Randomized phase II study of chemoradiotherapy with cisplatin + S-1 versus cisplatin + pemetrexed for locally advanced non-squamous non-small cell lung cancer: SPECTRA study

Journal Pre-proof Randomized phase II study of chemoradiotherapy with cisplatin + S-1 versus cisplatin + pemetrexed for locally advanced non-squamous non-small cell lung cancer: SPECTRA study Seiji Niho (Conceptualization) (Investigation) (Resources) (Writing original draft) (Writing - review and editing) (Project administration) (Funding acquisition), Tatsuya Yoshida (Conceptualization) (Resources) (Writing - review and editing), Tetsuo Akimoto (Investigation) (Writing - original draft) (Writing - review and editing), Kentaro Sakamaki (Methodology) (Formal analysis) (Visualization) (Writing - review and editing), Akira Ono (Resources) (Writing review and editing), Takashi Seto (Resources) (Writing - review and editing), Makoto Nishio (Resources) (Writing - review and editing), Noboru Yamamoto (Resources) (Writing - review and editing), Toyoaki Hida (Resources) (Writing - review and editing), Hiroaki Okamoto (Resources) (Writing - review and editing), Takayasu Kurata (Resources) (Writing - review and editing), Miyako Satouchi (Resources) (Writing - review and editing), Koichi Goto (Resources) (Writing - review and editing), Takeharu Yamanaka (Methodology) (Formal analysis) (Writing - review and editing), Yuichiro Ohe (Conceptualization) (Resources) (Writing - review and editing) (Supervision)

PII:

S0169-5002(20)30019-2

DOI:

https://doi.org/10.1016/j.lungcan.2020.01.008

Reference:

LUNG 6243

To appear in:

Lung Cancer

Received Date:

9 October 2019

Revised Date:

10 December 2019

Accepted Date:

9 January 2020

Please cite this article as: Niho S, Yoshida T, Akimoto T, Sakamaki K, Ono A, Seto T, Nishio M, Yamamoto N, Hida T, Okamoto H, Kurata T, Satouchi M, Goto K, Yamanaka T, Ohe Y, Randomized phase II study of chemoradiotherapy with cisplatin + S-1 versus cisplatin + pemetrexed for locally advanced non-squamous non-small cell lung cancer: SPECTRA study, Lung Cancer (2020), doi: https://doi.org/10.1016/j.lungcan.2020.01.008

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier.

Randomized phase II study of chemoradiotherapy with cisplatin + S-1 versus cisplatin + pemetrexed

for locally advanced non-squamous non-small cell lung cancer: SPECTRA study.

Seiji Niho a,* [email protected], Tatsuya Yoshida b, Tetsuo Akimoto c, Kentaro Sakamaki d, Akira

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Ono e, Takashi Seto f, Makoto Nishio g, Noboru Yamamoto b, Toyoaki Hida h, Hiroaki Okamoto i, Takayasu Kurata j, Miyako Satouchi k, Koichi Goto a, Takeharu Yamanaka d, Yuichiro Ohe b

Department of Thoracic Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha,

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a

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Kashiwa, 277-8577, Japan.

Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.

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Department of Radiation Oncology, National Cancer Center Hospital East, Kashiwa, Japan.

d

Department of Biostatistics, Yokohama City University School of Medicine, Yokohama, Japan.

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Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan.

f

Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center,

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b

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Fukuoka, Japan. g

Department of Thoracic Medical Oncology, The Cancer Institute Hospital of Japanese Foundation

for Cancer Research, Tokyo, Japan. h

Department of Thoracic Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.

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i

Department of Respiratory Medicine and Medical Oncology, Yokohama Municipal Citizen's

Hospital, Yokohama, Japan.

j Department of Thoracic Oncology, Kansai Medical University Hospital, Osaka, Japan.

Department of Thoracic Oncology, Hyogo Cancer Center, Japan.

*Corresponding

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author: Address for correspondence: Seiji Niho, MD, Department of Thoracic

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Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, 277-8577, Japan.

Highlights

S-1 is an oral agent composed of tegafur, dihydroxypyridine, and potassium oxonate.

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Pemetrexed (PEM) is a key drug to treat non-squamous non-small lung cancer.

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We compared cisplatin+S-1 and cisplatin+PEM combined with thoracic radiotherapy.

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The 2-year progression-free survival rate was higher in the cisplatin+S-1 arm.

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Both treatments were safe, with manageable toxicities.

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Abstract Objectives: SPECTRA is a multicenter, randomized phase II study of chemotherapy with cisplatin 2

(CDDP) plus S-1 versus CDDP plus pemetrexed (PEM) in combination with thoracic radiotherapy

(TRT) for locally advanced non-squamous non-small cell lung cancer, in order to determine which of

these two regimens might be preferable for comparison with standard therapies in a future phase III

study.

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Materials and methods: Patients were randomly assigned to receive CDDP+S-1 (CDDP 60mg/m2

on day 1 and S-1 80mg/m2 on days 1-14, every 4 weeks, up to 4 cycles) or CDDP+PEM (CDDP 75

mg/m2 + PEM 500 mg/m2 on day 1, every 3 weeks, up to 4 cycles) combined with TRT (60 Gy in 30

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fractions). The primary endpoint was the 2-year progression-free survival (PFS) rate. The sample

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size had been set at 100 patients.

