Plasma hepatocyte growth factor as a noninvasive biomarker in small cell lung cancer.

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.

Longitudinal detection of subcategorized CD44v6+ CTCs and circulating tumor endothelial cells (CTECs) enables novel clinical stratification and improves prognostic prediction of small cell lung cancer: A prospective, multi-center study.

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 up-regulated 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.

Survival Analysis of 159 Patients With Advanced Non-Small-Cell Lung Cancer Resistant to First-Generation Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor.

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.

Post-therapeutic circulating tumor cell-associated white blood cell clusters predict poor survival in patients with advanced driver gene-negative non-small cell lung cancer.

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(t0), after two cycles of therapy (t1) and at post-four-to-six treatment cycles (t2). 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.

Sintilimab plus chemotherapy for patients with EGFR-mutated non-squamous non-small-cell lung cancer with disease progression after EGFR tyrosine-kinase inhibitor therapy (ORIENT-31): second interim analysis from a double-blind, randomised, placebo-controlled, phase 3 trial.

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.

Beneficial effects of postoperative radiotherapy for IIIA­N2 non­small cell lung cancer after radical resection analysed using the propensity score­matching method.

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.

Toripalimab Plus Chemotherapy for Patients With Treatment-Naive Advanced Non-Small-Cell Lung Cancer: A Multicenter Randomized Phase III Trial (CHOICE-01).

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.

A single center analysis of first-line treatment in advanced KRAS mutant non-small cell lung cancer: real-world practice.

PURPOSE: For the first-line treatment of KRAS mutant non-small cell lung cancer (NSCLC) patients, immunotherapy or platinum-based chemotherapy are the main treatment method. Here, we investigated the clinical efficacy and prognosis those two regimens as first-line treatment in real-world practice. METHODS: KRAS mutant NSCLC patients received chemotherapy or immunotherapy as first-line treatment from September 2014 to March 2022 were enrolled. Clinical characteristics, treatment scheme, clinical curative effect and follow-up data of enrolled patients were collected for analysis. RESULTS: Fifty patients received immunotherapy and 115 patients received chemotherapy were enrolled. Patients who received immunotherapy (HR = 0.350, 95%CI 0.156-0.781, P = 0.010), or pemetrexed-based regimen (HR = 0.486, 95%CI 0.255-0.928, P = 0.029), or antiangiogenic therapy (HR = 0.355, 95%CI 0.159-0.790, P = 0.011) were at a low risk of disease progression. And patients received antiangiogenic therapy had lower risk of death than those not (HR = 0.333, 95%CI 0.120-0.926, P = 0.035). Subgroup analysis revealed the immunotherapy compared to chemotherapy alone had lower risk of disease progression (HR = 0.377, 95%CI 0.166-0.856, P = 0.020) in PD-L1 expression ≥1% subgroup. And in non-G12C KRAS subgroup, but not in G12C KRAS subgroup, patients who received antiangiogenic therapy had lower risk of disease progression (HR = 0.254, 95%CI 0.098-0.656, P = 0.005) and death than those not (HR = 0.197, 95%CI 0.056-0.692, P = 0.011). In terms of different chemotherapy regimen, platinum-paclitaxel combined with antiangiogenic therapy achieved the highest ORR and DCR (P < 0.05), while the platinum-pemetrexed combined with antiangiogenic therapy had the longest PFS and OS (P < 0.001). CONCLUSION: For the first-line treatment of KRAS mutant NSCLC patients, immunotherapy, antiangiogenic therapy, and pemetrexed-based regimen could obtain more benefits. Subgroup analysis revealed the benefits of immunotherapy compared to chemotherapy were applicable in PD-L1 expression≥1% subgroup, and antiangiogenic therapy could benefit non-G12C KRAS subgroup, but not G12C KRAS subgroup. In terms of different chemotherapy regimen, platinum-pemetrexed combined with antiangiogenic therapy may be the preferred chemotherapy regimen.

Evaluation of Clinical Outcomes of Icotinib in Patients With Clinically Diagnosed Advanced Lung Cancer With EGFR-Sensitizing Variants Assessed by Circulating Tumor DNA Testing: A Phase 2 Nonrandomized Clinical Trial.

