Efficacy of Osimertinib Plus Bevacizumab vs Osimertinib in Patients With EGFR T790M–Mutated Non–Small Cell Lung Cancer Previously Treated With Epidermal Growth Factor Receptor–Tyrosine Kinase Inhibitor: West Japan Oncology Group 8715L Phase 2 Randomized Clinical Trial | Lung Cancer | JAMA Oncology | JAMA Network
[Skip to Navigation]
Sign In
Visual Abstract. Efficacy of Osimertinib Plus Bevacizumab vs Osimertinib in Advanced Lung Cancer Previously Treated With Epidermal Growth Factor Receptor–Tyrosine Kinase Inhibitor (EGFR-TKI)
Efficacy of Osimertinib Plus Bevacizumab vs Osimertinib in Advanced Lung Cancer Previously Treated With Epidermal Growth Factor Receptor–Tyrosine Kinase Inhibitor (EGFR-TKI)
Figure 1.  Patient Flow of the Trial
Patient Flow of the Trial
Figure 2.  Waterfall Plot of Each Arm Showing Best Percentage Change in Tumor Burden From Baseline
Waterfall Plot of Each Arm Showing Best Percentage Change in Tumor Burden From Baseline

A, Complete response (n = 2), partial response (n = 21), stable disease (n = 17), and disease progression (n = 1). B, Complete response (n = 2), partial response (n = 25), stable disease (n = 11), disease progression (n = 1), not evaluable (n = 1).

Figure 3.  Kaplan-Meier Curves of Progression-Free Survival
Kaplan-Meier Curves of Progression-Free Survival

A, Kaplan-Meier curves of progression-free survival in the osimertinib arm (n = 41) and combination arm (n = 40). B, Subgroup analysis according to any history of anti–vascular endothelial growth factor (VEGF) therapy.

Figure 4.  Kaplan-Meier Curves of Time to Treatment Failure and Overall Survival
Kaplan-Meier Curves of Time to Treatment Failure and Overall Survival

Kaplan-Meier curves of time to treatment failure (A) and overall survival (B) in the osimertinib arm (n = 41) and combination arm (n = 40).

Table.  Patient Characteristics in Phase 2 Part
Patient Characteristics in Phase 2 Part
1.
Lee  CK, Davies  L, Wu  YL,  et al.  Gefitinib or erlotinib vs chemotherapy for EGFR mutation-positive lung cancer: individual patient data meta-analysis of overall survival.   J Natl Cancer Inst. 2017;109(6). doi:10.1093/jnci/djw279PubMedGoogle Scholar
2.
Sequist  LV, Yang  JC, Yamamoto  N,  et al.  Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations.   J Clin Oncol. 2013;31(27):3327-3334. doi:10.1200/JCO.2012.44.2806 PubMedGoogle ScholarCrossref
3.
Sequist  LV, Waltman  BA, Dias-Santagata  D,  et al.  Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors.   Sci Transl Med. 2011;3(75):75ra26. doi:10.1126/scitranslmed.3002003 PubMedGoogle Scholar
4.
Yver  A.  Osimertinib (AZD9291)—a science-driven, collaborative approach to rapid drug design and development.   Ann Oncol. 2016;27(6):1165-1170. doi:10.1093/annonc/mdw129 PubMedGoogle ScholarCrossref
5.
Mok  TS, Wu  Y-L, Ahn  M-J,  et al; AURA3 Investigators.  Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer.   N Engl J Med. 2017;376(7):629-640. doi:10.1056/NEJMoa1612674 PubMedGoogle ScholarCrossref
6.
Naumov  GN, Nilsson  MB, Cascone  T,  et al.  Combined vascular endothelial growth factor receptor and epidermal growth factor receptor (EGFR) blockade inhibits tumor growth in xenograft models of EGFR inhibitor resistance.   Clin Cancer Res. 2009;15(10):3484-3494. doi:10.1158/1078-0432.CCR-08-2904 PubMedGoogle ScholarCrossref
7.
Saito  H, Fukuhara  T, Furuya  N,  et al.  Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive advanced non-squamous non-small-cell lung cancer (NEJ026): interim analysis of an open-label, randomised, multicentre, phase 3 trial.   Lancet Oncol. 2019;20(5):625-635. doi:10.1016/S1470-2045(19)30035-X PubMedGoogle ScholarCrossref
8.
Nakagawa  K, Garon  EB, Seto  T,  et al; RELAY Study Investigators.  Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, phase 3 trial.   Lancet Oncol. 2019;20(12):1655-1669. doi:10.1016/S1470-2045(19)30634-5 PubMedGoogle ScholarCrossref
9.
Rosell  R, Dafni  U, Felip  E,  et al; BELIEF Collaborative Group.  Erlotinib and bevacizumab in patients with advanced non-small-cell lung cancer and activating EGFR mutations (BELIEF): an international, multicentre, single-arm, phase 2 trial.   Lancet Respir Med. 2017;5(5):435-444. doi:10.1016/S2213-2600(17)30129-7 PubMedGoogle ScholarCrossref
10.
World Medical Association. WMA Declaration of Helsinki: ethical principles for medical research involving human subjects. 64th WMA General Assembly, Fortaleza, Brazil. October 2013. Accessed November 30, 2020. https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/
11.
Chikaishi  Y, Kanayama  M, Taira  A,  et al.  Effect of erlotinib plus bevacizumab on brain metastases in patients with non-small cell lung cancer.   Ann Transl Med. 2018;6(20):401. doi:10.21037/atm.2018.09.33 PubMedGoogle ScholarCrossref
12.
Hosomi  Y, Seto  T, Nishio  M,  et al.  Erlotinib plus bevacizumab (EB) versus erlotinib alone (E) as first-line treatment for advanced non-squamous non–small-cell lung cancer (NSCLC) with activating EGFR mutation (mt): JO25567 exploratory subgroup analysis.  Abstract 420O.  Ann Oncol. 2015;26(suppl 9):ix125. doi:10.1093/annonc/mdv532.04Google ScholarCrossref
13.
Seto  T, Kato  T, Nishio  M,  et al.  Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study.   Lancet Oncol. 2014;15(11):1236-1244. doi:10.1016/S1470-2045(14)70381-X PubMedGoogle ScholarCrossref
14.
Stinchcombe  TE, Jänne  PA, Wang  X,  et al.  Effect of erlotinib plus bevacizumab vs erlotinib alone on progression-free survival in patients with advanced EGFR-mutant non-small cell lung cancer: a phase 2 randomized clinical trial.   JAMA Oncol. 2019;5(10):1448-1455. doi:10.1001/jamaoncol.2019.1847 PubMedGoogle ScholarCrossref
15.
Ichihara  E, Hotta  K, Nogami  N,  et al.  Phase II trial of gefitinib in combination with bevacizumab as first-line therapy for advanced non-small cell lung cancer with activating EGFR gene mutations: the Okayama Lung Cancer Study Group Trial 1001.   J Thorac Oncol. 2015;10(3):486-491. doi:10.1097/JTO.0000000000000434 PubMedGoogle ScholarCrossref
16.
Yu  HA, Schoenfeld  AJ, Makhnin  A,  et al.  Effect of osimertinib and bevacizumab on progression-free survival for patients with metastatic EGFR-mutant lung cancers: a phase 1/2 single-group open-label trial.   JAMA Oncol. 2020;6(7):1048-1054. doi:10.1001/jamaoncol.2020.1260 PubMedGoogle ScholarCrossref
17.
Paz-Ares  L, Planchard  D, Yang  JC,  et al.  CNS activity of ramucirumab in combination with osimertinib in patients with advanced T790M-positive EGFR-mutant NSCLC.   J Thorac Oncol. 2018;13(10)(suppl):S453-S454. doi:10.1016/j.jtho.2018.08.545Google ScholarCrossref
18.
Soria  JC, Ohe  Y, Vansteenkiste  J,  et al; FLAURA Investigators.  Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer.   N Engl J Med. 2018;378(2):113-125. doi:10.1056/NEJMoa1713137 PubMedGoogle ScholarCrossref
19.
Akamatsu  H, Katakami  N, Okamoto  I,  et al.  Osimertinib in Japanese patients with EGFR T790M mutation-positive advanced non-small-cell lung cancer: AURA3 trial.   Cancer Sci. 2018;109(6):1930-1938. doi:10.1111/cas.13623 PubMedGoogle ScholarCrossref
20.
Garon  EB, Ciuleanu  TE, Arrieta  O,  et al.  Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial.   Lancet. 2014;384(9944):665-673. doi:10.1016/S0140-6736(14)60845-X PubMedGoogle ScholarCrossref
21.
Bergers  G, Hanahan  D.  Modes of resistance to anti-angiogenic therapy.   Nat Rev Cancer. 2008;8(8):592-603. doi:10.1038/nrc2442 PubMedGoogle ScholarCrossref
22.
Itatani  Y, Kawada  K, Yamamoto  T, Sakai  Y.  Resistance to anti-angiogenic therapy in cancer-alterations to anti-VEGF pathway.   Int J Mol Sci. 2018;19(4):E1232. doi:10.3390/ijms19041232 PubMedGoogle Scholar
23.
Yoh  K, Hosomi  Y, Kasahara  K,  et al.  A randomized, double-blind, phase II study of ramucirumab plus docetaxel vs placebo plus docetaxel in Japanese patients with stage IV non-small cell lung cancer after disease progression on platinum-based therapy.   Lung Cancer. 2016;99:186-193. doi:10.1016/j.lungcan.2016.07.019 PubMedGoogle ScholarCrossref
24.
Takeda  M, Yamanaka  T, Seto  T,  et al.  Bevacizumab beyond disease progression after first-line treatment with bevacizumab plus chemotherapy in advanced nonsquamous non-small cell lung cancer (West Japan Oncology Group 5910L): an open-label, randomized, phase 2 trial.   Cancer. 2016;122(7):1050-1059. doi:10.1002/cncr.29893 PubMedGoogle ScholarCrossref
Limit 200 characters
Limit 25 characters
Conflicts of Interest Disclosure