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Results: A total of 102 patients were randomized to receive CDDP+S-1 or CDDP+PEM (CDDP+S1, n=52; CDDP+PEM, n=50) between January 2013 and October 2016. The results in the CDDP+S1

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group and CDDP+PEM group were as follows: completion rates of TRT (60Gy)/chemotherapy (4

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cycles) was 92%/73% and 98%/86%, respectively; the response rates were 60% and 64%,

respectively; median PFS after a median follow-up of 32.1 months, 12.7/13.8 months (hazard ratio

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[HR] = 1.16; 95% confidence interval [CI], 0.73 to 1.84); 2-year PFS rate, 36.5% (95% CI, 23.5 to

49.6)/32.1% (95%CI, 18.9 to 45.4); median OS, 48.3/59.1 months (HR=1.05; 95%CI, 0.58 to 1.90);

2-year OS rate, 69.2% (95%CI, 56.7 to 81.8)/66.4% (95%CI, 53.0 to 79.9); Grade 3 toxicities:

febrile neutropenia (12%/2%), anorexia (8%/16%), diarrhea (8%/0%), esophagitis (6%/8%), and

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neutropenia (35%/50%); Grade 2 or worse radiation pneumonitis, 15% (8 patients)/4% (2 patients).

Conclusion: The 2-year PFS rate in the CDDP+S-1 arm was higher than that in the CDDP+PEM arm. Both treatments were safe, with manageable toxicities.

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Keywords: cisplatin; S-1; pemetrexed; chemoradiotherapy; locally advanced non-squamous non-

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small cell lung cancer.

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1. Introduction

Lung cancer is a leading cause of cancer-related death worldwide. Non-small cell lung

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cancer (NSCLC) accounts for approximately 85% of all cases of lung cancer. Among all cases of

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NSCLC, about two-thirds are already advanced and inoperable at the time of diagnosis. Concurrent

chemoradiotherapy is the standard treatment for patients with unresectable locally advanced

NSCLC. Chemotherapy at full systemic doses combined with thoracic radiotherapy (TRT) is

employed to control the micro-metastases in such a condition.

Since 2000, two randomized phase III studies have been conducted in Japan for patients 4

with unresectable locally advanced NSCLC. The WJTOG 0105 study compared a so-called second-

generation regimen (cisplatin (CDDP) + vindesine + mitomycin) with two third-generation regimens

(weekly carboplatin + irinotecan and weekly carboplatin + paclitaxel) for use with concurrent TRT.

Non-inferiority of the third-generation regimens relative to the second-generation regimen, in terms

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of overall survival (OS), could not be demonstrated in this study; however, the survival curves

closely overlapped. Weekly carboplatin + paclitaxel combined with TRT was established as the

standard regimen among the three regimens, because of its favorable toxicity profile.[1] The OLSCG

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007 study compared chemotherapy with CDDP + vindesine + mitomycin versus CDDP + docetaxel

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in combination with concurrent TRT. The two-year survival rate was higher in the CDDP +

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docetaxel arm (60.3%) than in the CDDP + vindesine + mitomycin arm (48.1%), suggesting that

CDDP + docetaxel could also serve as a standard chemotherapy regimen for administration in

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combination with TRT.[2]

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S-1 is an oral anticancer agent composed of tegafur, 5-chloro-2, 4-dihydroxypyridine, and

potassium oxonate. A phase III trial demonstrated that S-1 plus CDDP was non-inferior in terms of

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the OS, as compared to docetaxel plus CDDP, in patients with stage IIIB, IV or recurrent NSCLC.[3]

The radiosensitizing effect of S-1 has been shown in preclinical models.[4, 5] Moreover, gimeracil, a

component of S-1, has been reported to inhibit the rapid repair of X-ray-induced DNA damage in

tumors using human cancer xenograft models.[6] Six previous phase II studies have demonstrated

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that full doses of CDDP plus S-1 can be safely combined with concurrent TRT to yield promising

treatment outcomes: the median progression-free survival (PFS) period ranged from 9 to 20 months,

and the 2-year survival rates ranged from 51% to 76%.[7-12]

Pemetrexed (PEM) is one of the key chemotherapeutic drugs for the treatment of non-

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squamous NSCLC.[13, 14] CDDP plus PEM is a standard chemotherapy regimen for patients with

metastatic non-squamous NSCLC.[15-18]. A previous dose-escalation study of TRT combined with

CDDP plus PEM, followed by PEM consolidation therapy in Japanese patients with locally

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advanced non-squamous NSCLC demonstrated the feasibility of CDDP plus PEM chemotherapy

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with concurrent TRT at a total dose of 66 Gy. However, grade 2 radiation pneumonitis was observed

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in 7 of 18 patients (39%) and one patient even developed grade 3 radiation pneumonitis.[19]

The PROCLAIM study was a global phase III study comparing CDDP plus PEM (3

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cycles) with concurrent TRT followed by PEM consolidation (3 cycles) and CDDP plus etoposide (2

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cycles) with concurrent TRT followed by 2 cycles of consolidation platinum-based doublet chemotherapy in patients with locally advanced non-squamous NSCLC. The patients were enrolled

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between 2008 and 2012. [20] When we planned the present study, the results of the PROCLAIM

study had not been reported.

