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Phase 2 Study of Nimotuzumab in Combination With Concurrent Chemoradiotherapy in Patients With Locally Advanced Non–Small-Cell Lung Cancer

Open AccessPublished:December 26, 2020DOI:https://doi.org/10.1016/j.cllc.2020.12.012

      Abstract

      Background

      We evaluated the tolerability and efficacy of nimotuzumab, a humanized IgG1 monoclonal anti–epidermal growth factor receptor antibody, with concurrent chemoradiotherapy in patients with unresectable locally advanced non–small-cell lung cancer.

      Patients and Methods

      In this multicenter, single-arm, open-label, phase 2 trial conducted in Japan (JapicCTI-090825), patients received thoracic radiotherapy (60 Gy, 2 Gy per fraction, 6 weeks) and four 4-week cycles of chemotherapy (day 1, cisplatin 80 mg/m2; days 1 and 8, vinorelbine 20 mg/m2). Nimotuzumab 200 mg was administrated weekly for 16 weeks. The primary endpoint was treatment completion rate, defined as the percentage of patients completing 60 Gy of radiotherapy within 8 weeks, 2 cycles of chemotherapy, and at least 75% of the required nimotuzumab dose during the initial 2-cycle concurrent chemoradiotherapy period.

      Results

      Of 40 patients enrolled, 39 received the study treatment, which was well tolerated, with a completion rate of 87.2%. Thirty-eight patients completed 60 Gy of radiotherapy within 8 weeks. Infusion reaction, grade 3 or higher rash, grade 3 or higher radiation pneumonitis, or grade 4 or higher nonhematologic toxicity were not observed. The objective response rate was 69.2%. The median progression-free survival (PFS) and 5-year PFS rate were 508 days and 29.0%, respectively. The 5-year PFS rate in patients with non–squamous cell carcinoma (n = 23) was 13.7% and in patients with squamous cell carcinoma (n = 16) was 50.0%. The 5-year overall survival rate was 58.4%.

      Conclusion

      Addition of nimotuzumab to the concurrent chemoradiotherapy regimen was well tolerated and showed potential for treating patients with locally advanced non–small-cell lung cancer, particularly squamous cell carcinoma.

      Graphical abstract

      Keywords

      Introduction

      The standard treatment for stage III unresectable locally advanced non–small-cell lung cancer (NSCLC) is concurrent chemoradiotherapy (CRT), with the aim of increasing locoregional disease control and preventing the development of systemic micrometastases.
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      2nd ESMO Consensus Conference in Lung Cancer: locally advanced stage III non–small-cell lung cancer.
      ,
      • Nguyen N.P.
      • Bishop M.
      • Borok T.J.
      • et al.
      Pattern of failure following chemoradiation for locally advanced non–small cell lung cancer: potential role for stereotactic body radiotherapy.
      However, the prognosis of this disease remains poor, with high rates of locoregional recurrence and distant metastasis.
      • Yoon S.M.
      • Shaikh T.
      • Hallman M.
      Therapeutic management options for stage III non–small cell lung cancer.
      Epidermal growth factor receptor (EGFR) overexpression is implicated in tumor cell proliferation, invasion, angiogenesis, and metastasis. Radiation activates EGFR and upregulates its expression in cancer cells, which subsequently correlates with radiation resistance.
      • Schmidt-Ullrich R.K.
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      Radiation-induced proliferation of the human A431 squamous carcinoma cells is dependent on EGFR tyrosine phosphorylation.
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      Integration of EGFR inhibitors with radiochemotherapy.
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      Inverse relationship between epidermal growth factor receptor expression and radiocurability of murine carcinomas.
      Nimotuzumab is a recombinant human immunoglobulin G1 monoclonal antibody against human EGFR.
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      Humanization of a mouse monoclonal antibody that blocks the epidermal growth factor receptor: recovery of antagonistic activity.
      In nonclinical studies, nimotuzumab has demonstrated antitumor effects in various types of cancers as well as a radio-sensitizing effect in EGFR-expressing NSCLC cell lines.
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      Enhancement of the antitumor activity of ionising radiation by nimotuzumab, a humanised monoclonal antibody to the epidermal growth factor receptor, in non–small cell lung cancer cell lines of differing epidermal growth factor receptor status.
      In a previous phase 1 study in Japan, the safety and tolerability of nimotuzumab were confirmed for weekly doses of up to 400 mg.
      • Okamoto W.
      • Yoshino T.
      • Takahashi T.
      • et al.
      A phase I, pharmacokinetic and pharmacodynamic study of nimotuzumab in Japanese patients with advanced solid tumors.
      Therefore, we conducted a phase 2 study to assess the feasibility of nimotuzumab plus cisplatin and vinorelbine with concurrent thoracic radiotherapy for stage III unresectable locally advanced NSCLC.

