Nedaplatin plus docetaxel versus cisplatin plus docetaxel for advanced or relapsed squamous cell carcinoma of the lung (WJOG5208L): a randomised, open-label, phase 3 trial

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Nedaplatin plus docetaxel versus cisplatin plus docetaxel for advanced or relapsed squamous cell carcinoma of the lung (WJOG5208L): a randomised, open-label, phase 3 trial Takehito Shukuya, Takeharu Yamanaka, Takashi Seto, Haruko Daga, Koichi Goto, Hideo Saka, Shunichi Sugawara, Toshiaki Takahashi, Soichiro Yokota, Hiroyasu Kaneda, Tomoya Kawaguchi, Seisuke Nagase, Tetsuya Oguri, Yasuo Iwamoto, Takashi Nishimura, Yoshihiro Hattori, Kazuhiko Nakagawa, Yoichi Nakanishi, Nobuyuki Yamamoto, on behalf of the West Japan Oncology Group

Summary Background The combination of nedaplatin, a cisplatin derivative, and docetaxel showed promising activity for advanced squamous cell lung carcinoma in a previous phase 1–2 study. We compared nedaplatin plus docetaxel with cisplatin plus docetaxel in patients with previously untreated advanced or relapsed squamous cell lung carcinoma to determine effects on overall survival. Methods We did a randomised, open-label, phase 3 study at 53 institutions in Japan. Eligibility criteria included pathologically proven squamous cell lung cancer with stage IIIB/IV or postoperative recurrence, age 20–74 years, Eastern Cooperative Oncology Group performance status of 0–1, no previous chemotherapy or recurrence more than a year after previous adjuvant chemotherapy, and adequate organ function. Patients were randomly assigned (1:1) to 100 mg/m² nedaplatin and 60 mg/m² docetaxel intravenously, or 80 mg/m² cisplatin and 60 mg/m² docetaxel, every 3 weeks for four to six cycles (at the treating oncologist’s discretion). Randomisation was done centrally at the West Japan Oncology Group data centre via a computer-generated allocation sequence with dynamic minimisation that balanced stage (IIIB/IV or postoperative recurrent), sex, and institution. The primary endpoint was overall survival in the modified intention-to-treat population (ie, all patients who were randomly assigned and met the inclusion criteria). Safety analyses were done in all randomly assigned patients who received at least one dose of the study regimen. This trial is registered with the UMIN Clinical Trials Registry, number UMIN000002015, and is closed to new participants. Findings Between July 6, 2009, and July 26, 2012, 355 patients were randomly assigned. 349 patients were included in the modified intention-to-treat analysis (177 in the nedaplatin group and 172 in the cisplatin group). Overall survival was significantly longer in the nedaplatin group (median 13·6 months, 95% CI 11·6–15·6) than in the cisplatin group (11·4 months,10·2–12·2; hazard ratio 0·81, 95% CI 0·65–1·02; p=0·037, one-sided stratified log-rank test). Grade 3 or worse nausea (seven of 177 patients in the nedaplatin group and 25 of 175 in the cisplatin group), fatigue (six vs 20), hyponatraemia (24 vs 53), and hypokalaemia (four vs 15) were more frequent in the cisplatin group than in the nedaplatin group, whereas grade 3 or worse leucopenia (98 vs 77), neutropenia (146 vs 123), and thrombocytopenia (16 vs none) were more frequent in the nedaplatin group than in the cisplatin group. Treatment-related deaths occurred in four and three patients in nedaplatin and cisplatin groups, respectively. Interpretation Overall survival was significantly longer with nedaplatin plus docetaxel than with cisplatin plus docetaxel, and the regimens had different safety profiles. Nedaplatin plus docetaxel could be a new treatment option for advanced or relapsed squamous cell lung cancer. Funding West Japan Oncology Group and Sanofi.

Introduction Lung cancer is the most prevalent cancer worldwide.1 More than half of patients have advanced disease at the time of diagnosis; these patients are candidates for chemotherapy treatment.2–4 However, lung cancer has a poor prognosis and is the leading cause of cancer-related deaths worldwide.1 Therefore, advances in treatment are urgently needed. Squamous histology accounts for 20–30% of lung cancer cases.5,6 Limited progress has been made in the treatment of advanced squamous cell lung cancer compared with that in non-squamous, non-small-cell lung cancer (NSCLC). Median survival of patients with squamous cell lung cancer who receive first-line platinum-based

chemotherapy is roughly 10–12 months.7 By contrast, that of patients with non-squamous NSCLC has increased to 14–30 months because of the introduction of treatment regimens including bevacizumab, pemetrexed, EGFR tyrosine-kinase inhibitors, and ALK tyrosine-kinase inhibitors.8–11 The combination of cisplatin or carboplatin with vinorelbine, gemcitabine, irinotecan, paclitaxel, nanoparticle albumin-bound paclitaxel, or docetaxel is standard-of-care first-line treatment in patients with advanced squamous cell lung cancer.2–4 The results of previous phase 3 studies12,13 suggest that cisplatin plus docetaxel is an effective first-line treatment for squamous cell lung cancer.