Based on the above background, we conducted a randomized phase II study to evaluate

safety and efficacy of chemotherapy with CDDP plus S-1 versus CDDP plus PEM with concurrent

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TRT in patients with unresectable locally advanced non-squamous NSCLC, in order to determine

which of these two regimens might be preferable for comparison with standard therapies, such as

weekly CBDCA plus paclitaxel, in a future phase III study.

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2. Patients and methods

2.1. Patients

The major eligibility criteria for inclusion in this study were: Patients diagnosed as having

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unresectable stage III (according to the Union Internationale Contre le Cancer [UICC] seventh TNM

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edition), aged 20 to 74 years, with an ECOG performance status of 0 or 1. Other criteria included a

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PaO2 in room air of ≥ 70 torr or an SpO2 in room air of ≥ 93%, and adequate organ functions (total bilirubin ≤ 1.5 mg/dL, AST and ALT ≤ 100 IU/L, serum creatinine ≤ 1.5 mg/dL, creatinine clearance

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estimated by Cockcroft-Gault equation ≥ 45 mL/min, leukocyte count ≥ 3,000 /mm3, neutrophil

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count ≥ 1,500 /mm3, hemoglobin ≥ 9.0 g/dL, and platelet count ≥ 100,000 /mm3).

The key exclusion criteria were, active concomitant malignancy; active infection; paralytic

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ileus, vomiting, or gastrointestinal obstruction; uncontrolled peptic ulcer; uncontrolled diabetes

mellitus; interstitial pneumonia as diagnosed by computed tomography (CT) of the chest; severe

drug allergy; concurrent use of phenytoin, warfarin, or flucytosine. All patients were required to

provide written informed consent prior to participation in the study, and the protocol was approved

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by the institutional review board (2012-121 at National Cancer Center). Driver oncogene status, such

as EGFR gene mutation, ALK or ROS-1 rearrangement, was not restricted.

2.2. Study Design and Treatment

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In this multicenter, open-label, phase II study, patients were randomly assigned, in a 1:1

ratio, to receive S-1 plus CDDP with concurrent TRT (CS arm) or PEM plus CDDP with concurrent

TRT (CP arm). The randomization was stratified according to the disease stage (IIIA or IIIB), tumor

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histology (adenocarcinoma or non-adenocarcinoma), patient gender, and institution. The CS arm

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received 4 cycles of intravenous CDDP at 60 mg/m2 on day 1 plus oral S-1 at the dose of 40 mg/m2

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twice daily on days 1-14 every 4 weeks. The actual dose of S-1 was selected as follows: patients with a body surface area (BSA) of o1.25m2 received 80 mg daily, those with a BSA of 1.25m2 or

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more but less than1.5m2 received 100 mg daily, and those with a BSA of 1.5m2 or more received 120

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mg daily. The CP arm received 4 cycles of intravenous CDDP at 75 mg/m2 and intravenous PEM at 500 mg/m2 on day 1 every 3 weeks; both treatment arms received concurrent TRT (Figure 1). All the

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patients in the CP arm received premedication, including folic acid and vitamin B12.

Concurrent TRT was started on day 1 of the first cycle; the targeted total dose was 60 Gy,

administered in 30 fractions, at the dose of 2 Gy/fraction daily on 5 days of the week. The overall

treatment time of radiotherapy was 42 days, but could be extended up to 63 days. For treatment

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planning, three-dimensional CT simulation was used, and in principle, 3-dimensional conformal

radiotherapy (3DCRT) was employed as a technique of radiotherapy. Patients receiving intensity-

modulated radiation therapy (IMRT) were excluded from this study, because IMRT was not routinely

used as a radiotherapeutic modality for local advanced lung cancer at the time of planning of this

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clinical trial in Japan. The gross tumor volume (GTV primary) was defined as the volume of the

primary tumor, as determined on CT images, plus any metastatic lymph nodes (GTV nodes)

measuring 1 cm or greater in its short axis. For this trial, the GTV and the clinical target volume

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(CTV primary or CTV nodes) for the primary tumor and metastatic lymph nodes were regarded as

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being the same. Elective nodal regions, including the ipsilateral hilar, paratracheal, and subcarinal

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nodal stations were included as CTV, subclinical. The planning target volume (PTV primary; PTV

nodes; PTV subclinical) was defined by adding margins to the CTVs at the discretion of the

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radiation oncologist in charge (typically, 0.5-1 cm for the lateral margins and 1-2 cm for the cranio-

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caudal margins, depending on the respiratory motions and patient fixation). After elective nodal

irradiation, including of the PTV primary, PTV nodes and PTV subclinical at the dose of 40Gy, the

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radiation field was boosted to PTV primary and PTV nodes at the dose of 20 Gy. A dose of 60 Gy

was prescribed at the center of the PTV. Pencil beam convolution (PBC) was used as the algorithm

for the dose calculations, and no tissue heterogeneity correction was used in this study. Based on the

Dose-Volume Histogram (DVH), the maximum dose (Dmax) to the spinal cord (less than 44Gy), the

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mean and Dmax to the heart and the V20 of the normal lung (V20≦35%) were also calculated, in addition to target coverage of the PTV.

