The Kaplan–Meier method and Cox regression analysis were used to evaluate factors associated with prognosis. Results: The study population consisted of 23 male patients and 1 female patient. Five patients were diagnosed with seminoma and 19 patients were diagnosed with nonseminoma. The median follow-up time for all patients was 15.8 (3.9–114.5) months. The 5-year overall survival (OS) and progression free survival (PFS) rates for all patients were 65.2 and 44.3%. For nonseminoma and seminoma, the 5-year OS rates were 54.1 and 100% (P = 0.093), respectively, and the 5-year PFS rates were 28.7 and 100%, respectively (P = 0.044). In patients with nonseminoma, first-line radiotherapy indicated superior OS and PFS (P = 0.037 and 0.027, respectively). The median survival time after recurrence was 4.3 months and the 1-year survival rate after recurrence was 23.4%. Conclusion: These results indicated that in PMGCTs, the prognosis of seminoma is superior to that of nonseminoma. Radiotherapy may be an essential treatment in patients with nonseminoma. Patients with relapse have unfavorable prognosis.

Background This study aimed to establish a novel nomogram prognostic model to predict death probability for non-small cell lung cancer (NSCLC) patients who received surgery.. Methods We collected data from the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute in the United States. A nomogram prognostic model was constructed to predict mortality of NSCLC patients who received surgery. Results A total of 44,880 NSCLC patients who received surgery from 2004 to 2014 were included in this study. Gender, ethnicity, tumor anatomic sites, histologic subtype, tumor differentiation, clinical stage, tumor size, tumor extent, lymph node stage, examined lymph node, positive lymph node, type of surgery showed significant associations with lung cancer related death rate (P Conclusions A prognostic nomogram model was constructed to give information about the risk of death for NSCLC patients who received surgery.

Background The functional role of lung microbiota has attracted an accumulating attention recently, but the profile and functional role of the lung microbiota in patients with lung cancer remained largely unknown. Methods To evaluate the association of the microbiota with lung cancer, we performed comparative analysis of the lung microbiota using 16S rRNA amplicon sequencing approach in the paired bronchoalveolar lavage fluid (BALF) samples (paired samples from cancerous lung and the contralateral non-cancerous lung) from 50 cancer patients with unilateral lobar masses. Results We found that the relative abundance of phylum Tenericutes, its class Mollicutes, its order Entomoplasmatales, its family Spiroplasmataceae, and its genus Spiroplasma was significantly increased in cancerous lung, but the relative abundance of phylum Bacteroidetes, its class Bacteroidia, and its order Bacteroidales was significantly decreased in cancerous lung. In addition, the relative abundance of family Leuconostocaceae and its genus Weissella was significantly increased in cancerous lung. Conclusion Our findings provide insights into a change of lung microbiota community associated with the development of lung cancer.

Purpose: We aimed to assess the survival benefit of surgery for patients with stage IA–IIB small cell lung cancer (SCLC) and construct a nomogram for predicting overall survival (OS).Methods: Patients who had been diagnosed with stage IA–IIB SCLC between 2004 and 2014 and who had received active treatment were selected from the Surveillance, Epidemiology, and End Results database. The primary endpoint was OS. Cox proportional hazards models and propensity score (PS) analyses were used to compare the associations between surgery and OS. The probability of 1- and 3-year OS was predicted using a nomogram.Results: We reviewed 2,246 patients. The median OS of the surgery and non-surgery groups was 35 months and 19 months, respectively. Multivariable Cox proportional hazards models showed a survival benefit in the surgery group (hazards ratio [HR], 0.642; 95% confidence interval [CI], 0.557–0.740; P < 0.001). To balance the between-group measurable confounders, the impact of surgery on OS was assessed using PS matching. After PS matching, OS analysis still favored surgical resection. The PS-stratification, PS-weighting, and PS-adjustment models showed similar results to demonstrate a statistically significant benefit for surgery. Further, the nomogram was well calibrated and had good discriminative ability (Harrell's C-index = 0.645).Conclusion: Our analysis suggests that surgery is a viable option for patients with early-stage SCLC. Our nomogram is a viable tool for quantifying treatment trade-off assumptions and may assist clinicians in decision-making. Future work is needed to validate our results and improve our tools.

BACKGROUND The PD-L1 antibody atezolizumab has shown promising efficacy in patients with advanced non-small cell lung cancer. But the predictive marker of clinical benefit has not been identified. OBJECTIVE This study aimed to search for potential predictive factors in circulating blood of patients receiving atezolizumab. METHODS Ten patients diagnosed with advanced non-small cell lung cancer were enrolled in this open-label observing study. Circulating immune cells and plasma tumor markers were examined in peripheral blood from these patients before and after atezolizumab treatment respectively. Relation between changes in circulating factors and anti-tumor efficacy were analyzed. RESULTS Blood routine test showed that atezolizumab therapy induced slightly elevation of white blood cells count generally. The lymphocyte ratio was increased slightly in disease controlled patients but decreased prominently in disease progressed patients in response to atezolizumab therapy. Flow cytometric analysis revealed changes in percentage of various immune cell types, including CD4+ T cell, CD8+ T cell, myeloid-derived suppressor cell, regulatory T cell and PD-1 expressing T cell after atezolizumab. Levels of plasma tumor marker CEA, CA125 and CA199 were also altered after anti-PD-L1 therapy. In comparison with baseline, the disease progressed patients showed sharp increase in tumor marker levels, while those disease controlled patients were seen with decreased regulatory T cell and myeloid-derived suppressor cell ratios. CONCLUSIONS The circulating immune cell ratios and plasma tumor marker levels were related with clinical efficacy of atezolizumab therapy. These factors could be potential predictive marker for anti-PD-L1 therapy in advanced non-small cell lung cancer.

