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Key Points Question What are the safety and IMPORTANCE There is currently no standard treatment strategy for patients with advanced efficacy of apatinib plus vinorelbine for non–small cell lung cancer (NSCLC) without driver gene variation after failure of 2 or more lines of patients with wild-type advanced chemotherapy. non–small cell lung cancer who are experiencing progression after 2 or OBJECTIVE To assess the efficacy and safety of apatinib combined with oral vinorelbine. more lines of chemotherapy? Findings In this phase 2 DESIGN, SETTING, AND PARTICIPANTS This phase 2 prospective nonrandomized clinical trial nonrandomized controlled trial of 30 evaluating the efficacy and safety of apatinib plus vinorelbine recruited patients from Hunan Cancer patients with wild-type advanced Center, Hunan, China, from January 1, 2017, to November 30, 2018. Eligible patients were those with non–small cell lung cancer, apatinib plus wild-type advanced NSCLC whose disease did not respond to at least 2 lines of chemotherapy. vinorelbine administered after failure Patients were evaluated until December 31, 2019. Data were analyzed from July 2019 to of at least 2 lines of previous December 2019. chemotherapy regimen was associated with significantly increased overall INTERVENTION Apatinib at an initial dose of 500 mg once daily and oral vinorelbine 60 mg/m response rate and prolonged median once weekly were administered until disease progression, patient withdrawal, or occurrence of progression-free survival and overall unacceptable toxic effects. survival, and they were associated with manageable toxic effects. The potential MAIN OUTCOMES AND MEASURES The primary end point was overall response rate. Secondary efficacy of apatinib plus vinorelbine end points were overall survival, progression-free survival, and safety. combination was identified using a 3-dimensional coculture platform. RESULTS The potential efficacy of apatinib plus vinorelbine was identified using drug susceptibility assay based on 3-dimensional coculture of tumor cells derived from 3 patients with lung Meaning These findings suggest that adenocarcinoma. Among 30 patients enrolled, the median (range) age was 63 (34-78) years and 18 apatinib plus vinorelbine may be an (60%) were men. Most patients (27 patients [90%]) had stage IV disease, and the median (range) effective and safe regimen as number of prior unsuccessful treatments was 2 (2-5) lines of chemotherapy. Twenty-five patients subsequent-line therapy in patients with (83%) completed the treatment, while 5 patients (17%) discontinued treatment owing to intolerable wild-type advanced non–small cell adverse events. The overall response rate was 36.7% (11 patients) and the disease control rate was lung cancer. 76.7% (23 patients). The median progression-free survival was 4.5 (95% CI, 2.4-6.6) months, and the median overall survival was 10.0 (95% CI, 4.8-17.1) months. Hand-foot syndrome was the most Supplemental content common adverse event observed, including grade 3 hand-foot syndrome observed in 5 patients (17%) and grade 4 hand-foot observed in 1 patient (3%). Grade 3 weakness was observed in 1 Author affiliations and article information are listed at the end of this article. patient (3%). CONCLUSIONS AND RELEVANCE These findings suggest that apatinib combined with oral vinorelbine is a potentially effective regimen with an acceptable safety profile. This regimen may (continued) Open Access. This is an open access article distributed under the terms of the CC-BY License. JAMA Network Open. 2020;3(3):e201226. doi:10.1001/jamanetworkopen.2020.1226 (Reprinted) March 19, 2020 1/11 JAMA Network Open | Oncology Efficacy and Safety of Apatinib Plus Vinorelbine in Patients With Wild-Type Advanced NSCLC Abstract (continued) have potential as a treatment option for patients with wild-type advanced NSCLC whose disease failed at least 2 prior lines of chemotherapy. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03652857 JAMA Network Open. 2020;3(3):e201226. doi:10.1001/jamanetworkopen.2020.1226 Introduction 1,2 Lung cancer is the leading cause of cancer-related death in China and worldwide. In China, approximately 750 000 people are diagnosed with lung cancer annually. Non–small cell lung cancer (NSCLC) accounts for 85% of lung cancers diagnosed. First- and second-line chemotherapies provide survival benefit to patients with advanced NSCLC without actionable variations in oncogenic 3-8 genes, including EGFR (OMIM 131550), ALK (OMIM 105590), and ROS1 (OMIM 165020). Some chemotherapy regimens, including gemcitabine and docetaxel, have also shown activity as third-line treatments but remain controversial as standard treatments. Angiogenesis is a hallmark of cancer and 10,11 is responsible for tumor spread and metastasis. Antiangiogenic therapies, including monoclonal antibodies against VEGF (OMIM 192240) and multireceptor tyrosine kinase inhibitors (TKIs), such as VEGF receptor TKIs, as single agents or in combination with other agents such as chemotherapy or 12-14 targeted therapy, have