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Lancet Oncol 2015 Published Online October 28, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)00305-8 See Online/Comment http://dx.doi.org/10.1016/ S1470-2045(15)00400-3 Department of Respiratory Medicine, Juntendo University, Tokyo, Japan (T Shukuya MD); Department of Biostatistics, Yokohama City University, Kanagawa, Japan (Prof T Yamanaka PhD); Department of Thoracic Oncology, National Kyushu Cancer Centre, Fukuoka, Japan (T Seto MD); Department of Clinical Oncology, Osaka City General Hospital, Osaka, Japan (H Daga MD); Department of Thoracic Oncology, National Cancer Centre Hospital East, Chiba, Japan (K Goto MD); Department of Respiratory Medicine and Medical Oncology, National Hospital Organisation Nagoya Medical Centre, Aichi, Japan (H Saka MD); Department of Pulmonary Medicine, Sendai Kousei Hospital, Miyagi, Japan (S Sugawara MD); Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan (T Takahasi MD); Department of Respiratory Medicine, National Hospital Organisation Toneyama National Hospital, Osaka, Japan (S Yokota MD); Department of Medical Oncology, Kinki University Faculty of Medicine, Osaka, Japan (H Kaneda MD, Prof K Nakagawa MD); Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, Osaka, Japan (T Kawaguchi MD); Department of Thoracic Surgery, Tokyo Medical University, Tokyo, Japan (S Nagase MD); Department of Respiratory Medicine, Allergy, and Clinical Immunology,

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Graduate School of Medical Sciences, Nagoya City University, Aichi, Japan (T Oguri MD); Department of Medical Oncology, Hiroshima City Hospital, Hiroshima, Japan (Y Iwamoto MD); Department of Respiratory Medicine, Kyoto-Katsura Hospital, Kyoto, Japan (T Nishimura MD); Department of Thoracic Oncology, Hyogo Cancer Center, Hyogo, Japan (Y Hattori MD); Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan (Prof Y Nakanishi MD); and Third Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan (Prof N Yamamoto MD) Correspondence to: Dr Nobuyuki Yamamoto, Third Department of Internal Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, Wakayama, 641-8509, Japan nbyamamo@wakayama-med. ac.jp

Research in context Evidence before this study We searched PubMed with the terms “non-small cell lung cancer”, “squamous cell lung cancer”, and “chemotherapy” for reports of randomised clinical trials published in any language up to May 21, 2015. We also searched the reference lists of articles identified by this search. The combination of cisplatin or carboplatin plus vinorelbine, gemcitabine, irinotecan, paclitaxel, nanoparticle albumin-bound paclitaxel, or docetaxel is standard first-line treatment in patients with advanced squamous cell carcinoma of the lung. Investigators in one randomised phase 3 study compared cisplatin plus docetaxel with cisplatin plus vindesine in patients with stage IV non-small-cell lung cancer (NSCLC) including squamous cell lung cancer; overall survival was significantly longer in the docetaxel group. In another prospective randomised phase 3 study, the cisplatin plus docetaxel regimen was compared with cisplatin plus vinorelbine in patients with advanced NSCLC (including squamous cell lung cancer). Overall survival was longer in the docetaxel than in the vinorelbine group. This evidence shows that cisplatin plus docetaxel is an effective first-line regimen for patients with squamous cell lung cancer. Nedaplatin was developed to decrease the toxic effects induced by cisplatin. Dose-limiting toxic effects were

Nedaplatin is a cisplatin derivative. It has the same ammine carrier ligands as cisplatin, but a different leaving group, consisting of a five-membered ring structure in which glycolate is bound to the platinum ion as a bidentate ligand. Nedaplatin was developed to decrease the toxic effects induced by cisplatin—eg, gastrointestinal and nephrotoxic effects. Moreover, nedaplatin does not require hydration for renal protection. In phase 1 studies,14,15 treatment with nedaplatin resulted in favourable tumour responses in NSCLC (especially squamous cell lung cancer); doselimiting toxic effects were neutropenia and thrombocytopenia.14 Of patients with squamous cell lung cancer who received nedaplatin monotherapy, about 40% achieved a tumour response in phase 2 clinical trials.16,17 Subsequently, a phase 1–2 study18 of nedaplatin plus docetaxel was done for advanced or relapsed squamous cell lung cancer. The regimen had promising activity: 62% of patients achieved an objective response, median progression-free survival was 7·4 months (95% CI 3·5–11·4), and median overall survival was 16·1 months (95% CI not reported). The most common adverse event was neutropenia (86% of patients had grade 3 or 4 neutropenia). Non-haematological adverse events were acceptable. The aim of this randomised phase 3 trial was to assess whether nedaplatin plus docetaxel increased overall survival compared with cisplatin plus docetaxel as first-line treatment for advanced or relapsed squamous cell lung cancer. 2

neutropenia and thrombocytopenia, and nedaplatin had favourable efficacy for NSCLC, especially squamous cell lung cancer in phase 1 studies. Subsequently, a phase 1–2 study of nedaplatin plus docetaxel was done for advanced or relapsed squamous cell lung cancer, and showed promising activity. Added value of this study Our results show that first-line treatment with nedaplatin plus docetaxel results in significantly longer overall survival compared with cisplatin plus docetaxel in patients with advanced or relapsed squamous cell lung cancer, with a different toxicity profile. Implications of all the available evidence Nedaplatin plus docetaxel can be thought of as a new treatment option for advanced or relapsed squamous cell lung cancer. However, this study was done in a Japanese population only. Pharmacogenomics differences exist between Japanese and western populations, and the response and adverse events to chemotherapeutic drugs differ between these populations. Furthermore, the dose of docetaxel in this study was lower than the standard dose given outside Japan. Therefore, further confirmatory studies, including one in a non-Japanese population, is warranted.