Ensartinib, an oral tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK), has shown systemic and central nervous system efficacy for patients with ALK-positive non-small cell lung cancer (NSCLC).To compare ensartinib with crizotinib among patients with advanced ALK-positive NSCLC who had not received prior treatment with an ALK inhibitor.This open-label, multicenter, randomized, phase 3 trial conducted in 120 centers in 21 countries enrolled 290 patients between July 25, 2016, and November 12, 2018. Eligible patients were 18 years of age or older and had advanced, recurrent, or metastatic ALK-positive NSCLC.Patients were randomized (1:1) to ensartinib, 225 mg once daily, or crizotinib, 250 mg twice daily.The primary end point was blinded independent review committee-assessed progression-free survival (PFS). Secondary end points included systemic and intracranial response, time to central nervous system progression, and overall survival. Efficacy was evaluated in the intent-to-treat (ITT) population as well as a prespecified modified ITT (mITT) population consisting of patients with central laboratory-confirmed ALK-positive NSCLC.A total of 290 patients (149 men [51.4%]; median age, 54 years [range, 25-90 years]) were randomized. In the ITT population, the median PFS was significantly longer with ensartinib than with crizotinib (25.8 [range, 0.03-44.0 months] vs 12.7 months [range, 0.03-38.6 months]; hazard ratio, 0.51 [95% CI, 0.35-0.72]; log-rank P .001), with a median follow-up of 23.8 months (range, 0-44 months) for the ensartinib group and 20.2 months (range, 0-38 months) for the crizotinib group. In the mITT population, the median PFS in the ensartinib group was not reached, and the median PFS in the crizotinib group was 12.7 months (95% CI, 8.9-16.6 months; hazard ratio, 0.45; 95% CI, 0.30-0.66; log-rank P .001). The intracranial response rate confirmed by a blinded independent review committee was 63.6% (7 of 11) with ensartinib vs 21.1% (4 of 19) with crizotinib for patients with target brain metastases at baseline. Progression-free survival for patients without brain metastases was not reached with ensartinib vs 16.6 months with crizotinib as a result of a lower central nervous system progression rate (at 12 months: 4.2% with ensartinib vs 23.9% with crizotinib; cause-specific hazard ratio, 0.32; 95% CI, 0.16-0.63; P = .001). Frequencies of treatment-related serious adverse events (ensartinib: 11 [7.7%] vs crizotinib: 9 [6.1%]), dose reductions (ensartinib: 34 of 143 [23.8%] vs crizotinib: 29 of 146 [19.9%]), or drug discontinuations (ensartinib: 13 of 143 [9.1%] vs crizotinib: 10 of 146 [6.8%]) were similar, without any new safety signals.In this randomized clinical trial, ensartinib showed superior efficacy to crizotinib in both systemic and intracranial disease. Ensartinib represents a new first-line option for patients with ALK-positive NSCLC.ClinicalTrials.gov Identifier: NCT02767804.

Purpose: The optimal systemic treatment for pulmonary large-cell neuroendocrine carcinoma (LCNEC) is still under debate. Previous studies showed that LCNEC with different genomic characteristics might respond differently to different chemotherapy regimens. In this study, we sought to investigate genomic subtyping using cell-free DNA (cfDNA) analysis in advanced LCNEC and assess its potential prognostic and predictive value. Experimental Design: Tumor DNA and cfDNA from 63 patients with LCNEC were analyzed by target-captured sequencing. Survival and response analyses were applied to 54 patients with advanced stage incurable disease who received first-line chemotherapy. Results: The mutation landscape of frequently mutated cancer genes in LCNEC from cfDNA closely resembled that from tumor DNA, which led to a 90% concordance in genomic subtyping. The 63 patients with LCNEC were classified into small-cell lung cancer (SCLC)-like and non–small cell lung cancer (NSCLC)-like LCNEC based on corresponding genomic features derived from tumor DNA and/or cfDNA. Overall, patients with SCLC-like LCNEC had a shorter overall survival than those with NSCLC-like LCNEC despite higher response rate (RR) to chemotherapy. Furthermore, treatment with etoposide-platinum was associated with superior response and survival in SCLC-like LCNEC compared with pemetrexed-platinum and gemcitabine/taxane-platinum doublets, while treatment with gemcitabine/taxane-platinum led to a shorter survival compared with etoposide-platinum or pemetrexed-platinum in patients with NSCLC-like LCNEC. Conclusions: Genomic subtyping has potential in prognostication and therapeutic decision-making for patients with LCNEC and cfDNA analysis may be a reliable alternative for genomic profiling of LCNEC.

