- Email: [email protected]
Randomized Phase III Study of Cisplatin With Pemetrexed and Cisplatin With Vinorelbine for Completely Resected Nonsquamous Non–Small-Cell Lung Cancer: The JIPANG Study Protocol
Current Trial Report
Randomized Phase III Study of Cisplatin With Pemetrexed and Cisplatin With Vinorelbine for Completely Resected Nonsquamous NoneSmall-Cell Lung Cancer: The JIPANG Study Protocol Nobuyuki Yamamoto,1 Hirotsugu Kenmotsu,2 Takeharu Yamanaka,3 Shinichiro Nakamura,4 Masahiro Tsuboi5 Abstract This trial report describes the background and design for the Japan Intergroup Trial of Pemetrexed Adjuvant Chemotherapy for Completely Resected Nonsquamous NoneSmall-Cell Lung Cancer (JIPANG) study (University Hospital Medical Information Network database: UMIN000006737). Various randomized trials have shown the efficacy of postoperative adjuvant chemotherapy regimens that include cisplatin for resected nonesmall-cell lung cancer (NSCLC), but the optimal regimen is not known. The JIPANG study is a randomized study comparing cisplatin (75 mg/m2, day 1) and pemetrexed (500 mg/m2, day 1) with cisplatin (80 mg/m2, day 1) and vinorelbine (25 mg/m2, days 1 and 8) for nonsquamous NSCLC as postoperative adjuvant chemotherapy. A total of 804 patients with pathological stage II to IIIA completely resected nonsquamous NSCLC were enrolled in this study between March 2012 and August 2016. These patients have been randomized in a 1:1 ratio and stratified according to sex (female vs. male), age (< 70 years vs. 70 years), pathologic stage (II vs. IIIA), mutation of the epidermal growth factor receptor (mutant vs. wild) and institution. Each treatment will be undertaken every 3 weeks until 4 cycles have been completed. The primary endpoint is overall survival and the secondary endpoints are disease-free survival, rate of treatment completion, and incidence of adverse events. This design has 80% power to detect overall survival with a hazard ratio of 0.786 (a ¼ 1-sided 0.05) with 5-year follow-up after registration of the final patient. This study will show a superior regimen for completely resected nonsquamous NSCLC. Biomarker analyses of the JIPANG study are ongoing. Clinical Lung Cancer, Vol. -, No. -, --- ª 2017 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Keywords: Adjuvant chemotherapy, Cisplatin, Nonsquamous nonesmall-cell lung cancer, Pemetrexed, Vinorelbine
Introduction The efficacy of postoperative adjuvant chemotherapy including cisplatin for nonesmall-cell lung cancer (NSCLC) was reported first in 2004.1-3 A meta-analysis of 4584 patients enrolled in a large-scale comparative study of cisplatin-based postoperative chemotherapy
Registered in the University Hospital Medical Information Network database (UMIN000006737). 1
Third Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan 2 Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan 3 Department of Biostatistics, Yokohama City University, Yokohama, Japan 4 West Japan Oncology Group Data Center, Osaka, Japan 5 Department of Thoracic Surgery, National Cancer Center Hospital East, Chiba, Japan
1525-7304/ª 2017 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). http://dx.doi.org/10.1016/j.cllc.2017.05.020
(the Lung Adjuvant Cisplatin Evaluation [LACE]) showed that the hazard ratio against death in all patients was 0.89 (95% confidence interval, 0.82-0.96), which corresponded to an absolute survival benefit of 5.4% at 5 years.4 In addition, subgroup analyses of the LACE study showed that only vinorelbine significantly prolonged
Submitted: May 24, 2017; Accepted: May 30, 2017 Address for correspondence: Hirotsugu Kenmotsu, MD, Division of Thoracic Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8777, Japan Fax: 81-55-989-5634; e-mail contact: [email protected]
Clinical Lung Cancer Month 2017