      Patients and Methods

      Patients

      Criteria for eligibility were histologically or cytologically confirmed unresectable stage IIIA or IIIB NSCLC; age 20 to 74 years; no prior treatment for NSCLC; no prior radiotherapy to the chest; measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1); Eastern Cooperative Oncology Group performance status of 0 or 1; adequate bone marrow, liver, and renal function; and arterial oxygen pressure ≥ 70 Torr. Exclusion criteria included other active malignancies, brain metastases requiring systemic medication, and obvious pulmonary fibrosis or interstitial pneumonitis confirmed by chest computed tomography (CT). Patients were also excluded if the normal volume at or above 20 Gy (V20) was > 35% in their radiation treatment plan.
      The study protocol was approved by the independent ethics committee of each study center and carried out according to the principles of the Declaration of Helsinki and good clinical practice guidelines. All patients provided written informed consent before participation.

      Study Design and Treatment Plan

      In this open-label phase 2 study, all eligible patients received concurrent combination therapy of nimotuzumab and CRT. Chemotherapy consisted of two 4-week cycles of cisplatin 80 mg/m2 on day 1 and vinorelbine 20 mg/m2 on days 1 and 8 (concurrent CRT phase) followed by two 4-week cycles of the same regimen (consolidation chemotherapy phase). Nimotuzumab was administered intravenously at a dose of 200 mg for 30 minutes once weekly from day 1 of cycle 1 until the end of cycle 4, and was administered before chemotherapy and thoracic radiotherapy on applicable days.
      During the concurrent CRT phase, thoracic radiotherapy was initiated on day 1 of cycle 1 of chemotherapy at 2.0 Gy per fraction, and administered 5 times per week for 6 weeks (total 30 times) using a linear accelerator photon beam of 6 to 10 MV. The total dose was 60 Gy. Treatment planning and lung heterogeneity corrections for all patients were based on 3D CT scanning, and intensity-modulated radiotherapy was not used.
      Gross tumor volume was defined as the primary tumor plus positive lymph nodes ≥ 1 cm (short axis) revealed by CT or fluorodeoxyglucose-positron emission tomography scan (not mandatory). The initial 40 Gy fractions were delivered to clinical target volume (CTV)1, which included the gross tumor volume (plus a margin of approximately 0.5 cm) and the regional nodes (ipsilateral hilum and mediastinal nodal areas from the paratracheal [no. 2] to the subcarinal [no. 7] lymph nodes, but not the contralateral hilum). A booster dose of 20 Gy was delivered to a reduced area defined as CTV2, which encompassed the gross tumor volume plus a margin of approximately 0.5 cm and excluded the spinal cord and normal lung using the oblique opposing method. The appropriate planning target volume margin (≥0.5 cm) and leaf margin were added for CTV1 and CTV2.

      Evaluation of Efficacy and Safety

      Tumor response was evaluated in accordance with RECIST 1.1, and antitumor activity was evaluated after cycles 2 and 4. For patients without disease progression at the end of the study treatment, posttreatment follow-up observation was performed for up to 5 years after the day of registration or until the occurrence of disease progression, whichever occurred first.
      Progression-free survival (PFS) was defined as the time from registration to the date of death from any cause, the date progressive disease was confirmed by radiologic assessment, or the date clinical progressive disease was confirmed, whichever occurred first. Overall survival (OS) was defined as the time from registration to death from any cause. Patients were considered to have completed treatment if they had received 60 Gy of radiotherapy within 8 weeks, 2 treatment cycles of chemotherapy (vinorelbine could be omitted on day 8), and at least 75% of the required dose of nimotuzumab during the first 2 treatment cycles. The presence of antidrug antibodies was determined by enzyme-linked immunosorbent assay.
      Throughout the treatment period, physical examination, vital signs, hematologic assessment, and serum chemistry were performed weekly, and chest X-ray was performed every 2 weeks. Toxicities were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE), version 3.0.