Background: Patients (pts) with advanced squamous NSCLC (sqNSCLC) have very limited second-line treatment options after failure of the platinum-based doublet chemotherapy. ORIENT-3 was conducted to compare the efficacy and safety of sintilimab, an anti-PD-1 antibody, with docetaxel in second-line treatment in sqNSCLC. (NCT03150875) Method: Pts with stage IIIB/IIIC or IV (ineligible for radical chemo-radiotherapy) sqNSCLC who have disease progression during or after first-line platimum-based chemotherapy were enrolled and randomized 1:1 to receive sintilimab 200mg (Sin arm) or docetaxel 75mg/m2 (Doc arm) intravenously, Q3W until disease progression or intolerable toxicity. Stratification factor was ECOG score (0 vs. 1). The primary endpoint was overall survival (OS). Results: As of July 31, 2020, 290 pts were enrolled with 145 in each treatment group. Efficacy analysis was based on FAS (n=280), and safety analysis was based on safety set (n=274). Baseline characteristics were well balanced between treatment groups, and most pts in efficacy analysis (75.9% in Sin arm, 77.0% in Doc arm) had ECOG PS score of 1. Pts received a median of 8.0 cycles (range: 1-45) of sintilimab, and 2.0 cycles of docetaxel (range: 1-15). With a median follow-up of 23.56 months, sintilimab had a significant improvement in OS versus docetaxel (median: 11.79 m [95% CI 10.28-15.57] vs. 8.25 m [95% CI 6.47-9.82]; HR 0.74, [95%CI 0.56-0.96], P = 0.02489). The median PFS was also significantly superior in Sin arm (4.30 m, 95% CI 4.04-5.78) to that in Doc arm (2.79 m, 95% CI 1.91-3.19) (HR 0.52, 95% CI 0.39-0.68, P Citation Format: Yuankai Shi, Lin Wu, Xinmin Yu, Yan Wang, Puyuan Xing, Jianying Zhou, Airong Wang, Jianhua Shi, Yi Hu, Ziping Wang, Guangyu An, Yong Fang, Sanyuan Sun, Caicun Zhou, Changli Wang, Feng Ye, Xingya Li, Junye Wang, Mengzhao Wang, Yunpeng Liu, Yanqiu Zhao, Jifeng Feng. ORIENT-3: A randomized, open-label, phase 3 study of sintilimab versus docetaxel in previously treated advanced/metastatic squamous non-small-cell lung cancer (sqNSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT041.

Results From RATIONALE 303: A Global Phase 3 Study of Tislelizumab (TIS) vs Docetaxel (TAX) as Second- or Third-Line Therapy for Patients With Locally Advanced or Metastatic NSCLC Background: Anti-PD-1/L1 therapies have improved OS by 2-4 mo vs TAX in patients (pts) with advanced NSCLC who progressed after platinum regimens. TIS is an anti-PD-1 antibody engineered to minimize FcγR binding on macrophages, a mechanism of T-cell clearance and potential anti-PD-1 resistance. Methods: RATIONALE 303 (BGB-A317-303; NCT03358875) compared efficacy and safety of TIS vs TAX as 2 or 3L therapy for pts with advanced NSCLC. Patients without oncogenic driver mutation who failed at least 1 prior systemic therapy including a platinum regimen were randomized 2:1 to receive TIS 200 mg IV Q3W (Arm A) or TAX 75 mg/m2 IV Q3W (Arm B). Dual primary endpoints were OS in the ITT analysis set and OS in the PD-L1 high (≥25% TC) analysis set. A prespecified interim analysis (IA) was conducted after ≈426 deaths (76% of planned events); in the IA, formal OS superiority testing was conducted only in the ITT. The IA results are presented. Results: Overall, 805 pts were randomized (n=535, TIS; n=270, TAX); demographics were generally balanced between arms. With a 19-mo median follow-up (441 OS events), median OSITT was significantly longer in Arm A vs B (17.2 vs 11.9 mo; HR=0.64 [95% CI: 0.53, 0.78]; P Conclusions: RATIONALE 303 demonstrated that, as 2 or 3L therapy in pts with advanced NSCLC, TIS was tolerable and prolonged OS by 5-7 mo with improved PFS and ORR vs TAX regardless of histology or PD-L1 expression. ITT Analysis Set (N=805)Arm A Tislelizumab (n=535)Arm B Docetaxel (n=270)EfficacyMedian OS, mo17.211.9OS difference, mo5.3HR (95% CI)a0.64 (0.53, 0.78)P-valuea,b Citation Format: Caicun Zhou, Dingzhi Huang, Xinmin Yu, Yunpeng Liu, Yun Fan, Yongqian Shu, Zhiyong Ma, Ziping Wang, Ying Cheng, Jie Wang, Sheng Hu, Zhihua Liu, Mikhail Dvorkin, Elena Poddubskaya, Umut Disel, Andrey Akopov, Yiyuan Ma, Yan Wang, Zhenyu Pan, Cunjing Yu, Gareth Rivalland. Results from RATIONALE 303: A global phase 3 study of tislelizumab (TIS) vs docetaxel (TAX) as second- or third-line therapy for patients with locally advanced or metastatic NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT039.