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The JIPANG Study Protocol
2
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survival among various drugs coadministered with cisplatin (P ¼ .005). Postoperative chemotherapy significantly improved survival time in stages II and III, and an improvement trend was shown in stage IB, whereas a deteriorating trend was found in stage IA.5 For patients with metastatic nonsquamous NSCLC, a combination of pemetrexed with cisplatin has been a standard treatment. A randomized phase III study showed the noninferiority in overall survival (OS) of pemetrexed in combination with cisplatin compared with gemcitabine in combination with cisplatin in untreated advanced NSCLC (hazard ratio, 0.94; 95% confidence interval, 0.84-1.05).6 A subgroup analysis of adenocarcinoma and large-cell carcinoma showed that a combination of pemetrexed with cisplatin showed significantly better survival (adenocarcinoma: 12.6 vs. 10.9 months, P ¼ .03; large-cell carcinoma: 10.4 vs. 6.7 months, P ¼ .03). In a phase III study of pemetrexed compared with docetaxel for previously treated NSCLC, the subgroup analysis of adenocarcinoma also showed that pemetrexed significantly prolonged the survival time.7 These results suggest that pemetrexed is highly effective for the treatment of nonsquamous NSCLC. In postoperative adjuvant chemotherapy, 2 randomized phase II studies evaluating a combination of pemetrexed with cisplatin have been reported. The randomized phase II Trial on Refinement of Early-stage NSCLC Adjuvant Chemotherapy with Cisplatin and Pemetrexed versus Cisplatin and Vinorelbine (TREAT) study evaluated the feasibility of 4 cycles of cisplatin (75 mg/m2, day 1) and pemetrexed (500 mg/m2, day 1) every 3 weeks as adjuvant chemotherapy for NSCLC patients.8 One-hundred thirty-two patients with completely resected stages IB to pT3N1 NSCLC were assigned randomly to vinorelbine with cisplatin or pemetrexed with cisplatin. The primary endpoint was the clinical feasibility (no Grade 4 neutropenia/thrombocytopenia or thrombocytopenia with bleeding, no Grade 3/4 febrile neutropenia or nonhematologic toxicity; no premature withdrawal/death). The feasibility rate was better for the combination of pemetrexed with cisplatin (95.5%) compared with the combination of vinorelbine with cisplatin (75.4%; P ¼ .001). After a 3-year follow-up of the TREAT study, there were no significant differences in the efficacies between these 2 chemotherapy regimens.9 Second, a randomized phase II study of pemetrexed in combination with cisplatin or carboplatin as adjuvant chemotherapy in patients with completely resected stage IB/II NSCLC has also been reported. The primary endpoint was treatment feasibility, defined as 4 cycles completed with no cycle delay > 42 days and 2 dose reductions, with a median relative dose intensity 95%; and no Grade 3 toxicities at the follow-up visit 30 days after the final dose. This study involved 122 patients, and neither regimen met the primary endpoint (feasibility rate: 59.4% for pemetrexed with cisplatin and 50% for pemetrexed with carboplatin).10 These results suggested that a combination of pemetrexed with cisplatin was also feasible as postoperative adjuvant chemotherapy. On the basis of this background, we conducted a randomized phase III study comparing cisplatin (75 mg/m2, day 1) and pemetrexed (500 mg/m2, day 1) with cisplatin (80 mg/m2, day 1) and vinorelbine (25 mg/m2, days 1 and 8) for patients with nonsquamous NSCLC as postoperative adjuvant chemotherapy. In Japan, pemetrexed is approved for the treatment of advanced or
Clinical Lung Cancer Month 2017
recurrent NSCLC, but not for postoperative adjuvant chemotherapy. Therefore, one of our objectives was to obtain approval for this regimen as adjuvant chemotherapy from Pharamceuticals and Medical Devices Agency (Japan).
