Japanese subgroup analysis of a phase III study of S-1 versus docetaxel in non-small cell lung cancer patients after platinum-based treatment: EAST-LC

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Abstract

Introduction

The East Asia S-1 Trial in Lung Cancer (EAST-LC) was a randomized phase III study conducted in East Asia that demonstrated the non-inferiority of S-1 to docetaxel in previously treated patients with advanced non-small cell lung cancer (NSCLC). Here, we reported the results of the Japanese subgroup treated with docetaxel 60 mg/m ², the standard dosage in Japan.

Patients and methods

Patients were randomized 1:1 to receive either S-1 or docetaxel. The primary endpoint was overall survival (OS); the secondary endpoints included progression-free survival (PFS), response rate (RR), quality of life (QOL), and safety.

Results

Patient characteristics in the Japanese subgroup ( n = 724) were similar to those in the overall EAST-LC population. Median OS was 13.4 months in the S-1 group and 12.6 months in the docetaxel group. In pemetrexed-pretreated patients, OS with S-1 was similar to that with docetaxel. Median PFS was 2.9 and 3.0 months in the S-1 and docetaxel groups, respectively. RR was 9.4% and 10.3% in the S-1 and docetaxel groups, respectively. The QOL of patients treated with S-1 was better compared with that of patients treated with docetaxel. Decreased appetite and diarrhea were more common in the S-1 group, whereas the frequency of neutropenia and febrile neutropenia was markedly higher in the docetaxel group.

Conclusions

This Japanese subgroup analysis showed that S-1 had similar efficacy to docetaxel in patients with previously treated advanced NSCLC. These results are similar to those of the overall EAST-LC population.

Electronic supplementary material

The online version of this article (10.1007/s10147-019-01396-z) contains supplementary material, which is available to authorized users.

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Most cited references 19

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Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial.

Martin Reck, Rolf Kaiser, Anders Mellemgaard … (2014)

The phase 3 LUME-Lung 1 study assessed the efficacy and safety of docetaxel plus nintedanib as second-line therapy for non-small-cell lung cancer (NSCLC). Patients from 211 centres in 27 countries with stage IIIB/IV recurrent NSCLC progressing after first-line chemotherapy, stratified by ECOG performance status, previous bevacizumab treatment, histology, and presence of brain metastases, were allocated (by computer-generated sequence through an interactive third-party system, in 1:1 ratio), to receive docetaxel 75 mg/m(2) by intravenous infusion on day 1 plus either nintedanib 200 mg orally twice daily or matching placebo on days 2-21, every 3 weeks until unacceptable adverse events or disease progression. Investigators and patients were masked to assignment. The primary endpoint was progression-free survival (PFS) by independent central review, analysed by intention to treat after 714 events in all patients. The key secondary endpoint was overall survival, analysed by intention to treat after 1121 events had occurred, in a prespecified stepwise order: first in patients with adenocarcinoma who progressed within 9 months after start of first-line therapy, then in all patients with adenocarcinoma, then in all patients. This trial is registered with ClinicalTrials.gov, number NCT00805194. Between Dec 23, 2008, and Feb 9, 2011, 655 patients were randomly assigned to receive docetaxel plus nintedanib and 659 to receive docetaxel plus placebo. The primary analysis was done after a median follow-up of 7·1 months (IQR 3·8-11·0). PFS was significantly improved in the docetaxel plus nintedanib group compared with the docetaxel plus placebo group (median 3·4 months [95% CI 2·9-3·9] vs 2·7 months [2·6-2·8]; hazard ratio [HR] 0·79 [95% CI 0·68-0·92], p=0·0019). After a median follow-up of 31·7 months (IQR 27·8-36·1), overall survival was significantly improved for patients with adenocarcinoma histology who progressed within 9 months after start of first-line treatment in the docetaxel plus nintedanib group (206 patients) compared with those in the docetaxel plus placebo group (199 patients; median 10·9 months [95% CI 8·5-12·6] vs 7·9 months [6·7-9·1]; HR 0·75 [95% CI 0·60-0·92], p=0·0073). Similar results were noted for all patients with adenocarcinoma histology (322 patients in the docetaxel plus nintedanib group and 336 in the docetaxel plus placebo group; median overall survival 12·6 months [95% CI 10·6-15·1] vs 10·3 months [95% CI 8·6-12·2]; HR 0·83 [95% CI 0·70-0·99], p=0·0359), but not in the total study population (median 10·1 months [95% CI 8·8-11·2] vs 9·1 months [8·4-10·4]; HR 0·94, 95% CI 0·83-1·05, p=0·2720). Grade 3 or worse adverse events that were more common in the docetaxel plus nintedanib group than in the docetaxel plus placebo group were diarrhoea (43 [6·6%] of 652 vs 17 [2·6%] of 655), reversible increases in alanine aminotransferase (51 [7·8%] vs six [0·9%]), and reversible increases in aspartate aminotransferase (22 [3·4%] vs three [0·5%]). 35 patients in the docetaxel plus nintedanib group and 25 in the docetaxel plus placebo group died of adverse events possibly unrelated to disease progression; the most common of these events were sepsis (five with docetaxel plus nintedanib vs one with docetaxel plus placebo), pneumonia (two vs seven), respiratory failure (four vs none), and pulmonary embolism (none vs three). Nintedanib in combination with docetaxel is an effective second-line option for patients with advanced NSCLC previously treated with one line of platinum-based therapy, especially for patients with adenocarcinoma. Boehringer Ingelheim. Copyright © 2014 Elsevier Ltd. All rights reserved.