Importance: The inability to obtain a pathological diagnosis in a certain proportion of patients with clinically diagnosed advanced lung cancer impedes precision treatment in clinical practice. Objective: To evaluate the clinical outcome of first-line icotinib in patients with clinically diagnosed advanced lung cancer with unknown pathological status and positive epidermal growth factor receptor (EGFR)-sensitizing variants assessed by circulating tumor DNA (ctDNA). Design, Setting, and Participants: The Efficiency of Icotinib in Plasma ctDNA EGFR Mutation-Positive Patients Diagnosed With Lung Cancer (CHALLENGE) trial is a prospective, multicentered, open-label, single-arm phase 2 nonrandomized clinical trial conducted between July 1, 2017, and July 31, 2019. Patients with systemic treatment-naive, clinically diagnosed advanced peripheral lung cancer, unknown pathological status, and positive pretreatment plasma EGFR-sensitizing variants were eligible. A total of 391 potentially eligible Chinese patients from 19 centers in China were screened for ctDNA EGFR variants by 3 independent detection platforms (Super amplification refractory mutation system [SuperARMS] polymerase chain reaction, droplet digital polymerase chain reaction, and next-generation sequencing), and those with EGFR variants tested by any platform were included. Analyses were conducted from September 9 to December 31, 2021. Interventions: Enrolled patients were treated with oral icotinib tablets (125 mg 3 times daily) until disease progression, death, or treatment discontinuation due to various reasons, such as toxic effects and withdrawing consent. Main Outcomes and Measures: The primary end point was objective response rate (ORR). The secondary end points included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and the concordance among the 3 detection platforms. Results: Of 116 included patients, 76 (65.5%) were female, and the median (range) age was 64 (37-85) years. The median (IQR) follow-up duration was 36.3 (30.2-40.7) months. The ORR was 52.6% (95% CI, 43.1%-61.9%). The median PFS and OS were 10.3 months (95% CI, 8.3-12.2) and 23.2 months (95% CI, 17.7-28.0), respectively, and the DCR was 84.5% (95% CI, 76.6%-90.5%). The concordance rate among the 3 detection platforms was 80.1% (313 of 391), and the clinical outcomes in patients identified as positive by any platform were comparable. Conclusions and Relevance: This prospective phase 2 nonrandomized clinical trial suggests that for patients with clinically diagnosed advanced lung cancer with unknown pathological status, ctDNA-based EGFR genotyping could help decision-making in particular clinical situations, while still warranting future larger-scaled real-world exploration. Trial Registration: ClinicalTrials.gov Identifier: NCT03346811.

Sintilimab plus bevacizumab biosimilar IBI305 and chemotherapy for patients with EGFR-mutated non-squamous non-small-cell lung cancer who progressed on EGFR tyrosine-kinase inhibitor therapy (ORIENT-31): first interim results from a randomised, double-blind, multicentre, phase 3 trial.