been shown to be effective therapeutic strategies for NSCLC. Apatinib is a novel VEGF receptor 2 TKI with encouraging antitumor activities and tolerable toxic effects in several 15-17 18 malignant tumors. In a 2018 phase 2 study by Liu et al, apatinib monotherapy administered as third-line therapy to 34 patients with advanced NSCLC achieved an objective response rate (ORR) of 5.9%, and median progression-free survival (PFS) of 4 months, although the authors did not report the median overall survival. Vinorelbine is a chemotherapeutic agent designed to inhibit microtubules of 19 20 cancer cells, which leads to cell death. In a 2018 phase 2 study, vinorelbine monotherapy administered to 159 patients with advanced NSCLC after multiline treatment failure achieved an ORR of 19.5% with median PFS of 3 months. The 3-dimensional (3-D) coculture platform has been demonstrated to accurately simulate in vivo tumor microenvironment and tumor in vivo progression events, including angiogenesis, growth, and metastasis, making it an attractive in vitro model for drug screening. The process of 3-D coculture involves the growth of various cell populations, including cells derived from patient tumor biopsy, within an intricate but well-organized extracellular matrix to simulate a physiological in vivo–like microenvironment by preserving the native signaling pathways, cell-cell and cell-matrix interactions, and cell morphology or phenotypes. To identify novel treatment strategies for wild-type advanced NSCLC, a 3-D coculture-based drug susceptibility assay was designed. Based on the promising results from this assay, apatinib plus vinorelbine was identified and a prospective nonrandomized clinical trial was initiated to determine the efficacy and safety of this combination in patients with wild-type advanced NSCLC whose disease had progressed on 2 or more lines of prior chemotherapy. Methods This phase 2, single-group, prospective nonrandomized clinical trial was performed at Hunan Cancer Hospital in Hunan, China. The trial was approved by the Research Ethics Board of Hunan Cancer Hospital and performed in accordance with the Declaration of Helsinki. All patients provided written informed consent. This study is reported following the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline. Full details of the trial protocol are avaiable in Supplement 1. JAMA Network Open. 2020;3(3):e201226. doi:10.1001/jamanetworkopen.2020.1226 (Reprinted) March 19, 2020 2/11 JAMA Network Open | Oncology Efficacy and Safety of Apatinib Plus Vinorelbine in Patients With Wild-Type Advanced NSCLC In Vitro 3-D Coculture Drug Susceptibility Test Three patients with wild-type advanced NSCLC whose disease had failed 2 prior lines of treatment were recruited for the preliminary phase of the study. None of these patients had received prior treatment of either vinorelbine or apatinib. Gene variant status of the 3 patients was confirmed with capture-based targeted next-generation sequencing of the needle biopsy specimen of their primary lung tumor. The 3-D coculture was performed according to published protocol by Fang and colleagues at the Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital. The primary lung tumor sample obtained by needle biopsy from the patient was collected in a tube and washed 3-fold with 1× phosphate-buffered saline. Using a disposable scalpel, the tumor sample was dissected into smaller pieces and stored on ice prior to seeding in a 96-well petri dish, which was precoated with 1.5% low–melting temperature agarose and preseeded with a layer of endothelial cells suspended with Geltrex matrix (Thermo Fisher Scientific). Each 3-D culture was allowed to form a tumor cell colony in the presence of endothelial cell growth basal medium-2 growth medium with endothelial cell growth medium-2 endothelial supplement SingleQuots kits (Lonza). The 3-D culture was then layered with culture media containing the inhibitor and observed under a fluorescence microscope after 24 to 48 hours to evaluate drug susceptibility by quantifying cell proliferation. The regimen that was found to be potentially effective in the in vitro drug susceptibility test was administered to 3 patients for the preliminary stage. The responses of the patients to the regimen were evaluated by computed tomography scans. Patient Selection for Prospective Clinical Study Patients aged 18 to 80 years with advanced NSCLC who experienced disease progression after 2 or more lines of chemotherapy were eligible to take part in the study. A sample size of 30 patients was fixed for the study. Patients whose disease progressed within 6 months of treatment with a non–platinum-containing regimen were also eligible if they were considered platinum resistant based on the last platinum-containing regimen received. Patient inclusion criteria included histologically confirmed adenocarcinoma, adenosquamous carcinoma, or squamous cell carcinoma; for patients with lung adenocarcinoma, driver variations in EGFR, ALK, and/or ROS1 were tested by next- generation sequencing (patients with squamous cell lung carcinoma were not