      Biomarker Analysis

      EGFR protein expression levels in tumor tissues were measured by immunohistochemistry. EGFR gene amplification in tumor tissues was measured by fluorescence in-situ hybridization. EGFR gene mutations were detected using PCR on genomic DNA extracted from tumor tissues.

      Statistical Analysis

      The primary endpoint of this study was the rate of treatment completion, which was calculated in the full analysis set as follows: (number of subjects who completed treatment/number of subjects who received any study treatment) × 100.
      Secondary endpoints were objective response rate, disease control rate, PFS, OS, PFS rate, OS rate, and safety profile. The Kaplan-Meier method was used to estimate PFS and OS, and 95% confidence intervals (CIs) were calculated using the method of Brookmeyer and Crowley. The log-rank test was used for comparison between squamous cell carcinoma (Sq) and non–squamous cell carcinoma (non-Sq). Adverse events were summarized using the Medical Dictionary for Regulatory Activities (MedDRA), version 14.0.

      Results

      Patient Characteristics

      Between June 2009 and May 2010, a total of 40 patients were enrolled at 7 institutions in Japan, and 39 eligible patients received the study treatment. For one patient, the study drug was not administered because the patient was found to be ineligible after enrollment but before treatment. Table 1 shows the patient characteristics; 34 patients (87%) were male, and the median age was 62 years. Sixteen patients (41%) had Sq, 14 patients (36%) had adenocarcinoma, and 9 patients (23%) had other forms of NSCLC.
      Table 1Characteristics of 39 Patients
      CharacteristicVariableN%
      SexMale3487
      Female513
      Age<65 years2769
      ≥65 years1231
      HistologySquamous1641
      Adenocarcinoma1436
      Other, unknown923
      Clinical stage (UICC)IIIA2154
      IIIB1846
      Lymph node metastasisN0, N1410
      N22769
      N3821
      Primary siteUpper3282
      Middle, lower718
      ECOG PS02564
      11436
      Smoking historyNever smoker25
      Smoker3795
      PETYes2667
      No1333
      V20≤20%1436
      >20%-25%718
      >25%-30%718
      >30%-35%1128
      Abbreviations: ECOG PS = Eastern Cooperative Oncology Group Performance Status; PET = positron emission tomography; UICC = Union for International Cancer Control; V20 = percentage of lung volume (minus tumor volume) receiving radiation dose of ≥ 20 Gy.

      Treatment of Eligible Patients

      The treatment completion rate was 87.2% (34/39). Five patients could not complete the study treatment: 1 patient did not receive 60 Gy of radiotherapy within 8 weeks, 3 patients did not receive 75% or more of the required dose of nimotuzumab during the first 2 treatment cycles, and 1 patient did not receive the first 2 treatment cycles of chemotherapy and nimotuzumab.