Identify all potential conflicts of interest that might be relevant to your comment.

Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

Err on the side of full disclosure.

If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response.

Not all submitted comments are published. Please see our commenting policy for details.

Limit 140 characters
Limit 3600 characters or approximately 600 words
    1 Comment for this article
    EXPAND ALL
    The positioning of Anti VEGF therapy in EGFR positive Lung cancers is now clearer.
    Arif Hakan ONDER, Oncology MD | University Of Health Sciences Antalya Training and Research 
    I think that the positive results obtained with the JO25567 and NEJ026 studies show us that the anti vegf and anti egft results show us that this combination will be an effective approach if used in the right place.
    Whatever the pathophysiological explanation in this study is, it is clear that in a T790M advanced lung adenolarcinoma, this combination may cause even worse outcomes than a single agent anti egfr.
    In one way or another, whether Ramurucimab in the RELAY study and the above-mentioned studies or the effects of anti-VEGF combination therapies obtained in preclinical studies on
    resistance, anti-VEGF cobbination therapy is available as an undeniable fact.
    I think the sequential anti-ALK therapy discussion discussed in ALK postive patients should be held here as well.
    Apparently, I think that the place where we should use Antivegf therapy is to obtain longer PFS with both first and second generation EGFR TKI in much earlier steps, and then, in case of progression, longer survival with Osimertinib treatment can be seen with this sequential treatment strategy.
    CONFLICT OF INTEREST: None Reported
    READ MORE
    Original Investigation
    January 7, 2021

    Efficacy of Osimertinib Plus Bevacizumab vs Osimertinib in Patients With EGFR T790M–Mutated Non–Small Cell Lung Cancer Previously Treated With Epidermal Growth Factor Receptor–Tyrosine Kinase Inhibitor: West Japan Oncology Group 8715L Phase 2 Randomized Clinical Trial