Patients and Methods Study Design and Objectives The Japan Intergroup Trial of Pemetrexed Adjuvant Chemotherapy for Completely Resected Nonsquamous NoneSmall-Cell Lung Cancer (JIPANG) study was designed as an open-label, randomized phase III trial to evaluate the efficacy of pemetrexed with cisplatin in patients with completely resected nonsquamous NSCLC compared with vinorelbine with cisplatin as postoperative adjuvant chemotherapy. Patients are randomized in a 1:1 ratio to the experimental arm (pemetrexed with cisplatin) or control arm (vinorelbine with cisplatin), stratified according to sex (female vs. male), age (< 70 years vs. 70 years), pathologic stage (II vs. IIIA), mutation of the epidermal growth factor receptor (EGFR; mutant vs. wild) and institution (Figure 1). The primary endpoint is OS. The secondary endpoints are disease-free survival, rate of treatment completion, and safety. In addition, biomarker analyses for patients enrolled in this study are ongoing. This study has been conducted in compliance with the principles of the Declaration of Helsinki, and is registered in the University Hospital Medical Information Network database (UMIN000006737).
Key Eligibility Criteria Key eligibility criteria are patients aged 20 to 75 years, histologically confirmed pathological stage II or IIIA nonsquamous NSCLC (Union for International Cancer Control Tumor, Node, Metastases classification, seventh edition), proven mutation of the EGFR gene, Eastern Cooperative Oncology Group performance status of 0 or 1, as well as adequate hematologic and organ function. Each patient receives complete resections using lobectomy or pneumonectomy with resection of any involved N1 lymph nodes within 3 to 8 weeks before patient enrollment. All patients must sign informed consent forms approved by the review board of each institution. Key exclusion criteria are severe postoperative complications, interstitial pneumonia on computed tomography of the chest, currently pregnant women, and other severe complications.
Treatment Plan Patients enrolled in this study will be randomized to receive pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) by intravenous infusion on the first day, or vinorelbine (25 mg/m2) on the first and eighth days and cisplatin (80 mg/m2) on the first day by intravenous infusion. This treatment, defined as “1 cycle,” will be repeated every 3 weeks until 4 cycles have been completed.
Statistical Design The primary endpoint of this study is OS, defined as the duration from patient enrollment to the date of death or the patient’s last visit. The 5-year survival rate of patients treated with vinorelbine with cisplatin as the control arm is estimated to be 50% on the basis of previous reports.
Nobuyuki Yamamoto et al Figure 1 Japan Intergroup Trial of Pemetrexed Adjuvant Chemotherapy for Completely Resected Nonsquamous NoneSmall-Cell Lung Cancer (JIPANG) Study Design
Randomize
p-Stage II-IIIA, completely resected nonsquamous NSCLC PS: 0-1 Age: 20–75 years
Cisplatin (75 mg/m2 , day 1) with Pemetrxed (500 mg/m2 , day 1) Every 3 weeks for 4 cycles (n = 400)
Cisplatin (80 mg/m2 , day 1) with Vinorelbine (25 mg/m2 , day 1 and 8) Every 3 weeks for 4 cycles (n = 400)
Abbreviations: NSCLC ¼ nonesmall-cell lung cancer; PS ¼ performance status.
In this study, the 5-year survival rate is expected to be improved by approximately 8%. To carry out the log rank test under the chosen condition (a ¼ 1-sided 0.05; 1-b ¼ 0.8; 3-year registration period and 5-year follow-up after registration of the last patient), 426 events and 777 patients are required. After allowance for exclusion of some patients from analyses, the sample size is planned at 400 patients per arm (a total of 800 patients). A total of 804 patients with pathological stage II to IIIA completely resected nonsquamous NSCLC were enrolled in this study between March 2012 and August 2016.
Discussion A study on the basis of a Japanese lung cancer registry showed that stage-specific prognoses improved over 1 decade.11 In addition, some Japanese phase II studies have reported that the 5-year OS rate was approximately 70% in patients with stage II to IIIA NSCLC who underwent postoperative adjuvant chemotherapy.12,13 This phenomenon might be influenced by recent advances in diagnostic and surgical procedures and the improved efficacy of chemotherapy, including molecular targeted therapies. Therefore, it might be acceptable to change the primary endpoint from OS to disease-free survival in this study. This JIPANG study is ongoing as an intergroup study among 7 clinical study groups in Japan14: Lung Oncology Group in Kyushu, Setouchi Lung Cancer Group, Japan Multinational Trial Organization, West Japan Oncology Group (WJOG), Central Japan Lung Study Group, Tokyo Cooperative Oncology Group, and the Thoracic Oncology Research Group.