Methods Study design and participants We did this randomised, open-label, phase 3 study at 53 institutions in Japan. Investigators at participating institutions enrolled patients with histologically or cytologically confirmed squamous cell lung cancer. We defined the distinction between squamous cell lung cancer and non-squamous NSCLC on the basis of previous clinical studies. The exclusion criterion applied in the AVAiL trial was mixed adenosquamous carcinoma with a predominant squamous component.19 Therefore, patients with an adenosquamous histology or NSCLC histology not otherwise specified were eligible for inclusion in this trial if the tumours were predominantly squamous in composition (≥50%). Other eligibility criteria were stage IIIB/IV (as defined by the Union for International Cancer Control TNM classifications, 6th edition) or postoperative recurrent squamous cell lung cancer not amenable to curative radiotherapy; no previous chemotherapy or recurrence more than a year after previous adjuvant chemotherapy; Eastern Cooperative Oncology Group performance status of 0 or 1; age of 20–74 years; assessable lesions (measurable lesions were not required); adequate major organ function; white blood cell count of 3 × 10⁹ cells per L or more; absolute neutrophil count of 1·5 × 10⁹ cells per L or more; haemoglobin concentrations of at least 90 g/L; platelet count of 100 × 10⁹ cells per L or more; total bilirubin concentration of 34 mmol/L or less; aspartate aminotransferase and alanine aminotransferase

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concentrations of 100 IU/L or less; creatinine clearance of 1 mL/s or more (the Cockcroft-Gault formula could be used instead of glomerular filtration rate); arterial oxygen pressure of 8 kPa or more or oxygen saturation of 90% or greater as measured by pulse oximetry without oxygen supplementation; and estimated life expectancy of 3 months or more. Exclusion criteria were symptomatic brain metastases or brain metastases necessitating treatment with steroids or anticonvulsants; second malignancy; superior vena cava syndrome; pericardial effusion, pleural effusion, or ascites necessitating chronic drainage or showing rapid reaccumulation after aspiration of the excess fluid; previous radiotherapy to the primary lesion; palliative radiotherapy for metastatic sites such as bone and brain within 2 weeks of enrolment; serious comorbidities including uncontrollable hypertension or diabetes mellitus, active gastrointestinal haemorrhage, poorly controlled cardiovascular diseases, active infection, or interstitial pneumonia or pulmonary fibrosis with an obvious shadow on chest radiography; pregnancy; and lactation. The study protocol was approved by the protocol review committee of the West Japan Oncology Group and the institutional review board of each participating institution. The study was undertaken in accordance with the Declaration of Helsinki, and all patients provided written informed consent.

Randomisation and masking Eligible patients were randomly assigned (1:1) to receive either nedaplatin plus docetaxel or cisplatin plus docetaxel. Staff at the West Japan Oncology Group’s data centre (Osaka, Japan) used a computer-generated allocation sequence with dynamic minimisation that balanced stage (IIIB/IV or postoperative recurrent), sex, and institution for randomisation, which was centrally implemented. They also assigned patients to groups. Investigators did not have access to the allocation sequence: randomisation was done via the computer screen developed by an outside contract research organisation (EPS, Tokyo, Japan), with a follow-up fax to notify investigators at each site of the allocation result. Masking was not done in this trial, and patients, investigators and other treating oncologists, staff at participating centres, central data centre staff, and the statistician (TY) were aware of patients’ assigned treatment.

Procedures Patients assigned to the nedaplatin group received intravenous 100 mg/m² nedaplatin and 60 mg/m² docetaxel on day 1. Patients in the cisplatin group received 80 mg/m² cisplatin and 60 mg/m² docetaxel on day 1. Both treatment regimens were repeated every 3 weeks for four to six cycles at the attending oncologists’ discretion (ie, after four cycles, the