9013 Background: Au is a novel, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) with favorable pharmacologic properties that selectively inhibits both EGFR sensitizing and resistance mutations. Au has been approved in China for treatment of patients (pts) with EGFR mutant NSCLC with EGFR T790M upon progression of disease on previous EGFR TKIs (Proc. AACR 2020, Abstract CT190). This Phase III trial assessed the efficacy and safety of Au versus G as initial treatment of patients with advanced NSCLC with EGFRm. Methods: Pts with previously untreated metastatic or locally advanced NSCLC and EGFR exon 19 deletion or L858R were randomly assigned in a 1:1 ratio to receive either Au (110 mg once daily) or G (250 mg once daily). The primary endpoint was progression-free survival (PFS) by RECIST v1.1 per investigator assessment. At 262 PFS events, the study had 90% power to detect a PFS HR = 0.67. Secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DoR) and safety. Results: Between Nov 30, 2018 and Sept 6, 2019, 429 patients across 53 sites in China were enrolled and randomized. Pt. characteristics were well-balanced. At the planned final event-driven PFS analysis, Au significantly prolonged PFS (median 19.3 vs 9.9 months, HR 0.46, p-value

e21072 Background: Penpulimab is a human IgG1 monoclonal antibody (mAb) directed against human programmed cell death-1 (PD-1). Penpulimab, with its unique binding epitope, was engineered to eliminate Fc-mediated effector function that compromises anti-tumor immune cell function, and to optimize receptor occupancy by improving duration of drug binding. As a promising multi-target tyrosine kinase inhibitor (TKI), anlotinib significantly improved overall survival in advanced NSCLC patients (pts) in the phase 3 trial ALTER0303. Antiangiogenesis therapy combined with PD-1/PD-L1 inhibitors has shown excellent efficacy in advanced NSCLC pts. This is the trial evaluating chemo-free combination of penpulimab plus anlotinib in treatment-naive advanced NSCLC pts regardless of PD-L1 expression (NCT03866980). Methods: Pts with previously untreated, stage IIIB/IIIC/IV non-squamous NSCLC without sensitizing mutation of the epidermal growth factor receptor (EGFR) gene or translocation of the anaplastic lymphoma kinase (ALK) gene were enrolled. Eligible pts received penpulimab 200mg Q3W in combination with anlotinib 12mg QD (2 weeks on 1 week off) until loss of clinical benefit or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included ORR, disease control rate (DCR), duration of response (DoR) and overall survival. Results: As of January 13, 2021, 26 pts had received the combination therapy of penpulimab plus anlotinib (median age 59.5yrs [range 30-71], 76.9% male, 76.9% ECOG PS 1), with a median treatment duration of 3.5 months. Of 21 pts who have had at least one tumor assessment, the ORR was 57.1% (12 PRs) and DCR was 90.5% (12 PRs, 7 SDs). Median PFS has not been reached, and eleven responders remain in response. Treatment-related adverse events (TRAEs) occurred in 53.8% of pts (≥G3 TRAEs occurred in 15.4% [4/26]). Treatment-related SAEs occurred in 15.4% [4/26], and 7.7% of pts [2/26] had drug interruption or discontinuation due to TRAEs. Most common TRAEs (≥15%) were ALT increased, AST increased, hyperthyroidism and hypertension (15.4% each). Conclusions: The combination of penpulimab plus anlotinib as first-line treatment for locally advanced/metastatic NSCLC showed the promising efficacy with a manageable safety profile, thereby suggesting that this combination therapy may be a viable chemo-free treatment strategy for locally advanced/metastatic NSCLC pts. Clinical trial information: NCT03866980.

e21053 Background: VEGF promotes an immunosuppressive microenvironment and contributes to resistance of immune checkpoint inhibitors in cancer treatment. VEGF inhibitors have been shown to enhance efficacy of checkpoint inhibitors in clinical studies. Vorolanib (CM082) is a multi-target tyrosine kinase inhibitor including VEGF, PDGF, c-kit, and Flt-3. Toripalimab (JS001) is a humanized IgG4 mAb against programmed death-1 (PD-1). This phase II study aims to evaluate efficacy and safety of the combination of vorolanib and JS001 in non-small cell lung cancer (NSCLC) patients who progressed with prior first-line standard therapy. Methods: This single-arm, single-center, phase II study (NCT03848611) enrolls NSCLC patients with measurable disease (RECIST 1.1) and Eastern Cooperative Oncology Group performance status ≤ 1, regardless of PD-L1 status. 15 patients received 150 mg oral CM082 daily plus 240 mg intravenous JS001 every 3 weeks while 3 patients received 100 mg oral CM082 daily plus 240 mg intravenous JS001 every 3 weeks until disease progression or intolerable toxicity. The primary endpoint is objective response rate (ORR). Results: Between April 2019 and July 2020, 18 patients were enrolled. Median age was 64 years. 9 of 18 patients (50%) were adenocarcinoma and 9 of 18 patients (50%) were squamous. Males account for 83% (15/18) with 4 non-smokers among the male patients. At the data cutoff (January 11, 2021), we observed 2 (11%) confirmed and 1 (6%) unconfirmed partial response (PR), 6 (33%) stable disease (SD) and 9 (50%, including 2 PR of the target lesions) progression disease (PD). Tumor shrinkage was seen in 6 (33%) of the 18 patients. Two (11%) patients were still on the study drugs. Interestingly, all the patients with confirmed PR or PR of the target lesions were squamous histology. The most common treatment-related adverse events were proteinuria (67%), elevated ALT (60%), elevated AST (53%), hypertension (40%), and increased bilirubin (40%). Grade 3 adverse events include elevated ALT (20%), elevated AST (20%), liver function damage (13%), elevated GGT (7%), fatigue (7%), bellyache (7%), ruptured and infected tumor (7%), and dysphagia (7%). One Grade 4 adverse event was pulmonary embolism. Conclusions: Vorolanib with toripalimab showed a promising antitumor activity with acceptable safety profiles for patients with NSCLC. We hypothesized that the potential benefits of combination therapy for patients with squamous cell carcinoma may be better than those for patients with adenocarcinoma, and the study is ongoing. Clinical trial information: NCT03848611.