      Safety

      Adverse events related to study treatment and reported in > 10% of participants are listed in Table 2. The most common any-grade adverse events were neutrophil count decreased (97.4%), white blood cell count decreased (97.4%), radiation esophagitis (89.7%), nausea (84.6%), decreased appetite (82.1%), and radiation pneumonitis (82.1%). The most common study treatment-related adverse events of grade 2 or higher were neutrophil count decreased (97.4%), white blood cell count decreased (97.4%), anemia (56.4%), radiation esophagitis (51.3%), radiation pneumonitis (30.8%), lymphocyte count decreased (23.1%), nausea (23.1%), and decreased appetite (23.1%). No patients had rash of grade 3 or higher, but treatment-related grade 2 and grade 1 rash were reported in 2 (5.1%) and 8 patients (20.5%), respectively. Furthermore, no patients had radiation pneumonitis of grade 3 or higher, but treatment-related grade 2 and grade 1 radiation pneumonitis were reported in 12 (30.8%) and 20 patients (51.3%), respectively. Infusion-related reaction or drug-induced interstitial pneumonia and pulmonary fibrosis was not observed. None of the 38 patients tested positive for antidrug antibodies.
      Table 2Adverse Events Related to Study Treatment Reported in > 10% of 39 Study Participants
      Preferred TermAny GradeGrade 2 or Higher
      N%N%
      Hematologic adverse events
       Neutrophil count decreased3897.43897.4
       White blood cell count decreased3897.43897.4
       Anemia2359.02256.4
       Platelet count decreased1230.825.1
       Lymphocyte count decreased923.1923.1
       Vasculitis820.5410.3
       Febrile neutropenia615.4615.4
       Hemoglobin decreased615.4615.4
      Nonhematologic adverse events
       Radiation esophagitis3589.72051.3
       Nausea3384.6923.1
       Decreased appetite3282.1923.1
       Radiation pneumonitis3282.11230.8
       Constipation3076.9717.9
       Radiation skin injury2666.712.6
       Hiccups1641.037.7
       Fatigue1435.912.6
       Vomiting1435.925.1
       Malaise1333.300
       Pyrexia1230.800
       Renal impairment1230.8512.8
       Rash1025.625.1
       Stomatitis1025.625.1
       Dysgeusia923.1410.3
       Diarrhea615.412.6
       Epistaxis615.400
       Alopecia512.800
       Blood creatinine increased512.800
       Blood magnesium decreased512.812.6
       Blood potassium increased512.837.7
       Insomnia512.800
       Neuropathy peripheral512.800
       Abdominal discomfort410.300
       Headache410.300
       Hypomagnesaemia410.312.6
       Pruritus410.312.6

      Efficacy

      The objective response rate for all patients was 69.2% (95% CI, 52.4-83.0) (Table 3). Complete response was observed in 4 patients with Sq. Figure 1 shows OS and PFS curves for the 39 patients enrolled onto the study. The median survival time was not reached. The 5-year OS rate was 58.4%. The median PFS time was 508 days, and the 5-year PFS rate was 29.0%. Figure 2 shows OS and PFS for patients with Sq and non-Sq. The median survival time was not reached for patients with Sq (95% CI, 953.0 to not reached) or with non-Sq (95% CI, 636.0 to not reached). The P value by log-rank test was .3458. The median PFS was not reached for patients with Sq (95% CI, 332.0 to not reached), but was 337.0 days (95% CI, 232.0-615.0) for patients with non-Sq. The P value by log-rank test was .0151. The 5-year OS rate was 68.8% in patients with Sq and 51.0% in patients with non-Sq, and the 5-year PFS rate was 50.0% in patients with Sq and 13.7% in patients with non-Sq. No correlation was observed between efficacy and EGFR protein expression or gene amplification level.
      Table 3Efficacy Results
      CharacteristicVariableN (%) [95% CI] for:
      All Patients (N = 39)Sq (N = 16)Non-Sq (N = 23)
      OS3 year25 (66.4) [49.2, 78.9]12 (75.0) [46.3, 89.8]13 (60.3) [37.5, 77.0]
      5 year22 (58.4) [41.3, 72.1]11 (68.8) [40.5, 85.6]11 (51.0) [29.1, 69.3]
      Median (days)NE [1088, NE]NE [953, NE]NE [636, NE]
      Log-rank test P = .3458
      PFS3 year12 (31.6) [17.8, 46.4]8 (50.0) [24.5, 71.0]4 (18.2) [5.7, 36.4]
      5 year9 (29.0) [15.7, 43.7]6 (50.0) [24.5, 71.0]3 (13.7) [3.4, 30.9]
      Median (days)508 [302, 1033]NE [332, NE]337 [232, 615]
      Log-rank test P = .0151
      Best overall responseCR4 (10.3%)4 (25.0%)0
      PR23 (59.0%)8 (50.0%)15 (65.2%)
      SD10 (25.6%)3 (18.8%)7 (30.4%)
      PD2 (5.1%)1 (6.3%)1 (4.3%)
      ORR (%)69.2 [52.4, 83.0]75.0 [47.6, 92.7]65.2 [42.7, 83.6]
      DCR (%)94.9 [82.7, 99.4]93.8 [69.8, 99.8]95.7 [78.1, 99.9]
      Abbreviations: CI = confidence interval; CR = complete response; DCR = disease control rate (CR + PR + SD); NE = not evaluable; Non-Sq = non–squamous cell carcinoma; ORR = objective response rate (CR + PR); OS = overall survival; PD = progressive disease; PFS = progression-free survival; PR = partial response; SD = stable disease; Sq = squamous cell carcinoma.
      Figure thumbnail gr1
      Figure 1Overall Survival (A) and Progression-free Survival (B) in All Patients
      Abbreviations: MST = median survival time; PFS = progression-free survival.
      Figure thumbnail gr2
      Figure 2Overall Survival (A) and Progression-free Survival (B) Stratified by Squamous Cell Versus Non–squamous Cell Carcinoma
      Abbreviations: Non-Sq = non–squamous cell carcinoma; Sq = squamous cell carcinoma.