oncologist decided whether a fifth and sixth dose was appropriate) and continued until disease progression, development of unacceptable toxic effects, or at patients’ request to stop treatment. Further treatment of any description after progression was at the attending oncologists’ discretion. Treatment was continued after the first cycle if patients’ performance status, white blood cell count, absolute neutrophil count, platelet count, and alanine and aspartate aminotransferase concentrations continued to meet inclusion criteria; axillary body temperature was less than 38°C within the past 24 h; creatinine concentrations were 132·2 μmol/L or less; and if they had only non-haematological toxic effects (excluding alopecia and weight loss) of grade 2 or lower. The dose of docetaxel after the first cycle was reduced by 10 mg/m² if the patient’s absolute neutrophil count was less than 0·5 × 10⁹ cells per L for 4 or more consecutive days or platelet count was less than 25 × 10⁹ cells per L, or if febrile neutropenia or other grade 3 nonhaematological toxic effects (excluding anorexia, nausea, vomiting, hyponatraemia, hypokalaemia, weight loss, and alopecia) developed. Additionally, doses of nedaplatin were reduced by 25 mg/m², and of cisplatin by 20 mg/m², if the patient met any of these criteria or if his or her creatinine concentrations were between 132·6 μmol/L and 176·8 μmol/L. Treatment was stopped if a patient did not meet the criteria to start the subsequent cycle by day 43, if two dose reductions were required, or if grade 4 non-haematological toxic effects occurred, creatinine concentrations were greater than 176·8 μmol/L, or grade 2–4 interstitial pneumonia occurred. Primary prophylactic granulocyte colony-stimulating factor or prophylactic antibiotics were not given. For patients who had developed grade 4 neutropenia or grade 3 febrile neutropenia during previous cycles of chemotherapy, secondary prophylactic granulocyte colonystimulating factor was allowed. Before enrolment, each patient provided a complete medical history and underwent physical examinations, full blood counts, biochemical laboratory examinations, chest radiography, pulse oximetry to measure oxygen saturation or arterial oxygen saturation, electrocardiography, chest and abdominal CT, whole-brain CT or MRI, and isotope bone scans or ¹⁸F-fluorodeoxyglucose PET. Chest radiography, full blood counts, and differential white blood cell counts were done, and other biochemical laboratory data measured, at least every 2 weeks during study treatment. For efficacy assessments, patients underwent imaging of assessable lesions every 2 months for the first 6 months, once every 3 months for months 7–12, and thereafter at the investigator’s discretion. When progression was suspected on the basis of worsening symptoms or abnormal laboratory results, site of suspected progression was examined radiologically. Presence or absence of postprotocol therapies (eg, drug name, start date) was investigated. In principle, after

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For the trial protocol see http:// www.wjog.org/index.html

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355 randomly assigned

178 allocated to nedaplatin plus docetaxel

177 allocated to cisplatin and docetaxel

1 ineligible* 1 palliative radiotherapy within 2 weeks of enrolment

177 included in modified intention-to-treat analysis

5 ineligible* 1 second malignancy 1 stage IIIA disease 1 interstitial pneumonia 1 palliative radiotherapy within 2 weeks of enrolment 1 adjuvant chemotherapy within a year of enrolment

172 included in modified intention-to-treat analysis

1 withdrew before treatment 1 symptom deterioration

2 withdrew before treatment 1 deterioration of complication 1 oncologist’s decision

175 included in safety analysis

177 included in safety analysis

Figure 1: Trial profile *Patients received at least one treatment.

completion or termination of protocol therapy, postprotocol therapy was not premitted until unequivocal disease progression was demonstrated. However, this principle was not be applied if the treating oncologist decided that postprotocol therapy was necessary in light of a patient’s request or for their benefit. For those who relapsed, any postprotocol therapies were allowed.

Outcomes The primary endpoint was overall survival from date of randomisation until death from any cause. Secondary endpoints were progression-free survival (calculated from the date of randomisation until the date of documented progression or death), the proportion of patients achieving an overall response, and safety. Responses were assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST), (version 1.1). The proportion of patients achieving a response and disease control were calculated in patients with measurable lesions only (patients had to have measureable lesions at baseline to be included in this analysis). To assign stable disease as the best overall response, a patient had to have stable disease for at least 6 weeks once or more after the initiation of protocol therapy. We assessed adverse events according to the National Cancer Institute’s Common Terminology Criteria (version 3.0).

Statistical analysis The initial target sample size was 250 and number of events was 218, with a one-sided α of 0·05 and 80% power to detect a hazard ratio (HR) of 0·714 between the groups on the basis of the assumption that median survival time would be 14 months with the nedaplatin 4

regimen and 10 months with the cisplatin regimen. In January, 2011, we decided to increase the statistical power to 90% under data masking. The revised targeted sample size was 350 and revised number of events was 303 (the HR remained unchanged). This proposal was approved by the independent data monitoring committee, which consisted of clinicians and biostatisticians, in April, 2011. The significance level was set at a one-sided α of 0·05, as specified in the protocol. The rationale for the choice of a one-sided α is that cisplatin plus docetaxel remains the standard treatment for NSCLC irrespective of whether nedaplatin plus docetaxel is significantly inferior to cisplatin plus docetaxel—ie, significance of inferiority does not contribute to the clinical decision. Therefore, a one-sided criterion was chosen to analyse overall survival. We scheduled two interim analyses. The first was done after half the planned sample size had been randomly assigned (July 1, 2011), and the second was done after accrual of patients was completed (Dec 12, 2013), with a multiplicity adjustment for analyses of the primary endpoint by the O’Brien-Fleming type α-spending function. After the sample size was increased, information time and α-spending were based on the revised targeted number of events and the significance level was maintained at a one-sided 5% level. TY was masked to the results of the interim analysis while he prepared the statistical analysis plan for the interim results. The analyses were done independently from all investigators. Results of the interim analyses were reviewed by the independent data monitoring committee, and investigators (including TY) were masked to the results. Efficacy analyses were done on a modified intention-totreat basis,20 and excluded enrolled patients who did not

