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.

Influence of VEGFR2 gene polymorphism on the clinical outcomes of apatinib for patients with chemotherapy-refractory extensive-stage SCLC: a real-world retrospective study.

PURPOSE: Great individual differences were observed regarding the efficacy of apatinib clinically. The aim of present study was to investigate the influence of vascular endothelial growth factor receptor2 (VEGFR2) gene polymorphism on the clinical outcomes of apatinib for patients with chemotherapy-refractory extensive-stage small cell lung cancer (ES-SCLC). METHODS: A total of 128 patients with chemotherapy-refractory ES-SCLC who were treated with apatinib at an initial dosage of 250 or 500 mg were included in this study. The change of target lesions was assessed. Overall response rate (ORR) was evaluated. Prognosis was carried out and safety profile was documented. Additionally, peripheral blood and biopsy cancer tissue specimens of the patients with SCLC were collected for the analysis of polymorphism and VEGFR2 gene mRNA expression, respectively. The association between genotype status and baseline characteristics was performed. Univariate analysis of genotype status and prognosis was carried out using Kaplan-Meier survival analysis and multivariate analysis were adjusted by Cox regression analysis. RESULTS: Efficacy of apatinib included partial response (PR) in 15 patients, stable disease (SD) in 86 patients, progressive disease (PD) in 27 patients. Therefore, ORR of the 128 patients with ES-SCLC was 11.7%, and disease control rate (DCR) was 78.9%. Prognosis suggested that the median progression-free survival (PFS) and overall survival (OS) of the 128 patients with ES-SCLC was 4.2 months and 8.2 months, respectively. The polymorphism analysis focusing on VEGFR2 gene indicated that one single nucleotide polymorphism 889C>T was of clinical significance. Prevalence of 889C>T among the 128 patients with SCLC were as follows: CC genotype 87 cases (68.0%), CT genotype 38 cases (29.7%) and TT genotype 3 cases (2.3%), the minor allele frequency of 889C>T was 0.17, which was in accordance with Hardy-Weinberg Equilibrium (P = 0.628). Patients with CT and TT genotypes were merged in the subsequent analysis. Prognosis analysis exhibited that the median PFS of patients with CT/TT genotype and CC genotype was 3.3 and 5.0 months, respectively (P = 0.02). Furthermore, the median OS of patients was 5.5 and 9.0 months, respectively (P = 0.008). Additionally, multivariate Cox regression analysis of OS demonstrated that CT/TT genotype was an independent factor for OS [Hazard ratio (HR) = 0.64, P = 0.019]. However, the safety profile according to genotype status of 889C>T failed to show significant difference. Interestingly, mRNA expression analysis suggested that the mRNA expression of VEGFR2 in cancer tissues were significantly different according to CC and CT/TT genotypes (P < 0.001). CONCLUSION: The administration with apatinib for patients with chemotherapy-refractory ES-SCLC was of potential clinical significance. The clinical outcomes of patients with ES-SCLC who were treated with apatinib could be impacted by VEGFR2 889C>T polymorphism through mediating the VEGFR2 mRNA expression.

The mRNA of solute carrier family 22, member 17 (SLC22A17) plays the potential diagnostic and prognostic role in advantage non-small cell lung cancer patients.

This study aims to evaluate the mRNA levels of solute carrier family 22, member 17 (SLC22A17) and its potential clinical value as a diagnostic and prognostic biomarker in non-small cell lung cancer. This prospective study measured SLC22A17 mRNA levels in lung cancer and paracancer tissues using quantitative reverse transcription-polymerase chain reaction (PCR). The levels of SLC22A17 mRNA in plasma samples from healthy control subjects and patients with lung cancer were also measured. The association between SLC22A17 mRNA levels in plasma and clinicopathological characteristics was determined. Receiver operating characteristic (ROC) curve analysis was performed to determine the diagnostic value of SLC22A17 in plasma. Survival curve analysis was performed using the Kaplan-Meier method. SLC22A17 mRNA levels were significantly higher in lung cancer samples than in the paired paracancerous tissues. Plasma SLC22A17 mRNA levels were also significantly higher in patients with lung cancer than in healthy controls. The COX analysis indicated that there was a significant correlation between elevated plasma SLC22A17 mRNA levels and lymph node metastasis, distant metastasis, and TNM stage. Furthermore, the ROC curve analysis demonstrated that plasma SLC22A17 had high diagnostic value. High plasma SLC22A17 mRNA levels are associated with a significantly shorter survival time. SLC22A17 is upregulated in lung cancer and may serve as a novel diagnostic and prognostic biomarker.

Foritinib in advanced ROS1-rearranged non-small-cell lung cancer in China: a multicentre, open-label, single-arm, phase 2 study.