The radiotherapy data for all patients were submitted to the Study Secretariat for

Radiotherapy for quality assurance. The submitted data included the pretreatment images (contrast-

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enhanced chest CT and PET images, if available) and radiotherapy data (treatment planning CT

images with target delineation, beam data, dose distribution, and DVH).

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2.3. Evaluations.

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Pretreatment evaluations consisted of a complete medical history, determination of the

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performance status, physical examination, hematologic and biochemical profiling, measurement of

the peripheral arterial oxygen saturation or arterial blood gas profile, chest X-ray, CT of the chest

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and abdomen, magnetic resonance imaging or CT of the whole brain, and a bone scan or PET scan.

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For the toxicity assessment, blood samples were obtained at least once a week during the

concurrent chemoradiotherapy and once every two weeks during the consolidation chemotherapy.

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Plain chest radiographs were also obtained weekly during the treatment. Chest CT was performed

within 4 weeks of completion of the TRT, at 4 to 8 weeks thereafter, every 3 months thereafter during the first year after the start of treatment, and every 6 months from the 13th to the 24th month

after the start of treatment.

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The RECIST guideline, version 1.1, was used to evaluate tumor response.[21] Toxicities

were graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version

4.0.

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2.4. Statistical Analyses The primary endpoint was the 2-year PFS rate. Previous randomized phase III studies of

chemoradiotherapy in patients with locally advanced NSCLC conducted in Japan revealed a 2-year

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PFS rate of 20% to 30%.[1, 2] If the 2-year PFS rate were assumed to be 25% in the inferior therapy

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group and 15% higher in the superior therapy group in this study, the sample size needed for

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selection of the optimum treatment group at a probability of 90% or higher will be 32 cases/group with the Simon’s selection design. The sample size was set at 35 patients per arm (70 patients in

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total) and the follow-up period for the primary decision-making was set at 2 years. Initially, only 3

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institutes participated in this study; however, eventually the number of participating institutions

increased to 9. Accordingly, the sample size was changed from 70 to 100 after a protocol

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amendment. The probability of selecting the optimum treatment group was set as 95% or higher.

The secondary endpoints were the treatment completion rate, toxicity, response rate, and

OS. PFS was defined as the interval from enrollment in this study to establishment of objective

evidence of disease progression, or death from any cause. OS was defined as the interval from

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enrollment in this study to death or the date of the final follow-up visit. Survival was estimated using

the Kaplan-Meier method. Patient characteristics other than age were compared with the use of Fisher’s exact test. Patients’ age between two arms were compared with the use of Wilcoxon test.

The statistical analyses were performed using SAS version 9.2 (SAS Institute, Cary, NC, USA). All

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the study data were managed by the Center for Novel and Exploratory Clinical Trials at Yokohama

City University Hospital.

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This trial is registered with the UMIN Clinical Trials Registry (number UMIN000009914).

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3. Results

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3.1. Patient characteristics

A total of 102 patients from 9 institutions in Japan were enrolled between January 2013

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and December 2016. The clinical data cutoff date was November 28, 2018. All of the 102 patients

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were found to be eligible for inclusion in the study; 52 patients were allocated to the CS arm and 50

patients to the CP arm. All the randomly allocated patients to the two treatment arms received the

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respective trial treatment (supplementary Figure S.1). The baseline characteristics, including the age,

gender, Eastern Cooperative Group performance status score, disease stage, tumor histologic type,

and smoking status, were well balanced between the two treatment arms. Of the 102 patients, 13 had

EGFR active mutations (17% of the patients in the CS arm and 8% in the CP arm), and the EGFR

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gene status was unknown in 14 patients (Table 1). Data on the ROS1 fusion status or PD-L1 score

were not available, because these tests were not routinely performed at the time of patient enrollment

into this study.

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3.2. Treatment delivery

A total of 40 (77%) and 43 (86%) patients received the targeted 4 cycles of chemotherapy

in the CS and CP arms, respectively, and 48 (92%) and 49 (98%) patients completed TRT (60 Gy)

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within 56 days in the two arms, respectively. Among those 48 patients in the CS arm, 32 patients

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(62%) completed 2 cycles of CDDP plus S-1 for 14 days before the completion of TRT (60 Gy). On

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the other hand, among the 49 patients in the CP arm, 48 patients (96%) and 23 patients (46%)

completed 2 and 3 cycles of CDDP+PEM before the completion of TRT (60 Gy). All four cycles of

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chemotherapy plus TRT (60 Gy) was completed in 38 (73%) and 43 (86%) patients in the CS and CP

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arms, respectively (Table 2). Seven and 6 patients discontinued the study treatment due to toxicity,

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and 4 and 1 patients due to progressive disease in the CS and CP arms, respectively.

3.3. Efficacy

Partial response was observed in 31 and 32 patients in the CS and CP arms, respectively.