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Development of a novel form of an oral 5-fluorouracil derivative (S-1) directed to the potentiation of the tumor selective cytotoxicity of 5-fluorouracil by two biochemical modulators.

T Shirasaka, Y Shimamato, H Ohshimo … (1996)

We have focused our attention on the development of a novel form of a tegafur-based [FT; a prodrug of 5-fluorouracil (5-FU)] antitumor agent. We have used two biochemical and pharmacological modulators of 5-FU to improve its overall activity. To potentiate the antitumor activity of FT, 5-chloro-2,4-dihydroxypyridine (CDHP) was used as a potent reversible inhibitor of 5-FU degradation. The reduction of gastrointestinal (GI) toxicity, induced in the host by 5-FU, was modulated by potassium oxonate (Oxo), an inhibitor of orotate phosphoribosyltransferase that catalyzes the phosphorylation of 5-FU, a process believed to be responsible for the toxic effects of 5-FU. When CDHP and FT were simultaneously given orally to Yoshida sarcoma-bearing rats in various molar ratios, the antitumor effect of FT was significantly potentiated by the combination consisting of at least a 0.2 versus 1 molar ratio of CDHP to FT, respectively. This augmentation of an antitumor activity was supported by potent and prolonged inhibition of dihydrouracil dehydrogenase activity (5-FU degrading activities) in the liver of tumor-bearing rats after oral CDHP (0.2:0.8 molar ratio) and furthermore by elevation and over 12 h retention of 5-FU levels in the tumors following combined administration of FT and CDHP at a molar ratio of 1:0.4, respectively. Moreover, to reduce the severe GI injury and subsequent loss of body weight, observed in parallel with an increased antitumor efficacy, Oxo was given orally to Yoshida sarcoma-bearing rats and nude rats xenografted with H-81 human gastric carcinoma, during consecutive administration of the FT-CDHP mixture. Combined treatment with Oxo and FT (1:2 molar ratio) supplemented with 0.4 molar CDHP resulted in protection of body weight loss without affecting the high antitumor efficacy of the FT-CDHP mixture. When [2-14C]FT plus CDHP was administered with Oxo, the 14C-labeled fluoronucleotide content was objectively decreased in the GI tract of the tumor-bearing rats but not in the tumor and bone marrow, which supports our initial hypothesis. Based on these promising data, we propose a suitable formulation of a FT-based anticancer drug, called S-1, and consisting of FT, CDHP and Oxo at a 1:0.4:1 molar ratio and showing tumor-selective cytotoxicity of 5-FU.

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Randomized phase III trial of erlotinib versus docetaxel as second- or third-line therapy in patients with advanced non-small-cell lung cancer: Docetaxel and Erlotinib Lung Cancer Trial (DELTA).

TOMOYA KAWAGUCHI, Masahiko Ando, KAZUHIRO ASAMI … (2014)

To investigate the efficacy of erlotinib versus docetaxel in previously treated patients with advanced non-small-cell lung cancer (NSCLC) in an epidermal growth factor receptor (EGFR) -unselected patient population.

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Author and article information

Contributors

Tomohide Tamura:

ORCID: http://orcid.org/0000-0003-3601-8889

+81-3-3541-5151 , tamuratomohide@gmail.com

Journal

Journal ID (nlm-ta): Int J Clin Oncol

Journal ID (iso-abbrev): Int. J. Clin. Oncol

Title: International Journal of Clinical Oncology

Publisher: Springer Singapore (Singapore )

ISSN (Print): 1341-9625

ISSN (Electronic): 1437-7772

Publication date (Electronic): 4 March 2019

Publication date PMC-release: 4 March 2019

Publication date (Print): 2019

Volume: 24

Issue: 5

Pages: 485-493

Affiliations

[1 ]GRID grid.415501.4, Department of Pulmonary Medicine, , Sendai Kousei Hospital, ; Miyagi, Japan

[2 ]ISNI 0000 0004 1936 9967, GRID grid.258622.9, Department of Medical Oncology, Faculty of Medicine, , Kindai University, ; Osaka, Japan