BACKGROUND: Currently approved targeted treatment for ROS1-rearranged non-small-cell lung cancer (NSCLC) has either inadequate intracranial activity or CNS-related toxicities. We evaluated the efficacy and safety of foritinib, a novel ALK and ROS1 inhibitor, in patients with advanced ROS1-rearranged NSCLC. METHODS: This two-part (phase 2a and 2b), multicentre, single-arm, open-label, phase 2 study was done in 29 centres in China. Eligible participants were adults (aged ≥18 years) with histologically or cytologically confirmed ROS1-rearranged, locally advanced or metastatic stage IIIB-IV NSCLC, with an Eastern Cooperative Oncology Group performance status of 2 or less. Patients who had previously received no or one ROS1 inhibitor were enrolled into phase 2a, and patients who were naive to ROS1 inhibitor therapy were enrolled into phase 2b cohort 1. Participants in phase 2a received 80, 120, 160, or 210 mg foritinib succinate (foritinib) orally once daily over 21-day cycles; patients in phase 2b received the recommended phase 2 dose of 160 mg. The primary endpoint was objective response rate, assessed by the independent review committee in the full analysis set (ie, all participants who received at least one dose of study treatment). The safety analysis set included all participants who received at least one dose of study treatment and had available safety assessments. This study is ongoing and is registered with ClinicalTrials.gov, NCT04237805. FINDINGS: Between March 26, 2020, and Dec 29, 2022, 104 patients were enrolled and treated. Six patients who had previously received more than one ROS1 inhibitor were enrolled in phase 2a before a protocol amendment stating that patients in this phase should have received no more than one ROS1 inhibitor; these patients were included in the safety analysis but excluded from the efficacy analysis of the ROS1-inhibitor-pretreated cohort. Therefore, the efficacy analysis set (n=98) included 42 patients from phase 2a (17 who were ROS1 inhibitor naive and 25 who had previously received ROS1 inhibitor) and 56 patients from phase 2b cohort 1. In phase 2a, the objective response rate was 94% (95% CI 71-100; 16 of 17 patients) in patients who were ROS1 inhibitor naive and 40% (21-61; ten of 25) in patients who had previously received ROS1 inhibitor. In phase 2b cohort 1, the objective response rate was 88% (95% CI 76-95; 49 of 56 patients). In a prespecified exploratory analysis in 41 patients with CNS metastases at baseline, the objective response rate was 100% (95% CI 48-100; five of five patients) in patients in phase 2a who were ROS1 inhibitor naive, 40% (16-68; six of 15) in patients in phase 2a who had previously received ROS1 inhibitor, and 90% (70-99; 19 of 21) in patients in phase 2b cohort 1. Grade 3-4 treatment-related adverse events occurred in 33 (32%) of 104 patients; the most common were hyperglycaemia (12 [12%] patients) and electrocardiogram prolonged QT interval (six [6%]). Serious treatment-related adverse events occurred in 11 (11%) patients, with hyperglycaemia (six [6%]) being most common. No treatment-related adverse events led to death. INTERPRETATION: Foritinib showed systemic and intracranial antitumour activity and good tolerability in ROS1-inhibitor-naive patients with ROS1-rearranged NSCLC. Foritinib represents a promising treatment for these patients, especially in those with CNS metastases. FUNDING: Fosun Pharma, Wanbang Biopharmaceuticals, and Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer.

Sunvozertinib for patients in China with platinum-pretreated locally advanced or metastatic non-small-cell lung cancer and EGFR exon 20 insertion mutation (WU-KONG6): single-arm, open-label, multicentre, phase 2 trial.

BACKGROUND: Sunvozertinib is an oral, irreversible, and selective tyrosine kinase inhibitor that has a favourable safety profile and encouraging antitumour activity, as shown in phase 1 studies of patients with heavily pretreated non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutation (exon20ins). We aimed to assess the antitumour efficacy of sunvozertinib in patients with platinum-pretreated locally advanced or metastatic NSCLC with EGFR exon20ins. METHODS: WU-KONG6 is a single-group, open-label, multicentre phase 2 trial of sunvozertinib monotherapy, conducted across 37 medical centres in China. We enrolled adult patients with pathologically or cytologically confirmed locally advanced or metastatic NSCLC whose tumour tissue carried an EGFR exon20ins mutation. All patients had received at least one line of previous systemic therapy, with at least one line containing platinum-based chemotherapy. The primary endpoint was objective response rate (ORR), as assessed by the independent review committee. The ORR was defined as the percentage of patients who achieved complete or partial response, confirmed by two separate assessments with at least 4-week time interval, until disease progression or initiation of any new anti-cancer therapy. Enrolled patients received sunvozertinib 300 mg once daily until meeting discontinuation criteria per the protocol. Patients who received at least one dose of treatment and were evaluable for efficacy analysis were included in the primary analysis, and all patients who received at least one dose of treatment were included in the safety analysis. This study is registered with ChinaDrugTrials.org, CTR20211009, and ClinicalTrials.gov, NCT05712902, and efficacy and safety follow-up are ongoing. FINDINGS: Between July 19, 2021, and May 6, 2022, 104 patients were enrolled. At data cutoff (Oct 17, 2022), the last enrolled patient had been followed up for about 6 months. Among 97 patients evaluable for efficacy analysis, 59 (61%) patients achieved tumour response, with a confirmed ORR of 61% (95% CI 50-71). All tumour responses were partial responses. Tumour responses were observed irrespective of age, sex, smoking history, EGFR exon20ins subtypes, brain metastasis at baseline, previous lines of therapy, and history of onco-immunotherapy. In total, 19 death events occurred over a median follow-up period of 7·6 months (IQR 6·1-9·4). Sunvozertinib was well tolerated at 300 mg once daily. The most common grade 3 or worse treatment-related adverse events were blood creatine phosphokinase increased (18 [17%] of 104), diarrhoea (eight [8%]), and anaemia (six [6%]). The most common serious treatment-related adverse events were interstitial lung disease (five [5%] of 104), anaemia (three [3%]), vomiting (two [2%]), nausea (two [2%]) and pneumonia (two [2%]). INTERPRETATION: In this phase 2 study, sunvozertinib demonstrated antitumour efficacy in patients with platinum-based chemotherapy pretreated NSCLC with EGFR exon20ins, with a manageable safety profile. A multinational randomised, phase 3 study of sunvozertinib versus platinum-doublet chemotherapy in EGFR exon20ins NSCLC is ongoing (NCT05668988). FUNDING: Dizal Pharmaceutical.