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meet inclusion criteria. Safety analyses included all enrolled patients who received at least one dose of study drug. Both overall and progression-free survival were estimated by the Kaplan-Meier method and were analysed by log-rank testing stratified by stage and sex. HRs were estimated with a Cox regression model, stratified by stage and sex. We used log–log plots to graphically assess the proportional hazards assumption. p values of log-rank testing for overall survival and progression-free survival were denoted as one sided, whereas all other analyses were exploratory, and thus two sided. 95% CIs were used throughout this Article. The proportion of patients who achieved a response and disease control were compared between groups with Fisher’s exact test. We did preplanned subgroup analyses for age (≥70 years vs <70 years), sex (male vs female), Eastern Cooperative Oncology Group performance status (0 vs 1), disease stage (IIIB or postoperative recurrence vs IV), and smoking history (current or former smoker vs never smoker). In the analysis of treatment-by-factor interaction, p values of less than 0.10 were deemed significant. All analyses were done by the West Japan Oncology Group’s data centre with SAS (version 9.1.3). This trial is registered with UMIN Clinical Trials Registry, number UMIN000002015.

one-sided stratified log-rank p=0·037; figure 2A). There was no deviation from the proportional hazards assumption. In the nedaplatin group, median overall survival was 13·6 months (95% CI 11·6–15·6), 1-year overall survival was 55·9% (48·3–62·9), and 2-year overall survival was 27·1% (20·7–33·8). In the cisplatin group, median overall survival was 11·4 months (95% CI 10·2–12·2); 1-year overall survival was 43·5% (35·9–50·8) and 2-year overall survival was 18·1% (12·7–24·3). Of the pre-planned subgroup analyses, only performance status (0 vs 1; pinteraction=0·011) and stage (IIIB or postoperative recurrence vs IV; pinteraction=0·057) showed a significant treatment interaction; there was no significant interaction for age (≥70 years vs <70 years; pinteraction=0·757), sex (male vs female; pinteraction=0·915); or smoking status (smoker vs never smoker; pinteraction=0·133; appendix). Progression-free survival was not significantly different between the two groups (HR 0·83, 95% CI 0·67–1·04; onesided stratified log-rank p=0·050; figure 2B). In the nedaplatin group, median progression-free survival was 4·9 months (95% CI 4·5–5·6) and 6-month progression-free survival was 35·6% (28·6–42·6). In the cisplatin group, median progression-free survival was 4·5 months (95% CI 4·2–4·8) and 6-month progression-free survival was 27·9% (21·4–34·7).

See Online for appendix

Role of the funding source The West Japan Oncology Group (a non-profit organisation supported by donations) designed the trial and was independently responsible for it. Sanofi did not provide the study drugs and had no role in study design; collection, analysis, or interpretation of data; or writing of the Article. TSh, TY, and NY had full access to all study data, and NY had final responsibility for the decision to submit for publication.

Results Between July 6, 2009, and July 26, 2012, 355 patients enrolled at 53 institutions were randomly assigned to nedaplatin plus docetaxel (n=178) or cisplatin plus docetaxel (177; figure 1). One patient in the nedplatin group and five in the cisplatin group were ineligible after enrolment and were excluded from efficacy analyses (figure 1). One patient in the nedaplatin group and two in the cisplatin group withdrew before study treatment and were excluded from safety analyses (figure 1). Baseline characteristics were well balanced between the two groups (table 1). The median number of treatment cycles and dose intensity did not differ between groups (table 2). Median follow-up of the 349 patients in the modified intention-to-treat population was 39·3 months (IQR 31·3–48·7): 40·5 months (IQR 30·2–48·7) in the nedplatin group and 38·4 months (34·3–49·4) in the cisplatin group. 307 patients died, 153 (86%) in the nedaplatin group and 154 (90%) in the cisplatin group. Overall survival was significantly longer in the nedaplatin than in the cisplatin group (HR 0·81, 95% CI 0·65–1·02;

Nedaplatin plus Cisplatin plus docetaxel (n=177) docetaxel (n=172) Age (years) Median years (IQR)

64 (61·0–68·0)

65 (61·5–68·5)

Range (years)

37–74

41–74

≥70

33 (19%)

31 (18%)

<70

144 (81%)

141 (82%)

157 (89%)

153 (89%)

20 (11%)

19 (11%)

Sex Male Female Smoking status Never smoker Current or former smoker

5 (3%)

10 (6%)

172 (97%)

162 (94%)

ECOG performance status 0

81 (46%)

63 (37%)

1

96 (54%)

109 (63%)

Stage at screening IIIB

56 (32%)

56 (33%)

IV

107 (61%)

106 (62%)

14 (8%)

10 (6%)

Postoperative recurrence Histology Squamous cell cancer

171 (97%)

169 (98%)

Adenosquamous cell cancer

3 (2%)

2 (1%)

Not otherwise specified

3 (2%)

1 (1%)

Data are n (%), unless otherwise specified. ECOG=Eastern Cooperative Oncology Group.