Conclusion Cisplatin-based chemotherapy remains standard treatment for patients who have undergone complete resection of stage II to III NSCLC. The JIPANG study will show the optimal chemotherapy regimen for completely resected nonsquamous NSCLC.
Acknowledgments We thank the patients, their families, and all of the JIPANG investigators who are participating in this study. This study is
supported by Seiko Tanaka and other staff members of the WJOG Data Center (data management) and the Pharma-Valley Center, Shizuoka Industrial Foundation (study management). Pemetrexed for this study was provided by Eli Lilly (Tokyo, Japan). This study was funded by the Japan Agency for Medical Research and Development (grant number 16lk0201005h0005).
References 1. Arriagada R, Bergman B, Dunant A, et al. Cisplatin-based adjuvant chemotherapy in patients with completely resected nonesmall-cell lung cancer. N Engl J Med 2004; 350:351-60. 2. Winton T, Livingston R, Johnson D, et al. Vinorelbine plus cisplatin vs. observation in resected nonesmall-cell lung cancer. N Engl J Med 2005; 352:2589-97. 3. Douillard JY, Rosell R, De Lena M, et al. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA nonesmallcell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol 2006; 7:719-27. 4. Pignon JP, Tribodet H, Scagliotti GV, et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol 2008; 26:3552-9. 5. Douillard JY, Tribodet H, Aubert D, et al. Adjuvant cisplatin and vinorelbine for completely resected nonesmall-cell lung cancer: subgroup analysis of the Lung Adjuvant Cisplatin Evaluation. J Thorac Oncol 2010; 5:220-8. 6. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage nonesmall-cell lung cancer. J Clin Oncol 2008; 26:3543-51. 7. Scagliotti G, Hanna N, Fossella F, et al. The differential efficacy of pemetrexed according to NSCLC histology: a review of two phase III studies. Oncologist 2009; 14:253-63. 8. Kreuter M, Vansteenkiste J, Fischer JR, et al. Randomized phase 2 trial on refinement of early-stage NSCLC adjuvant chemotherapy with cisplatin and pemetrexed versus cisplatin and vinorelbine: the TREAT study. Ann Oncol 2013; 24:986-92. 9. Kreuter M, Vansteenkiste J, Fischer JR, et al. Three-year follow-up of a randomized phase II trial on refinement of early-stage NSCLC adjuvant chemotherapy with cisplatin and pemetrexed versus cisplatin and vinorelbine (the TREAT study). J Thorac Oncol 2016; 11:85-93. 10. Schmid-Bindert G, Engel-Riedel W, Reck M, et al. A randomized phase 2 study of pemetrexed in combination with cisplatin or carboplatin as adjuvant chemotherapy in patients with completely resected stage IB or II nonesmall-cell lung cancer. Lung Cancer 2015; 90:397-404. 11. Sawabata N, Miyaoka E, Asamura H, et al. Japanese lung cancer registry study of 11,663 surgical cases in 2004: demographic and prognosis changes over decade. J Thorac Oncol 2011; 6:1229-35. 12. Iwamoto Y, Mitsudomi T, Sakai K, et al. Randomized phase II study of adjuvant chemotherapy with long-term S-1 versus cisplatinþS-1 in completely resected stage II-IIIA nonesmall-cell lung cancer. Clin Cancer Res 2015; 21:5245-52. 13. Sonobe M, Okubo K, Teramukai S, et al. Phase II study of adjuvant vinorelbine and cisplatin in Japanese patients with completely resected stage II and III nonesmall-cell lung cancer. Cancer Chemother Pharmacol 2014; 74:1199-206. 14. Kawano Y, Okamoto I, Fukuda H, et al. Current status and future perspectives of cooperative study groups for lung cancer in Japan. Respir Investig 2014; 52:339-47.