Befotertinib for patients with pretreated EGFR T790M mutated locally advanced or metastatic NSCLC: Final overall survival results from a phase 2 trial.

BACKGROUND: In the initial analysis of a pivotal phase 2 single-arm study (NCT03861156), befotertinib (D-0316) showed clinical benefit with a manageable safety profile in pretreated patients with EGFR T790M mutated non-small cell lung cancer (NSCLC), including those with brain metastases. METHODS: Eligible patients received oral befotertinib of 50 mg (cohort A) or 75-100 mg (cohort B) once daily until disease progression, withdrawal of informed consent, or death. The primary endpoint for the initial analysis was objective response rate (ORR) assessed by an independent review committee. OS and safety were secondary endpoints. Herein, we present the final OS and safety data. RESULTS: A total of 176 patients in cohort A and 290 patients in cohort B were finally enrolled. At data cutoff (May 31, 2023), the median duration of follow-up was 47.9 months (95 % CI: 47.1-48.3) in cohort A and 36.7 months (35.9-37.9) in cohort B. The median OS was 23.9 months (95 % CI: 21.1-27.2) in cohort A and 31.5 months (26.8-35.3) in cohort B. The median OS for patients with and without brain metastasis in cohort A was 18.6 months (95 % CI: 14.9-26.3) and 26.4 months (95 % CI: 23.0-29.0), respectively. In cohort B, these data was 23.0 months (95 % CI: 18.6-29.1) and 35.5 months (95 % CI: 29.3-NE), respectively. The safety profile of befotertinib remained consistent with previous data. Grade 3 or higher treatment-emergent adverse events were 38.1 % in the cohort A and 50.3 % in the cohort B, and 22.2 % and 31.7 % were related to the study drug. CONCLUSION: Befotertinib demonstrated a more profound OS benefit compared to other 3rd-generation EGFR TKI, despite that cross trial data comparison should be interpreted with caution. The safety profile was manageable and consistent with previously report data in pretreated patients with confirmed T790M mutation-positive NSCLC.

[Efficacy and safety of rh-endostatin combined with docetaxel in second-line or intolerant toxicity for first-line treatment in patients with advanced non-small cell lung cancer].

OBJECTIVE: To analyze the efficacy and safety of combination of rh-endostatin (Endostar) with docetaxel treatment on patients of non-small cell lung cancer (NSCLC) who presented PD or intolerable toxicity in/after first-line chemotherapy. METHODS: A randomized, double-blind, placebo-controlled and multi-center clinical trial was conducted. Patients with stage IIIB/IV of NSCLC experienced previous chemotherapy of one-regimen were screened for this trial. A total of 68 cases were included in this study. Single docetaxel and that combined with endostar were conducted in two arms. The response, time to progression (TTP) and adverse effects were observed in both arms. RESULTS: The objective response rate (ORR) and clinical benefit rate (CBR) were 0 and 62.5% in the combined arm, along with 0 and 53.3% in the single docetaxel arm, with a non-significant difference between the two groups (all P > 0.05), respectively. The median TTPs in the combined and single docetaxel arms were 2.63 and 2.07 months, respectively (P = 0.079). The median TTPs of the participants with progressive disease (PD) after first-line chemotherapy were 1.33 and 1.67 months in the combined and single docetaxel arms, respectively (P = 0.946). The median TTPs of the participants with intolerant adverse effects in first-line chemotherapy were 4.70 months and 3.17 months in the combined and single docetaxel arms, respectively (P = 0.070). The median TTPs of the patients with SD after 2 therapeutic cycles in the combined and single docetaxel arms were 6.23 months and 3.27 months, respectively (P = 0.040). The differences between two arms were non-significant in adverse, serious adverse and cardiovascular adverse effects (all P > 0.05). CONCLUSIONS: Endostar may prolong TTP in patients with advanced NSCLC benefited from docetaxel treatment without increased toxicities.