    Author Affiliations
    • 1Internal Medicine III, Wakayama Medical University, Wakayama, Japan
    • 2Department of Pulmonary Medicine, Sendai Kousei Hospital, Miyagi, Japan
    • 3Department of Medical Oncology, Faculty of Medicine, Kindai University, Osaka, Japan
    • 4Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Hyogo, Japan
    • 5Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Hyogo, Japan
    • 6Division of Respiratory Medicine, Department of Internal Medicine, St Marianna University School of Medicine, Kanagawa, Japan
    • 7Department of Respiratory Medicine, Kitasato University School of Medicine, Kanagawa, Japan
    • 8Department of Thoracic Oncology, Aichi Cancer Center Hospital, Aichi, Japan
    • 9Department of Medical Oncology, Department of Pulmonary Medicine, Chemotherapy Center and Division of Clinical Research, Takarazuka City Hospital, Hyogo, Japan
    • 10Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Fukuoka, Japan
    • 11Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan
    • 12Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan
    • 13Department of Respiratory Medicine, Itami City Hospital, Hyogo, Japan
    • 14Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto, Japan
    JAMA Oncol. 2021;7(3):386-394. doi:10.1001/jamaoncol.2020.6758
    Visual Abstract. Efficacy of Osimertinib Plus Bevacizumab vs Osimertinib in Advanced Lung Cancer Previously Treated With Epidermal Growth Factor Receptor–Tyrosine Kinase Inhibitor (EGFR-TKI)
    Efficacy of Osimertinib Plus Bevacizumab vs Osimertinib in Advanced Lung Cancer Previously Treated With Epidermal Growth Factor Receptor–Tyrosine Kinase Inhibitor (EGFR-TKI)
    Key Points

    Question  Can osimertinib plus bevacizumab work synergistically and be tolerable in patients with advanced non–small cell lung cancer (NSCLC) that harbors EGFR T790M mutation?

    Findings  In this phase 2 randomized clinical trial of 81 patients with NSCLC with EGFR T790M mutation, osimertinib plus bevacizumab failed to show prolongation of progression-free survival and overall survival compared with osimertinib alone, although toxic effects were tolerable.

    Meaning  In patients with NSCLC with EGFR T790M mutation, osimertinib plus bevacizumab was tolerable but not efficacious , which had been suggested by recent single-arm studies.

    Abstract

    Importance  Although treatment with first-generation epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor (TKI) plus antiangiogenic inhibitor has shown promising efficacies in patients with EGFR-mutated lung adenocarcinoma, recent single-arm studies have suggested that osimertinib plus antiangiogenic inhibitor might not work synergistically.

    Objective  To explore the efficacy and safety of osimertinib plus bevacizumab compared with osimertinib alone in patients with lung adenocarcinoma with EGFR T790M mutation.

    Design, Setting, and Participants  Patients with advanced lung adenocarcinoma that progressed with prior EGFR-TKI treatment (other than third-generation TKI) and acquired EGFR T790M mutation were enrolled. This study comprises a lead-in part with 6 patients and a subsequent phase 2 part. In phase 2, patients were randomized to osimertinib plus bevacizumab or osimertinib alone in a 1:1 ratio.

    Interventions  The combination arm received oral osimertinib (80 mg, every day) plus intravenous bevacizumab (15 mg/kg, every 3 weeks) until progression or unacceptable toxic effects. The control arm received osimertinib monotherapy.

    Main Outcomes and Measures  The primary end point was progression-free survival (PFS) assessed by investigators. Secondary end points consisted of overall response rate, time to treatment failure, overall survival, and safety.

    Results  From August 2017 through September 2018, a total of 87 patients were registered (6 in the lead-in part and 81 in the phase 2 part [intention-to-treat population]). Among those randomized, the median (range) age was 68 (41-82) years; 33 (41%) were male; 37 (46%) had an Eastern Cooperative Oncology Group performance status of 0; and 21 (26%) had brain metastasis. Although the overall response rate was better with osimertinib plus bevacizumab than osimertinib alone (68% vs 54%), median PFS was not longer with osimertinib plus bevacizumab (9.4 months vs 13.5 months; adjusted hazard ratio, 1.44; 80% CI, 1.00 to 2.08; P = .20). Median time to treatment failure was also shorter in the combination arm vs the osimertinib arm (8.4 months vs 11.2 months; P = .12). Median overall survival was not different in the combination arm vs osimertinib arm (not reached vs 22.1 months; P = .96). In the combination arm, common adverse events of grade 3 or higher were proteinuria (n = 9; 23%), hypertension (n = 8; 20%).

    Conclusions and Relevance  In this randomized clinical trial comparing osimertinib plus bevacizumab vs osimertinib alone, the combination arm failed to show prolongation of PFS in patients with advanced lung adenocarcinoma with EGFR T790M mutation.

    Trial Registration  UMIN Clinical Trials Registry Identifier: UMIN000023761

    Introduction

    Among metastatic non–small cell lung cancer (NSCLC), EGFR mutation is the second most frequent genetic driver. First-generation and second-generation epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitors (TKIs) have shown favorable efficacy over cytotoxic chemotherapy in patients with NSCLC with EGFR mutation.1,2 However, these patients ultimately experience disease progression within 10 to 13 months. Translational analyses revealed that about half of tumors acquired EGFR exon 20 T790M mutation as the most common mechanism of resistance.3

    Osimertinib is an orally available covalent third-generation EGFR-TKI that has shown activity in both EGFR sensitizing (exon 19 deletion or exon 21 L858R) and exon 20 T790M mutations in a preclinical study.4 Among patients with NSCLC with EGFR T790M mutation, a phase 3 trial (AURA3)5 showed significant prolongation of progression-free survival (PFS) compared with platinum doublet chemotherapy. However, median PFS with osimertinib was again almost 10 months. Considering the tolerability of osimertinib monotherapy, a novel combination strategy to delay progression has been warranted.

    Vascular endothelial growth factor (VEGF) plays a crucial role in cancer through its proliferation or metastasis, and several anti-VEGF inhibitors have already been developed. Bevacizumab is a humanized monoclonal IgG1 antibody that binds to VEGF and has shown clinical efficacy against various types of malignant neoplasms. In a preclinical study, EGFR-TKI plus anti-VEGF inhibitor showed synergistic effect in EGFR T790M xenograft model.6 Moreover, several prospective studies have shown preferable efficacy among patients with EGFR sensitizing7,8 and preexisting T790M variants.9 However, the efficacy and safety of osimertinib in combination with bevacizumab have not yet been elucidated. This study aims to test this combination in patients with EGFR-mutated NSCLC that progressed with prior EGFR-TKI treatment and acquired EGFR T790M mutation.