Objective Adjuvant chemotherapy (AC) after curative resection is known to improve the survival of patients with non-small cell lung cancer (NSCLC); however, few studies have reported the correlation between the time to initiation of AC (TTAC) and survival in NSCLC patients. Methods The clinical data of 925 NSCLC patients who received curative resection and post-operative AC at the Cancer Hospital of Chinese Academy of Medical Sciences between 2003 and 2013 were retrospectively analyzed. TTAC was measured from the date of surgery to the initiation of AC. Disease-free survival (DFS) was defined as the duration from surgery to the time of tumor recurrence or last follow-up evaluation. The optimal cut-off value of TTAC was determined by maximally selected log-rank statistics. The DFS curve was estimated using the Kaplan-Meier method, and the Cox proportional hazards regression model was used to identify risk factors independently associated with DFS. Propensity score matching (PSM) was performed for survival analysis using the match data. Results The optimal discriminating cut-off value of TTAC was set at d 35 after curative resection based on which the patients were assigned into two groups: group A (≤35 d) and group B (>35 d). There was no significant difference in the DFS between the two groups (P=0.246), indicating that the TTAC is not an independent prognostic factor for DFS. A further comparison continued to show no significant difference in the DFS among 258 PSM pairs (P=0.283). Conclusions There was no significant correlation between the TTAC and DFS in NSCLC patients. Studies with larger samples are needed to further verify this conclusion.

Adjuvant chemotherapy (ACT) after radical surgery is known to improve the survival of patients with non–small cell lung cancer (NSCLC). However, there are few studies reporting the impact of age on the efficacy of ACT in NSCLC patients. All patients who received postoperative ACT in the Cancer Hospital, the Chinese Academy of Medical Sciences, between 2001 and 2013 with complete records in the database of the hospital and met the inclusion criteria were enrolled in this study for analysis. The primary end point was disease‐free survival (DFS) in terms of age. Survival analysis was performed using Kaplan–Meier estimates, log‐rank tests, and Cox's proportional hazards regression analysis. Propensity score matching (PSM) was used, survival analysis and subgroup analysis of the match data were carried out. Of 1095 patients with stage IB to stage IIIA NSCLC who underwent radical resection, 865 cases who met the inclusion criteria were analyzed. Of them, 156 (18.0%) patients were 65 years old or older, and the remaining 709 (82.0%) patients were younger than 65. The DFS between the younger group and the elderly group was not significantly different neither before PSM (100.714 weeks [95% CI: 84.421, 117.007] vs. 99.571 weeks [95% CI: 82.621, 116.522]; P = 0.555) nor after PSM (104.857 weeks [95% CI: 81.495, 128.220] vs. 97.429 weeks [95% CI: 81.743, 113.114]; P = 0.328) using the Kaplan–Meier method.The results suggest that the benefit on DFS was similar regardless of age of NSCLC patients. ACT should not be withheld from elderly patients. However, these conclusions are limited by the nature of this retrospective study, and therefore prospective trials are required for further verification.

Poor prognosis of advanced non‐small‐cell lung cancer (NSCLC) patients and the promising therapeutic effect of platinum urge the oncologists to evaluate the role of platinum doublet as second‐line chemotherapy and establish the definition of platinum sensitivity in NSCLC. We retrospectively analyzed 364 advanced NSCLC patients who received platinum‐doublet regimens as second‐line chemotherapy after platinum‐based first‐line treatment. Patients were divided into four groups by their time‐to‐progression (TTP) after first‐line chemotherapy: 0–3, 4–6, 7–12, and >12‐month group, respectively. Treatment efficacy of patients' overall survival (OS), progression‐free survival (PFS), and response rate (RR), as well as treatment‐related toxicity, were compared among the four groups. A prognosis score system and a nomogram were established by Cox proportional hazard model, and validated by concordance index (c‐index). Median OS was 14.0, 16.0, 20.0, 25.0 months for patients in the 0–3, 4–6, 7–12, >12‐month group, respectively. Age ≤60 years (P = 0.002), female (P = 0.019), and TTP>12 months (P = 0.003) were independent prognostic factors. Prognostic score was calculated by adding 1 point each for any of the above three indicators, with a c‐index of 0.590 (95% confidential interval [CI], 0.552–0.627). Median OS were equal to 25.0, 16.0, and 11.0 months for best (2–3 points), intermediate (1 point) and worst (0 point) category, respectively (P