Difference of serum tumor markers in different clinical stages of elderly patients with non-small cell lung cancer and evaluation of diagnostic value.

Background: To explore the difference and diagnostic value evaluation of serum tumor markers in different clinical stages of elderly non-small cell lung cancer (NSCLC) patients. Methods: Select 100 elderly NSCLC patients admitted to our hospital from June 2018 to June 2021, collect the general data, pathology data and imaging data of the patients, and the patients were divided into I-IV clinical stages according to the International Union Against Cancer (UICC) 8th edition lung cancer TNM staging standard. Detect the subjects' peripheral serum tumor markers, serum carcinoembryonic antigen (CEA), cytokeratin fragment 21-1 (CYFRA21-1), squamous cell carcinoma-associated antigen (SCCA), carbohydrate antigen 125 (CA125) and sugar Class antigen 199 (CA199). Compare the differences of serum CEA, CYFRA21-1, SCCA, CA125, CA199 levels in different clinical stages of elderly NSCLC patients, and the diagnostic value of the above indicators for elderly NSCLC patients was analyzed by receiver operating characteristic curve (ROC curve) and area under the curve (AUC).

Exosomes derived from M1 macrophages inhibit the proliferation of the A549 and H1299 lung cancer cell lines via the miRNA-let-7b-5p-GNG5 axis.

Background: Almost all cells are capable of secreting exosomes (Exos) for intercellular communication and regulation. Therefore, Exos can be used as a natural therapeutic platform to regulate genes or deliver drugs to treat diseases. M1 macrophages inhibit tumor growth by releasing pro-inflammatory factors. This study explored the applicability of M1 macrophage exosomes (M1-Exos) as gene carriers and the effects on GNG5 protein, and further examined whether macrophage repolarization could inhibit tumor activity. Methods: M0 macrophages were polarized toward M1 using vitexin. Exos were obtained from M1 macrophages by ultra-centrifugation. The transwell non-contact co-culture system was used to co-culture M1 macrophages with HLF-α human lung epithelial cells or A549 or H1299 lung cancer cells. MTT, scratch, and transwell assays were used to detect the cell viability, migration, and invasion ability of cells in the four groups. Flow cytometry was used to detect the apoptosis rate of each group, and western blot (WB) analysis was performed to detect the change in the expression of proliferation- and apoptosis-related proteins. We screened the differentially expressed microRNAs using quantitative polymerase chain reaction technology. Luciferase reporter analysis was performed to explore the interaction between miRNA and protein. We used Xenografted A549 tumors in nude mice to study the effect of M1-Exos on tumor cell growth in vivo. Results: The results showed that, under the M1 macrophage co-culture system, lung cancer cell viability, invasion, and migration ability decreased, and the number of apoptotic cells increased, will all indicators being statistically significant (P < 0.05). The expression levels of PCNA, KI67, and Bcl-2 decreased significantly, but that of Bax increased (P < 0.05). Exosomes can have the same effect on tumor cells as M1 macrophages. Exosomes can transport miR-let-7b-5p to tumor cells, and miR-let-7b-5p can inhibit tumor cell proliferation and promote tumor cell apoptosis by regulating the GNG5 protein level. Conclusions: M1-Exos inhibit the proliferation, invasion, and metastasis of lung cancer cells through miRNA-let-7b-5p and GNG5 signaling pathways and inhibit the anti-apoptotic ability of lung cancer cells.

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.

Camrelizumab Plus Carboplatin and Pemetrexed as First-Line Treatment for Advanced Nonsquamous NSCLC: Extended Follow-Up of CameL Phase 3 Trial.

INTRODUCTION: In CameL phase 3 study (ClinicalTrials.gov: NCT03134872), addition of camrelizumab to first-line chemotherapy significantly improved the progression-free survival in patients with stages IIIB to IV nonsquamous NSCLC. Here, we present outcomes after a minimum follow-up of 43.9 months since last patient randomization. METHODS: Eligible patients were randomized 1:1 to 4 to 6 cycles of camrelizumab plus carboplatin and pemetrexed or chemotherapy alone every 3 weeks, followed by maintenance camrelizumab plus pemetrexed or pemetrexed only (n = 205 and 207, respectively). Total camrelizumab exposure was up to 2 years. RESULTS: As of January 31, 2022, camrelizumab plus chemotherapy exhibited substantially improved overall survival over chemotherapy alone (median, 27.1 versus 19.8 mo; hazard ratio = 0.72 [95% confidence interval: 0.57-0.92]). In the chemotherapy-alone group, 95 patients (45.9%) crossed over to camrelizumab monotherapy. After adjustment for crossover, the survival benefit with camrelizumab plus chemotherapy was more pronounced (adjusted hazard ratio = 0.55 [95% confidence interval: 0.42-0.71]). In camrelizumab plus chemotherapy group, 33 patients completed 2 years of camrelizumab. Objective response rate was 97.0%, with ongoing responses in 17 of the 32 responses (53.1%), and 93.9% (31 of 33) of the patients were alive at data cutoff. Safety profiles were consistent with the previous report, and no obvious evidence of cumulative toxicity was found with long exposure to camrelizumab. CONCLUSIONS: Camrelizumab plus carboplatin and pemetrexed provides long-term survival benefit over chemotherapy, with manageable toxicity and remarkable and durable response in patients receiving 2 years of camrelizumab, further supporting camrelizumab combination as first-line treatment for advanced nonsquamous NSCLC.