Clinical Lung Cancer Month 2017
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Randomized Phase III Study of Cisplatin With Pemetrexed and Cisplatin With Vinorelbine for Completely Resected Nonsquamous NoneSmall-Cell Lung Cancer: The JIPANG Study Protocol Nobuyuki Yamamoto,1 Hirotsugu Kenmotsu,2 Takeharu Yamanaka,3 Shinichiro Nakamura,4 Masahiro Tsuboi5 Abstract This trial report describes the background and design for the Japan Intergroup Trial of Pemetrexed Adjuvant Chemotherapy for Completely Resected Nonsquamous NoneSmall-Cell Lung Cancer (JIPANG) study (University Hospital Medical Information Network database: UMIN000006737). Various randomized trials have shown the efficacy of postoperative adjuvant chemotherapy regimens that include cisplatin for resected nonesmall-cell lung cancer (NSCLC), but the optimal regimen is not known. The JIPANG study is a randomized study comparing cisplatin (75 mg/m2, day 1) and pemetrexed (500 mg/m2, day 1) with cisplatin (80 mg/m2, day 1) and vinorelbine (25 mg/m2, days 1 and 8) for nonsquamous NSCLC as postoperative adjuvant chemotherapy. A total of 804 patients with pathological stage II to IIIA completely resected nonsquamous NSCLC were enrolled in this study between March 2012 and August 2016. These patients have been randomized in a 1:1 ratio and stratified according to sex (female vs. male), age (< 70 years vs. 70 years), pathologic stage (II vs. IIIA), mutation of the epidermal growth factor receptor (mutant vs. wild) and institution. Each treatment will be undertaken every 3 weeks until 4 cycles have been completed. The primary endpoint is overall survival and the secondary endpoints are disease-free survival, rate of treatment completion, and incidence of adverse events. This design has 80% power to detect overall survival with a hazard ratio of 0.786 (a ¼ 1-sided 0.05) with 5-year follow-up after registration of the final patient. This study will show a superior regimen for completely resected nonsquamous NSCLC. Biomarker analyses of the JIPANG study are ongoing. Clinical Lung Cancer, Vol. -, No. -, --- ª 2017 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Keywords: Adjuvant chemotherapy, Cisplatin, Nonsquamous nonesmall-cell lung cancer, Pemetrexed, Vinorelbine
Introduction The efficacy of postoperative adjuvant chemotherapy including cisplatin for nonesmall-cell lung cancer (NSCLC) was reported first in 2004.1-3 A meta-analysis of 4584 patients enrolled in a large-scale comparative study of cisplatin-based postoperative chemotherapy
Registered in the University Hospital Medical Information Network database (UMIN000006737). 1
Third Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan 2 Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan 3 Department of Biostatistics, Yokohama City University, Yokohama, Japan 4 West Japan Oncology Group Data Center, Osaka, Japan 5 Department of Thoracic Surgery, National Cancer Center Hospital East, Chiba, Japan
1525-7304/ª 2017 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). http://dx.doi.org/10.1016/j.cllc.2017.05.020
(the Lung Adjuvant Cisplatin Evaluation [LACE]) showed that the hazard ratio against death in all patients was 0.89 (95% confidence interval, 0.82-0.96), which corresponded to an absolute survival benefit of 5.4% at 5 years.4 In addition, subgroup analyses of the LACE study showed that only vinorelbine significantly prolonged
Submitted: May 24, 2017; Accepted: May 30, 2017 Address for correspondence: Hirotsugu Kenmotsu, MD, Division of Thoracic Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8777, Japan Fax: 81-55-989-5634; e-mail contact: [email protected]
Clinical Lung Cancer Month 2017
-1
The JIPANG Study Protocol
2
-