The objective response rate was 59.6% (95% confidence interval [CI], 45.1 to 73.0) in the CS arm

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and 64.0% (95%CI: 49.2 to 77.1) in the CP arm. The disease control (PR+SD) rate was 86.5% in the

CS arm and 92.0% in the CP arm (Table 2).

After a median follow-up of 32.1 months, 72 PFS events were observed. The 2-year PFS

rate was 36.5% (95% CI, 23.5 to 49.6) in the CS arm and 32.1% (95%CI, 18.9 to 45.4) in the CP arm

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(P=0.64), and the median PFS was 12.7 months in the CS arm and 13.8 months in the CP arm

(HR=1.16; 95% CI, 0.73 to 1.84, p=0.538), and the 2-year PFS rate was 36.5% (95% CI, 23.5 to

49.6) in the CS arm and 32.1% (95%CI, 18.9 to 45.4) in the CP arm (Figure 2). After a median

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follow-up of 34.6 months, 44 OS events were observed. The median OS was 48.3 months in the CS

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arm and 59.1 months in the CP arm (HR=1.05; 95%CI, 0.58 to 1.90, p=0.883), and the 2-year OS

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rate was 69.2% (95%CI, 56.7 to 81.8) in the CS arm and 66.4% (95%CI, 53.0 to 79.9) in the CP arm

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3.4. Toxicities

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(Figure 3).

The most common toxicity was neutropenia. Grade 3 or worse neutropenia was frequently

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observed in the CP arm (52%) as compared with in the CS arm (38%); however, febrile neutropenia

was more common in the CS arm (n=5, 10%) than in the CP arm (n=1, 2%). Other grade 3 toxicities

in the CS/CP arm included anorexia (8%/16%), diarrhea (8%/0%), esophagitis (6%/8%), pneumonia

(4%/4%), neutropenia (35%/50%), anemia (8%/12%), thrombocytopenia (4%/6%), and

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hyponatremia (12%/12%) (Table 3).

Grade 3 or worse radiation pneumonitis was observed in 2 (8%) patients in the CS arm and

one (2%) patient in the CP arm. Grade 2 or worse radiation pneumonitis was observed in 8 (15%)

and 10 (20%) patients in the CS and CP arms, respectively. No significant association was observed

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between the severity grade of radiation pneumonitis and the V20 of the lung (Table S.1). One patient assigned to the CS arm developed grade 3 radiation pneumonitis 2 months and 3 weeks after the

completion of 4 cycles of CDDP+S-1 with concurrent TRT (60 Gy). The patient had underlying

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COPD and received steroid pulse therapy for radiation pneumonitis, but he eventually died. The

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death in this case was considered to be a treatment-related death. Thrombosis of the pulmonary

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artery (n=3) and portal vein thrombosis (n=1) were encountered only in the CS arm. The condition

was asymptomatic in all, but one patient and the patients were treated with anti-coagulants. One

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patient complained of edema of the lower extremity during the 4th course of cisplatin plus S-1

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chemotherapy. Contrast-enhanced CT revealed thrombosis of the deep veins of the lower extremities

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and pulmonary artery. He improved with anti-coagulant treatment.

3.5. Relapse sites and post-study treatment

Disease progression was observed in 33 and 36 patients in the CS and CP arms,

respectively. Distant metastases were the first evidence of relapse in 24 and 31 patients in the CS and

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CP arms, respectively. Local relapse was the first evidence of relapse in 14 and 13 patients in the CS

and CP arms, respectively. (Table S2).

After disease progression, 27 patients each from the two treatment arms received post-

study chemotherapy, including EGFR-TKIs (n=7/n=5), ALK-TKIs (n=0/n=3), and immune

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checkpoint inhibitors (n=6/n=10). Thirteen and 18 patients received third-line therapy in the CS and

CP arms, respectably.

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4. Discussion

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Concurrent TRT combined with CDDP+S-1 or CDDP+PEM chemotherapy yielded similar

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efficacy. The survival curves for the PFS and OS in the two treatment arms almost overlapped with

each other. However, the 2-year PFS rate, the primary endpoint, in the CS arm (36.5%) was higher

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than that in the CP arm (32.1%). The 2-year OS rate was 69.2% in the CS arm and 66.4% in the CP

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arm. In the PROCLAIM study, the 2-year OS rates were 52% in both the CDDP plus PEM and

CDDP plus etoposide arms. [20] The OS rate in our study was higher than that in the PROCLAIM

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study, which could, however, also be attributable to the differences in the patient characteristics, such

as the PS, disease stage, and EGFR gene mutation status, between the two studies.