To observe drug-induced hepatotoxicity by long-term gefitinib administration in the treatment of non-small-cell lung cancer. The data of 101 patients with locally advanced or metastatic non-small-cell lung cancer, for which gefitinib had been used orally for 3 months or longer, were retrospectively analyzed. The median duration of gefitinib administration was 14 months (3-60 months). Forty patients (39.6%) developed abnormal hepatic function, among whom 30 patients (29.7%) had grade I hepatotoxicity, six patients (5.9%) had grade II, and four patients (4.0%) had grade III, respectively. The median time from starting gefitinib oral therapy to developing liver dysfunction was 4 months (1-23 months) for the entire cohort. The incidence of hepatotoxicity in the group with a duration of more than 14 months was much higher than that in the group with a duration of less than 14 months (52.0 vs. 27.5%, P=0.012). In thirty-two patients (32/40), abnormal liver function resolved with hepatoprotective treatment, whereas eight patients (8/40) had persistent grade I hepatotoxicity until the last follow-up. Our study showed that long-term gefitinib-induced hepatotoxicity was a common adverse event, especially for the cohort with a duration of longer than 14 months. In most patients with hepatotoxicity, normal liver function was restored and discontinuation of gefitinib was not necessary.

Background Although programmed cell death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) checkpoint inhibitors have shown prominent efficacy for treatment of advanced lung cancer, the outcomes of metastatic lung cancer remain poor throughout the world. Although progression-free survival (PFS) and overall survival (OS) have improved in the first- and second-line therapy settings for advanced lung cancer, the response rates to PD-1/PD-L1 inhibition range from 20% to 40%. Furthermore, patients may be at risk for immune-related adverse events (irAEs); hence, appropriate patient selection is crucial. This study aimed to identify a panel of plasma cytokines representing prognostic and predictive biomarkers of the response to anti-PD-1/PD-L1 treatment. Methods We prospectively studied 32 lung cancer patients who received anti-PD-1/PD-L1 antibody immunotherapy. Plasma cytokines in peripheral blood samples were evaluated and analyzed using flow cytometry at the time of diagnosis and at 2 months after the initiation of PD-1/PD-L1 inhibition. Results The baseline plasma concentrations of interleukin-18 (IL-18) and C-X-C motif chemokine ligand 10 (CXCL10) were correlated with the degree of tumor response. Moreover, the magnitude of plasma IL-18 and CXCL10 level fluctuations were correlated significantly with the objective tumor response to anti-PD-1/PD-L1 immunotherapy, and patients with high CXCL10 expression had significantly shorter PFS than those with low CXCL10 expression. A strong positive correlation between the fluctuation of IL-18 and interleukin-8 (IL-8) levels was detected, as was a negative correlation between the fluctuation of IL-18 and CXCL10 levels. The level of plasma C-C motif chemokine ligand 5 (CCL5) was significantly higher in patients with irAEs than in those without irAEs. Conclusions Plasma cytokines are related to the clinical efficacy of PD-1/PD-L1 inhibitors. IL-18 and CXCL10 are potential predictive markers for anti-PD-1/PD-L1 therapy in lung cancer patients and may play an important role in selecting patients who would benefit from PD-1/PD-L1 inhibitors.

Background: Almonertinib (HS-10296) is an oral, potent, high selective third generation EGFR-tyrosine kinase inhibitor (EGFR-TKI) for sensitizing mutations and EGFR T790M mutation. The preliminary clinical data of almonertinib reported in WCLC showed favorable efficacy and safety in target populations. Here, we presented the latest efficacy data, including the subgroup analysis of central nervous system (CNS) response. Methods: Patients aged at least 18 years with centrally confirmed EGFR T790M mutation, locally advanced or metastatic non-small cell lung cancer (NSCLC) progressing on prior EGFR-TKI treatment, received almonertinib 110 mg orally once daily until disease progression. Patients with asymptomatic, stable brain metastases not requiring steroids were enrolled. The primary endpoint was objective response rate (ORR) by independent central review (ICR) using RECIST v1.1. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), depth of response (DepOR), overall survival (OS) and safety. Response endpoints were assessed in full analysis set (NCT02981108). Results: From May 2018 to October 2018, 244 patients entered study in 36 sites in mainland China (189 patients) and Taiwan (55 patients). Of 88 patients with CNS metastases on baseline brain scans, 23 had at least one intracranial measurable target lesion. At cutoff date (Aug 1, 2019), the median duration of follow-up for progression-free survival was 11.8 months. 168 of 244 patients achieved confirmed partial responses. The ORR was 68.9% (95% CI: 62.6, 74.6). The DCR was 93.4% (95% CI: 89.6, 96.2). The mPFS (48.0% maturity) and mDOR were 12.3 (95% CI: 9.6, 13.8) and 12.4 (95% CI: 11.3, NA) months, respectively. The confirmed CNS ORR and DCR were 60.9% (95% CI: 38.5, 80.3) and 91.3% (95% CI: 72.0, 98.9), respectively. The CNS mPFS (47.8% maturity) was 10.8 (95% CI: 5.5, 12.6) months. The safety profile was consistent with the previous report. The most common grade 3 and 4 adverse reactions were increased blood creatine phosphokinase (17 [7.0%]) and pulmonary embolism (6 [2.5%]). There was no interstitial lung disease reported. Conclusions: Almonertinib demonstrated progression-free survival benefit in EGFR T790M positive NSCLC patients who had progressed after previous EGFR-TKI treatment, especially showed clinically meaningful efficacy against CNS metastases, and the safety profile was consistent with that reported previously. A randomized, controlled, double-blinded, phase III study is ongoing comparing almonertinib with gefinitib in first-line treatment of advanced NSCLC patients. Citation Format: Shun Lu, Qiming Wang, Guojun Zhang, Xiaorong Dong, Cheng-Ta Yang, Yong Song, Gee-Chen Chang, You Lu, Hongming Pan, Chao-Hua Chiu, Zhehai Wang, Jifeng Feng, Jianying Zhou, Xingxiang Xu, Renhua Guo, Jianhua Chen, Haihua Yang, Yuan Chen, Zhuang Yu, Her-Shyong Shiah, Chin-Chou Wang, Nong Yang, Jian Fang, Ping Wang, Kai Wang, Yanping Hu, Jianxing He, Ziping Wang, Jianhua Shi, Shaoshui Chen, Qiong Wu, Changan Sun, Chuan Li, Hongying Wei, Ying Cheng, Wu-Chou Su, Te-Chun Hsia, Jiuwei Cui, Yuping Sun, James Chih-Hsin Yang. A multicenter, open-label, single-arm, phase II study: The third generation EGFR tyrosine kinase inhibitor almonertinib for pretreated EGFR T790M-positive locally advanced or metastatic non-small cell lung cancer (APOLLO) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT190.