BACKGROUND: VEGF inhibitors can enhance the efficacy of immunotherapy. However, despite high initial response rates, almost all patients eventually develop treatment resistance to EGFR tyrosine-kinase inhibitors. We aimed to evaluate the efficacy and safety of sintilimab with or without IBI305 plus pemetrexed and cisplatin, compared with pemetrexed and cisplatin alone, for the treatment of patients with locally advanced or metastatic EGFR-mutated non-small-cell lung cancer (NSCLC) who had disease progression after receiving EGFR tyrosine-kinase inhibitor therapy. METHODS: This randomised, double-blind, multicentre, phase 3 trial was conducted at 52 hospitals in China. Eligible participants were adults aged 18-75 years with locally advanced or metastatic NSCLC and EGFRmut who progressed after receiving a EGFR tyrosine-kinase inhibitor, had an Eastern Cooperative Oncology Group performance status of 0 or 1 with at least one measurable lesion, and an estimated life expectancy of at least 3 months. Participants were randomly assigned (1:1:1) to receive sintilimab (200 mg) plus IBI305 (15 mg/kg) plus pemetrexed (500 mg/m2) and cisplatin (75 mg/m2), sintilimab plus pemetrexed and cisplatin, or pemetrexed and cisplatin (chemotherapy alone) using block randomisation with stratification according to sex and presence or absence of brain metastases. All study drugs were administered intravenously on day 1 of each cycle, once every 3 weeks. Except for cisplatin, which was only given in the first four cycles, treatment was given for 24 months or until disease progression, intolerable toxic effects, withdrawal of consent, death, or other protocol-specified conditions, whichever occurred first. The primary endpoint was progression-free survival in the intention-to-treat population. We herein report the first planned interim analysis, with progression-free survival results for the comparison between sintilimab plus IBI305 plus chemotherapy versus chemotherapy alone. The progression-free survival results for the sintilimab plus pemetrexed and cisplatin group are immature and not reported here. This study is registered with ClinicalTrials.gov, NCT03802240 (recruiting). FINDINGS: Between July 11, 2019, and July 31, 2021, 936 patients were screened and 444 were randomly assigned (148 to the sintilimab plus IBI305 plus chemotherapy group, 145 to the sintilimab plus chemotherapy group, and 151 to the chemotherapy alone group). Data cutoff for this interim analysis was July 31, 2021. After a median follow-up of 9·8 months (IQR 4·4-13·3), progression-free survival was significantly longer in the sintilimab plus IBI305 plus chemotherapy group versus the chemotherapy alone group (median 6·9 months [95% CI 6·0-9.3] vs 4·3 months [4·1-5·4]; hazard ratio 0·46 [0·34-0·64]; p<0·0001). The most common grade 3 or 4 treatment-related adverse events were decreased neutrophil count (30 [20%] in the sintilimab plus IBI305 plus chemotherapy group vs 26 [18%] in the sintilimab plus chemotherapy group vs 27 [18%] in the chemotherapy alone group), decreased white blood cell count (17 [11%] vs 12 [8%] vs 13 [9%]), and anaemia (18 [12%] vs ten [7%] vs 15 [10%]). Potentially treatment-related deaths occurred in six patients (intestinal obstruction, gastrointestinal haemorrhage, and myelosuppression in one patient each, and three deaths of unknown cause) in the sintilimab plus IBI305 plus chemotherapy group, and in one patient in the chemotherapy alone group (unknown cause). INTERPRETATION: In this interim analysis, sintilimab plus IBI305 plus cisplatin and pemetrexed was generally efficacious and well tolerated in patients with EGFR-mutated NSCLC who progressed after receiving EGFR tyrosine-kinase inhibitor therapy. FUNDING: Innovent Biologics and the National Natural Science Foundation of China. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

The efficacy of anlotinib as third-line treatment for non-small cell lung cancer by EGFR mutation status: a subgroup analysis of the ALTER0303 randomized phase 3 study.

Background: Anlotinib demonstrated improved overall survival (OS) and progression-free survival (PFS) compared with placebo as a third-line or subsequent therapy in patients with non-small cell lung cancer (NSCLC) in the ALTER0303 trial. The status of epidermal growth factor receptor (EGFR) mutation, different previous treatment may affect the efficacy of subsequent therapy, and we did this subgroup analysis to characterize the efficacy of anlotinib in patients with and without EGFR mutation. Methods: The ALTER0303 trial was a randomized, double-blind, phase 3 study of anlotinib in patients with NSCLC who failed at least 2 lines of treatment. In the study, 138 of 437 randomized patients were EGFR mutation positive. A Cox model was used to examine the influence of previous treatment on the efficacy of anlotinib according to EGFR mutation status. Results: For patients with EGFR mutation, the OS was 10.7 and 6.3 months (HR 0.59; 95% CI: 0.38-0.94, P=0.025) in the anlotinib and placebo group, respectively. The PFS was 5.6 and 0.8 months (HR 0.21; 95% CI: 0.13-0.32, P<0.0001) in the anlotinib and placebo group, respectively. For patients without EGFR mutation, the OS was 8.9 months for anlotinib and 6.5 months for placebo (HR 0.73; 95% CI: 0.55-0.97, P=0.029), and the PFS was 5.4 months for anlotinib and 1.6 months for placebo (HR 0.29; 95% CI: 0.22-0.39, P<0.0001). In the anlotinib group, the OS and PFS for patients with and without EGFR mutation was 10.7 and 8.9 months (HR 0.69; 95% CI: 0.50-0.95, P=0.021), 5.6 and 5.4 months (HR 1.00; 95% CI: 0.75-1.34, P=1.000), respectively. The incidence of adverse events was similar in subgroups. Conclusions: This analysis demonstrated that the benefit of anlotinib as a third-line therapy for patients with NSCLC was independent of EGFR mutation status.

