Retrospective study on bevacizumab in the treatment of non-small cell lung cancer with brain metastases.

BACKGROUND: Bevacizumab was demonstrated to have efficacy in patients with non-small cell lung cancer (NSCLC) and brain metastases. However, cerebral toxicities were a major concern. This study aims to investigate the efficacy and risk factors of toxicity of bevacizumab in brain metastases. METHODS: All patients with advanced NSCLC hospitalized in our institute were screened and only those, who underwent bevacizumab administration after the diagnosis of brain metastases, were included. RESULTS: Fifty-one patients, who were treatment naïve or pretreated prior to bevacizumab regimens, were enrolled. Regardless of treatment lines, the objective response rate (ORR) was 62.7% (32/51), progression free survival (PFS) and overall survival were 6.2 months (95%CI, 5.0-7.4) and 14.0 months (95%CI, 9.6-18.4), respectively, and intracranial PFS was 7.8 months (95%CI, 7.1-8.5). For 41 patients with measurable brain metastatic lesions, the intracranial ORR was 46.3% (19/41). Ten patients (19.6%, 10/51) experienced cerebral toxicities (seven cases of grade 1 and three cases of grade 3), including cerebral or intratumoral hemorrhage and ischemic stroke. Cardiovascular disease was the risk factor contributing to cerebral toxicities (OR 16.645; 95%CI, 2.443-113.430; P = 0.004). CONCLUSIONS: This retrospective study shows that bevacizumab has efficacy and favorable toxicity in patients with NSCLC and brain metastases and cardiovascular disease might be a risk factor for cerebral toxicity.

Recursive partitioning analysis of patients with oligometastatic non-small cell lung cancer: a retrospective study.

BACKGROUND: Local consolidative treatment (LCT) is important for oligometastasis, defined as the restricted metastatic capacity of a tumor. This study aimed to determine the effects and prognostic heterogeneity of LCT in oligometastatic non-small cell lung cancer. METHODS: This retrospective study identified 436 eligible patients treated for oligometastatic disease at the Guangdong Provincial People's Hospital during 2009-2016. A Cox regression analysis was used to identify potential predictors of overall survival (OS). After splitting cases randomly into training and testing sets, risk stratification was performed using recursive partitioning analysis with a training dataset. The findings were confirmed using a validation dataset. The effects of LCT in different risk groups were evaluated using the Kaplan-Meier method. RESULTS: The T stage (p = 0.001), N stage (p = 0.008), number of metastatic sites (p = 0.031), and EGFR status (p = 0.043) were identified as significant predictors of OS. A recursive partitioning analysis was used to establish a prognostic risk model with the following four risk groups: Group I included never smokers with N0 disease (3-year OS: 55.6%, median survival time [MST]: 42.8 months), Group II included never smokers with N+ disease (3-year OS: 32.8%, MST: 26.5 months), Group III included smokers with T0-2 disease (3-year OS: 23.3%, MST: 19.4 months), and Group IV included smokers with T3/4 disease (3-year OS: 12.5%, MST: 11.1 months). Significant differences in OS according to LCT status were observed in all risk groups except Group IV (p = 0.45). CONCLUSIONS: Smokers with T3/4 oligometastatic non-small cell lung cancer may not benefit from LCT.

Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II-IIIA (N1-N2) EGFR-mutant NSCLC (ADJUVANT/CTONG1104): a randomised, open-label, phase 3 study.