Lung infection caused by Blastoschizomyces capitatus without immunodeficiency: a case report and review of the literature.

BACKGROUND: Blastoschizomyces capitatus infection is a rare fungal infection; mainly occurring in immunodeficient patients, which can cause multiple organ involvement. At present, there is no clear designated treatment regimen. This case was a rare example of Blastoschizomyces capitatus lung infection in patient with normal immune function, which was effectively controlled by combined antifungal therapy. CASE DESCRIPTION: We report a 67-year-old male smoker, who, after cleaning a small bungalow for a long period, without any protective measures, developed cough with expectoration, fever and dyspnea. Pre-admission anti-infective medication (amoxicillin and roxithromycin) had little effect, and the patient's condition worsened. He had a past history of pulmonary tuberculosis with pleurisy 6 years before. Chest computed tomography (CT) showed evidence of old tuberculosis in the right upper lobe and inflammation in both lower lobes. White blood cell count was 14.51×109/L, neutrophils was 13.39×109/L and C-reactive protein (CRP) was 170 mg/L. Broad-spectrum antibiotics piperacillin sodium 4.0 g and tazobactam sodium 0.5 g q8h were administered empirically for 5 days. Blastoschizomyces capitatus infection was confirmed by next generation of macro genome sequencing (NGS) of bronchoalveolar lavage fluid and mass spectrum analysis of sputum. He was then switched to voriconazole antifungal therapy combined with aerosol inhalation of amphotericin B. His temperature normalized, expectoration and dyspnea were relieved. Total white cell count fell to 8.10×109/L, neutrophils to 5.81×109/L, and CRP to 76.8 mg/L. CONCLUSIONS: This case demonstrates that Blastoschizomyces capitatus infection can occur in patients with normal immune function. Mass spectrometry and metagenomic NGS methods may have an advantage over traditional methods in identifying this fungal infection. In addition, the combination of voriconazole and nebulized amphotericin B can be employed as a novel regimen for treating Blastoschizomyces capitatus infection. For pulmonary infection with a history of environmental exposure, early pathogen identification and culture, and appropriate antibiotic treatment are key to optimizing outcome.

A systematic review and meta-analysis of circulating cell-free DNA as a diagnostic biomarker for non-small cell lung cancer.

Background: Early diagnosis of non-small cell lung cancer (NSCLC) is crucial for treatment. Circulating cell-free DNA (cfDNA) is an extracellular nucleic acid found in serum, and tumor cfDNA circulating in the blood may be used as a biomarker for early diagnosis. The purpose of this study was to evaluate the application value of cfDNA as a biomarker for the diagnosis of NSCLC through meta-analysis. Methods: We searched the China National Knowledge Infrastructure (CNKI), Wanfang, VIP, PubMed, Cochrane Central Register of Controlled Trials, Embase, and Web of Science databases using the following search terms: lung cancer, NSCLC, biomarkers, circulating cfDNA, cfDNA, circulating tumor DNA (ctDNA), circulating cell-free tumor DNA, and diagnosis. The retrieval period was set until September 2021. According to PICOS (patients, intervention, comparison, outcomes, and study design) principles the inclusion criteria were: aged ≥18 years; at least 10 NSCLC cases; NSCLC patients diagnosed by histopathology or cytology; circulating cfDNA was detected; outcome data could be completely extracted. Bias risk assessment was conducted according to the QUADAS (Quality Assessment of Diagnostic Accuracy Studies). RevMan 5.3 was used for meta-analysis. Results: Eight studies met the inclusion criteria, including a total of 618 NSCLC patients and 635 healthy subjects. The overall sensitivity and specificity were 0.79 [95% confidence interval (CI): 0.75-0.82] and 0.81 (95% CI: 0.78-0.84), respectively. The area under the curve (AUC) of the summary receiving operating characteristic (SROC) curve was 0.8941. The pooled positive likelihood ratio, pooled negative likelihood ratio, and pooled diagnostic odds ratio were 5.37 (95% CI: 2.67-10.81), 0.24 (95% CI: 0.15-0.38), and 24.68 (95% CI: 8.85-68.84), respectively. The patient selection bias was high in two articles was high, unclear in one article, and low in the remaining five ones. The risk of bias in the research index test was unclear in one article, and low in the remaining seven articles. The reference standard bias, and flow and time bias of all articles was low. Conclusions: Circulating cfDNA is an efficacy biomarker in diagnosis of NSCLC. Its clinical application technology is worthy of further research.