required to undergo variation testing); Eastern Cooperative Oncology Group performance status score of 0 to 2; life expectancy of at least 3 months; no prior exposure to vinorelbine or apatinib; adequate bone marrow function (defined as white blood cell count of3000 cells/μL [to convert to ×10 cells per liter, multiply by 0.001], absolute neutrophil count of1500 cells/μL, platelet count of70 ×10 cells/μL [to convert to ×10 cells per liter, multiply by 1], and hemoglobin concentration of8.0g/dL[to convert to grams per liter, multiply by 10]); adequate liver function (defined as alanine aminotransferase or aspartate aminotransferase levels80 U/L [to convert to microkatals per liter, multiply by 0.0167] and total bilirubin level 342.12 mg/dL [to convert to millimoles per liter, multiply by 17.104]); and adequate renal function (defined as creatinine level7930 mg/dL [to convert to millimoles per liter, multiply by 76.25]). Key exclusion criteria included previous exposure to apatinib or vinorelbine, confirmed EGFR, ALK or ROS1 driver variations, contraindication of chemotherapy, and women who were pregnant or lactating. Prior exposure to other antiangiogenic agents, including bevacizumab, was not grounds for exclusion. Procedures Our study treatment consisted of oral apatinib administered at an initial dose of 500 mg once daily and oral vinorelbine at a dose of 60 mg/m once weekly. Dose reductions were planned according to the drug brochures. Dose reescalation was not allowed. Treatment was continued until disease progression, patient withdrawal, or unacceptable toxic effects. Dose modifications, including dose interruptions and reductions, were allowed for the management of adverse events. One dose reduction was permitted for apatinib (500 mg or 250 mg JAMA Network Open. 2020;3(3):e201226. doi:10.1001/jamanetworkopen.2020.1226 (Reprinted) March 19, 2020 3/11 JAMA Network Open | Oncology Efficacy and Safety of Apatinib Plus Vinorelbine in Patients With Wild-Type Advanced NSCLC used on alternate days or 250 mg once daily). For grade 4 nonhematological toxic effects, apatinib was delayed until recovery to grade 1 or better and then resumed with a reduced dose. At the first occurrence of either grade 3 nonhematological or grade 3 or 4 hematological toxic effects, apatinib was delayed until recovery to grade 1 or below for nonhematological toxic effects and grade 2 or below for hematological toxic effects, then treatment was resumed at the standard dose. After the second occurrence of either grade 3 nonhematological or grade 3 or 4 hematological toxic effects, patients who had dose reduction (to either 500 mg or 250 mg used on alternate days or 250 mg once daily) were treated depending on the dose level they were receiving when the toxic effects occurred. For any grade 3 or 4 toxic effects (except hypertension, hand-foot syndrome, and proteinuria), oral vinorelbine was withheld until resolution to grade 2 or less for hematological toxic effects or grade 1 or less for nonhematological toxic effects, then treatment was resumed with a reduced dose. Dose was reduced for intolerable grade 2 adverse events as necessary. Measurable disease was assessed and documented before initiating treatment. Patients were examined after the first month of receiving the regimen. Radiological assessments of target and nontarget lesions were performed every 8 weeks by computed tomography scan during the treatment phase until confirmation of disease progression. During follow-up, patients underwent physical examinations that included 12-lead electrocardiogram examination, vital signs testing, routine urine examination, and blood testing, including hematological testing, serum chemistry testing, and testing for biomarkers associated with tumors. Adverse events were graded according to Common Terminology Criteria for Adverse Events version 4.03 and monitored on a weekly basis for the first month, then at least once every 4 weeks until disease progression or last follow-up date of December 31, 2019. Outcomes The primary end point was the proportion of patients who achieved overall response (ie, complete or partial). Secondary end points were PFS (measured from the treatment start date until disease progression or death), overall survival (measured from treatment start date until death), and safety. Objective responses were determined according to Response Evaluation Criteria in Solid Tumors version 1.1. Disease control rate was defined as the proportion of patients with complete response, partial response, and stable disease. Statistical Analysis All statistical analyses were conducted using SPSS statistical software version 22.0 (IBM Corp). The proportions of responders were calculated with 95% CIs using the Clopper-Pearson method. The Kaplan-Meier method was used to estimate the median durations of response and PFS with corresponding 95% CIs. We only analyzed data that were collected by the cutoff date of December 31, 2019. Data analysis was conducted from July 2019 to December 2019. Results 3-D Coculture Platform Three male patients who were formerly smokers and who had