Efficacy and Safety of Limertinib (ASK120067) in Patients With Locally Advanced or Metastatic EGFR Thr790Met-Mutated NSCLC: A Multicenter, Single-Arm, Phase 2b Study.

INTRODUCTION: Limertinib (ASK120067) is a newly developed third-generation EGFR tyrosine kinase inhibitor targeting both sensitizing EGFR and EGFR Thr790Met (T790M) mutations. This study aimed to evaluate the efficacy and safety of limertinib in patients with locally advanced or metastatic EGFR T790M-mutated NSCLC. METHODS: This is a single-arm, open-label, phase 2b study conducted at 62 hospitals across the People's Republic of China. Patients with locally advanced or metastatic NSCLC with centrally confirmed EGFR T790M mutations in tumor tissue or blood plasma who progressed after first- or second-generation EGFR tyrosine kinase inhibitors or with primary EGFR T790M mutations were enrolled. Patients received limertinib 160 mg orally twice daily until disease progression or unacceptable toxicity. The primary end point was objective response rate (ORR) assessed by independent review committee per the Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included disease control rate, progression-free survival (PFS), duration of response (DoR), overall survival, and safety. Safety was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. RESULTS: From July 16, 2019, to March 10, 2021, a total of 301 patients were enrolled and started the treatment of limertinib. All patients entered the full analysis set and safety set. By the data cutoff date on September 9, 2021, 76 (25.2%) remained on treatment. The median follow-up time was 10.4 months (range: 0.3-26.3). On the basis of full analysis set, the independent review committee-assessed ORR was 68.8% (95% confidence interval [CI]: 63.2%-74.0%) and disease control rate was 92.4% (95% CI: 88.8%-95.1%). The median PFS was 11.0 months (95% CI: 9.7-12.4), median DoR was 11.1 months (95% CI: 9.6-13.8), and median OS was not reached (95% CI 19.7 months-not evaluable). Objective responses were achieved across all prespecified subgroups. For 99 patients (32.9%) with central nervous system (CNS) metastases, the ORR was 64.6% (95% CI: 54.4%-74.0%), median PFS was 9.7 months (95% CI: 5.9-11.6), and median DoR was 9.6 months (95% CI: 8.1-15.2). For 41 patients who had assessable CNS lesion, the confirmed CNS-ORR was 56.1% (95% CI: 39.7%-71.5%) and median CNS-PFS was 10.6 months (95% CI: 5.6-not evaluable). In safety set, 289 patients (96.0%) experienced at least one treatment-related adverse event (TRAE), with the most common being diarrhea (81.7%), anemia (32.6%), rash (29.9%), and anorexia (28.2%). Grade ≥3 TRAEs occurred in 104 patients (34.6%), with the most common including diarrhea (13.0%), hypokalemia (4.3%), anemia (4.0%), and rash (3.3%). TRAEs leading to dose interruption and dose discontinuation occurred in 24.6% and 2% of patients, respectively. No TRAE leading to death occurred. CONCLUSIONS: Limertinib (ASK120067) was found to have promising efficacy and an acceptable safety profile for the treatment of patients with locally advanced or metastatic EGFR T790M-mutated NSCLC. CLINICAL TRIAL INFORMATION: NCT03502850.

AENEAS: A Randomized Phase III Trial of Aumolertinib Versus Gefitinib as First-Line Therapy for Locally Advanced or MetastaticNon-Small-Cell Lung Cancer With EGFR Exon 19 Deletion or L858R Mutations.

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.

Combined application of bevacizumab and PD-1 blockade displays durable treatment effects by increasing the infiltration and cytotoxic function of CD8+ T cells in lung cancer.