Immune checkpoint inhibitor-related adverse events in lung cancer: Real-world incidence and management practices of 1905 patients in China.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are the standard treatment for advanced lung cancer, but immune-related adverse events (irAEs) remain poorly understood, especially in a real-world setting. METHODS: A multicenter observational study was conducted. Medical records of lung cancer patients treated with ICIs at 26 hospitals from January 1, 2015, to February 28, 2021, were retrieved. Types of ICIs included antiprogrammed cell death 1 or antiprogrammed cell death ligand 1 (PD-L1) monotherapy, anticytotoxic T-lymphocyte antigen-4 monotherapy, or combination therapy. RESULTS: In total, 1905 patients with advanced lung cancer were evaluated. The median age was 63 (range 28-87) years, and the male/female ratio was 3.1:1 (1442/463). The primary histological subtype was adenocarcinoma (915). A total of 26.9% (512/1905) of the patients developed 671 irAEs, and 5.8% (110/1905) developed 120 grade 3-5 irAEs. Median duration from ICI initiation to irAEs onset was 56 (range 0-1160) days. The most common irAEs were thyroid dysfunction (7.2%, 138/1905), pneumonitis (6.5%, 124/1905), and dermatological toxicities (6.0%, 115/1905). A total of 162 irAEs were treated with steroids and 11 irAEs led to death. Patients with positive PD-L1 expression (≥1%) and who received first-line ICI treatment developed more irAEs. Patients who developed irAEs had a better disease control rate (DCR, 71.3% [365/512] vs. 56.0% [780/1145]; p < 0.001). CONCLUSIONS: The incidence rate of irAEs was 26.9% in a real-world setting. IrAEs might be related to a better DCR, but clinicians should be more aware of irAE recognition and management in clinical practice.

Efficacy and Safety of Befotertinib (D-0316) in Patients With EGFR T790M-Mutated NSCLC That Had Progressed After Prior EGFR Tyrosine Kinase Inhibitor Therapy: A Phase 2, Multicenter, Single-Arm, Open-Label Study.

INTRODUCTION: Befotertinib (D-0316) is a novel, third-generation EGFR tyrosine kinase inhibitor (TKI). This study evaluated befotertinib in patients with locally advanced or metastatic NSCLC who developed an EGFR T790M mutation after progression on first- or second-generation EGFR TKI therapy. METHODS: This was a single-arm, open-label, phase 2 study at 49 hospitals across mainland China. Patients with locally advanced or metastatic NSCLC harboring EGFR T790M mutations with disease progression after prior first- or second-generation EGFR TKI therapy received oral befotertinib of 50 mg (cohort A) or 75 to 100 mg (cohort B) once daily. The primary end point was objective response rate (ORR) assessed by an independent review committee in intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT03861156. RESULTS: A total of 176 patients and 290 patients were included in cohorts A (50 mg) and B (75-100 mg), respectively. At data cutoff (August 15, 2021), independent review committee-assessed ORR was 67.6% (95% confidence interval [CI]: 61.9%-72.9%) in cohort B. The investigator-assessed ORR was 54.0% (95% CI: 46.3%-61.5%) in cohort A and 65.9% (95% CI: 60.1%-71.3%) in cohort B. The median investigator-assessed progression-free survival was 11.0 (95% CI: 9.6-12.5) months in cohort A and 12.5 (95% CI: 11.1-13.8) months in cohort B. The median independent review committee-assessed progression-free survival in cohort B was 16.6 (95% CI: 15.0-not evaluable [NE]) months. The intracranial ORR was 26.7% (95% CI: 7.8%-55.1%) in cohort A by investigator assessment, while 57.1% (95% CI: 34.0%-78.2%) and 55.9% (95% CI: 37.9%-72.8%) in cohort B by investigator and independent review committee assessment, respectively. The median investigator-assessed intracranial progression-free survival was 16.5 (95% CI: 8.6-NE) months in cohort A, while the median intracranial progression-free survival was not evaluable in cohort B due to immature data regardless of investigator or independent review committee assessment. and NE (95% CI: 13.8-NE) in cohort B. The overall survival was immature. Grade 3 or higher treatment-related adverse events and treatment-related serious adverse events occurred in 20.5% and 11.4% of patients in cohort A and in 29.3% and 10.0% of patients in cohort B, respectively. CONCLUSIONS: Befotertinib of 75 to 100 mg has satisfying efficacy and manageable toxicity in patients with locally advanced or metastatic NSCLC harboring T790M mutation with resistance to first- or second-generation EGFR TKIs. A phase 3 randomized trial is underway (NCT04206072).