wild-type advanced lung adenocarcinoma after failure of 2 previous lines of treatment were included in this study (eTable 2 in Supplement 2). Primary lung tumor biopsy samples were obtained, cocultured, and used to perform drug screening of a total of 49 single and combination drugs (eFigure 1 and eTable 1 in Supplement 2). According to the results of the screening using the coculture platform with patient-derived tumor cells, the combination of apatinib and vinorelbine was potentially effective. Patient 1 had undergone at least 2 prior platinum-based doublet chemotherapy regimens combined with pemetrexed and paclitaxel (eFigure 2A in Supplement 2) and had a confirmed diagnosis of lung adenocarcinoma based on the pathological examination and immunohistochemistry (eFigure 2B in Supplement 2). The results of 3-D in vitro drug susceptibility JAMA Network Open. 2020;3(3):e201226. doi:10.1001/jamanetworkopen.2020.1226 (Reprinted) March 19, 2020 4/11 JAMA Network Open | Oncology Efficacy and Safety of Apatinib Plus Vinorelbine in Patients With Wild-Type Advanced NSCLC testing showed that the effects of either apatinib or vinorelbine as single agents, as well as paclitaxel and pemetrexed, were not satisfactory, while the combination of apatinib and vinorelbine had the best inhibitory association with tumor cell proliferation (eFigure 2C and D in Supplement 2). Based on the promising results from the 3-D coculture assay, the patient was administered with apatinib and oral vinorelbine. Review of this patient’s computed tomography results showed a significant reduction in primary lesions, evaluated as partial response, after 2 months of treatment with apatinib plus vinorelbine (eFigure 2E in Supplement 2). This patient’s response remained durable as of December 31, 2019, after 45 months of therapy. Similarly, patients 2 and 3 also had received diagnoses of lung adenocarcinoma and responded to apatinib and vinorelbine therapy at the third- line setting, which lasted for 12 months for patient 2 and 15 months for patient 3. Table 1. Baseline Characteristics of Included Patients Characteristic No. (%) (N = 30) Age, median (range), y 63 (34-78) Sex Men 18 (60) Women 12 (40) Cigarette smoking status None 14 (477) Former 16 (53) Histologic type Adenocarcinoma 19 (63) Squamous cell carcinoma 9 (30) Adenosquamous carcinoma 2 (7) Cancer stage Stage IV 27 (90) Stage IIIB or IIIC 3 (10) ECOG performance status score 0-1 20 (67) ≥2 10 (33) Brain metastasis Yes 2 (7) No 28 (93) Driver oncogenes EGFR 1 (3) EML4-ALK 1 (3) ROS1 0 None 28 (93) Prior chemotherapy regimens received, 2 (2-5) median (range), No. 2 27 (90) 3 1 (3) 4 1 (3) 5 1 (3) Prior surgical procedure 6 (20) Prior radiotherapy 3 (10) Abbreviations: ALK, anaplastic lymphoma kinase; ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; EML4, echinoderm microtubule-associated protein-like 4 gene; PS, performance status. Patient’s squamous cell lung carcinoma was initially identified as wild type, but retrospective analysis of specimen using next-generation sequencing revealed EGFR exon 19 deletion. Patient’s squamous cell lung carcinoma was initially identified as wild type, but retrospective analysis of specimen using next-generation sequencing revealed EML4-ALK fusion. JAMA Network Open. 2020;3(3):e201226. doi:10.1001/jamanetworkopen.2020.1226 (Reprinted) March 19, 2020 5/11 JAMA Network Open | Oncology Efficacy and Safety of Apatinib Plus Vinorelbine in Patients With Wild-Type Advanced NSCLC Patient Characteristics and Treatment Between January 1, 2017, and November 30, 2018, a total of 32 patients with advanced NSCLC were screened for eligibility. Of them, 30 patients were enrolled in the cohort (eFigure 3 in Supplement 2). Table 1 summarizes the baseline demographic characteristics of the study cohort. The median (range) age of the cohort was 63 (34-78) years, and 18 patients (60%) were men. Nineteen patients (63%) had received diagnoses of adenocarcinoma, all of whom underwent variation testing for EGFR, ALK, and ROS1, while samples from patients with squamous cell lung carcinoma (11 patients [37%]) were tested retrospectively. Among patients with squamous cell lung carcinoma, 1 patient was found to have EGFR exon 19 deletion and 1 patient was found to have EML4-ALK rearrangement. Prior to enrollment in the study, patients had already received a median (range) of 2 (2-5) chemotherapy regimens (eTable 3 in Supplement 2). Sixteen patients (53%) had received pemetrexed combined with a platinum-based chemotherapy regimen as first-line therapy. The remaining patients had received platinum-based chemotherapy combined with docetaxel (7 patients [23%]), paclitaxel (4 patients [13%]), or gemcitabine (3 patients [10%]). A total of 3 patients (10%) received bevacizumab in either the first- or second-line setting. By December 31, 2019, the data cutoff date, all 30 patients had discontinued the treatment, with a median (interquartile range) follow-up of 11.0 (4.5-14.1) months. Patients received apatinib plus vinorelbine for a median (range) of 4 (1-22) months. Ten patients (33%) received treatment for less than 