Aim: VEGF/VEGFR inhibitors may help immune checkpoint inhibitors expand the population that will benefit from treatment. The authors investigated the efficacy of combined bevacizumab and PD-1 antibody. Materials & methods: C57BL/6J mice were injected subcutaneously with 1 × 106 Lewis lung carcinoma cells. The mice were intraperitoneally injected with 0.25 mg anti-PD-1 inhibitors and/or 15 mg/kg bevacizumab. Tumor tissues were harvested. The authors reported that a non-small cell lung cancer patient received 200 mg PD-1 antibody combined with 7.5 mg/kg bevacizumab as fourth-line treatment. Results: Bevacizumab combined with PD-1 antibody induced a strong and durable antitumor effect. Bevacizumab combined with PD-1 antibody improved abnormal tumor vessels and enhanced the cytotoxic function and infiltration of T lymphocytes. The patient's survival time was significantly prolonged. Conclusion: Bevacizumab combined with anti-PD-1 antibody induces a durable antitumor effect by increasing the infiltration and cytotoxic function of CD8+ T cells in lung cancer.

Immune checkpoint inhibitors can improve long-term survival in advanced non-small-cell lung cancer, but the promising clinical benefit was only observed in a minority of patients. The combination of VEGF/VEGFR inhibitors and immune checkpoint inhibitors has become an attractive strategy. In this study, lung carcinoma mouse models were used to investigate the therapeutic efficacy of combined bevacizumab and anti-PD-1 antibody. The authors demonstrated that the combined application of bevacizumab and PD-1 blockade displays durable treatment effects by increasing the infiltration and cytotoxic function of CD8⁺ T cells. This study also reports a non-small-cell lung cancer patient who benefited from this treatment regimen as fourth-line therapy.

Updated Overall Survival Data and Predictive Biomarkers of Sintilimab Plus Pemetrexed and Platinum as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC in the Phase 3 ORIENT-11 Study.

INTRODUCTION: Sintilimab plus chemotherapy significantly prolonged progression-free survival (PFS) compared with chemotherapy alone in nonsquamous NSCLC in the ORIENT-11 study. Updated overall survival (OS) and PFS data and corresponding biomarker analyses are reported here. METHODS: In this study, a total of 397 patients with previously untreated, locally advanced or metastatic nonsquamous NSCLC were assigned to sintilimab plus chemotherapy combination treatment (combo) group or placebo plus chemotherapy treatment group. The patients were stratified by programmed death-ligand 1 (PD-L1) expression levels. Immune signature profiles from tumor RNA sequencing and PD-L1 immunohistochemistry were correlated with clinical outcome to identify predictive biomarkers. RESULTS: As of January 2021, with median follow-up of 22.9 months, median OS was significantly improved in the combo group compared with the placebo plus chemotherapy treatment group (not reached versus 16.8 mo; hazard ratio [HR] = 0.60, 95% confidence interval [CI]: 0.45-0.79, p = 0.0003). High or medium immune cell infiltration was strongly associated with improved PFS in the combo group, in contrast to absent or low immune cell infiltration, which suggests that chemotherapy could not prime "immune deserts" to obtain benefit from programmed cell death protein-1 inhibition. In particular, high major histocompatibility complex (MHC) class II presentation pathway expression was significantly correlated with prolonged PFS (HR = 0.32, 95% CI: 0.19-0.54, p < 0.0001) and OS (HR = 0.36, 95% CI: 0.20-0.64, p = 0.0005) in the combo group. Importantly, patients with low or absent PD-L1 but high MHC class II expression could still benefit from the combo treatment. In contrast, MHC class I antigen presentation pathway was less relevant in this combination setting. CONCLUSIONS: The addition of sintilimab to chemotherapy resulted to significantly longer OS in nonsquamous NSCLC. Expression of MHC class II antigen presentation pathway could identify patients benefiting most from this combination.

Role of aneuploid circulating tumor cells and CD31+ circulating tumor endothelial cells in predicting and monitoring anti-angiogenic therapy efficacy in advanced NSCLC.