BACKGROUND: Cisplatin-based adjuvant chemotherapy is the standard of care for patients with resected stage II-IIIA non-small-cell lung cancer (NSCLC). RADIANT and SELECT trial data suggest patients with EGFR-mutant stage IB-IIIA resected NSCLC could benefit from adjuvant EGFR tyrosine kinase inhibitor treatment. We aimed to compare the efficacy of adjuvant gefitinib versus vinorelbine plus cisplatin in patients with completely resected EGFR-mutant stage II-IIIA (N1-N2) NSCLC. METHODS: We did a randomised, open-label, phase 3 trial at 27 centres in China. We enrolled patients aged 18-75 years with completely resected (R0), stage II-IIIA (N1-N2), EGFR-mutant (exon 19 deletion or exon 21 Leu858Arg) NSCLC. Patients were stratified by N stage and EGFR mutation status and randomised (1:1) by Pocock and Simon minimisation with a random element to either gefitinib (250 mg once daily) for 24 months or intravenous vinorelbine (25 mg/m2 on days 1 and 8) plus intravenous cisplatin (75 mg/m2 on day 1) every 3 weeks for four cycles. The primary endpoint was disease-free survival in the intention-to-treat population, which comprised all randomised patients; the safety population included all randomised patients who received at least one dose of study medication. Enrolment to the study is closed but survival follow-up is ongoing. The study is registered with ClinicalTrials.gov, number NCT01405079. FINDINGS: Between Sept 19, 2011, and April 24, 2014, 483 patients were screened and 222 patients were randomised, 111 to gefitinib and 111 to vinorelbine plus cisplatin. Median follow-up was 36·5 months (IQR 23·8-44·8). Median disease-free survival was significantly longer with gefitinib (28·7 months [95% CI 24·9-32·5]) than with vinorelbine plus cisplatin (18·0 months [13·6-22·3]; hazard ratio [HR] 0·60, 95% CI 0·42-0·87; p=0·0054). In the safety population, the most commonly reported grade 3 or worse adverse events in the gefitinib group (n=106) were raised alanine aminotransferase and asparate aminotransferase (two [2%] patients with each event vs none with vinorelbine plus cisplatin). In the vinorelbine plus cisplatin group (n=87), the most frequently reported grade 3 or worse adverse events were neutropenia (30 [34%] patients vs none with gefitinib), leucopenia (14 [16%] vs none), and vomiting (eight [9%] vs none). Serious adverse events were reported for seven (7%) patients who received gefitinib and 20 (23%) patients who received vinorelbine plus cisplatin. No interstitial lung disease was noted with gefitinib. No deaths were treatment related. INTERPRETATION: Adjuvant gefitinib led to significantly longer disease-free survival compared with that for vinorelbine plus cisplatin in patients with completely resected stage II-IIIA (N1-N2) EGFR-mutant NSCLC. Based on the superior disease-free survival, reduced toxicity, and improved quality of life, adjuvant gefitinib could be a potential treatment option compared with adjuvant chemotherapy in these patients. However, the duration of benefit with gefitinib after 24 months might be limited and overall survival data are not yet mature. FUNDING: Guangdong Provincial Key Laboratory of Lung Cancer Translational Medicine; National Health and Family Planning Commission of People's Republic of China; Guangzhou Science and Technology Bureau; AstraZeneca China.

Crizotinib in advanced non-small-cell lung cancer with concomitant ALK rearrangement and c-Met overexpression.

OBJECTIVE: Crizotinib can target against mesenchymal-epithelial transition (MET) and anaplastic lymphoma kinase (ALK), which has been considered as a multi-targeted tyrosine kinase inhibitor (TKI). The objective of this study was to explore the efficacy of crizotinib in advanced non-small-cell lung cancer (NSCLC) with concomitant ALK rearrangement and c-Met overexpression. METHODS: Totally, 4622 advanced NSCLC patients from two institutes (3762 patients at the Guangdong Lung Cancer Institute from January 2011 to December 2016 and 860 cases at the Perking Cancer Hospital from January 2015 to December 2016) were screened for ALK rearrangement with any method of IHC, RACE-coupled PCR or FISH. C-Met expression was performed by IHC in ALK-rearranged patients, and more than 50% of cells with high staining were defined as c-Met overexpression. The efficacy of crizotinib was explored in the ALK-rearranged patients with or without c-Met overexpression. RESULTS: Sixteen patients were identified with c-Met overexpression in 160 ALK-rearranged cases, with the incidence of 10.0% (16/160). A total of 116 ALK-rearranged patients received the treatment of crizotinib. Objective response rate (ORR) was 86.7% (13/15) in ALK-rearranged patients with c-Met overexpression and 59.4% (60/101)in those without c-Met overexpression, P = 0.041. Median PFS showed a trend of superiority in c-Met overexpression group (15.2 versus 11.0 months, P = 0.263). Median overall survival (OS) showed a significant difference for ALK-rearranged patients with c-Met overexpression group of 33.5 months with the hazard ratio (HR) of 3.2. CONCLUSIONS: C-Met overexpression co-exists with ALK rearrangement in a small population of advanced NSCLC. There may be a trend of favorable efficacy of crizotinib in such co-altered patients.

Mixed Responses to Systemic Therapy Revealed Potential Genetic Heterogeneity and Poor Survival in Patients with Non-Small Cell Lung Cancer.

BACKGROUND: A subset of patients with non-small cell lung cancer (NSCLC) fosters mixed responses (MRs) to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) or chemotherapy. However, little is known about the clinical and molecular features or the prognostic significance and potential mechanisms. METHODS: The records of 246 consecutive patients with NSCLC receiving single-line chemotherapy or TKI treatment and who were assessed by baseline and interim positron emission tomography/computed tomography scans were collected retrospectively. The clinicopathological correlations of the MR were analyzed, and a multivariate analysis was performed to explore the prognostic significance of MR. RESULTS: The overall incidence of MR to systemic therapy was 21.5% (53/246) and predominated in patients with stage IIIB-IV, EGFR mutations and those who received TKI therapy (p < .05). Subgroup analyses based on MR classification (efficacious versus inefficacious) showed significant differences in subsequent treatment between the two groups (p < .001) and preferable progression-free survival (PFS) and overall survival (OS) in the efficacious MR group. Multivariate analyses demonstrated that the presence of MR was an independent unfavorable prognostic factor for PFS (hazard ratio [HR], 1.474; 95% confidence interval [CI], 1.018-2.134; p = .040) and OS (HR, 1.849; 95% CI, 1.190-2.871; p = .006) in patients with NSCLC. Induced by former systemic therapy, there were more T790M (18%), concomitant EGFR mutations (15%), and changes to EGFR wild type (19%) in the MR group among patients with EGFR mutations, which indicated higher incidence of genetic heterogeneity. CONCLUSION: MR was not a rare event in patients with NSCLC and tended to occur in those with advanced lung adenocarcinoma treated with a TKI. MR may result from genetic heterogeneity and is an unfavorable prognostic factor for survival. Further studies are imperative to explore subsequent treatment strategies. The Oncologist 2017;22:61-69Implications for Practice: Tumor heterogeneity tends to produce mixed responses (MR) to systemic therapy, including TKI and chemotherapy; however, the clinical significance and potential mechanisms are not fully understood, and the subsequent treatment after MR is also a clinical concern. The present study systemically assessed patients by PET/CT and differentiated MR and therapies. The study identified a relatively high incidence of MR in patients with advanced NSCLC, particularly those treated with targeted therapies. An MR may be an unfavorable prognostic factor and originate from genetic heterogeneity. Further studies are imperative to explore subsequent treatment strategies.