2 months, 4 patients (13%) received treatment for 2 to 4 months, 7 patients (23%) received treatment for 4 to 6 months, 3 patients (10%) received treatment for 6 to 8 months, and 6 patients (20%) received the treatment for longer than 8 months (eTable 4 in Supplement 2). Most patients (25 patients [83%]) continued the treatment until disease progression, while the remaining 5 patients (17%) discontinued the treatment owing to adverse events. Efficacy Assessment Table 2 summarizes the response assessments for the cohort. Overall response was achieved in 11 patients (37%). Meanwhile, disease control was achieved in 23 patients (77%), and 7 patients (23%) did not respond to the treatment regimen. Figure 1 illustrates the tumor shrinkage and duration of response. The maximum reduction in size of target lesions from the baseline was 33%. The median PFS was 4.5 (95% CI, 2.4-6.6) months (Figure 2A). Median overall survival was 10.0 (95% CI, 4.8-17.1) months (Figure 2B). The dosage of apatinib had to be reduced for 13 patients (43%) owing to intolerable toxic effects. All patients who had dose reduction only had the apatinib dose reduced once to 250 mg once daily (eTable 4 in Supplement 2). Apatinib doses were adjusted for almost half of the patients who had apatinib dose reduction during or at the completion of the first cycle (6 patients [46%]); 3 patients (23%) had dose reduction during the second cycle, 3 patients (23%) had dose reduction during the third cycle, and 1 patient (8%) had dose reduction during the fourth cycle. No dose adjustment was necessary for oral vinorelbine. Safety The incidence of adverse events at any grade regardless of causality was 86.7% (eTable 5 in Supplement 2). Most adverse events observed were grade 1 to 2, including hypertension (3 patients Table 2. Objective Response of the Cohort No. (%) Group Total CR PR SD PD DCR ORR P Value Total 30 (100) 0 11 (37) 12 (40) 7 (23) 23 (77) 11 (37) Apatinib dose, mg 500 17 (57) 0 6 (35) 7 (25) 4 (24) 11 (65) 6 (35) 250 13 (43) 0 5 (39) 5 (39) 3 (23) 10 (77) 5 (39) Abbreviations: CR, complete response; DCR, disease control rate; ORR, overall response Includes all patients who did not require dose reduction. rate; PD, progressive disease; PR, partial response; SD, stable disease. JAMA Network Open. 2020;3(3):e201226. doi:10.1001/jamanetworkopen.2020.1226 (Reprinted) March 19, 2020 6/11 JAMA Network Open | Oncology Efficacy and Safety of Apatinib Plus Vinorelbine in Patients With Wild-Type Advanced NSCLC [10%]), proteinuria (7 patients [23%]), and hand-foot syndrome (13 patients [43%]). Hand-foot syndrome was the most common adverse event observed, including grade 3 hand-foot syndrome observed in 5 patients (17%) and grade 4 hand-foot observed in 1 patient (3%). Five patients (12%) Figure 1. Clinical Outcomes of the Cohort A Waterfall plot illustrating maximum change in target lesion size 120 Partial response Stable disease 90 Progressive disease EGFR exon19del EML4-ALK –30 –60 –90 7 8 1 14 2 3 5 2317 9 10 24 4 11202227 15 13262925162128 19 181230 6 Patient B Swimmer plot illustrating progression-free survival Partial response Stable disease Progressive disease Disease progression Adverse event EGFR exon19del EML4-ALK 1 2 3456789 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 Patient Figure 2. Survival Outcomes of the Cohort A Progression-free survival B Overall survival 100 100 Median (IQR), 4.5 (2.4-6.6) mo Median (IQR), 10.0 (4.8-17.1) mo 80 80 60 60 40 40 20 20 0 0 0 5 10 15 20 0 10 20 30 Progression-free survival, mo Progression-free survival, mo No. at risk 30 11 7 1 1 No. at risk 30 15 4 2 Shaded areas indicate 95% CI; dotted line, median survival; and IQR, interquartile range. Tick marks (B) indicate patients who were still alive as of the cutoff date of December 31, 2019. JAMA Network Open. 2020;3(3):e201226. doi:10.1001/jamanetworkopen.2020.1226 (Reprinted) March 19, 2020 7/11 Maximum change, % Time to treatment failure, mo Probability, % Probability, % JAMA Network Open | Oncology Efficacy and Safety of Apatinib Plus Vinorelbine in Patients With Wild-Type Advanced NSCLC discontinued the study owing to adverse events, including grade 3 weakness (1 patient [20%]), pleural effusion (1 patient [20%]), fungal infection (1 patient [20%]), and grade 3 hand-foot syndrome (2 patients [40%]). No febrile neutropenia, perforation or fistulation events, or fatal adverse events were observed in our cohort. Discussion The findings of this nonrandomized clinical trial suggest the 3-D coculture model is promising for initiating future clinical trials based on potentially efficacious agents identified from drug susceptibility tests using patient-derived cells grown in 3-D coculture platform. Three-dimensional in vitro cell culture models are more accurate than 2-dimensional (2-D) cell culture models, as well as faster and cheaper than animal models. Compared with 2-D cell cultures, 3-D cell cultures can preserve the in vivo signaling pathways that are critical in driving tumor cell proliferation, progression, and metastatic spread, which allows a more accurate response to