Prognosticating the efficacy of anti-angiogenic therapy through longitudinal monitoring and early detection of treatment resistance in cancer patients remain highly challenging. In this study, co-detection and comprehensive phenotypic and karyotypic molecular characterization of aneuploid circulating tumor cells (CTCs) and circulating tumor endothelial cells (CTECs) were conducted on non-small cell lung cancer (NSCLC) patients receiving bevacizumab plus chemotherapy. Prognostic values of the cell-based significant univariate risk factors identified by Cox regression analyses were progressively investigated. Subjects showing an increase in total post-therapeutic platelet endothelial cell adhesion molecule-1 (CD31)- CTCs and CD31+ CTECs exhibited a significantly reduced median progression-free survival (mPFS) and overall survival. Further stratification analyses indicated that pretherapeutic patients bearing vimentin (Vim)+ CTECs (mesenchymal M-type) at baseline revealed a significantly shortened mPFS compared with patients with Vim- CTECs. Post-therapeutic patients harboring epithelial cell adhesion molecule (EpCAM)+ CTCs and CTECs (epithelial E-type), regardless of Vim expression or not, showed a significantly reduced mPFS. Post-therapeutic patients possessing de novo EpCAM+ /Vim+ (hybrid E/M-type) CTECs displayed the shortest mPFS. Patients harboring either pre- or post-therapeutic EpCAM- /Vim- null CTECs (N-type) exhibited a better response to therapy compared to patients harboring EpCAM+ and/or Vim+ CTECs. The presented results support the notion that baseline Vim+ CTECs and post-therapeutic EpCAM+ CTCs and CTECs are predictive biomarkers for longitudinal monitoring of response to anti-angiogenesis combination regimens in NSCLC patients.

Occurrence of hypertension during third-line anlotinib is associated with progression-free survival in patients with squamous cell lung cancer (SCC): A post hoc analysis of the ALTER0303 trial.

BACKGROUND: There is a lack of targeted therapeutic options for squamous cell lung cancer (SCC). Accelerated hypertension is an issue with many targeted therapies for lung cancer. This study aimed to analyze the efficacy of anlotinib, based on progression-free survival (PFS) and overall survival (OS) in patients with SCC, stratified by hypertension and Eastern Cooperative Oncology Group (ECOG) score. METHODS: This was a post hoc analysis of a multicenter, double-blind, phase III ALTER0303 randomized controlled trial. Only patients with SCC were included. The occurrence of hypertension during the study period was defined according to CTCAE 4.03. OS and PFS were the primary and secondary endpoints, respectively. The patients were stratified according to hypertension and ECOG score, respectively. RESULTS: The median PFS in the patients who developed hypertension was longer than in those who did not (7.2 (95% CI: 3.5-11.0) versus 3.2 (95% CI: 1.2-5.3) months, p = 0.001; HR (95% CI), 0.4 (0.2-0.8)). In the ECOG 0 patients, the median PFS in the patients who developed hypertension versus those who did not was 5.6 vs. 1.8 months, respectively (Figure 2(d)). In the ECOG 1 patients, the median PFS in the patients who developed hypertension versus those who did not was 7.0 (95% CI: 3.0-11.0) vs. 4.8 (95% CI: 1.2-8.5) months (p = 0.043). No statistically significant differences were found in OS in the stratified analyses. CONCLUSIONS: The occurrence of hypertension might be a clinical indicator predicting the efficacy of third-line anlotinib treatment in patients with SCC.

[Expression of CD44 in Tumor Tissue and Serum of Small Cell Lung Cancer and Its Clinical Prognostic Significance].