// Chunlei Ge 1,* , Shikai Wu 2,* , Weiwei Wang 3,* , Zhimin Liu 1 , Jianhua Zhang 1 , Zhenyu Wang 4 , Ruilei Li 1 , Zhiwei Zhang 1 , Zhen Li 1 , Suwei Dong 1 , Ying Wang 1 , Yuanbo Xue 1 , Jinyan Yang 1 , Qinghua Tan 1 , Ziping Wang 5 and Xin Song 1 1 Department of Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan, People’s Republic of China 2 Department of Radiation Oncology, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, People’s Republic of China 3 Department of Thoracic Surgery, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan, People’s Republic of China 4 Department of Biomedical Engineering Research Center, Kunming Medical University, Kunming, Yunnan, People’s Republic of China 5 Department of Medical Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences (CAMS), Beijing, People’s Republic of China * These authors have contributed equally to this work Correspondence to: Xin Song, email: // Ziping Wang, email: // Keywords : miR-942, cancer stem cells, Wnt/β-catenin signalling pathway, esophageal squamous cell carcinoma Received : December 20, 2014 Accepted : March 02, 2015 Published : March 30, 2015 Abstract The Wnt/β-catenin signalling pathway is known to play a vital role in the maintenance of cancer stem cells (CSCs), which are reported to be the origine of malignant cancers, and result in poor prognosis of multiple kinds of cancer. Therefore, it is of great importance to illuminate the mechanism by which the Wnt/β-catenin pathway regulates the cancer stem cell-like traits in cancers. Here, we report that miR-942 is significantly upregulated in esophageal squamous cell carcinoma (ESCC), and miR-942 levels are associated with poor prognosis in ESCC patients. Overexpression of miR-942 promotes, whereas inhibition of miR-942 decreases, the tumor sphere formation, the CD90 + subpopulation cells and the expression of pluripotency associated markers. Moreover, in vivo assay shows that miR-942 overexpressing cells form larger tumors and display higher tumourigenesis. Furthermore, we demonstrate that miR-942 upregulates the Wnt/β-catenin signaling activity via directly targeting sFRP4, GSK3β and TLE1, which are multiple level negative regulators of the Wnt/β-catenin signaling cascade. In addition, our results indicate that c-myc directly binds to the miR-942 promoter and promotes its expression. Taken together, our findings establish an oncogenic role of miR-942 in ESCC and indicate that miR-942 might be an effective therapeutic target for ESCC.

Objective Although superior clinical benefits of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in the treatment of advanced non-small-cell lung cancer (NSCLC) had been reported, the survival difference between exon 19 deletion (Del19) and exon 21 Leu858Arg substitution (L858R) remains controversial. The purpose of this study is to investigate the differences in progression-free survival (PFS) and overall survival (OS) between different EGFR mutant subtypes among advanced NSCLC patients receiving gefitinib. Methods There were 204 advanced NSCLC patients with EGFR mutations treated with gefitinib were enrolled in this retrospective cohort study. Patients were divided into the EGFR Del19 group and the L858R mutated group according to their mutant subtype. Propensity score matching (PSM) was conducted by using a nearest-neighbor algorithm (1:1) to adjust for demographical and clinical covariates. Survival curves were constructed with the Kaplan-Meier method and compared by using the log-rank test. Results The PFS in Del19 group was similar to that in the L858R group [before PSM 8.6 vs. 7.2 months, P=0.072; after PSM 7.3 vs. 7.2 months, P=0.155]. No differences were detected in OS between the L858R and the Del19 group (before PSM 17.8 vs. 13.1 months, P=0.253; after PSM 16.9 vs. 13.1 months, P=0.339). The Del19 group was significantly younger compared with the L858R mutation group in age (P=0.015). Conclusions No significant difference was found in the PFS or OS between the Del19 and L858R mutant NSCLC patients receiving gefitinib. The age gap might contribute to the survival differences between Del19 and L858R groups. PSM is of important value to the elimination of potential bias.