Prophylactic cranial irradiation confers favourable prognosis for patients with limited-stage small cell lung cancer in the era of MRI: A propensity score-matched analysis.

INTRODUCTION: Prophylactic cranial irradiation (PCI) is recommended for patients with limited-stage small cell lung cancer (LS-SCLC) who achieve good response after chemoradiotherapy. But PCI is neurotoxic. Magnetic resonance imaging (MRI) is the standard tool for evaluating brain metastasis (BM). This study was to retrospectively analyse the necessity of PCI in the era of MRI in LS-SCLC. METHODS: From July 2013 to June 2017, 190 patients with LS-SCLC who were treated with definitive chemoradiotherapy were included and analysed in this study. They were divided into the PCI group and non-PCI group. Propensity score matching (PSM) analysis was used to balance the variable differences. The Kaplan-Meier method was applied to estimate survival with log-rank test to ascertain significance between different groups. RESULTS: Seventy-seven patients (40.5%) received PCI after chemoradiotherapy. After adjustment for propensity scores, 69 pairs of patients were matched between two groups. After PSM, the 1-year and 3-year OS rates were 96.9% and 48.5% in PCI group versus 89.9% and 25.0% in non-PCI group (HR: 0.419, 95% CI: 0.251-0.701, P = 0.001). The 1-year and 3-year BMFS in PCI group were 96.8% and 67.5% versus 62.3% and 37.9% in non-PCI group (HR: 0.247, 95% CI: 0.132-0.460, P < 0.001). CONCLUSION: For patients showing no BM on MRI after definitive CRT, PCI confers less BM and better OS in LS-SCLC.

Tumor-associated eosinophilia in a patient with EGFR-positive, MET-amplified lung adenocarcinoma refractory to targeted therapy: a case report and review of literature.

Paraneoplastic eosinophilia is a rare complication observed in 1% solid tumor cases and appears to have tumor type-dependent prognostic impact, in which the increased eosinophil count was generally associated with unfavorable prognosis. In the English literature, more than 20 patients have been reported of eosinophilia associated with primary non-small cell lung cancer (NSCLC) at diagnosis, all of whom underwent either surgery, chemotherapy, or symptomatic therapy. Herein, we describe clinical course a stage IV NSCLC patient with paraneoplastic eosinophilia and leukocytosis and receiving targeted therapy. A 64-year-old male former smoker was diagnosed with lung adenocarcinoma harboring EGFR L858R mutation and MET amplification. Blood eosinophilia was manifested at diagnosis and confirmed to be paraneoplastic by eliminating other potential causes. The disease progressed rapidly within a month on EGFR inhibitor icotinib and then within three months on icotinib plus crizotinib after rapid response within the first month. A multi-target kinase inhibitor anlotinib was added, and the disease progressed one month later despite initial self-reported asymptomatic high-performance status. The patient was lost to subsequent follow-ups. Radiographic evaluation of disease control or progression coincided with respective distinct alleviation or worsening of eosinophilia. Consistent with previous reports of poor clinical outcome associated with blood eosinophilia, our results suggested a negative prognostic impact in EGFR-/MET-altered NSCLC. This case is, to the best of our knowledge, the first to provide evidence for blood eosinophilia paralleling disease progression in an EGFR- and MET-altered lung adenocarcinoma under targeted therapy, which suggested negative prognostic impact of blood eosinophilia in driver-positive NSCLC.

The role of autoantibody detection in the diagnosis and staging of lung cancer.

BACKGROUND: Previously, the clinical value of seven autoantibodies (p53, PGP9.5, SOX2, GAGE7, GBU4-5, MAGEA1, and CAGE) has been surveyed in our pilot observation and other published studies. Herein, we aimed to further investigate the role of these autoantibodies in the diagnosis and staging of LC. METHODS: We included a total of 135 individuals, who were divided into a Lung cancer (LC) group and a control group according to the final diagnosis. Seven autoantibody detection kits were used (ELISA method) for the expression measurement. The patients' demographics information (e.g., age, gender, and smoking history) were also documented. RESULTS: Among the seven types of autoantibodies, only P53 and GBU4-5 were significantly increased in the LC group compared to the controls. Also, the P53 autoantibody was markedly different among the various subtype groups. Meanwhile, the GBU4-5 level was significantly higher in the small cell lung cancer (SCLC) patients compared to patients with adenocarcinoma (ADC). Autoantibodies against PGP9.5, SOX2, GBU4-5, and CAGE were found to be associated with stages. Their expressions were notably higher in the advanced stage (IV) versus early stages (I-II). Using logistic regression, the outcomes of LC prediction and stage prediction showed that the area under curve (AUCs) of the receiver operating characteristic (ROC) curves were 0.743 and 0.798, respectively. CONCLUSIONS: In summary, our study confirmed the diagnostic value of tumor-associated autoantibodies, which may be useful as latent tumor markers to facilitate the detection of early LC. Single autoantibody testing is not yet sufficient in LC cancer screening, and the combined detection of autoantibodies can improve the sensitivity of detection compared with single antibody detection, especially for P53, PGP9.5, SOX2, GBU4-5, and CAGE autoantibodies.