BACKGROUND: Small cell lung cancer (SCLC) is a highly aggressive malignancy characterized by rapid growth, early metastasis and acquired therapeutic resistance, and the prognosis is extremely poor. Studies have proved that the stem cell marker CD44 is correlated with tumor recurrence and treatment resistance, however, there are limited reports yet concerning on the CD44 expression and its clinical prognostic significance in SCLC patients. The purpose of this study is to investigate the expression of CD44 in tumor tissues as well as serum of SCLC patients and explore its correlation with the clinical characteristics, therapeutic effect and prognosis. METHODS: The tumor tissues and serum samples of 47 newly diagnosed SCLC patients were collected. Immunohistochemistry and enzyme-linked immunosorbent assay were applied to detect CD44. The relationship between CD44 level and the clinical characteristics as well as prognosis of the patients was analyzed. RESULTS: The stem cell marker CD44 was detectable both in serum sample and tumor tissue of SCLC patients. The positive rate of CD44 in tumor tissue was significantly higher in patients with performance status (PS) 2 than that of patients with PS 0-1 (85.71% vs 30%, P=0.017). Patients were divided in to different groups according to the treatment efficacy. The CD44 immunohistochemical score and serum level in the disease progression group were significantly higher than those in the disease control group, and the differences were statistically significant (P=0.006, P=0.034), Univariate analysis depicted that the progression-free survival (PFS) of CD44 positive patients was significantly shorter than that of CD44 negative patients (5.23 mon vs 9.03 mon, P=0.036). CONCLUSIONS: The positive expression of CD44 in tumor tissues of pre-treatment SCLC patients is correlated with poor PFS. The clinical significance of CD44 is worthy to be further studied.

Sintilimab Plus Platinum and Gemcitabine as First-Line Treatment for Advanced or Metastatic Squamous NSCLC: Results From a Randomized, Double-Blind, Phase 3 Trial (ORIENT-12).

INTRODUCTION: The standard chemotherapy for squamous NSCLC (sqNSCLC) includes platinum plus gemcitabine. Sintilimab, an anti-programmed cell death protein 1 antibody, plus platinum and gemcitabine (GP) has revealed encouraging efficacy as first-line therapy for sqNSCLC in a phase 1b study. We conducted a randomized, double-blind, phase 3 study to further compare the efficacy and safety of sintilimab with placebo, both in combination with GP. METHODS: ORIENT-12, a randomized, double-blind, phase 3 study, was conducted at 42 centers in the People's Republic of China (ClinicalTrials.gov, number NCT03629925). Patients with locally advanced or metastatic sqNSCLC and without EGFR-sensitive mutations or ALK rearrangements were enrolled in the study. The stratification factors included clinical stage, choice of platinum, and programmed death-ligand 1 tumor proportion score. The patients, investigators, research staff, and sponsor team were masked to treatment assignment. Eligible patients were randomized 1:1, using an integrated web-response system, to receive sintilimab 200 mg or placebo plus GP every 3 weeks for four or six cycles, followed by sintilimab or placebo as maintenance therapy until disease progression or 2 years. The primary end point was progression-free survival (PFS), assessed by an independent radiographic review committee. RESULTS: Between September 25, 2018 and July 26, 2019, a total of 543 patients were screened, of whom 357 patients were randomized to the sintilimab-GP group (n = 179) and the placebo-GP group (n = 178). After a median follow-up period of 12.9 months, sintilimab-GP continued to reveal a meaningful improvement in PFS than placebo-GP (hazard ratio = 0.536 [95% confidence interval: 0.422-0.681], p < 0.00001). Treatment-emergent adverse events of grade 3 or worse occurred in 86.6% patients in the sintilimab-GP group and in 83.1% in the placebo-GP group. The incidence of treatment-emergent adverse event leading to death was 4.5% and 6.7% in the two treatment groups, respectively. CONCLUSIONS: Regarding PFS, sintilimab plus GP reveals clinical benefit than GP alone as first-line therapy in patients with locally advanced or metastatic sqNSCLC. The toxicity was acceptable, and no new unexpected safety signals were observed.

[Application Progress of Immune Checkpoint Inhibitors 
in Oncogene-driven Advanced Non-small Cell Lung Cancer].

With the development of precise medicine, targeted therapy has greatly improved the survival and prognosis of patients in advanced non-small cell lung cancer (NSCLC) with oncogenic drivers. However, no matter which kinds of targeted therapy are inevitable to develop therapeutic resistance, treatment options upon exhaustion of targeted therapies are limited. Immune checkpoint inhibitors (ICIs) can bring long-term survival to some patients with advanced NSCLC because of its unique long tailing effect. More and more studies have shown that ICIs can also benefit NSCLC patients with oncogenic drivers. However, the timing of ICIs intervention, the therapeutic regimen and the predictive biomarkers are actually debated, underscoring the need to explore the potential interest of ICIs in these populations.
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