Supraclavicular lymph node incisional biopsies have no influence on the prognosis of advanced non-small cell lung cancer patients: a retrospective study.

BACKGROUND: Supraclavicular lymph node (SCLN) biopsies play an important role in diagnosing and staging lung cancer. However, not all patients with SCLN metastasis can have a complete resection. It is still unknown whether SCLN incisional biopsies affect the prognosis of non-small cell lung cancer (NSCLC) patients. METHODS: Patients who were histologically confirmed to have NSCLC with SCLN metastasis were enrolled in the study from January 2007 to December 2012 at Guangdong Lung Cancer Institute. The primary endpoint was OS, and the secondary endpoints were complications and local recurrence/progression. RESULTS: Two hundred two consecutive patients who had histologically confirmed NSCLC with SCLN metastasis were identified, 163 with excisional and 39 with incisional biopsies. The median OS was not significantly different between the excisional (10.9 months, 95% CI 8.7-13.2) and incisional biopsy groups (10.1 months, 95% CI 6.3-13.9), P = 0.569. Multivariable analysis showed that an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥2 (HR = 2.75, 95% CI 1.71-4.38, P < 0.001) indicated a worse prognosis. Having an epidermal growth factor receptor (EGFR) mutation (HR = 0.58, 95% CI 0.40-0.84, P = 0.004) and receiving systemic treatment (HR = 0.36, 95% CI 0.25-0.53, P < 0.001) were associated with a favorable OS. Neither the number (multiple vs. single) nor site (bilateral vs. unilateral) of SCLNs was associated with an unfavorable OS, and SCLN size or fixed SCLNs did not affect OS. CONCLUSIONS: SCLN incisional biopsies did not negatively influence the prognosis of NSCLC patients. It was safe and feasible to partly remove a metastatic SCLN as a last resort in advanced NSCLC.

Multiple primary malignancies involving lung cancer.

BACKGROUND: The incidence of multiple primary malignancies (MPM) has increased sharply in recent decades. However, the clinical characteristics and prognosis of MPM patients involving lung cancer were not fully elucidated. This retrospective study was designed to explore the clinical characteristics and prognosis of MPM patients involving lung cancer in the People's Republic of China. METHODS: Of 5405 lung cancer cases diagnosed at the Guangdong Lung Cancer Institute between 2005 and 2013, we analyzed 185 patients (3.4 %) with MPM involving lung cancer. RESULTS: Among 185 patients with MPM involving lung cancer, 10 (5.4 %)had three malignancies and 175 (94.6 %) had two malignancies. 10 patients with three malignancies were excluded from the analysis to avoid misunderstanding. Of 175 accompanying malignancies, 64 (36.6 %) were synchronous MPM patients and 111 (63.4 %) were metachronous MPM patients; 49 (28.0 %) were lung cancer first MPM patients and 126 (72.0 %) were other cancer first MPM patients. The most frequent accompanying malignancy was colon cancer (25/175), followed by rectal cancer (18/175), esophageal cancer (17/175), and thyroid cancer (13/175). Metachronous MPM patients showed significantly better overall survival (OS) than synchronous MPM, with a median OS of 72.8 (range 12.2-391.0) and 12.9 (range 0.8-86.3)months, respectively (P < 0.001). Cox regression analysis revealed that time of occurrence and stage were independent factors for OS. CONCLUSIONS: Colorectal cancer, esophageal cancer, and thyroid cancer were the tumors that most frequently accompanying lung cancer. Metachronous MPM patients showed significantly better OS compared with synchronous MPM patients.

Venous thromboembolism risk factors in Chinese non-small cell lung cancer patients.