Recently, immune checkpoint inhibitors have been introduced, not only as a standard

second-line treatment after platinum-based chemotherapy, but also as first-line treatment as a single

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agent or in combination with platinum-based chemotherapy for metastatic NSCLC.[22-29] The

PACIFIC study was a global phase III study comparing durvalumab, a PD-L1 inhibitor, as

consolidation therapy with placebo in patients with stage III, locally advanced, unresectable NSCLC

after platinum-based chemoradiotherapy. It demonstrated that consolidation therapy with

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durvalumab significantly prolonged the PFS and OS as compared to placebo. Consolidation therapy

with durvalumab after chemoradiotherapy had been a standard of care for patients with unresectable,

locally advanced NSCLC, and was approved in 2018 worldwide including Japan. Therefore, no

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patient in our current study received durvalumab. Eligibility criteria for durvalumab treatment were

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absence of disease progression after the chemoradiotherapy and absence of grade 2 or worse

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pneumonitis. Subgroup analysis suggested that an interval of less than 14 days from the last radiation

to randomization might be associated with a greater survival benefit of durvalumab consolidation

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therapy.[30, 31] The disease control rates were 86.5% and 92.0%, and the incidence rates of grade 2

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or worse radiation pneumonitis were 15% and 20% in the CS and CP arms, respectively. Therefore,

the transfer rate to durvalumab consolidation therapy was equally expected in both arms. At the time

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of completion of TRT (60Gy), 62% and 86% of patients completed 2 cycles of chemotherapy in the

CS and CP arms, respectively, Furthermore, 46% of patients in the CP arm completed 3 cycles of

chemotherapy before they completed the TRT (60Gy). If consolidation durvalumab therapy is

planned after the chemoradiotherapy in this study, the rate of shift to consolidation durvalumab

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therapy would be expected to be similar in the CS and CP arms. However, only patients in the CP

arm can receive 3 cycles of chemotherapy before the completion of TRT (60Gy) and they can shift to

the durvalumab consolidation therapy earlier after the completion of TRT as compared to those in

the CS arm.

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The most frequently encountered toxicity was neutropenia. Grade 3 or worse neutropenia

was observed in 38% and 52% in the CS and CP arms, respectively. However, febrile neutropenia

was observed in 10% and 2% of patients in the CS and CP arms. In previous phase III studies, the

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incidence of grade 3 or worse neutropenia was 23.1% in the concurrent phase of weekly carboplatin

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plus paclitaxel with TRT and 62% in the CDDP plus docetaxel with TRT arm. The incidence of

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febrile neutropenia was 3.4% and 22%, respectively.[1, 2] These toxicities in both the CS and CP

arms were intermediate in incidence between patients receiving weekly carboplatin plus paclitaxel

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and CDDP plus docetaxel concurrently with TRT.

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Mainly based on the analysis of stage IV or resectable stage I to II pulmonary

adenocarcinoma patients, EGFR mutations in the tumors occur at a frequency of 40% to 50% in

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Asian patients.[32, 33] In our study, the EGFR gene status was investigated in 88 of the 102 patients,

and the result revealed 13 of the 88 (15%) patients had EGFR mutations. According to previously

reported studies, the prevalence of EGFR mutations in patients with stage III non-squamous NSCLC

is in the range of 17% to 30%,[34-37] which is lower than that in patients with stage IV disease. The

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prevalence of EGFR mutations in our study (15%) is comparable to that in these previous reports.

The final OS results of the PROCLAIM study were reported at the Annual Meeting of the

American Society of Clinical Oncology in 2015, while the enrollment for this study was still

ongoing; the OS in the CDDP + PEM arm was not significantly longer than that in the CDDP + ETP

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arm (HR=0.98; 95% CI, 0.79 to 1.20).[20] By early June 2015, we had enrolled 53 patients for this

study. Because consolidation chemotherapy was not identical between the CP arm in our study and

the PROCLAIM (CDDP plus PEM versus single-agent PEM), and ethnic difference, such as the

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incidence of EGFR mutation could affect the efficacies of the chemotherapy regimens, we decided to

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continue the patient enrollment as planned.

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The present study had several limitations. First, the number of patients included in the

study was small. Therefore, even a slight imbalance in patient characteristics, such as the EGFR

na

gene mutation status, between the two arms could have influenced the clinical outcomes. Second, no

ur

independent central review for the responses and/or state of disease progression was conducted.

Third, pulmonary function test data of the patients were not available; while spirometry is routinely

Jo

conducted in clinical practice before definitive TRT, spirometry data were not collected in this study.

Fourth, the percentage of patients who were staged by PET was not available; PET is usually

performed to stage the disease in clinical practice in Japan, and most patients would have been

expected to have undergone PET rather than bone scintigraphy.

19

In conclusion, the 2-year PFS rate, the primary endpoint, was higher in the CS arm

(36.5%) than in the CP arm (32.1%), although the PFS was not significantly different between two

arms. Both the chemotherapy regimens were safe, with manageable toxicities. Whereas durvalumab

consolidation therapy was not planned in our study, considering the high rate of delivery of two/three

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cycles of chemotherapy before the completion of TRT, it was deemed that patients in the CP arm

would be suitable candidates for chemoradiotherapy prior to the durvalumab consolidation therapy.

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Conflict of interest statement

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S.N. reports grants and personal fees from AstraZeneca, Chugai, Taiho, Bristol-Myers Squibb,

lP

Novartis, Boehringer Ingelheim, Shionogi, and Yakult, grants and personal fees from Pfizer, MSD,

and Eli Lilly, grants from Merck Serono, outside the submitted work. T.Y. reports personal fees from

na

Chugai, Boehringer Ingelheim, AstraZeneca, and Bristol‐Myers Squibb, outside the submitted

ur

work. K.S. reports personal fees from Chugai, Ono, Novartis, and Taiho, outside the submitted work.