therapeutic agents. Single-agent apatinib or vinorelbine has been used in the management of NSCLC after failure of prior lines of chemotherapy or targeted therapy. Based on the clinical and survival outcomes, the results of our study suggest that the combination of apatinib and oral vinorelbine is potentially efficacious in the third-line setting and beyond among patients with variation-negative advanced NSCLC, suggesting its potential as treatment option in this subset of patients. In our cohort, an ORR of 37% was associated with treatment with apatinib combined with oral vinorelbine in the third-line setting. In a trial on apatinib combined with docetaxel in advanced lung adenocarcinoma patients with wild-type EGFR, median PFS was 2.76 months. We hypothesize that the observed extension in progression-free survival or treatment effect was associated with a potential the synergistic effect of both antiangiogenic (apatinib) and antimicrotubule(vinorelbine) drugs. Since antiangiogenic drugs and antimicrotubule drugs are capable of inhibiting tumor growth as single agents, the use of these drugs in combination may be associated with a synergistic effect, which enhances their inhibitory effect, leading to an improvement in the survival time of patients. Another advantage is that the combination of both drugs is not associated with cumulative adverse effects, as opposed to treatment with doublet cytotoxic chemotherapy. Moreover, this combination therapy has an additional advantage in that both apatinib and vinorelbine were orally administered and did not require hospital admission or an infusion pump, which could improve the adherence of the patient to the treatment regimen, in turn possibly leading to better therapeutic results. In our trial, most experiences of hypertension, proteinuria, and hand-foot syndrome were grade 1 to 2, with incidences of 10% for hypertension, 23% for proteinuria, and 63% for hand-foot syndrome, which were generally consistent with results reported in a 2019 study of apatinib. All the toxic effects observed in our cohort were manageable and no treatment-related deaths were recorded. Limitations This study has some limitations. Since our study has single-group design, our conclusions are inherently limited by the lack of a control group, and thus selection bias could not be ruled out. Additionally, the proportion of patients who received dose modification was higher than expected. Conclusions This nonrandomized clinical trial found that the combination of apatinib and oral vinorelbine has promising efficacy and manageable toxic effects as a third-line or subsequent-line treatment in patients with driver variation–negative advanced NCSLC. Further evaluation of this combination in phase 3 trials is warranted. JAMA Network Open. 2020;3(3):e201226. doi:10.1001/jamanetworkopen.2020.1226 (Reprinted) March 19, 2020 8/11 JAMA Network Open | Oncology Efficacy and Safety of Apatinib Plus Vinorelbine in Patients With Wild-Type Advanced NSCLC ARTICLE INFORMATION Accepted for Publication: January 18, 2020. Published: March 19, 2020. doi:10.1001/jamanetworkopen.2020.1226 Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Zhang X et al. JAMA Network Open. Corresponding Author: Yongchang Zhang, MD, Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, China (zhangyongchang@csu.edu.cn). Author Affiliations: Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China (X. Zhang, Xiong, Wu, Lingli Liu, Y. Zhou, Zeng, C. Zhou, Jiang, Xiao, Li Liu, H. Yang, Guan, Y. Zhang, N. Yang); State Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Department of Oncology, Shanghai Jiao Tong University School of Medicine, Shanghai, China (Q. Xia, Lingli Liu, Y. Zhou); Graduate Schools, University of South China, Hengyang, China (Wu); Department of Hepatology, Hunan Cancer Hospital, Changsha, China (C. Xia); Department of Pharmacy, Hunan Cancer Hospital, Changsha, China (Liao); Center of New Drug Clinical Trials, Hunan Cancer Hospital, Changsha, China (Li); Hunan Clinical Research Center in Gynecologic Cancer, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China (Wang); Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston (Lei). Author Contributions: Dr Y. Zhang had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Dr X. Zhang, Mr Xiong, Dr Xia, and Dr Wu contributed equally as joint first authors. Drs Y. Zhang and N. Yang contributed equally as joint senior authors. Concept and design: Zeng, Guan, Y. Zhang, N. Yang. Acquisition, analysis, or interpretation of data: X. Zhang, Xiong, Q. Xia, Wu, Lingli Liu, Y. Zhou, Zeng, C. Zhou, C. Xia, Jiang, Liao, Xiao, Li Liu, H. Yang, Li, Wang, Lei, Y. Zhang, N. Yang. Drafting of the manuscript: Y. Zhang. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: X. Zhang, Q. Xia, Lei. Obtained funding: Guan, Y. Zhang, N. Yang. Administrative, technical, or material support: Y. Zhang. Conflict of Interest Disclosures: Dr Q. Xia reported receiving grants from the National Natural Science Foundation of China during the conduct of the study. Dr Y. Zhang reported receiving grants from the National Natural Science Foundation of China and National Natural Science Foundation of Hunan Province during the conduct of the study. Dr N. Yang reported receiving grants from the Natural Science Foundation of Hunan province during the conduct of the study. No other disclosures were reported. Funding/Support: This study was supported by grants 81401902 (Dr Y. Zhang), 81702843 (Dr Xia), and 81501992 (Dr Guan) from the National Natural Science Foundation of China and grants 2018RS3106 (Dr Y. Zhang), 2018JJ2238 (Dr Y. Zhang), and 2017SK2134 (Dr N. Yang) from the Hunan Natural Science Foundation. Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Additional Contributions: Robert Pirker, MD (Medical University of Vienna), provided technical support and discussions throughout the study. Analyn Lizaso, PhD (Burning Rock Biotech), provided critical editing of the manuscript. Xinru Mao, MD (Burning Rock Biotech), provided administrative support. They were not compensated for their work. REFERENCES 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7-30. doi:10.3322/caac.21442 2. 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Trial Protocol JAMA Network Open. 2020;3(3):e201226. doi:10.1001/jamanetworkopen.2020.1226 (Reprinted) March 19, 2020 10/11 JAMA Network Open | Oncology Efficacy and Safety of Apatinib Plus Vinorelbine in Patients With Wild-Type Advanced NSCLC SUPPLEMENT 2. eFigure 1. Schematic Diagram of the 3-Dimensional Coculture-Based Clinical Trial eFigure 2. Efficacy Apatinib and Vinorelbine Guided by 3-Dimensional Coculture Platform eFigure 3. Clinical Study Design eTable 1. Drugs Included in the Screening Package eTable 2. Baseline Characteristics of Patients Whose Tissues Were Used for the 3-Dimensional Coculture Assay For Drug Susceptibility eTable 3. Treatment History of Each Patient eTable 4. Treatment Duration eTable 5. Adverse Events JAMA Network Open. 2020;3(3):e201226. doi:10.1001/jamanetworkopen.2020.1226 (Reprinted) March 19, 2020 11/11 1 2 Protocol 3 Main inclusion criteria: 4 Age 18 Pathologically identified non-small cell lung cancer 5 Adenocarcinoma, No-drive gene mutations (with EGFR ALK ROS1 included detected by next 6 generation sequencing, NGS) 7 Squamous cell carcinoma there is no need to perform gene detection but will be retrospectively 8 detected by NGS 9 Progression disease after second line treatment 10 Patients have not been administrated with Vinorelbine or apatinib 11 PS score 2 12 Estimated survival time more than 3 months 14 Main exclusion criteria: 15 Patients received treatment of apatinib or Vinorelbine before 16 EGFR, ALK or ROS1 mutation positive for Lung Adenocarcinoma patients 17 EGFR, ALK or ROS1 mutation positive for Squamous cell carcinoma if the patients have 18 performed gene detection by NGS 19 Patients with contraindication of chemotherapy 20 Pregnant or breast feeding women 22 Outcome Measures: 23 Primary Outcome: Objective Response Rate (ORR) 24 ORR means the best response status during the whole treatment line. 25 Secondary Outcome Measures: Progression free survival (PFS), OS (Overall survival) and safety 27 Sample size calculation: 28 We have chosen a fixed sample size of 30 30 Statistical analysis: 31 SPSS (version 22.0) was used for statistical analyses. Proportion of responders were calculated 32 with the 95% confidence intervals (CI) using the Clopper-Pearson method. Kaplan-Meier method 33 was used to estimate the median duration of response and PFS with corresponding 95% CIs. eFigure 1. Schematic Diagram of the 3-Dimensional Coculture-Based Clinical Trial Apatinib and vinorelbine was identified from the 3D co-culture of patient-derived tumor cells obtained from lung tumor biopsy after disease progression. The biopsy specimen was dissected and 3D co-cultured with endothelial cells in culture plate containing growth media. Drug screening was performed using the patient-derived cells treated with indicated concentration of various drugs listed in Table S1. Based on the drug susceptibility test, apatinib and vinorelbine had the most potential in inhibiting the growth of tumor cells and was then administered to the three patients whose tumors were used for the drug screening. The clinical outcomes of the patients were observed prior to initiating the clinical trials for the combination therapy. The clinical trial (NCT03652857) enrolled 30 patients between January 2017 to November 2018 and had overall response rate as the primary endpoint and progression-free survival, overall survival, and safety as the secondary endpoints. eFigure 2. Efficacy of Apatinib and Vinorelbine Guided by 3-Dimensional Coculture Platform eFigure 3. Clinical Study Design eTable 1. Drugs Included in the Screening Package Monotherapy Combination therapy Vinorelbine Apatinib and vinorelbine Cisplatin Apatinib and docetaxel Carboplatin Apatinib and ALIMTA Gemcitabine Cisplatin and vinorelbine Etoposide Injection Cisplatin and Etoposide Injection Nimustine Cisplatin and vinblastinum Carmustine Cisplatin and eldisine ALIMTA Cisplatin and Gemcitabine Cyclophosphamide Cisplatin and Paclitaxel Glyciphosphoramide Paclitaxel and Gemcitabine