PURPOSE: Certain clinicopathological factors contribute to the development of venous thromboembolism (VTE) in lung cancer. The aim of the current study was to assess the incidence of and the potential risk factors associated with the development of VTE in Chinese lung cancer patients. METHODS: Patients with lung cancer in our center were screened for VTE from January 2004 to July 2013. One VTE case was matched with two controls according to gender, pathology, clinical stage, and anticancer therapy. RESULTS: Among the 4,726 patient records screened, 61 (1.3 %) VTE cases with non-small cell lung cancer (NSCLC) were identified, including 58 (95.1 %) with adenocarcinoma and 59 (96.7 %) with advanced stage tumors (IIIb and IV). Serous effusion (OR 2.089, 95 % CI 1.022-4.270, P = 0.043), fever (OR 8.999, 95 % CI 1.688-47.968, P = 0.010), increased leukocytes (OR 4.136, 95 % CI 1.957-8.738, P < 0.001), hyponatremia (< 130 mmol/L, OR 5.335, 95 % CI 1.366-20.833, P = 0.016), and increased alanine aminotransferase (ALT) (OR 3.879, 95 % CI 1.514-9.936, P = 0.005) were associated with an increased risk of VTE. Patients with poor performance status (PS) (≥ 2 vs. < 1) (HR 1.574, 95 % CI 1.112-2.228, P = 0.010) and serous effusion (HR 1.571, 95% CI 1.114-2.215, P = 0.010) tended to have a poor prognosis. There was no difference in overall survival between VTE (median 15.2 months, 95 % CI 11.6-18.9) and control patients (median 16.3 months, 95 % CI 14.1-18.4, P = 0.184; HR 1.273, 95 % CI 0.890-1.820, P = 0.185). CONCLUSIONS: Clinical characteristics such as serous effusion, fever, increased leukocytes, hyponatremia, and increased ALT are potential risk factors for VTE in NSCLC. Poor PS and serous effusion imply poor prognosis for NSCLC patients, most of which have adenocarcinomas and advanced stage.

Lung cancer treatment disparities in China: a question in need of an answer.

BACKGROUND: Substantial progress has been made in the treatment of malignancies in the People's Republic of China in recent years. The goal of this study was to identify the extent to which national treatment guidelines are being used to customize patient care in lung cancer and to analyze the reasons for treatment disparities. METHODS: Patient characteristics and treatments were investigated retrospectively for the period from October 2004 to January 2013 using the outpatient database of the Guangdong Lung Cancer Institute (GLCI) in China. RESULTS: A total of 2,535 outpatients with lung cancer were studied in this retrospective analysis. The treatment disparity was 45.3%. Overall, 20.6% of patients with stage I non-small cell lung cancer (NSCLC) were overtreated, and 20.1% of stage II patients were undertreated. Only 19.6% of stage IIIA patients and 30.7% of stage IIIB patients underwent the recommended combination of chemotherapy and radiotherapy, respectively. For advanced NSCLC, the greatest treatment disparity appeared in the second-line setting and beyond. Patients who were positive for epidermal growth factor receptor (EGFR) and receiving EGFR tyrosine kinase inhibitors experienced significant prolongation of survival compared with patients who were EGFR negative or whose EGFR mutation status was unknown (hazard ratio: 0.79; p = .037). The treatment disparities were significantly larger among patients aged younger than 65 years and in patients from developing regions compared with patients aged 65 years and older and from developed regions, respectively (p < .001, p = .046). The difference in treatment disparity was statistically significant between GLCI and other hospitals (p < .001). CONCLUSION: This retrospective study of a large number of patients from an outpatient oncology database demonstrated large disparities in the treatment of lung cancer in China. It is important to develop a new guideline for recommendations that are based on resource classification.

A randomized phase II clinical trial of nab-paclitaxel and carboplatin compared with gemcitabine and carboplatin as first-line therapy in locally advanced or metastatic squamous cell carcinoma of lung.

BACKGROUND: Recent advances have shown that histology and genetic biomarkers are important in patient selection, which have led to significantly better outcomes for lung cancer patients. However, most new treatments only apply to adenocarcinoma or non-squamous, and in squamous carcinoma there is little breakthrough. In a phase III trial nab-paclitaxel plus carboplatin showed superior response rate over paclitaxel and carboplatin. In subgroup analysis the squamous histology appeared to be a predictive factor to nab-paclitaxel treatment. METHODS/DESIGN: This is an open-label, randomized, active controlled phase II trial. A total of 120 untreated advanced squamous lung cancer patients are randomized at a 1:1 ratio to receive nab-paclitaxel (135 mg/m2, d1, 8, q3w) plus carboplatin (AUC 5, d1, q3w) or gemcitabine (1,250 mg/m2, d1, 8, q3w) and carboplatin (AUC 5, d1, q3w). The primary endpoint is objective response rate and the second endpoints are progression free survival, overall survival, safety and biomarkers associated with nab-paclitaxel. The treatment will continue up to six cycles or intolerable toxicity. DISCUSSION: This ongoing trial will be the first prospective randomized trial to explore the efficacy of nab-paclitaxel as the first-line treatment specifically in squamous carcinoma of lung. STUDY NUMBER: CTONG1002 TRIAL REGISTRATION: Clinicaltrials.gov reference: NCT01236716.

Detecting the spectrum of multigene mutations in non-small cell lung cancer by Snapshot assay.