      First Relapse Pattern by Histology

      Table 4 shows the first relapse pattern organized by histologic type. Relapse was observed in a total of 27 patients (69.2%). Six patients (15.4%) had a first recurrence inside the radiation field only, 2 patients (5.1%) experienced a first recurrence both inside and outside the radiation field, and 19 patients (48.7%) had a first recurrence outside the radiation field only. In patients with Sq, 8 patients (50.0%) experienced relapse, of whom 4 patients (25.0%) had a first recurrence inside the radiation field only and 4 patients (25.0%) had a first recurrence outside the radiation field only. In patients with non-Sq, 19 patients (82.6%) experienced relapse, of whom 2 patients (8.7%) had a first recurrence inside the radiation field only, 2 patients (8.7%) had a first recurrence both inside and outside the radiation field, and 15 patients (65.2%) had a first recurrence outside the radiation field only.
      Table 4First Relapse Pattern by Histology
      Relapse PatternAll Patients (N = 39)Sq (N = 16)Non-Sq (N = 23)
      N%N%N%
      Not relapsed1230.8850.0417.4
      Relapsed2769.2850.01982.6
       In field615.4425.028.7
       In and out field25.10028.7
       Out field1948.7425.01565.2
      Abbreviations: Non-Sq = non–squamous cell carcinoma; Sq = squamous cell carcinoma.

      Biomarker Analysis

      Immunohistochemistry was used to measure EGFR protein expression in 20 samples: 5 had scores of 0, 3 scored 1+, and 6 each had scores of 2+ and 3+. EGFR protein expression was positive in 9 (90.0%) of 10 patients with Sq and 2 (40.0%) of 5 patients with adenocarcinoma. Eighteen tumor samples were assessed by fluorescence in-situ hybridization: 5 had gene amplification or high polysomy, and 13 did not. EGFR gene amplification or high polysomy was detected in 3 (30.0%) of 10 patients with Sq and 1 (33.3%) of 3 patients with adenocarcinoma. Of the 20 patients assessed for EGFR exon 19 deletion and T790M and L858R mutations, 17 carried wild-type EGFR, 2 had mutations (exon 19 deletion), and the data of 1 were not analyzable.