    Methods
    Study Design

    This open-label, multi-institutional study comprises a lead-in part to assess the feasibility of combination treatment, followed by a randomized phase 2 part. In the lead-in part, 6 patients were treated with a fixed dose of osimertinib (80 mg/d) and bevacizumab (15 mg/kg, every 3 weeks). If more than 2 patients in this cohort experienced dose-limiting toxicity (DLT) in the first cycle, this study would be terminated. The definition of DLT was as follows: (1) nonhematologic toxic effect of grade 3 or greater, (2) hypertension of grade 4, or (3) interstitial lung disease of grade 2 or greater. After confirming the feasibility of this lead-in part, the phase 2 part was initiated, and eligible patients were equally randomized to the osimertinib arm or the combination arm. Randomization was stratified according to sex (male vs female), number of prior cytotoxic chemotherapy treatments (0 vs ≥1), and institution. The primary end point of the phase 2 part was PFS assessed by investigators. Secondary end points were overall response rate (ORR), time to treatment failure (TTF), overall survival (OS), and safety. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.

    Ethical Considerations

    The study was conducted in compliance with the principles of the Declaration of Helsinki,10 and the institutional review board of each participating institution approved the protocol. Written informed consent was obtained from all patients before any screening or inclusion procedures. The trial protocol is available in Supplement 1.

    Eligibility and Exclusion Criteria

    Eligible patients were (1) those with pathologically confirmed lung adenocarcinoma with EGFR sensitizing mutation, (2) those diagnosed as stage IIIB or IV in accordance with the seventh version of the American Joint Committee on Cancer staging criteria for lung cancer, or relapsed as metastatic disease after curative treatment, (3) those previously treated with the first-generation or second-generation EGFR-TKI and confirmed radiological progression, (4) those whose cancer was confirmed to acquire EGFR exon 20 T790M mutation after EGFR-TKI treatment, (5) those with Eastern Cooperative Oncology Group performance status of 0 or 1, (6) those with a measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1., (7) those with adequate organ function, and (8) those who provided written informed consent for inclusion in this study. Testing for EGFR mutation was done by local sites using polymerase chain reaction–based methods. Patients were excluded if they had (1) interstitial lung disease at the time of registration, (2) higher risk of bleeding or embolism, (3) uncontrolled hypertension, (4) leptomeningeal disease, or (5) positivity for hepatitis B virus antigen. Those who had brain metastasis were eligible for inclusion unless they were symptomatic at the time of registration. Patients who had a prior history of cytotoxic chemotherapy treatment were also eligible, and those who received radiotherapy to the brain were allowed after a 14-day interval after the last fraction of radiotherapy.

    Study Treatment and Assessment Procedures

    All patients were orally administered 80 mg of osimertinib every day. Patients who participated in the lead-in part or were allocated to the combination arm in the phase 2 part were intravenously administered 15 mg/kg of bevacizumab on day 1, every 3 weeks. Both drugs were continued until disease progression, but patients were allowed to continue the study treatment beyond radiological progression when it was considered to be clinically beneficial. Osimertinib treatment could be suspended due to toxic effects and resumed at 40 mg per day. Bevacizumab treatment could be suspended due to toxic effects but should be resumed at the same dose. Bevacizumab treatment was discontinued if patients experienced severe toxic effects (ie, gastrointestinal perforation [any grade], thromboembolism, pulmonary hemorrhage [grade ≥2] or other hemorrhages, allergic reaction, or cardiac toxic effects [grade ≥3]). Bevacizumab treatment was also to be discontinued if patients had not recovered within 42 days from a toxic effect requiring suspension (ie, serum creatinine >1.5 mg/dL, proteinuria greater than 2+ or hypertension [grade 4]). These patients were allowed to continue osimertinib treatment.

    To assess the efficacy, computed tomography of the chest and upper abdomen was assessed every 6 weeks. Brain magnetic resonance imaging was assessed every 6 weeks if patients had detected brain metastasis at the time of study entry. Adverse events (AEs) were graded using the Common Terminology Criteria for Adverse Events, version 4.0.

    Sample Size Calculation

    Previous studies7,8 compared the efficacy of adding anti-VEGF inhibitor to the first-generation EGFR-TKIs and showed a hazard ratio (HR) of 0.44 to 0.54 in PFS compared with EGFR-TKI alone. We therefore assumed that osimertinib plus bevacizumab would lead to a PFS about 7.4 months longer than with osimertinib monotherapy, which corresponded to an HR of 0.55. Based on previous studies, 74 patients were required to ensure a statistical power of 0.80 at a 2-sided α error of 0.20. Considering a dropout rate of 8%, 80 patients were finally required.

    Statistical Analysis

    The PFS was estimated using Kaplan-Meier curves. Median PFS with 95% CI was reported for each treatment arm. The difference in PFS between the 2 treatment arms was examined at the significance level of 0.20 using a stratified log-rank test using the stratification factors (sex, number of prior cytotoxic chemotherapy treatments, and institution). A Cox regression model was used to estimate the adjusted HR stratified by sex (male/female) and history of cytotoxic chemotherapy treatment (yes/no) and its 80% and 95% CIs. All tests for the secondary end points were carried out at a 5% α level. The TTF and OS were analyzed in a similar way to PFS. For the ORR, the point estimates and the 95% CI with the Pearson-Clopper method were provided. Difference in the ORR was estimated using the χ2 test. Characteristics of the 2 arms were compared using the χ2 test or analysis of variance. Statistical analyses were conducted with JMP software, version 11 (SAS Institute) and GraphPad Prism, version 7.00 for Windows (GraphPad Software). A P value less than .05 was considered to be significant.

    Results

    The flowchart of the participants is shown in Figure 1. From August 2017 through September 2018, a total of 87 patients were registered (6 in the lead-in part and 81 in the phase 2 part [intention-to-treat population]). Of 81 patients registered in the phase 2 part, 41 were allocated to the osimertinib arm, and 40 were allocated to the combination arm. All received at least 1 dose of study treatment; they were therefore analyzed as a safety population. At the time of data cutoff, all patients in the lead-in part finished study treatment, while 26 patients were still receiving treatment in the phase 2 part. The median (range) follow-up time in the phase 2 part was 16.2 (2.8-24.0) months in the osimertinib arm and 16.0 (2.4-22.6) months in the combination arm.