As molecular targets continue to be identified and more targeted inhibitors are developed for personalized treatment of non-small cell lung cancer (NSCLC), multigene mutation determination will be needed for routine oncology practice and for clinical trials. In this study, we evaluated the sensitivity and specificity of multigene mutation testing by using the Snapshot assay in NSCLC. We retrospectively reviewed a cohort of 110 consecutive NSCLC specimens for which epidermal growth factor receptor (EGFR) mutation testing was performed between November 2011 and December 2011 using Sanger sequencing. Using the Snapshot assay, mutation statuses were detected for EGFR, Kirsten rate sarcoma viral oncogene homolog (KRAS), phosphoinositide-3-kinase catalytic alpha polypeptide (PIK3CA), v-Raf murine sarcoma viral oncogene homolog B1 (BRAF), v-ras neuroblastoma viral oncogene homolog (NRAS), dual specificity mitogen activated protein kinase kinase 1 (MEK1), phosphatase and tensin homolog (PTEN), and human epidermal growth factor receptor 2 (HER2) in patient specimens and cell line DNA. Snapshot data were compared to Sanger sequencing data. Of the 110 samples, 51 (46.4%) harbored at least one mutation. The mutation frequency in adenocarcinoma specimens was 55.6%, and the frequencies of EGFR, KRAS, PIK3CA, PTEN, and MEK1 mutations were 35.5%, 9.1%, 3.6%, 0.9%, and 0.9%, respectively. No mutation was found in the HER2, NRAS, or BRAF genes. Three of the 51 mutant samples harbored double mutations: two PIK3CA mutations coexisted with KRAS or EGFR mutations, and another KRAS mutation coexisted with a PTEN mutation. Among the 110 samples, 47 were surgical specimens, 60 were biopsy specimens, and 3 were cytological specimens; the corresponding mutation frequencies were 51.1%, 41.7%, and 66.7%, respectively (P = 0.532). Compared to Sanger sequencing, Snapshot specificity was 98.4% and sensitivity was 100% (positive predictive value, 97.9%; negative predictive value, 100%). The Snapshot assay is a sensitive and easily customized assay for multigene mutation testing in clinical practice.

Comparison of three mathematical prediction models in patients with a solitary pulmonary nodule.

BACKGROUND: Effective methods for managing patients with solitary pulmonary nodules (SPNs) depend critically on the predictive probability of malignancy. METHODS: Between July 2009 and June 2011, data on gender, age, cancer history, tumor familial history, smoking status, tumor location, nodule size, spiculation, calcification, the tumor border, and the final pathological diagnosis were collected retrospectively from 154 surgical patients with an SPN measuring 3-30 mm. Each final diagnosis was compared with the probability calculated by three predicted models-the Mayo, VA, and Peking University (PU) models. The accuracy of each model was assessed using area under the receiver operating characteristics (ROC) and calibration curves. RESULTS: The area under the ROC curve of the PU model [0.800; 95% confidence interval (CI): 0.708-0.891] was higher than that of the Mayo model (0.753; 95% CI: 0.650-0.857) or VA model (0.728; 95% CI: 0.623-0.833); however, this finding was not statistically significant. To varying degrees, calibration curves showed that all three models overestimated malignancy. CONCLUSIONS: The three predicted models have similar accuracy for prediction of SPN malignancy, although the accuracy is not sufficient. For Chinese patients, the PU model may has greater predictive power.

Plasma ddPCR for the detection of MET amplification in advanced NSCLC patients: a comparative real-world study.

Background: Mesenchymal-epithelial transition (MET) amplification is a crucial oncogenic driver and a resistance mechanism to epidermal growth factor receptor tyrosine kinase inhibitors (TKIs) of non-small-cell lung cancer (NSCLC). Fluorescence in situ hybridization (FISH) is the gold standard for MET amplification detection. However, it is inapplicable when tissue samples are unavailable. Objective: This study assessed the performance of plasma droplet digital polymerase chain reaction (ddPCR) in MET amplification detection in NSCLC patients. Design and methods: A total of 87 NSCLC patients were enrolled, and 94 paired tissue and plasma samples were analyzed for the concordance between FISH and plasma ddPCR/tissue next-generation sequencing (NGS) in detecting MET amplification. In addition, the efficacy of patients with MET amplification using different detection methods who were treated with MET-TKIs was evaluated. Results: Plasma ddPCR showed substantial concordance with FISH (74.1% sensitivity, 92.5% specificity, and 87.2% accuracy with a kappa value of 0.68) and outperformed tissue NGS (kappa value of 0.64) in MET amplification detection. Combined plasma ddPCR and tissue NGS showed substantial concordance with FISH (92.3% sensitivity, 89.2% specificity, and an accuracy of 90.1% with a kappa value of 0.77). The efficacy is comparable in these NSCLC patients with MET amplification detected by FISH and plasma ddPCR who were treated with MET-TKIs. Conclusion: Plasma ddPCR is a potentially reliable method for detecting MET amplification in advanced NSCLC patients. Combined plasma ddPCR and tissue NGS might be an alternative or complementary method to MET amplification detection.