Table 1: Baseline characteristics of patients in the modified intention-to-treat population

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Cisplatin plus Nedaplatin plus docetaxel docetaxel (n=172) (n=177) Cycles received 0

1 (1%)

2 (1%)

1–3

48 (27%)

64 (37%)

4

68 (38%)

72 (42%)

5

20 (11%)

11 (6%)

6

40 (23%)

23 (13%)

4 (1–6)

4 (1–6)

Median (range) Median relative dose intensity

93%

··

Cisplatin

Nedaplatin

··

92%

Docetaxel

93%

95%

Data are n (%) unless otherwise specified.

Table 2: Treatment exposure in the modified intention-to-treat population

A 100

Nedaplatin + docetaxel Cisplatin + docetaxel

90

Overall survival (%)

80 70 60 50 40 HR 0·81 (95% CI 0·65–1·02); p=0·037

30 20 10 0 0

3

6

9

12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 Months

Number at risk Nedaplatin + docetaxel 177 170 144 125 99 81 67 58 46 34 24 17 13 11 Cisplatin + docetaxel 172 162 137 105 73 52 43 34 30 28 26 20 14 9

7 6

5 4

4 2

2 0

1 0

0 0

B 100

Progression-free survival (%)

90 80 70 60 50 40 30

HR 0·83 (95% CI 0·67–1·04); p=0·050

20

Discussion

10 0 0 Number at risk Nedaplatin + docetaxel 177 Cisplatin + docetaxel 172

3

6

9

12 Months

15

18

21

24

136 129

63 48

22 18

15 12

12 6

9 5

8 5

6 4

Figure 2: Kaplan-Meier graphs of overall survival (A) and progression-free survival (B) in the nedaplatin and cisplatin groups p values were calculated by stratified log-rank tests (one sided).

Of the 172 patients with a target lesion in the nedaplatin group, the proportion of patients who achieved a response was 56%, and 85% achieved disease control (three [2%] 6

patients had complete responses, 93 [54%] had partial responses, and 50 [29%] had stable disease). Of the 168 patients with a target lesion in the cisplatin group, the proportion of patients who achieved a response was 53%, and 81% achieved disease control (one patient [1%] had a complete response, 88 [52%] had partial responses, and 47 [30%] had stable disease). There was no significant difference between treatment groups in the proportion of patients who achieved a response (two-sided Fisher’s exact test p=0·66) or disease control (0·39). Grade 3 or worse adverse events were observed in 162 (92%) of 177 patients in the nedaplatin group and 157 (90%) of 175 in the cisplatin group. Table 3 shows all adverse events with a frequency of greater than 10% and additional adverse events of special interest. Grade 3 or worse adverse events of nausea, fatigue, hyponatraemia, and hypokalaemia were less frequent in the nedaplatin group than in the cisplatin group. Grade 3 or worse adverse events of leucopenia, neutropenia and thrombocytopenia were more frequent in the nedaplatin than in the cisplatin group (table 3). However, only one patient in the nedaplatin group had grade 4 thrombocytopenia, and no differences were noted in in grade 3 or worse febrile neutropenia or infection. Other grade 3, 4, and 5 adverse events are listed in the appendix. 52 (29%) of 177 patients in the nedaplatin group and 52 (30%) of 175 patients in the cisplatin group required dose reductions. Adverse events leading to discontinuation of the study drug were not significantly more common in the cisplatin group (23%) than in the nedaplatin group (15%; p=0·077). Four treatment-related deaths were recorded in the nedaplatin group (infection with grade 3 or higher neutropenia, pneumonia and renal failure, gastrointestinal bleeding, and pneumonitis), and three in the cisplatin group (cardiac failure, hyponatraemia, and pneumonia with sepsis). 138 (78%) of 177 patients in the nedaplatin group and 132 (77%) of 172 in the cisplatin group received secondline chemotherapy (appendix); regimens did not substantially differ between groups. The proportion of patients who received third-line chemotherapy was significantly higher in the nedaplatin than in the cisplatin group (54% vs 40%, p=0·014).

First-line treatment with nedaplatin and docetaxel was associated with significantly longer overall survival than was cisplatin and docetaxel, and had a different safety profile. Median overall survival was 13·6 months (95% CI 11·6–15·6) in the nedaplatin group and 11·4 months (10·2–12·2) in the cisplatin group, which was reasonably consistent with our protocol estimates of 14 and 10 months, respectively. Nedaplatin has antitumour activity against squamous cell carcinomas originating from several organs, including the lung, oesophagus, head and neck, and uterine cervix.21

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Nedaplatin plus docetaxel (n=177) Grade 1–2

Grade 3

Cisplatin plus docetaxel (n=175)

Grade 4

Grade 5

Grade 1–2

Grade 3

Grade 4

Grade 5

0

Adverse events with frequency >10% Leucopenia

70 (40%)

84 (48%)

14 (8%)

0

86 (49%)

64 (37%)

13 (7%)

Neutropenia

24 (14%)

48 (27%)

98 (55%)

0

41 (23%)

58 (33%)

65 (37%)

0

111 (63%)