Paclitaxel Carboplatin and Paclitaxel Doxifluridine Gemcitabine and docetaxel 5-Fluorouracil Carboplatin and Paclitaxel Mercaptopurine Cytarabine Tegafur Carmofur Hydroxyurea Methotrexate Ancitabine Dactinomycin Adriamycin Daunorubicin Epirubicin Mitomycin Peplomycin Pirarubicin Irinotecan Harringtonine Hydroxycamptothecin Taxol Vincristine Vindesine sulfate Vinblastine Teniposide Atamestane eTable 2. Baseline Characteristics of Patients Whose Tissues Were Used for the 3-Dimensional Coculture Assay For Drug Susceptibility Abbreviations: ECOG PS, Eastern Cooperative Oncology Group Performance Status; ORR, Objective response rate; PFS, progression-free survival; OS, overall survival; Ad, adenocarcinoma; nL, number of lines eTable 3. Treatment History of Each Patient History of History of First-line Second-line Third-line Fourth-line Fifth-line Sixth-line NO surgery radiotherapy 1 Docetaxel+Nedaplatin Pemetrexed vinorelbine+Apatinib Yes none 2 Pemetrexed+Cisplatin Docetaxel Tegafur vinorelbine+Apatinib none none 3 Pemetrexed+Cisplatin Endostatin+Docetaxel vinorelbine+Apatinib none none 4 Gemcitabine+cisplatin Endostatin+Paclitaxel+Cisplatin vinorelbine+Apatinib none Yes 5 Pemetrexed+Cisplatin Docetaxel vinorelbine+Apatinib Yes Yes 6 Gemcitabine+cisplatin Paclitaxel vinorelbine+Apatinib Yes none 7 Docetaxel+Carboplatin Icotinib vinorelbine+Apatinib none none 8 Paclitaxel+Carboplatin Gemcitabine vinorelbine+Apatinib none none 9 Docetaxel+Carboplatin Gemcitabine vinorelbine+Apatinib Yes none 10 Pemetrexed+Cisplatin Docetaxel vinorelbine+Apatinib none none 11 Docetaxel+Cisplatin+Endostatin Pemetrexed+Carboplatin vinorelbine+Apatinib none none 12 Pemetrexed+Nedaplatin nivolumab vinorelbine+Apatinib none none 13 Paclitaxel+Carboplatin+Endostatin Docetaxel vinorelbine+Apatinib none Yes 14 Pemetrexed+Carboplatin+Bevacizumab Docetaxel+Bevacizumab vinorelbine+Apatinib none none 15 Pemetrexed+Cisplatin Docetaxel vinorelbine+Apatinib none none 16 Pemetrexed+Cisplatin Paclitaxel+cisplatin Paclitaxel Gemcitabine vinorelbine+Apatinib none none 17 Docetaxel+Carboplatin Pemetrexed vinorelbine+Apatinib none none 18 Pemetrexed+Carboplatin Docetaxel vinorelbine+Apatinib none none 19 Pemetrexed+Carboplatin Docetaxel vinorelbine+Apatinib Yes none 20 Gemcitabine+Nedaplatin Tegafur vinorelbine+Apatinib none none 21 Docetaxel+Carboplatin Pemetrexed vinorelbine+Apatinib none none 22 Pemetrexed+Cisplatin Docetaxel+Bevacizumab vinorelbine+Apatinib none none 23 Pemetrexed+Cisplatin Docetaxel Paclitaxel Gemcitabine Tegafur vinorelbine+Apatinib Yes none 24 Pemetrexed+Bevacizumab Docetaxel vinorelbine+Apatinib none none 25 Paclitaxel+Carboplatin Icotinib vinorelbine+Apatinib none none 26 Paclitaxel+Carboplatin Docetaxel vinorelbine+Apatinib none none 27 Docetaxel+Cisplatin erlotinib vinorelbine+Apatinib none none 28 Pemetrexed+Nedaplatin Gemcitabine vinorelbine+Apatinib none none 29 Pemetrexed+Cisplatin Docetaxel vinorelbine+Apatinib none none 30 Pemetrexed+Cisplatin Gemcitabine vinorelbine+Apatinib none none eTable 4. Treatment Duration Characteristics N=30, N(%) Total duration of treatment cycles, 4(1-22) [median(range), month] Duration of treatment administration 8 months 6(20.0%) 6months <8months 3(10.0%) 4months <6months 7(23.3%) 2months <4months 4(13.3%) <2months 10(33.3%) No. of patients with dose reduction 13(43.3%) Reasons for dose reduction (n=13) Grade II-IV Hand-foot syndrome 8(61.5%) Grade II Leukopenia 1(7.7%) Grade II Proteinuria 1(7.7%) Grade II Elevated transaminase 1(7.7%)* Grade II Fungal infection 1(7.7%) Grade III Weakness 1(7.7%) No. of patients who 30(100%) discontinued treatment Reasons for treatment discontinuation Grade III Weakness 1(3.3%) Grade III hand-foot syndrome* 2(6.7%) Accumulation of pleural effusion 1(3.3%) Fungal infection 1(3.3%) Disease progression 25(83.3%) Note: Hash(#) indicates the patient who still had grade II elevated transaminaseeven after rescue treatment, so following the principa reduce the apatinib dose to 250 mg once daily. Asterisk (*) indicates the two patients who still had grade III hand-foot syndrome even after apatinib dose reduction. Hence, both patients discontinued treatment following the principa eTable 5. Adverse Events Adverse events Grade I Grade II Grade III Grade IV Grade I-IV Grade III or IV Hematologic (n=30) Leukopenia 2(6.7%) 2(6.7%) 0(0%) 0(0%) 4(13.3%) 0(0%) Neutrophil reduction 1(3.3%) 2(6.7%) 0(0%) 0(0%) 3(10.0%) 0(0%) Anemia 7(23.3%) 2(6.7%) 0(0%) 0(0%) 9(30.0%) 0(0%) Thrombocytopenia 0(0%) 2(6.7%) 0(0%) 0(0%) 2(6.7%) 0(0%) Non-hematologic (n=30) Hand-foot syndrome 8(26.7%) 5(16.7%) 5(16.7%) 1(3.3%) 19(63.3%) 6(20.0%) Proteinuria 6(20%) 1(3.3%) 0(0%) 0(0%) 7(23.3%) 0(0%) Hypertension 2(6.7%) 1(3.3%) 0(0%) 0(0%) 3(10.0%) 0(0%) Elevated transaminase 14(46.7%) 1(3.3%) 0(0%) 0(0%) 15(50.0%) 0(0%) Elevated bilirubin 4(13.3%) 1(3.3%) 0(0%) 0(0%) 5(16.7%) 0(0%) Decreased appetite 9(30.0%) 3(10.0%) 0(0%) 0(0%) 12(40.0%) 0(0%) Diarrhea 6(20.0%) 6(20.0%) 0(0%) 0(0%) 12(40.0%) 0(0%)
JAMA Network Open – American Medical Association
Published: Mar 19, 2020
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