Impact of preoperative [18F]FDG PET/CT vs. contrast-enhanced CT in the staging and survival of patients with clinical stage I and II non-small cell lung cancer: a 10-year follow-up study.

OBJECTIVES: To elucidate the impact of [18F]FDG positron emission tomography/computed tomography (PET/CT) vs. CT workup on staging and prognostic evaluation of clinical stage (c) I-II NSCLC. METHODS: We retrospectively identified 659 cI-II NSCLC who underwent CT (267 patients) or preoperative CT followed by PET/CT (392 patients), followed by curative-intended complete resection in our hospital from January 2008 to December 2013. Differences were assessed between preoperative and postoperative stage. Five-year disease-free survival (DFS) and overall survival (OS) rates were calculated using the Kaplan-Meier approach and compared with log-rank test. Impact of preoperative PET/CT on survival was assessed by Cox regression analysis. RESULTS: The study included 659 patients [mean age, 59.5 years ± 10.8 (standard deviation); 379 men]. The PET/CT group was superior over CT group in DFS [12.6 vs. 6.9 years, HR 0.67 (95% CI 0.53-0.84), p < 0.001] and OS [13.9 vs. 10.5 years, HR 0.64 (95% CI 0.50-0.81), p < 0.001]. In CT group, more patients thought to have cN0 migrated to pN1/2 disease as compared with PET/CT group [26.4% (66/250) vs. 19.2% (67/349), p < 0.001], resulting in more stage cI cases being upstaged to pII-IV [24.7% (49/198) vs. 16.1% (47/292), p = 0.02], yet this was not found in cII NSCLC [27.5% (19/69) vs. 27.0% (27/100), p = 0.94]. Cox regression analysis identified preoperative PET/CT as an independent prognostic factor of OS and DFS (p = 0.002, HR = 0.69, 95% CI 0.54-0.88; p = 0.004, HR = 0.72, 95% CI 0.58-0.90). CONCLUSION: Addition of preoperative [18F]FDG PET/CT was associated with superior DFS and OS in resectable cI-II NSCLC, which may result from accurate staging and stage-appropriate therapy.

PD-L1 expression guidance on sintilimab versus pembrolizumab with or without platinum-doublet chemotherapy in untreated patients with advanced non-small cell lung cancer (CTONG1901): A phase 2, randomized, controlled trial.

No direct comparison has been performed between different programmed cell death-1 (PD-1) inhibitors for first-line treatment in patients with advanced non-small cell lung cancer (NSCLC). The feasibility of using PD-L1-expression-guided immunotherapy remains unknown. In this open-label, phase 2 study (NCT04252365), patients with advanced NSCLC without EGFR or ALK alterations were randomized (1:1) to receive sintilimab or pembrolizumab monotherapy (PD-L1 expression ≥ 50%), or sintilimab or pembrolizumab plus platinum-based chemotherapy (PD-L1 expression < 50%). The sample size was calculated by optimal two-stage design. The primary endpoint was the objective response rate (ORR). The study included 71 patients (sintilimab arms, n = 35; pembrolizumab arms, n = 36) and met its primary endpoint, with a confirmed ORR of 51.4% (18/35) in the sintilimab arms. The confirmed ORR (95% confidence interval) was 46.2% (19.2%, 74.9%) and 42.9% (17.7%, 71.1%) for patients treated with sintilimab and pembrolizumab monotherapy; and 54.5% (32.2%, 75.6%) and 45.4% (24.4%, 67.8%) for those treated with sintilimab- and pembrolizumab-based combination therapies. The median progression-free survival was 6.9 versus 8.1 months for all sintilimab-treated versus all pembrolizumab-treated patients, respectively, in which it was 7.6 versus 11.0 months in monotherapy and 7.4 versus 7.1 months in combination therapies. The median overall survival was 14.9 versus 21.3 months for all sintilimab-treated versus all pembrolizumab-treated patients, respectively, in which it was 14.9 versus 22.6 months in monotherapy and 14.7 versus 17.3 months in combination therapies. Treatment-related adverse events were consistent with safety outcomes of monotherapy and combination therapy in previous phase III studies. However, the incidence of rash was higher with sintilimab than pembrolizumab monotherapy. This is the first prospective phase 2 study to directly compare two anti-PD-1 antibodies as first-line treatment in advanced NSCLC. Sintilimab was efficacious and well-tolerated irrespective of PD-L1 expression level in patients with advanced NSCLC and had similar efficacy and safety to pembrolizumab.

Adjuvant Therapy-Free Strategy for Stage IB to IIIA Non-Small-Cell Lung Cancer Patients After Radical Resection Based on Longitudinal Undetectable Molecular Residual Disease: Prospective, Multicenter, Single-Arm Study (CTONG 2201).