A.O. reports personal fees from Taiho, Ono, Chugai, Novartis, AstraZeneca, and MSD, outside the

Jo

submitted work. T.S reports grants and personal fees from Astellas, AstraZeneca, Chugai, Eli Lilly,

Kissei, MSD, Boehringer Ingelheim, Novartis, Pfizer, and Takeda, personal fees from Bristol-Myers

Squibb, Kyowa Hakko Kirin, Nippon Kayaku, Ono, Roche, Taiho, Thermo Fisher Scientific, and

Yakult, grants from Bayer, Daiichi Sankyo, Eisai, LOXO Oncology, Merck Serono, outside the

20

submitted work. M.N. reports grants and non-financial support from F. Hoffmann-La Roche,

during the conduct of the study; grants and personal fees from Ono, Bristol-Myers Squibb, Pfizer,

Chugai, Eli Lilly, Taiho, AstraZeneca, MSD, Novartis, personal fees from Boehringer-Ingelheim,

Sankyo Healthcare, Taiho, Merck Serono, grants from Astellas, outside the submitted work. N.Y.

ro of

reports grants and personal fee from Chugai, Eisai, Eli Lilly, Bristol-Myers Squibb, Pfizer,

Boehringer Ingelheim, Ono, and Takeda, grants from Taiho, Quintiles, Astellas, Novartis, Daiichi-

Sankyo, Kyowa-Hakko Kirin, Bayer, Janssen Pharma, MSD, and Merck, personal fees from

-p

AstraZeneca, Otsuka, Cimic, and Sysmex, outside the submitted work. T.H. reports grants and

re

personal fees from Ono, Chugai, AstraZeneca, Boehringer Ingelheim, Novartis, Eli Lilly, Kissei,

lP

Taiho, Pfizer, Clovis Oncology, MSD, and Ignyta, grants from Merck Serono, Eisai, Takeda,

Dainippon Sumitomo, Abbvie, Kyowa Hakko Kirin, Daiichi Sankyo, Astellas, Servier, Janssen,

na

outside the submitted work. H.O. reports grants from Takeda, MSD, Ono, AstraZeneca, Merck,

ur

Chugai, Taiho, Bristol-Myers Squibb, Eli Lilly, Daiich Sankyo, outside the submitted work. T.K.

reports grants and personal fee from AstraZeneca, MSD, and Chugai, personal fees from Eli Lilly,

Jo

Ono, Bristol-Myers Squibb, and Boehringer Ingelheim, outside the submitted work. M.S. reports

grants and personal fees from Chugai, Eli Lilly, Pfizer, AstraZeneca, Bristol-Myers Squibb, Ono,

MSD, and Novartis, grants from Takeda, AbbVie, Ignyta, and Loxo Oncology, personal fees from

Taiho, and Boehringer Ingelheim, outside the submitted work. K.G. reports grants and personal fees

21

from Taiho, Chugai, Ono, AstraZeneca, Bristol-Myers Squibb, MSD, DAIICHI SANKYO, Pfizer,

Novartis, Takeda, Eli Lilly, Merck Serono, Boehringer Ingelheim, RIKEN GENESIS, AbbVie, and

Life Technologies, grants from Sumitomo Dainippon, Astellas, Eisai, Kyowa Hakko Kirin, Ignyta,

Janssen, Loxo Oncology, Sysmex Corporation, and Oxonc, personal fees from F.Hoffmann-La

ro of

Roche, SRL, and Nippon Kayaku, outside the submitted work. T.Y. reports grants and personal fees

from Takeda, Chugai, Boehringer Ingelheim, Daiichi-Sankyo, and Bayer, grants from Ono, Merck

Serono, Astellas, and Eli Lilly, personal fees from Taiho, Pfizer, Sysmex, Huya Biosciences, and

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Gilead Sciences, outside the submitted work. Y.O. reports grants and personal fees from Lilly,

re

Bristol-Myers Squibb, Taiho, AstraZeneca, Chugai, ONO, Pfizer, MSD, Kyorin, Takeda, Novartis,

lP

AbbVie, grants from Amgen, Boehringer Ingelheim, LOXO, and Janssen, personal fees from

Celltrion, outside the submitted work.

na

T.A. declares no conflict of interest.

ur

Author Contributions

Jo

Seiji Niho: Conceptualization, Investigation, Resources, Writing - Original Draft, Writing Review & Editing, Project administration, Funding acquisition Tatsuya Yoshida: Conceptualization, Resources, Writing - Review & Editing Tetsuo Akimoto: Investigation, Writing - Original Draft, Writing - Review & Editing Kentaro Sakamaki: Methodology, Formal analysis, Visualization, Writing - Review & Editing Akira Ono: Resources, Writing - Review & Editing Takashi Seto: Resources, Writing - Review & Editing Makoto Nishio: Resources, Writing - Review & Editing 22

Noboru Yamamoto: Resources, Writing - Review & Editing Toyoaki Hida: Resources, Writing - Review & Editing Hiroaki Okamoto: Resources, Writing - Review & Editing Takayasu Kurata: Resources, Writing - Review & Editing Miyako Satouchi: Resources, Writing - Review & Editing Koichi Goto: Resources, Writing - Review & Editing Takeharu Yamanaka: Methodology, Formal analysis, Writing - Review & Editing

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Yuichiro Ohe: Conceptualization, Resources, Writing - Review & Editing, Supervision

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Funding

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Conflict of interest: none

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Clinical Trial Registration: UMIN000009914.