18 (10%)

2 (1%)

0

123 (70%)

26 (15%)

1 (1%)

0

26 (15%)

Anaemia Thrombocytopenia Febrile neutropenia Infection Nausea

59 (33%)

15 (9%)

1 (1%)

0

22 (12%)

1 (1%)

1 (1%)

19 (11%)

29 (16%)

0

2 (1%)

119 (67%)

7 (4%)

0

0

0

0

0 (0%) 26 (15%)

0

0

1 (1%)

0

20 (11%)

26 (15%)

1 (1%)

1 (1%)

113 (65%)

25 (14%)

0

0

Vomiting

45 (25%)

5 (3%)

0

0

55 (31%)

6 (3%)

0

0

Anorexia

120 (68%)

23 (13%)

0

0

111 (63%)

46 (26%)

0

0

Constipation

80 (45%)

2 (1%)

0

0

99 (57%)

0

0

0

Diarrhoea

67 (38%)

7 (4%)

0

0

85 (49%)

9 (5%)

0

0

117 (66%)

6 (3%)

0

0

117 (67%)

19 (11%)

1 (1%)

0 0

Fatigue Fever

63 (36%)

0

0

1 (1%)

58 (33%)

1 (1%)

0

Rash

33 (19%)

0

0

0

26 (15%)

1 (1%)

0

0

Mucositis

43 (24%)

1 (1%)

0

0

28 (16%)

2 (1%)

0

0

Alopecia

118 (67%)

Sensory neuropathy

38 (22%)

0

0

0

116 (66%)

0

0

0

2 (1%)

0

0

31 (18%)

1 (1%)

0

0

Tumour pain

18 (10%)

2 (1%)

0

0

16 (9%)

1 (1%)

0

0

Pain (not otherwise specified)

36 (20%)

0

0

0

33 (19%)

1 (1%)

0

0

Hiccups

7 (4%)

0

0

0

21 (12%)

1 (1%)

0

0

Albumin

106 (60%)

8 (5%)

0

0

119 (68%)

3 (2%)

0

0

Alkaline phosphatase

49 (28%)

0

0

0

41 (23%)

0

0

0

Aspartate aminotransferase

70 (40%)

2 (1%)

0

0

44 (25%)

2 (1%)

0

0 0

Alanine aminotransferase

71 (40%)

3 (2%)

0

0

59 (34%)

3 (2%)

0

Total bilirubin

30 (17%)

2 (1%)

0

0

18 (10%)

0 (0·0%)

0

0

Creatinine

17 (10%)

1 (1%)

0

0

82 (47%)

3 (2%)

0

0

Hyponatraemia

85 (48%)

23 (13%)

1 (1%)

0

90 (51%)

47 (27%)

Hyperkalaemia

55 (31%)

4 (2%)

1 (1%)

0

57 (33%)

1 (1%)

Hypokalaemia

18 (10%)

4 (2%)

0

0

38 (22%)

Hypocalcaemia

100 (57%)

2 (1%)

0

0

105 (60%)

4 (2%)

1 (1%)

0

1 (1%)

12 (7%)

1 (1%)

3 (2%)

0

5 (3%)

1 (1%)

0

0

12 (7%)

3 (2%)

0

4 (2%)

2 (1%)

0

5 (3%)

4 (2%)

0

0

5 (3%)

2 (1%)

0

0

Additional adverse events of special interest Pneumonitis Allergic reaction Motor neuropathy

5 (3%)

0

1 (1%)

0

4 (2%)

2 (1%)

0

0

Hypernatraemia

5 (3%)

0

0

0

3 (2%)

0

0

0

Hypercalcaemia

3 (2%)

1 (1%)

1 (1%)

0

3 (2%)

0

0

0

Data are n (%). Adverse events are presented irrespective of treatment attribution. Patients with events in more than one category are counted once in each of those categories. The table includes grade 1–2 adverse events that occurred in >10% of patients, all grade 3–5 events, and events of special interest.

Table 3: Common adverse events

In a preclinical study,22 uptake of nedaplatin by seven human lung cancer cell lines was measured. The intracellular concentration of nedaplatin rose promptly and was higher in squamous cells (PC-10) than adenocarcinoma cells (PC-3), suggesting that nedaplatin has more antitumour activity against squamous cell carcinoma than adenocarcinoma. The combination chemotherapy of nedaplatin and docetaxel was well tolerated and efficacious as second-line chemotherapy in patients with cisplatin-pretreated refractory metastatic or recurrent oesophageal squamous cell carcinoma.23

Several important non-haematological adverse events (nausea, anorexia and fatigue) were less frequent and milder in the nedaplatin than in the cisplatin group. In the nedaplatin group, important symptomatic adverse events were less frequent than they were in the cisplatin group, and the number of patients who could receive third-line chemotherapy was significantly higher. Progression-free survival did not differ significantly between groups in our study. In a subgroup analysis of a phase 3 trial24 of cisplatin plus pemetrexed versus cisplatin plus gemcitabine in patients with NSCLC, overall survival