BACKGROUND: The utility of circulating tumor DNA to monitor molecular residual disease (MRD) has been clinically confirmed to predict disease recurrence in non-small cell lung cancer (NSCLC) patients after radical resection. Patients with longitudinal undetectable MRD show a favorable prognosis and might not benefit from adjuvant therapy. PATIENTS AND METHODS: The CTONG 2201 trial is a prospective, multicenter, single-arm study (ClinicalTrials.gov identifier, NCT05457049), designed to evaluate the hypothesis that no adjuvant therapy is needed for patients with longitudinal undetectable MRD. Pathologically confirmed stage IB-IIIA NSCLC patients who have undergone radical resection will be screened. Only patients with 2 consecutive rounds of undetectable MRD will be enrolled (first at days 3-10, second at days 30 ± 7 after surgery), and admitted for imaging and MRD monitoring every 3 months without adjuvant therapy. The primary endpoint is the 2-year disease-free survival rate for those with longitudinal undetectable MRD. The recruitment phase began in August 2022 and 180 patients will be enrolled. CONCLUSIONS: This prospective trial will contribute data to confirm the negative predictive value of MRD on adjuvant therapy for NSCLC patients. CLINICAL TRIAL REGISTRATION: NCT05457049 (CTONG 2201).

Circulating Tumor DNA-Guided De-Escalation Targeted Therapy for Advanced Non-Small Cell Lung Cancer: A Nonrandomized Clinical Trial.

Importance: Uninterrupted targeted therapy until disease progression or intolerable toxic effects is currently the routine therapy for advanced non-small cell lung cancer (NSCLC) involving driver gene variations. However, drug resistance is inevitable. Objective: To assess the clinical feasibility of adaptive de-escalation tyrosine kinase inhibitor (TKI) treatment guided by circulating tumor DNA (ctDNA) for achieving complete remission after local consolidative therapy (LCT) in patients with advanced NSCLC. Design, Setting, and Participants: This prospective nonrandomized trial was conducted at a single center from June 3, 2020, to July 19, 2022, and included 60 patients with advanced NSCLC with driver variations without radiologically detectable disease after TKI and LCT. The median (range) follow-up time was 19.2 (3.8-29.7) months. Data analysis was conducted from December 15, 2022, to May 10, 2023. Intervention: Cessation of TKI treatment and follow-up every 3 months. Treatment was restarted in patients with progressive disease (defined by the Response Evaluation Criteria in Solid Tumors 1.1 criteria), detectable ctDNA, or elevated carcinoembryonic antigen (CEA) levels, whichever manifested first, and treatment ceased if all indicators were negative during follow-up surveillance. Main Outcomes and Measures: Progression-free survival (PFS). Secondary end points were objective response rate, time to next treatment, and overall survival. Results: Among the total study sample of 60 participants (median [range] age, 55 [21-75] years; 33 [55%] were female), the median PFS was 18.4 (95% CI, 12.6-24.2) months and the median (range) total treatment break duration was 9.1 (1.5-28.1) months. Fourteen patients (group A) remained in TKI cessation with a median (range) treatment break duration of 20.3 (6.8-28.1) months; 31 patients (group B) received retreatment owing to detectable ctDNA and/or CEA and had a median PFS of 20.2 (95% CI, 12.9-27.4) months with a median (range) total treatment break duration of 8.8 (1.5-20.6) months; and 15 patients (group C) who underwent retreatment with TKIs due to progressive disease had a median PFS of 5.5 (95% CI, 1.5-7.2) months. For all participants, the TKI retreatment response rate was 96%, the median time to next treatment was 29.3 (95% CI, 25.3-35.2) months, and the data for overall survival were immature. Conclusions and Relevance: The findings of this nonrandomized trial suggest that this adaptive de-escalation TKI strategy for patients with NSCLC is feasible in those with no lesions after LCT and a negative ctDNA test result. This might provide a de-escalation treatment strategy guided by ctDNA for the subset of patients with advanced NSCLC. Trial Registration: ClinicalTrials.gov Identifier: NCT03046316.

KRAS mutation in patients with lung cancer: a predictor for poor prognosis but not for EGFR-TKIs or chemotherapy.

BACKGROUND: The prognostic and predictive value of KRAS mutations in patients with lung cancer is controversial. Biases in disease stage, treatment regimen, small-scale patient studies, and biomarker status have led to inconsistent results in previous reports. METHODS: The KRAS and EGFR genes were examined in 1935 consecutive patients with non-small cell lung cancer. All patients were divided into KRAS mutation (KRAS group), EGFR mutation (EGFR group), and KRAS/EGFR wild type (WT group) groups. Randomly selected cases were paired with patients with the KRAS mutation, the EGFR mutation, and KRAS/EGFR wild type patients according to tumor, node, metastasis stage, time of first visit within 1 year, and pathology. Progression-free survival (PFS) and overall survival were evaluated by Kaplan-Meier and Cox models. RESULTS: The KRAS mutation rate for lung adenocarcinoma was 5.90 %. The overall survival was 14.47, 20.57, and 42.73 months for the KRAS group, WT group, and EGFR group, respectively (P < 0.001). Multivariate analysis indicated that KRAS mutation status was an independent prognostic factor (hazard ratio 2.69, 95 % confidence interval 1.91-3.80, P < 0.001). No difference was found in PFS and tumor responsiveness between patients with a KRAS mutation and those with wild type KRAS/EGFR for chemotherapy and EGFR tyrosine kinase inhibitors (TKI). PFS did not significantly differ for chemotherapy among the three groups (P = 0.270). CONCLUSIONS: KRAS mutation is a poor prognosis factor, but it is not an independent predictor of response to EGFR-TKI or chemotherapy in patients with lung cancer.