      Discussion

      This study confirmed the feasibility of combining nimotuzumab with CRT in NSCLC patients, with a treatment completion rate of 87.2%, median PFS time of 508 days, and 5-year OS rate of 58.4%. Our results were comparable with those reported in previous trials of CRT in combination with cisplatin and vinorelbine,
      • Sekine I.
      • Nokihara H.
      • Sumi M.
      • et al.
      Docetaxel consolidation therapy following cisplatin, vinorelbine, and concurrent thoracic radiotherapy in patients with unresectable stage III non–small cell lung cancer.
      ,
      • Naito Y.
      • Kubota K.
      • Nihei K.
      • et al.
      Concurrent chemoradiotherapy with cisplatin and vinorelbine for stage III non–small cell lung cancer.
      and indicate that nimotuzumab plus cisplatin and vinorelbine with concurrent thoracic radiotherapy is a feasible treatment strategy for stage III unresectable locally advanced NSCLC.
      In this study, longer PFS was observed in patients with Sq compared to non-Sq (P = .0151), although a statistically significant difference was not observed in OS. Several treatment options for non-Sq are available, including tyrosine kinase inhibitors of EGFR and anaplastic lymphoma kinase, which may prolong survival time in patients with this histologic subtype of lung cancer. In general, adenocarcinoma and large-cell carcinoma, which account for most cases of non-Sq, are likely to develop distant metastasis.
      • Cox J.D.
      • Scott C.B.
      • Byhardt R.W.
      • et al.
      Addition of chemotherapy to radiation therapy alters failure patterns by cell type within non–small cell carcinoma of lung (NSCCL): analysis of radiation therapy oncology group (RTOG) trials.
      In this study, 15 patients (65.2% of patients with non-Sq) had a first recurrence outside the radiation field compared to 4 patients (25.0%) with Sq. In a comparison of continuous hyperfractionated accelerated radiotherapy and conventional fractionation radiotherapy, the former significantly improved the local control rate and survival rate in patients with Sq, but no treatment benefits were observed in patients with non-Sq.
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      The expression levels of EGFR, which is the target of nimotuzumab, are particularly high in Sq.
      • Ito T.
      • Ishii G.
      • Nagai K.
      • et al.
      Low podoplanin expression of tumor cells predicts poor prognosis in pathological stage IB squamous cell carcinoma of the lung, tissue microarray analysis of 136 patients using 24 antibodies.
      In our study, PFS in patients with Sq was longer than that of patients with non-Sq, possibly because of improved local control inside the radiation field by nimotuzumab. Of note, nimotuzumab in combination with CRT has also been reported to confer a survival benefit to patients with advanced esophageal Sq.
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      • Gu Q.
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      • et al.
      Combined nimotuzumab with chemoradiotherapy in patients with locally advanced or metastatic esophageal squamous cell carcinoma: a retrospective study.
      The limitations of this study include the open-label design and the small number of patients enrolled. To validate our preliminary results, randomized controlled studies in larger patient populations are required.

      Conclusion

      Nimotuzumab can be used in combination with CRT without potentiating its toxicity. This combination may potentially improve survival, particularly in patients with Sq.

      Clinical Practice Points

      • Despite the use of concurrent chemoradiotherapy, which aims to control locoregional disease and prevent metastasis, the prognosis for stage III unresectable locally advanced non–small-cell lung cancer (NSCLC) remains poor. This may be in part because radiotherapy promotes epidermal growth factor receptor (EGFR), resulting in resistance to radiotherapy.
      • We found that combining the EGFR inhibitor nimotuzumab with cisplatin/vinorelbine and thoracic radiotherapy was well tolerated in patients with locally advanced unresectable NSCLC, with 87.2% of the 39 patients who began treatment completing the full course and 38 patients receiving 60 Gy of radiotherapy in 8 weeks. The objective response rate was 69.2%, and median progression-free survival (PFS) and 5-year PFS rate were 508 days and 29.0%, respectively. The 5-year PFS was considerably higher in patients with squamous cell versus non–squamous cell NSCLC.
      • The high completion rate indicates that the combination was well tolerated, and the efficacy results show that it may potentially improve survival, particularly in patients with squamous cell NSCLC.

