Patients and Methods
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.
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.
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.
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.
- Saunders M.
- Dische S.
- Barrett A.
- et al.
Continuous, hyperfractionated, accelerated radiotherapy (CHART) versus conventional radiotherapy in non–small cell lung cancer: mature data from the randomised multicentre trial.
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.
- Lai X.
- Gu Q.
- Zheng X.
- 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.
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.