    Lead-in Part

    Baseline characteristics of the 6 patients are shown in eTable 1 in Supplement 2. No DLT was observed during the first cycle, and AEs during the whole study period were mostly grade 1 or 2 (eTable 2 in Supplement 2). Grade 3 AEs were hypertension, decreased neutrophil count, rash, and anemia (2 cases each). One patient had interstitial lung disease on day 31 but finally improved on day 46. Regarding efficacy, there were 5 patients with partial responses and 1 patient with stable disease. The median PFS was 11.5 months (95% CI, 3.7 months to not reached; eFigure 1 in Supplement 2).

    Phase 2 Part

    Baseline characteristics of the 81 patients are summarized in the Table. The median (range) age was 68 (41-82) years; 33 (41%) were male; 4 (5%), 59 (73%), and 18 (22%) had a clinical stage IIIB, IV, and recurrence, respectively; 37 patients (46%) had an Eastern Cooperative Oncology Group performance status of 0 or and 44 (54%) had a status of 1; and 21 patients (26%) had brain metastasis. A total of 17 patients (21%) had prior history of cytotoxic chemotherapy treatment and 12 (15%) had prior history of anti-VEGF therapy. About 20% (n = 18) of the patients were diagnosed with EGFR T790M–mutated disease using peripheral blood samples, and about 12% (n = 10) were diagnosed using pleural effusion samples. There were no significant differences between the arms, but the combination arm tended to have fewer patients with recurrence after curative therapy or never received anti-VEGF therapy.

    Although ORR was higher in the combination arm (71.8%; 95% CI, 50.9%-81.4%) than in the osimertinib arm (55.0%; 95% CI, 37.4%-69.3%; Figure 2), it did not contribute to prolongation of PFS (13.5 months in the osimertinib arm vs 9.4 months in the combination arm; adjusted HR, 1.44; 80% CI, 1.00-2.08, and 95% CI, 0.83-2.52, respectively; P = .20; Figure 3A). Any subset analysis did not show significant difference in PFS (eFigure 2 in Supplement 2). Of those, prior history of anti-VEGF inhibitor seemed to have a detrimental effect on the combination treatment. In the combination arm, patients who had any history of anti-VEGF therapy showed significantly shorter PFS than those who did not (4.6 months vs 11.1 months; HR, 0.41; 95% CI, 0.13-1.27; P = .03; Figure 3B) while prior exposure of anti-VEGF therapy did not affect PFS in the osimertinib arm (15.1 months vs 13.7 months; HR, 1.19; 95% CI, 0.31-4.61; P = .85). The TTF was also longer in the osimertinib arm than in the combination arm (11.2 months vs 8.4 months; adjusted HR, 1.54; 95% CI, 0.90-2.69; P = .12; Figure 4A). Finally, median OS was not different between the arms (22.1 months in osimertinib arm vs not reached in the combination arm; adjusted HR, 1.02; 95% CI, 0.43-2.44; P = .96; Figure 4B).

    Adverse events are shown in eTable 3 in Supplement 2. Like those observed in the lead-in part, most AEs were generally mild (grade 1 or 2). Common AEs observed in the combination arm were proteinuria (grade 1-2, n = 22, 55%; and grade 3, n = 9, 23%) and hypertension (grade 1-2, n = 16, 40%; and grade ≥3, n = 8; 20%). The rates of proteinuria (n = 31; 78%) and hypertension (n = 24; 60%) were significantly higher in the combination arm, while the incidence of anemia (n = 27; 66%)was significantly higher in the osimertinib arm. The number of hematologic toxic effects and skin-related AEs was not increased by adding bevacizumab. There was no serious bleeding or embolism in the combination arm. About 11% (9 patients) of the entire population experienced interstitial lung disease, but all were grade 1 or 2.

    Treatment exposure is summarized in eTable 4 in Supplement 2. Twenty-seven patients (33%) experienced dose interruption with osimertinib, but the proportion was similar between the arms (13 in the osimertinib arm vs 14 in the combination arm). Of the 55 patients who discontinued study treatment, 37 were due to disease progression and 15 were due to toxic effects. In the combination arm, 11 patients (28%) discontinued bevacizumab due to AEs, and median (range) number of bevacizumab administrations was 7.5 (1-28). However, post-hoc analysis showed that discontinuation of bevacizumab due to AEs did not affect PFS in the combination arm (eFigure 3 in Supplement 2).

    At the data cutoff time, 53 patients finished study treatment and about 45 of them (85%) received poststudy treatment (eTable 5 in Supplement 2). Common treatment regimens were platinum doublet chemotherapy (22 patients) and EGFR-TKI rechallenge (21 patients).

    Discussion

    To our knowledge, this is the first randomized clinical trial to explore the efficacy of adding anti-VEGF inhibitor to osimertinib. Although ORR was slightly better in the combination arm, we could not show advantages in PFS and OS. Previous reports have suggested that EGFR-TKI plus anti-VEGF inhibitor might be more beneficial in patients with brain metastasis11 or pleural effusion12; however, none of our subgroup analyses could identify its advantage.

    In patients with advanced NSCLC with EGFR mutation, 1 randomized-phase 2 trial13 and 2 phase 3 trials7,8 showed benefits in PFS with erlotinib plus anti-VEGF inhibitor compared with erlotinib alone. On the other hand, a recent phase 2 randomized clinical trial14 had negative results (median PFS, 17.9 months vs 13.5 months; HR, 0.81; P = .39), and similar unfavorable results have been reported in single-arm trials9,15 (median PFS, 13.2 months and 14.4 months, respectively). Regarding osimertinib, 2 single-arm studies reported the preliminary results of combining anti-VEGF inhibitors. Among 49 treatment-naive patients with EGFR sensitizing variants, osimertinib plus bevacizumab demonstrated an ORR of 80% and a median PFS of 18.4 months.16 Another phase 2 study of osimertinib plus ramucirumab in 25 patients with EGFR T790M variant showed an ORR of 76% and median PFS of 11.0 months.17 Considering the efficacy data of osimertinib monotherapy in pivotal trials (18.9 months among EGFR-TKI–naive patients and 10.1 months among patients with EGFR T790M–mutated disease),5,18 these phase 2 results were not so intriguing. The present study provided more reliable evidence by adopting a randomized study design. Our control arm showed outstanding PFS (median, 13 months), but this was comparable with the Japanese subset of AURA3.19