Association Between PDL1 Genetic Variation and Efficacy of Apatinib Monotherapy in Patients with Previously Treated Advanced NSCLC: A Real-World Retrospective Study.

BACKGROUND: This study aimed to explore associations between PDL1 polymorphisms and efficacy of apatinib for patients with previously treated advanced non-small cell lung cancer (NSCLC) in a real-world setting. METHODS: We retrospectively recruited 148 patients with previously treated advanced NSCLC from January 2015 to December 2019 continuously. Clinical efficacy in patients receiving apatinib treatment was evaluated. Adverse reactions were documented during treatment. Biological specimens of peripheral blood and cancer tissue biopsies were obtained for the genotyping of genetic variations in PDL1 and corresponding gene-mRNA expression, respectively. Univariate association analysis between the status of PDL1 genetic variations and survival was performed with Kaplan-Meier survival analysis. RESULTS: The objective response rate of the 148 patients was 17.6% and disease-control rate 68.9%. Prognostic data suggested that median progression-free survival (PFS) was 3.8 (95% CI 3.13-4.47) months and median overall survival (OS) 10.5 (95% CI 9.06-11.95) months. Regarding PDL1 genetic variation, only rs2297136 was of clinical significance. Prognosis analysis revealed that PFS and OS for the rs2297136 genotype were significantly different. Median PFS of patients with TC/CC and TT genotypes was 3 and 4.5 months, respectively (P=0.006). Median OS of the two genotypes was 9 and 11.6 months, respectively (P=0.04). Furthermore, the safety profile suggested that the most common adverse reactions were hypertension, dermal toxicity, fatigue, and oral toxicity. This study failed to find any significant association between adverse reactions and rs2297136. Interestingly, mRNA-expression analysis demonstrated that mRNA expression of PDL1 in biopsy cancer-tissue specimens was significantly different based on rs2297136-genotype status (P<0.001). CONCLUSION: The PDL1 polymorphism rs2297136 could be used as a potential biomarker for the prognosis of patients with NSCLC receiving apatinib monotherapy.

The Influence of KDR Genetic Variation on the Efficacy and Safety of Patients With Advanced NSCLC Receiving First-Line Bevacizumab Plus Chemotherapy Regimen.

OBJECTIVE: Angiogenesis plays an important role in the growth and metastasis of non-small cell lung cancer (NSCLC). Bevacizumab is a humanized monoclonal antibody that mainly acts on vascular endothelial growth factor A (VEGFA). Kinase insert domain receptor (KDR) is the most important target of VEGFA. The aim of present study was to investigate the influence of KDR genetic variation on the efficacy and safety of patients with advanced NSCLC receiving first-line bevacizumab plus chemotherapy regimen. METHODS: A total of 169 patients with advanced NSCLC who received bevacizumab combined with chemotherapy were recruited in this study. Clinical outcome of the regimens was evaluated in the hospital. Peripheral blood and biopsy tissue specimens of patients were collected for the genotyping of KDR genetic variation and KDR mRNA expression, respectively. The association between KDR genotype status and other variables were analyzed. Univariate analysis of genotype status and prognosis was implemented using the Kaplan-Meier survival analysis method. Multivariate Cox regression analysis was performed to adjust the confounding factors. RESULTS: Of the polymorphisms analyzed, only V297 L was of clinical significance. The prevalence of V297 L among the study population were as follows: CC genotype 123 cases (72.8%), CT genotype 41 cases (24.3%), TT genotype 5 cases (2.9%). The minimum allele frequency is 0.15. The distribution frequencies of the 3 genotypes corresponded with Hardy-Weinberg equilibrium (P = 0.489). Patients with TT and CT genotypes were merged in the subsequent comparison of clinical outcomes. The analysis of efficacy exhibited that the objective response rates (ORR) of patients with CC genotype and CT/TT genotypes were 52.8% and 47.8% (P = 0.561), respectively. Prognosis indicated that the median progression free survival (PFS) of patients with CC genotype and CT/TT genotype were 8.9 and 5.5 months, respectively (P = 0.006). The median OS of the 2 genotypes were 20.0 and 14.9 months, respectively (P = 0.021). Adjusted in multivariate Cox regression analysis of PFS, CT/TT genotypes were an independent factor for PFS [hazard ratio (HR) = 1.59, P = 0.011). Safety profile according to genotype status of V297 L failed to find significant difference. Interestingly, the expression of KDR mRNA of patients with CT/TT genotype was significantly higher than that of patients with CC genotype in the 58 cancer tissue specimens (P < 0.001). CONCLUSION: The clinical comes of patients with advanced NSCLC receiving first-line bevacizumab plus chemotherapy regimens might be impacted by polymorphism V297 L through mediating the mRNA expression of KDR.