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was significantly longer in the pemetrexed than in the gemcitabine group, but progression-free survival did not differ significantly between groups in patients with nonsquamous disease. The safety profiles of the experimental group and control group differed both in that study and in ours, which could have affected adherence to subsequent chemotherapy and resulted in discrepancies between overall and progression-free survival. Because we thought most progression-free-survival events would occur during the first 6 months, we performed tumour assessments more regularly then. However, the scheduling of these assessments in general was not precise (eg, every 8 weeks until progression), which might have increased the difficulty of detecting a significant difference in progression-free survival between groups. Our subgroup analysis showed a significant relation between performance status and overall survival and stage and overall survival only. The combination of cisplatin or carboplatin plus vinorelbine, gemcitabine, irinotecan, paclitaxel, nanoparticle albumin-bound paclitaxel, or docetaxel is the standard first-line treatment in patients with advanced squamous cell lung cancer. The combination of carboplatin plus nanoparticle albumin-bound paclitaxel resulted in significantly higher proportions of patients achieving a response than did carboplatin plus paclitaxel in advanced NSCLC, especially squamous cell lung cancer.25 41% of patients with squamous disease in the nanoparticle albumin-bound paclitaxel group achieved a response. The higher proportion of patients achieving a response in our study (56% in the nedaplatin group and 53% in the cisplatin group) might be related to the absence of an independent radiology assessment; the use of RECIST version 1.1, which, unlike version 1.0, does not require such confirmation to determine complete or partial response; or differences in the ethnic make-up of the trial populations. Our study had several limitations. Firstly, this study was done in a Japanese population, which is pharmacogenomically different from western populations, which could lead to different responses and adverse events.26 Thus clinical trials including pharmacogenomic analyses are warranted in populations of different ethnicities. Secondly, in view of the efficacy of carboplatin plus nanoparticle albumin-bound paclitaxel, perhaps this regimen would have been a better control group.26 However, progression-free and overall survival did not differ significantly between carboplatin plus paclitaxel and carboplatin plus nanoparticle albuminbound paclitaxel,25 and cisplatin plus docetaxel is an acceptable control regimen. Although 80 mg/m² cisplatin plus 60 mg/m² docetaxel was associated with significantly longer overall survival than was cisplatin plus vindesine, the dose of docetaxel in that trial and our study was lower than the standard dose outside Japan.12,27 This dose difference warrants a confirmatory study including a non-Japanese population. Thirdly, the 8

significance of overall survival differences was based on one-sided rather than two-sided, testing. However, we think that the HR of 0·81 shows a clear benefit for nedaplatin in this population, when the HRs of overall survival in positive trials presented by the American Society of Clinical Oncology are taken into account.7,28,29 Finally, our study lacked a quality-of life assessment which would have been informative. In conclusion, nedaplatin plus docetaxel could be a new treatment option for advanced or relapsed squamous cell lung cancer. Further investigation is needed to elucidate the mechanism of sensitivity of squamous cell lung cancer to nedaplatin and to determine predictive biomarkers for the drug’s efficacy. Contributors TSh, TY, TSe, TT, KN, YN, and NY conceived and designed the study (TY was in charge of study design). KN and YN supervised the study. All authors were involved in the provision of study material and patients, and data acquisition. TSh, TY, and NY were responsible for data management, statistical analysis, and data interpretation. All authors were involved in writing the report and approved the final version. Declaration of interests KG received personal fees from Sanofi. TO received grants from Nippon Kayaku. YH received personal fees from Sanofi. All other authors declare no competing interests. Acknowledgments This study was done and funded by the West Japan Oncology Group, a non-profit organisation. This study was also partly supported by Sanofi. We thank the patients and their families for their support and participation in this trial. We thank the data managers and other supporting staff of the West Japan Oncology Group, especially Kaori Mori and Shinichiro Nakamura. References 1 Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin 2015; 65: 87–108. 2 Peters S, Adjei AA, Gridelli C, Reck M, Kerr K, Felip E. Metastatic non-small-cell lung cancer (NSCLC): ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012; 23 (suppl 7): vii56–64. 3 National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN guidelines) Version 5. http://www. nccn.org/professionals/physician_gls/f_guidelines.asp (accessed Aug 25, 2015). 4 Japan Lung Cancer Society. Guidelines for the treatment of lung cancer. https://www.haigan.gr.jp/modules/guideline/index. php?content_id=3 (accessed Aug 25, 2015, in Japanese). 5 Meza R, Meernik C, Jeon J, Cote ML. Lung cancer incidence trends by gender, race and histology in the United States, 1973–2010. PLoS One 2015; 10: e0121323. 6 Sawabata N, Asamura H, Goya T, et al. Japanese Lung Cancer Registry study: first prospective enrollment of a large number of surgical and nonsurgical cases in 2002. J Thorac Oncol 2010; 5: 1369–75. 7 Thatcher N, Hirsch FR, Luft AV, et al, for the SQUIRE Investigators. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial. Lancet Oncol 2015; 16: 763–74. 8 Sandler A, Gray R, Perry MC, et al. Paclitaxel–carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006; 355: 2542–50. 9 Paz-Ares LG, de Marinis F, Dediu M, et al. PARAMOUNT: final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Clin Oncol 2013; 31: 2895–902.

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