    The reason why every single study did not show advantages with osimertinib plus anti-VEGF inhibitor has not been fully discussed. Both Paz-Ares et al17 and the present study enrolled patients who had progression despite prior EGFR-TKI treatment; it is therefore possible to speculate that exposure to prior treatment and tumor regrowth could confer microenvironmental changes of the tumor that lead to resistance to anti-VEGF agents. Another possible explanation indicated from the subset analysis is that prior exposure to anti-VEGF inhibitor may induce a different tumor environment that prevents synergy between osimertinib and bevacizumab. Based on prior evidence,20 we allowed inclusion of patients who had prior anti-VEGF inhibitor treatment. However, as shown in Figure 3B, prior exposure to anti-VEGF inhibitor had a detrimental effect in the combination arm. Nonetheless, the PFS among those without any history of anti-VEGF inhibitor in the combination arm was not superior to that in patients receiving osimertinib monotherapy. Indeed, these hypotheses may not be applicable to the result from the first-line trial by Yu et al.16 We did not prepare any collections of tissue or plasma samples before and after treatment, so we could not discuss any potential resistance mechanism with bevacizumab21,22 in the current study.

    Limitations

    Our trial has several limitations. First, owing to the small number of patients, this single study may not be conclusive. However, we think it is important that this randomized study clearly replicated the findings from previous single-arm studies. The data will draw attention to the development of osimertinib plus anti-VEGF inhibitors in any lines of treatment while several trial groups are conducting larger studies. Second, regarding toxic effects, our participants showed relatively higher incidence of proteinuria. Previously, Japanese patients with NSCLC were more likely to show a higher rate of proteinuria with anti-VEGF inhibitors. For example, the incidence of proteinuria with chemotherapy plus anti-VEGF inhibitor was much higher in Japanese studies (any grade, 26%-50%; grade 3-4, 4%) than in global studies (any grade, 4%; grade 3-4, 1%),20,23,24 and similar tendency was observed between Yu et al16 and the current study. This racial difference could affect the feasibility of bevacizumab to some extent; however, post-hoc analysis (eFigure 3 in Supplement 2) denied its influence on PFS. Nevertheless, the current study provides meaningful information; adding anti-VEGF to osimertinib did not have the desired affect among patients with EGFR T790M–mutated disease.

    The results may also have implications for the choice of first-line regimen in patients with EGFR variant. Recent studies reported comparable PFS data between osimertinib alone (18.9 months in the FLAURA trial18) and erlotinib plus anti-VEGF inhibitors (16.9 months in the NEJ026 trial7 and 19.4 months in the RELAY trial8). The current study’s data suggested that the prior exposure to anti-VEGF inhibitors clearly had detrimental effect on second-line osimertinib plus bevacizumab. More importantly, this combination itself is no longer effective in patients with EGFR T790M–mutated disease. Reflecting the results of the current trial, the efficacy of osimertinib plus anti-VEGF therapy should be explored as first-line treatment. Several randomized studies (ie, WJOG 9717L trial [UMIN000030206] and NCT04181060) are ongoing, and these results are anticipated with interest.

    Conclusions

    Compared with osimertinib monotherapy, osimertinib plus bevacizumab failed to show prolongation of PFS in patients with EGFR T790M–mutated advanced lung adenocarcinoma.

    Back to top
    Article Information

    Accepted for Publication: October 1, 2020.

    Published Online: January 7, 2021. doi:10.1001/jamaoncol.2020.6758

    Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License. © 2021 Akamatsu H et al. JAMA Oncology.

    Corresponding Author: Hiroaki Akamatsu, MD, PhD, Internal Medicine III, Wakayama Medical University, 811-1, Kimiidera, Wakayama, Japan (hiroakiakamatsu@gmail.com).

    Author Contributions: Dr Akamatsu (principal investigator) 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.

    Concept and design: Akamatsu, Furuya, Nishino, Morita, Nakagawa, Yamamoto.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Akamatsu, Hayashi, Fujimoto, Furuya, Otani, Shimizu, Nishino, Hara, Morita, Yamamoto.

    Critical revision of the manuscript for important intellectual content: Akamatsu, Toi, Tachihara, Furuya, Shimizu, Katakami, Azuma, Miura, Nishino, Teraoka, Nakagawa, Yamamoto.

    Statistical analysis: Akamatsu, Katakami, Morita.

    Obtained funding: Akamatsu.

    Administrative, technical, or material support: Akamatsu, Hayashi, Fujimoto, Tachihara, Furuya, Otani, Shimizu, Hara, Yamamoto.

    Supervision: Nakagawa, Yamamoto.