[3 ]ISNI 0000 0004 1763 1087, GRID grid.412857.d, Third Department of Internal Medicine, , Wakayama Medical University, ; Wakayama, Japan

[4 ]ISNI 0000 0001 2168 5385, GRID grid.272242.3, Department of Thoracic Oncology, , National Cancer Center Hospital, ; Tokyo, Japan

[5 ]ISNI 0000 0001 0037 4131, GRID grid.410807.a, Department of Thoracic Medical Oncology, , The Cancer Institute Hospital of Japanese Foundation for Cancer Research, ; Tokyo, Japan

[6 ]ISNI 0000 0004 1774 9501, GRID grid.415797.9, Division of Thoracic Oncology, , Shizuoka Cancer Center, ; Shizuoka, Japan

[7 ]ISNI 0000 0001 2168 5385, GRID grid.272242.3, Department of Thoracic Oncology, , National Cancer Center Hospital East, ; Kashiwa, Japan

[8 ]ISNI 0000 0004 5899 0430, GRID grid.419939.f, Department of Respiratory Medicine, , Miyagi Cancer Center, ; Miyagi, Japan

[9 ]Department of Cancer Information Research, National Kyushu Cancer Center, Clinical Research Institute, Fukuoka, Japan

[10 ]GRID grid.415613.4, Department of Thoracic Oncology, , National Kyushu Cancer Center, ; Fukuoka, Japan

[11 ]ISNI 0000 0000 8855 274X, GRID grid.416695.9, Department of Thoracic Oncology, , Saitama Cancer Center, ; Saitama, Japan

[12 ]ISNI 0000 0001 2173 8328, GRID grid.410821.e, Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, , Nippon Medical School, ; Tokyo, Japan

[13 ]GRID grid.489169.b, Department of Thoracic Oncology, , Osaka International Cancer Institute, ; Osaka, Japan

[14 ]ISNI 0000 0004 1764 921X, GRID grid.418490.0, Division of Respirology, , Chiba Cancer Center, ; Chiba, Japan

[15 ]ISNI 0000 0004 0378 7902, GRID grid.410840.9, Department of Respiratory Medicine and Medical Oncology, , National Hospital Organization Nagoya Medical Center, ; Aichi, Japan

[16 ]ISNI 0000 0001 2248 6943, GRID grid.69566.3a, Department of Palliative Medicine, , Tohoku University School of Medicine, ; Miyagi, Japan

[17 ]ISNI 0000 0004 1764 9308, GRID grid.416948.6, Department of Medical Oncology, , Osaka City General Hospital, ; Osaka, Japan

[18 ]ISNI 0000 0001 2242 4849, GRID grid.177174.3, Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, , Kyushu University, ; Fukuoka, Japan

[19 ]ISNI 0000 0001 1302 4472, GRID grid.261356.5, Department of Hematology, Oncology, and Respiratory Medicine, , Okayama University Graduate School of Medicine, ; Okayama, Japan

[20 ]ISNI 0000 0004 0372 2033, GRID grid.258799.8, Department of Biomedical Statistics and Bioinformatics, , Kyoto University Graduate School of Medicine, ; Kyoto, Japan

[21 ]GRID grid.430395.8, Thoracic Center, , St Luke’s International Hospital, ; 9-1 Akashi-cho, Chuo-ku, Tokyo, 104-8560 Japan

Author information

Tomohide Tamura http://orcid.org/0000-0003-3601-8889

Article

Publisher ID: 1396

DOI: 10.1007/s10147-019-01396-z

PMC ID: 6469651

PubMed ID: 30830659

SO-VID: a92c2723-eabf-43bd-a05e-044129ffe643

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Date received : 5 October 2018

Date accepted : 30 December 2018

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100009954, Taiho Pharmaceutical;

Award ID: NA

Custom metadata

Keywords: tegafur–gimeracil–oteracil,second line,third line,chemotherapy,japan,phase iii

Data availability:

Keywords: tegafur–gimeracil–oteracil, second line, third line, chemotherapy, japan, phase iii

Japanese subgroup analysis of a phase III study of S-1 versus docetaxel in non-small cell lung cancer patients after platinum-based treatment: EAST-LC

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Abstract

Introduction

Patients and methods

Results

Conclusions

Electronic supplementary material

Related collections

Model Reduction of Parametrized Systems 2015

Most cited references 19

Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial.

Development of a novel form of an oral 5-fluorouracil derivative (S-1) directed to the potentiation of the tumor selective cytotoxicity of 5-fluorouracil by two biochemical modulators.

Randomized phase III trial of erlotinib versus docetaxel as second- or third-line therapy in patients with advanced non-small-cell lung cancer: Docetaxel and Erlotinib Lung Cancer Trial (DELTA).

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