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This research was supported by AMED under Grant Number JP19ck0106312.

Acknowledgements

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We thank the patients and their families, the investigators and our colleagues at all the

Jo

participating institutions. We also thank Takako Ishibashi for her able assistance with the data

management. This study was previously partly presented at a Poster Session of the Annual Meeting

of European Society of Medical Oncology (ESMO 2017), Madrid, Spain, and an Oral Session of the

World Conference on Lung Cancer (WCLC 2019), Barcelona, Spain.

23

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https://doi.org/10.1016/j.cllc.2016.12.013.

28

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-p

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lP

na

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Jo Fig 1

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Fig. 2

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Fig. 3

31

Table 1. Patient characteristics

CDDP + S-1 +

PEM + CDDP +

TRT (CS arm)

TRT

(n=52)

(CP arm) (n=50)

P-value

Median (range)

64.5 (39-73)

63.5 (32-74)

0.7

Gender

Male

35

33

1

Female

17

17

0

38

36

1

14

14

IIIA

31

29

IIIB

21

Adenocarcinoma

47

44

NSCLC-NOS

5

6

Histological type

EGFR gene

9

4

Wild

36

39

7

7

Positive

2

3

Negative

30

22

Unknown

20

25

Never

12

12

Current/former

40

38

ur

na

Unknown

ALK fusion

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Smoking history

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Exon 19 del/L858R

mutation status

1

1

21

re

Stage

lP

PS

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Age (years)

0.75

0.38

0.36

1

CDDP, cisplatin; PEM, pemetrexed; TRT, thoracic radiotherapy; PS, performance status; NSCLC-NOS, non-small cell lung cancer not otherwise specified; EGFR, epidermal growth factor receptor; ALK, anaplastic lymphoma kinase.

32

Table 2. Treatment delivery and response

Number of chemotherapy

S-1 + CDDP + TRT

PEM + CDDP + TRT

(CS arm) (n=52)

(CP arm) (n=50)

1

5

1

2

5

3

3

2

3

4

40

43

Median

60

(range)

(38-60)

Total dose of TRT (Gy)

60

48

Completed TRT (60 Gy)

chemotherapy before

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completion of TRT (60 Gy) -

Completed 3 cycles of

completion of TRT (60 Gy) Treatment completion*

ur

Overall response rate (%)

23

38 (73%)

43 (86%)

PR

31

32

SD

14

14

PD

4

2

NE

3

2

59.6 (45.1-73.0)

64.0 (49.2-77.1)

na

Response

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chemotherapy before

48

-p

32

(56-60) 49

within 56 days Completed 2 cycles of

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cycles

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(95% CI)

*Treatment completion was defined as 4 cycles of chemotherapy and 60 Gy of TRT. CDDP, cisplatin; PEM, pemetrexed; TRT, thoracic radiotherapy; PR, partial response; SD, stable disease; PD, progressive disease; NE, not evaluable; CI, confidence interval.

33

Table 3. Toxicities

S-1 + CDDP + TRT (CS arm) (n=52)

PEM + CDDP + TRT (CP arm) (n=50)

2

3

4

5

≥3 (%)

2

3

4

≥3 (%)

Neutropenia

16

18

2

0

20 (38)

17

25

1

26 (52)

Anemia

18

4

0

0

4 (8)

16

6

0

6 (12)

Thrombocytopenia

6

1

1

0

2 (4)

9

3

0

3 (6)

Febrile neutropenia

-

5

0

0

5 (10)

-

1

0

1 (2)

Broncho-pneumonia

1

0

0

0

0

2

2

0

2 (4)

AST elevation

1

0

0

0

0

3

0

0

0

ALT elevation

1

1

0

0

1 (2)

Creatinine elevation

0

1

0

0

1 (2)

Hyponatremia

0

6

0

0

6 (12)

Anorexia

9

4

0

0

4 (8)

Vomiting

1

1

0

0

1 (2)

Diarrhea

2

4

0

0

Mucositis

0

0

0

0

Esophagitis

19

3

0

0

Pneumonitis

6

1

0

Dermatitis

7

0

0

Thrombosis

0

PS

7

ro of

Grade

3

0

3 (6)

1

0

0

0

0

6

0

6 (12)

10

8

0

8 (16)

1

0

0

0

-p

3

0

0

0

0

0

0

1

0

1 (2)

3 (6)

20

4

0

4 (8)

1

2 (4)

9

1

0

1 (2)

0

0

8

0

0

0

lP

re

4 (8)

4

0

0

4 (8)

0

0

0

0

3

0

0

3 (6)

3

1

0

1 (2)

Jo

ur

na

AST, aspartate aminotransferase; ALT, alanine aminotransferase.

34