    Conflict of Interest Disclosures: Dr Akamatsu reported receiving grants and personal fees from Chugai Pharmaceutical and MSD KK and personal fees from AstraZeneca KK, Boehringer Ingelheim Japan Inc, Bristol Myers Squibb, Eli Lilly Japan KK, Novartis Pharma KK, Ono Pharmaceutical, and Taiho Pharmaceutical outside the submitted work. Dr Toi reported receiving personal fees from AstraZeneca, Bristol Myers Squibb, MSD, and Ono Pharmaceutical during the conduct of the study. Dr Hayashi reported receiving grants and personal fees from AstraZeneca KK and Chugai Pharmaceutical during the conduct of the study; and grants and personal fees from Boehringer Ingelheim Japan, Ono Pharmaceutical, and Bristol Myers Squibb and personal fees from Eli Lilly Japan KK, Kyorin Pharmaceutical, Merck Biopharma, MSD KK, Novartis Pharmaceuticals KK, Pfizer Japan Inc, Shanghai HaiHe Biopharma, and Taiho Pharmaceutical outside the submitted work. Dr Fujimoto reported receiving grants and personal fees from AstraZeneca KK and personal fees from Boehringer Ingelheim Japan Inc, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan KK, MSD KK, Novartis Pharma KK, Ono Pharmaceutical, and Taiho Pharmaceutical outside the submitted work. Dr Tachihara reported receiving grants and personal fees from AstraZeneca KK and personal fees from Boehringer Ingelheim Japan Inc, Chugai Pharmaceutical, Eli Lilly Japan KK, MSD KK, and Olympus outside the submitted work. Dr Furuya reported receiving personal fees from Eli Lilly Japan, Chugai, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim Japan, Taiho, Ono Pharmaceutical, and Pfizer Japan outside the submitted work. Dr Shimizu reported receiving honoraria from AstraZeneca KK, MSD KK, Ono Pharmaceutical, Taiho Pharmaceutical, and Chugai Pharmaceutical outside the submitted work. Dr Katakami reported receiving grants and personal fees from AstraZeneca KK, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan KK, MSD KK, and Ono Pharmaceutical, and personal fees from Boehringer Ingelheim Japan, Novartis Pharma KK, and Taiho Pharmaceutical outside the submitted work. Dr Azuma reported receiving personal fees from Chugai Pharma, AstraZeneca, MSD, Bristol Myers Squibb, and Ono Pharmaceutical outside the submitted work. Dr Nishino reported receiving personal fees from Nippon Boehringer Ingelheim, AstraZeneca KK, Novartis Pharma KK, Eli Lilly Japan KK, Roche Diagnostics KK, Chugai Pharma, and Ono Pharmaceutical outside the submitted work. Dr Teraoka reported receiving personal fees from AstraZeneca and Chugai Pharmabody Research outside the submitted work. Dr Morita reported receiving personal fees from AstraZeneca KK, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan KK, MSD KK, Pfizer Japan, Taiho Pharmaceutical, and Ono Pharmaceutical outside the submitted work. Dr Nakagawa reported receiving grants and personal fees from AstraZeneca KK, Astellas Pharma, MSD KK, Nippon Boehringer Ingelheim, Novartis Pharma KK, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, and Merck Serono/Merck Biopharma and grants, personal fees, and other from Ono Pharmaceutical, Pfizer Japan, and Eli Lilly Japan KK, during the conduct of the study; grants from inVentiv Health Japan, ICON Japan KK, Gritstone Oncology, Parexel International, Kissei Pharmaceutical, EPS Corporation, Syneos Health, Pfizer R&D Japan GK, A2 Healthcare, Quintiles/IQVIA Services JAPAN KK, EP-CRSU, Linical, Eisai, CMIC Shift Zero KK, Kyowa Hakko Kirin, Bayer Yakuhin, EPS International, and Otsuka Pharmaceutical; grants and personal fees from Takeda Pharmaceutical, Taiho Pharmaceutical, and SymBio Pharmaceuticals; personal fees from Clinical Trial Co, Medicus Shuppan Publishers, Care Net, Reno Medical KK, Medical Review, Roche Diagnostics KK, Bayer Yakuhin, Medical Mobile Communications, 3H Clinical Trial, Nichi-Iko Pharmaceutical, Nanzando, Yodosha, Nikkei Business Publications, Thermo Fisher Scientific KK, Yomiuri Telecasting Corporation, and Nippon Kayaku; personal fees and other from Kyorin Pharmaceutical; and grants and personal fees from AbbVie outside the submitted work. Dr Yamamoto reported receiving grants from AstraZeneca during the conduct of the study; grants from Astellas, Shionogi, Tumura, AbbVie GK, Amgen, Kyorin, Eisai, Terumo, Toppan Printing, and Tosoh; grants and personal fees from Eli Lilly, AstraZeneca, Ono Pharmaceutical, Daiichi Sankyo, Taiho, Takeda, Chugai, MSD, Novartis, Pfizer, and Boehringer Ingelheim; personal fees from Bristol Myers Squibb, Thermo Fisher Scientific, Life Technologies Japan, Nippon Kayaku, and Merck Biopharma, outside the submitted work. No other disclosures were reported.

    Funding/Support: This work was supported by AstraZeneca Japan.

    Role of the Funder/Sponsor: AstraZeneca Japan was involved with review of the manuscript and its approval but was not involved with design and conduct of the study (collection, management, analysis, and interpretation of the data and decision to submit the manuscript for publication).

    Meeting Presentation: This study was presented at the European Society for Medical Oncology Virtual Congress 2020; September 19-21, 2020.

    Data Sharing Statement: See Supplement 3.

    Additional Contributions: We are grateful to data managers and other support staff of the West Japan Oncology Group, especially Koji Takeda, MD, and Shinichiro Nakamura, MD, PhD. The present study was conducted with support from the West Japan Oncology Group Data Center, Osaka, Japan. We acknowledge proofreading and editing by Benjamin Phillis, BA, at the Clinical Study Support Center, Wakayama Medical University. These individuals did not receive compensation for their contributions.