Prognostic features and comprehensive genomic analysis of NF1 mutations in EGFR mutant lung cancer patients.

OBJECTIVE: NF1 is a tumor suppressor gene that encodes the neurofibromin protein and negatively regulates Ras signaling. This study was aimed to investigate the molecular, clinical characteristics, and prognostic features of NF1 gene in EGFR mutant lung cancer patients. METHOD: The next-generation sequencing (NGS) was used to analyze the data from lung cancer patients in the Guangdong Lung Cancer Institute (GLCI) from June 2016 to December 2020. RESULTS: Somatic NF1 mutations were present in 4.2% (135/3220) of Chinese lung cancer patients. NF1 mutations where clearly enriched in older (p < 0.001), male (p < 0.001), and smoking (p < 0.001) patients. Patients with NF1 mutations were more likely to have TP53 (p = 0.003), BRAF (p = 0.001) and RASA1 (p = 0.026) mutations and mutually exclusive with EGFR mutations (p = 0.006). TP53 mutation had worsen prognosis in cases of NF1 mutant (p = 0.026) or EGFR/NF1 co-mutant (p = 0.031) lung adenocarcinomas (LUAD) patients. There was no effect on overall survival (OS) in LUAD patients with and without NF1 mutations, even in LUAD driver-gene negative patients. NF1/EGFR co-mutation patients had a longer OS than a single mutation of either the EGFR gene (median OS: 47.7 m vs. 30.2 m, hazard ratio [95% CI], 0.47 [0.30-0.74], p = 0.004) or NF1 gene (47.7 m vs. 19.0 m, 0.44 [0.27-0.73], p = 0.003). Furthermore, NF1 mutations significantly prolonged OS in EGFR mutant/TP53 wild-type LUAD patients (106.5 m vs. 25.5 m, 0.28 [0.13-0.59], p = 0.003) but not in patients with EGFR/TP53 co-mutations (36.8 m vs. 30.2 m, 0.70 [0.39-1.26], p = 0.280). CONCLUSION: Our results indicated NF1 mutations served as a good prognostic factor in EGFR mutant/TP53 wild-type lung cancer patients in this single-center study. TP53 mutation was obviously enriched in NF1 mutant patients and had shorter OS.

A potential treatment option for transformed small-cell lung cancer on PD-L1 inhibitor-based combination therapy improved survival.

OBJECTIVES: Transformed small-cell lung cancer (T-SCLC) has an extremely poor prognosis, and no remedies based on immunotherapy have been evaluated among T-SCLC patients. We retrospectively analysed the efficacy and safety of combining atezolizumab with chemotherapy for T-SCLC. METHODS: Forty-seven patients harbouring EGFR mutations who developed T-SCLC were enrolled. Eleven patients who used immunotherapy were defined as the I/O group, and the remaining 36 were defined as the Non-I/O group. Clinical characteristics, pathological data, and survival outcomes were collected. RNA sequencing and whole-exome sequencing (WES) were performed for in-depth analysis. RESULTS: All patients received at least one line of EGFR-TKI before rebiopsy to confirm T-SCLC. Nine patients received atezolizumab-bevacizumab-carboplatin-paclitaxel (albumin-bound) (ABCP), and the remaining 2 received atezolizumab-etoposide-carboplatin (ECT) in the I/O group. The objective response rate was 73 % (8/11). The median progression-free survival (mPFS) of T-SCLC on post-transformation therapy with I/O group and Non-I/O group was 5.1 m and 4.1 m, respectively. The median post-T-SCLC overall survival of the I/O group was significantly longer than that Non-I/O group (20.2 m vs 7.9 m, P ＜ 0.01). T-SCLC harbouring EGFR L858R tended to be longer than EGFR 19del (mPFS: not reached vs 3.7 m, P = 0.11). Positive PD-L1 status was also associated with PFS benefits (mPFS: 6.0 m vs 3.7 m, P = 0.20). Furthermore, RNA sequencing revealed that expression of SFTPA1 is significantly higher in the durable clinical benefit group. WES showed that STC2 mutation is more frequently observed at the time-point immunotherapy acquired resistance. Combination therapy based on a PD-L1 inhibitor was well tolerated, and the safety profile was consistent with previously reported studies. CONCLUSION: Our study first demonstrated that a PD-L1 inhibitor combined with chemotherapy ± bevacizumab could be a potential safe option for specific SCLC-transformed patients. Subsequent studies with more patients are essential to verify the efficacy and potential biomarkers.