      Disclosure

      This work was supported by Daiichi Sankyo Co Ltd. The sponsor played a role in the study design; in the collection, analysis, and interpretation of data; and in the writing of the report.
      N.Y. received personal fees from Daiichi Sankyo relevant to the present work; outside the submitted work: grants and personal fees from MSD , Eli Lilly, Chugai Pharmaceutical , and Nippon Boehringer Ingelheim ; and personal fees from AstraZeneca, Ono Pharmaceutical, Novartis Pharma, Pfizer, and Bristol-Myers Squibb. H.H. received personal fees from Daiichi Sankyo relevant to the present work; outside the submitted work: personal fees from Daiichi Sankyo, AstraZeneca, Brainlab, and Chugai Pharmaceutical; and grants from the Japan Agency for Medical Research and Development , and The National Cancer Center Research and Development Fund. I.O. received grants and personal fees from AstraZeneca , Taiho Pharmaceutical , Nippon Boehringer Ingelheim , Ono Pharmaceutical , MSD Oncology , Eli Lilly , Bristol-Myers Squibb , and Chugai Pharmaceutical; grants from Astellas Pharma and Novartis Pharma ; and personal fees from Pfizer outside the submitted work. M.S. received grants and personal fees from Chugai Pharmaceutical , Eli Lilly , Pfizer , AstraZeneca , Nippon Boehringer Ingelheim , Bristol-Myers Squibb , Ono Pharmaceutical , Novartis Pharm , and MSD; grants from Astellas Pharma and Takeda Pharmaceutical ; and personal fees from Taiho Pharmaceutical relevant to the present work. M.N. received grants and personal fees from Ono Pharmaceutical , Bristol-Myers Squibb , Pfizer , Chugai Pharmaceutical , Eli Lilly , Taiho Pharmaceutical , AstraZeneca , Nippon Boehringer Ingelheim , MSD , and Novartis Pharma ; grants from Astellas Pharma ; and personal fees from Daiichi Sankyo and Merck Serono outside the submitted work. T.K. received research funding from Daiichi Sankyo relevant to the present work. K.T. received a grant from Daiichi Sankyo relevant to the present work; outside the submitted work: grants and personal fees from Nippon Boehringer Ingelheim , Bristol-Myers Squibb , Chugai Pharmaceutical , Eli Lilly , Ono Pharmaceutical , and Pfizer ; grants from AbbVie , Astellas Pharma , Merck Serono , and MSD ; and personal fees from AstraZeneca, Daiichi Sankyo, Kyowa Kirin, Novartis Pharma, and Taiho Pharmaceutical. M.T. received personal fees from Daiichi Sankyo relevant to the present work; outside the submitted work: grant from Japan Agency for Medical Research and Development . T.S. received a grant from Daiichi Sankyo relevant to the present work. Outside the submitted work: grants and personal fees from Astellas Pharma , AstraZeneca , Chugai Pharmaceutical , Daiichi Sankyo , Eli Lilly , Kissei Pharmaceutical , MSD , Nippon Boehringer Ingelheim , Pfizer , and Yakult Honsha ; grants from Bayer Yakuhin , Eisai , Merck Serono , Novartis Pharma , and Verastem ; and personal fees from Bristol-Myers Squibb, Kyowa Kirin, Mochida Pharmaceutical, Nippon Kayaku, Ono Pharmaceutical, Roche Singapore, Sanofi, Showa Yakuhin, Taiho Pharmaceutical, and Takeda Pharmaceutical. K.N. received grants and personal fees from AstraZeneca , MSD , Chugai Pharmaceutical , Eli Lilly , Taiho Pharmaceutical , Ono Pharmaceutical , Nippon Boehringer Ingelheim , Bristol-Myers Squibb , and Pfizer ; and grants from Daiichi Sankyo and Takeda Pharmaceutical relevant to the present work; outside the submitted work: grants and personal fees from Astellas Pharma , Novartis Pharma , and Kyowa Kirin ; grants from A2 Healthcare Corp , inVentiv Health Japan , AbbVie , Quintiles , ICON Japan, EP-CRSU , Gritstone Oncology , Linical , Eisai , Parexel International , EPS International , Yakult Honsha , Otsuka Pharmaceutical , AC Medical , Merck Serono , EPS Associates , Japan Clinical Research Operations , PPD-SNBL , and Covance ; and personal fees from SymBio Pharmaceuticals, EPS Holdings, Showa Yakuhin Kako, Ayumi Pharmaceutical Corporation, and Kissei Pharmaceutical. H.T. and Y.K. are employees of Daiichi Sankyo. The other authors have stated that they have no conflict of interest.

      Acknowledgments

      We thank the patients, their families, the investigators, and their team members for their participation in this trial. We also thank the following board members: individual efficacy and safety evaluation committee, Keiichi Nagao, Masahiko Shibuya, and Kenji Eguchi; medical advisors, Yutaka Ariyoshi and Masahiro Fukuoka; and molecular biology advisor, Kazuto Nishio. We would like to thank Susan Cottrell, PhD, and Clare Cox, PhD, of Edanz Medical Writing for editorial support.

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