    References
    1.
    Lee  CK, Davies  L, Wu  YL,  et al.  Gefitinib or erlotinib vs chemotherapy for EGFR mutation-positive lung cancer: individual patient data meta-analysis of overall survival.   J Natl Cancer Inst. 2017;109(6). doi:10.1093/jnci/djw279PubMedGoogle Scholar
    2.
    Sequist  LV, Yang  JC, Yamamoto  N,  et al.  Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations.   J Clin Oncol. 2013;31(27):3327-3334. doi:10.1200/JCO.2012.44.2806 PubMedGoogle ScholarCrossref
    3.
    Sequist  LV, Waltman  BA, Dias-Santagata  D,  et al.  Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors.   Sci Transl Med. 2011;3(75):75ra26. doi:10.1126/scitranslmed.3002003 PubMedGoogle Scholar
    4.
    Yver  A.  Osimertinib (AZD9291)—a science-driven, collaborative approach to rapid drug design and development.   Ann Oncol. 2016;27(6):1165-1170. doi:10.1093/annonc/mdw129 PubMedGoogle ScholarCrossref
    5.
    Mok  TS, Wu  Y-L, Ahn  M-J,  et al; AURA3 Investigators.  Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer.   N Engl J Med. 2017;376(7):629-640. doi:10.1056/NEJMoa1612674 PubMedGoogle ScholarCrossref
    6.
    Naumov  GN, Nilsson  MB, Cascone  T,  et al.  Combined vascular endothelial growth factor receptor and epidermal growth factor receptor (EGFR) blockade inhibits tumor growth in xenograft models of EGFR inhibitor resistance.   Clin Cancer Res. 2009;15(10):3484-3494. doi:10.1158/1078-0432.CCR-08-2904 PubMedGoogle ScholarCrossref
    7.
    Saito  H, Fukuhara  T, Furuya  N,  et al.  Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive advanced non-squamous non-small-cell lung cancer (NEJ026): interim analysis of an open-label, randomised, multicentre, phase 3 trial.   Lancet Oncol. 2019;20(5):625-635. doi:10.1016/S1470-2045(19)30035-X PubMedGoogle ScholarCrossref
    8.
    Nakagawa  K, Garon  EB, Seto  T,  et al; RELAY Study Investigators.  Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, phase 3 trial.   Lancet Oncol. 2019;20(12):1655-1669. doi:10.1016/S1470-2045(19)30634-5 PubMedGoogle ScholarCrossref
    9.
    Rosell  R, Dafni  U, Felip  E,  et al; BELIEF Collaborative Group.  Erlotinib and bevacizumab in patients with advanced non-small-cell lung cancer and activating EGFR mutations (BELIEF): an international, multicentre, single-arm, phase 2 trial.   Lancet Respir Med. 2017;5(5):435-444. doi:10.1016/S2213-2600(17)30129-7 PubMedGoogle ScholarCrossref
    10.
    World Medical Association. WMA Declaration of Helsinki: ethical principles for medical research involving human subjects. 64th WMA General Assembly, Fortaleza, Brazil. October 2013. Accessed November 30, 2020. https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/
    11.
    Chikaishi  Y, Kanayama  M, Taira  A,  et al.  Effect of erlotinib plus bevacizumab on brain metastases in patients with non-small cell lung cancer.   Ann Transl Med. 2018;6(20):401. doi:10.21037/atm.2018.09.33 PubMedGoogle ScholarCrossref
    12.
    Hosomi  Y, Seto  T, Nishio  M,  et al.  Erlotinib plus bevacizumab (EB) versus erlotinib alone (E) as first-line treatment for advanced non-squamous non–small-cell lung cancer (NSCLC) with activating EGFR mutation (mt): JO25567 exploratory subgroup analysis.  Abstract 420O.  Ann Oncol. 2015;26(suppl 9):ix125. doi:10.1093/annonc/mdv532.04Google ScholarCrossref
    13.
    Seto  T, Kato  T, Nishio  M,  et al.  Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study.   Lancet Oncol. 2014;15(11):1236-1244. doi:10.1016/S1470-2045(14)70381-X PubMedGoogle ScholarCrossref
    14.
    Stinchcombe  TE, Jänne  PA, Wang  X,  et al.  Effect of erlotinib plus bevacizumab vs erlotinib alone on progression-free survival in patients with advanced EGFR-mutant non-small cell lung cancer: a phase 2 randomized clinical trial.   JAMA Oncol. 2019;5(10):1448-1455. doi:10.1001/jamaoncol.2019.1847 PubMedGoogle ScholarCrossref
    15.
    Ichihara  E, Hotta  K, Nogami  N,  et al.  Phase II trial of gefitinib in combination with bevacizumab as first-line therapy for advanced non-small cell lung cancer with activating EGFR gene mutations: the Okayama Lung Cancer Study Group Trial 1001.   J Thorac Oncol. 2015;10(3):486-491. doi:10.1097/JTO.0000000000000434 PubMedGoogle ScholarCrossref
    16.
    Yu  HA, Schoenfeld  AJ, Makhnin  A,  et al.  Effect of osimertinib and bevacizumab on progression-free survival for patients with metastatic EGFR-mutant lung cancers: a phase 1/2 single-group open-label trial.   JAMA Oncol. 2020;6(7):1048-1054. doi:10.1001/jamaoncol.2020.1260 PubMedGoogle ScholarCrossref
    17.
    Paz-Ares  L, Planchard  D, Yang  JC,  et al.  CNS activity of ramucirumab in combination with osimertinib in patients with advanced T790M-positive EGFR-mutant NSCLC.   J Thorac Oncol. 2018;13(10)(suppl):S453-S454. doi:10.1016/j.jtho.2018.08.545Google ScholarCrossref
    18.
    Soria  JC, Ohe  Y, Vansteenkiste  J,  et al; FLAURA Investigators.  Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer.   N Engl J Med. 2018;378(2):113-125. doi:10.1056/NEJMoa1713137 PubMedGoogle ScholarCrossref
    19.
    Akamatsu  H, Katakami  N, Okamoto  I,  et al.  Osimertinib in Japanese patients with EGFR T790M mutation-positive advanced non-small-cell lung cancer: AURA3 trial.   Cancer Sci. 2018;109(6):1930-1938. doi:10.1111/cas.13623 PubMedGoogle ScholarCrossref
    20.
    Garon  EB, Ciuleanu  TE, Arrieta  O,  et al.  Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial.   Lancet. 2014;384(9944):665-673. doi:10.1016/S0140-6736(14)60845-X PubMedGoogle ScholarCrossref
    21.
    Bergers  G, Hanahan  D.  Modes of resistance to anti-angiogenic therapy.   Nat Rev Cancer. 2008;8(8):592-603. doi:10.1038/nrc2442 PubMedGoogle ScholarCrossref
    22.
    Itatani  Y, Kawada  K, Yamamoto  T, Sakai  Y.  Resistance to anti-angiogenic therapy in cancer-alterations to anti-VEGF pathway.   Int J Mol Sci. 2018;19(4):E1232. doi:10.3390/ijms19041232 PubMedGoogle Scholar
    23.
    Yoh  K, Hosomi  Y, Kasahara  K,  et al.  A randomized, double-blind, phase II study of ramucirumab plus docetaxel vs placebo plus docetaxel in Japanese patients with stage IV non-small cell lung cancer after disease progression on platinum-based therapy.   Lung Cancer. 2016;99:186-193. doi:10.1016/j.lungcan.2016.07.019 PubMedGoogle ScholarCrossref
    24.
    Takeda  M, Yamanaka  T, Seto  T,  et al.  Bevacizumab beyond disease progression after first-line treatment with bevacizumab plus chemotherapy in advanced nonsquamous non-small cell lung cancer (West Japan Oncology Group 5910L): an open-label, randomized, phase 2 trial.   Cancer. 2016;122(7):1050-1059. doi:10.1002/cncr.29893 PubMedGoogle ScholarCrossref
    ×