e20546 Background: Anti-programmed death-1 antibodies (PD-1 Abs) have shown benefits in advanced NSCLC. The efficacy and safety of sintilimab, a PD-1 Ab, in combination with chemotherapy for 1L NSCLC is evaluated in this phase Ib study (NCT02937116). Methods: The study enrolled treatment-naïve unresectable locally advanced or metastatic non-squamous (nsq-) and squamous (sq-) NSCLC patients with neither EGFR mutations nor ALK rearrangements in cohort D and E respectively. Patients received sintilimab 200mg IV q3w in combination with pemetrexed 500mg/m2 and cisplatin 75mg/m2 IV q3w (4 cycles) in cohort D, or gemcitabine 1250mg/m2 D1,8 and cisplatin 75mg/m2 D1 IV q3W (6 cycles) in cohort E until disease progression, unacceptable toxicity or death. The primary objective was to evaluate the efficacy and safety of the combination. Results: As data cutoff (15 Jan 2019), 21 and 20 patients were enrolled in cohort D and E respectively. ORR in nsq- and sq-NSCLC were 68.4% (95%CI, 43.4 to 87.4) and 64.7% (95%CI, 38.3 to 85.8) respectively based on data of 19 and 17 patients with at least one radiological assessment. Median PFS was 11.4 months (95%CI, 3.1 to NA) and 6.5 months (95%CI, 5.3 to 8.0) respectively (Table). Totally 38 (92.7%) patients experienced at least one treatment emergent adverse event (TEAE). Treatment-related AEs (TRAEs) occurred in 28 (68.3%) patients. TRAE ≥grade 3 occurred in 4 (9.8%) patients. Immune related AEs occurred in 10 patients (24.4%), the most common of which were skin rash (N = 5), pneumonitis (N = 3) and hypothyroidism (N = 2). There was no AEs leading to death. The biomarker analysis was ongoing. Conclusions: The combination of sintilimab and chemotherapy showed efficacy with an acceptable safety profile in 1L nsq- and sq-NSCLC. Two phase III trials are ongoing to evaluate the combination in 1L nsq- (NCT03607539) and sq-NSCLC (NCT03629925) respectively. Clinical trial information: NCT02937116. [Table: see text]

e20509Background: Previous data suggested that right- versus left-sided cancer location was not an independent prognostic factor for long-term survival in lung cancer. However, few studies reported...

8524Background: This study aimed to investigate the survival difference between right-sided and left-sided pneumonectomy in stage I-IIIA NSCLC patients, and to further develop the best treatment st...

8525Background: This study aimed to predict the probability of death for non-small cell lung cancer (NSCLC) patients who received surgery and construct a comprehensive nomogram prognostic model to ...

TPS3112Background: Non-small cell lung cancer (NSCLC) accounts for 80–85% of all lung cancers and has a poor prognosis in later stages. Although lung cancers are not typically immunogenic, recent s...

Objectives Tumor heterogeneity, which causes different EGFR mutation abundance, is believed to be responsible for varied progression-free survival (PFS) in lung adenocarcinoma (ADC) patients receiving EGFR-TKI treatment. Frequent EGFR amplification and its common affection in EGFR mutant allele promote the hypothesis that EGFR mutant abundance might be determined by EGFR copy number variation and therefore examination of EGFR amplification status in EGFR mutant patients could predict the efficacy of EGFR-TKI treatment. Materials and methods In this study, 86 lung ADC patients, who harbored EGFR activating mutations and received EGFR-TKI treatment, were examined for EGFR amplification and expression by Dual-color Silver in situ Hybridization (DISH) and immunohistochemistry analysis, respectively. Results and conclusion Forty-one of 86 (47.7%) samples with EGFR activating mutations were identified with EGFR amplification. Patients with EGFR gene amplification had a significantly longer PFS than those without (16.3 vs. 9.1 months, p =0.004). The EGFR expression was then examined by immunohistochemistry analysis. Thirty-nine of 86 (45%) tumors had EGFR overexpression, which was significantly correlated with EGFR amplification ( p =0.000). However, patients with EGFR overexpression exhibited no difference in PFS (14.1 vs. 13.3 months, p =0.797). In conclusion, EGFR amplification occurs frequently in lung ADC patients harboring EGFR activating mutations, and could serve as an indicator for better response from EGFR-TKI treatment.

e20011Background: Adjuvant chemotherapy improves the survival for completely resected non-small cell lung cancer (NSCLC) patients. Platinum/pemetrexed is known to be less toxicity ,better chemother...

e20064Background: Gender was an important prognostic factor in patients with advanced non-small cell lung cancer(NSCLC). However, there are few studies reporting the impact of gender difference on ...