survival among various drugs coadministered with cisplatin (P ¼ .005). Postoperative chemotherapy significantly improved survival time in stages II and III, and an improvement trend was shown in stage IB, whereas a deteriorating trend was found in stage IA.5 For patients with metastatic nonsquamous NSCLC, a combination of pemetrexed with cisplatin has been a standard treatment. A randomized phase III study showed the noninferiority in overall survival (OS) of pemetrexed in combination with cisplatin compared with gemcitabine in combination with cisplatin in untreated advanced NSCLC (hazard ratio, 0.94; 95% confidence interval, 0.84-1.05).6 A subgroup analysis of adenocarcinoma and large-cell carcinoma showed that a combination of pemetrexed with cisplatin showed significantly better survival (adenocarcinoma: 12.6 vs. 10.9 months, P ¼ .03; large-cell carcinoma: 10.4 vs. 6.7 months, P ¼ .03). In a phase III study of pemetrexed compared with docetaxel for previously treated NSCLC, the subgroup analysis of adenocarcinoma also showed that pemetrexed significantly prolonged the survival time.7 These results suggest that pemetrexed is highly effective for the treatment of nonsquamous NSCLC. In postoperative adjuvant chemotherapy, 2 randomized phase II studies evaluating a combination of pemetrexed with cisplatin have been reported. The randomized phase II Trial on Refinement of Early-stage NSCLC Adjuvant Chemotherapy with Cisplatin and Pemetrexed versus Cisplatin and Vinorelbine (TREAT) study evaluated the feasibility of 4 cycles of cisplatin (75 mg/m2, day 1) and pemetrexed (500 mg/m2, day 1) every 3 weeks as adjuvant chemotherapy for NSCLC patients.8 One-hundred thirty-two patients with completely resected stages IB to pT3N1 NSCLC were assigned randomly to vinorelbine with cisplatin or pemetrexed with cisplatin. The primary endpoint was the clinical feasibility (no Grade 4 neutropenia/thrombocytopenia or thrombocytopenia with bleeding, no Grade 3/4 febrile neutropenia or nonhematologic toxicity; no premature withdrawal/death). The feasibility rate was better for the combination of pemetrexed with cisplatin (95.5%) compared with the combination of vinorelbine with cisplatin (75.4%; P ¼ .001). After a 3-year follow-up of the TREAT study, there were no significant differences in the efficacies between these 2 chemotherapy regimens.9 Second, a randomized phase II study of pemetrexed in combination with cisplatin or carboplatin as adjuvant chemotherapy in patients with completely resected stage IB/II NSCLC has also been reported. The primary endpoint was treatment feasibility, defined as 4 cycles completed with no cycle delay > 42 days and 2 dose reductions, with a median relative dose intensity 95%; and no Grade 3 toxicities at the follow-up visit 30 days after the final dose. This study involved 122 patients, and neither regimen met the primary endpoint (feasibility rate: 59.4% for pemetrexed with cisplatin and 50% for pemetrexed with carboplatin).10 These results suggested that a combination of pemetrexed with cisplatin was also feasible as postoperative adjuvant chemotherapy. On the basis of this background, we conducted a randomized phase III study comparing cisplatin (75 mg/m2, day 1) and pemetrexed (500 mg/m2, day 1) with cisplatin (80 mg/m2, day 1) and vinorelbine (25 mg/m2, days 1 and 8) for patients with nonsquamous NSCLC as postoperative adjuvant chemotherapy. In Japan, pemetrexed is approved for the treatment of advanced or
Clinical Lung Cancer Month 2017
recurrent NSCLC, but not for postoperative adjuvant chemotherapy. Therefore, one of our objectives was to obtain approval for this regimen as adjuvant chemotherapy from Pharamceuticals and Medical Devices Agency (Japan).
Patients and Methods Study Design and Objectives The Japan Intergroup Trial of Pemetrexed Adjuvant Chemotherapy for Completely Resected Nonsquamous NoneSmall-Cell Lung Cancer (JIPANG) study was designed as an open-label, randomized phase III trial to evaluate the efficacy of pemetrexed with cisplatin in patients with completely resected nonsquamous NSCLC compared with vinorelbine with cisplatin as postoperative adjuvant chemotherapy. Patients are randomized in a 1:1 ratio to the experimental arm (pemetrexed with cisplatin) or control arm (vinorelbine with cisplatin), stratified according to sex (female vs. male), age (< 70 years vs. 70 years), pathologic stage (II vs. IIIA), mutation of the epidermal growth factor receptor (EGFR; mutant vs. wild) and institution (Figure 1). The primary endpoint is OS. The secondary endpoints are disease-free survival, rate of treatment completion, and safety. In addition, biomarker analyses for patients enrolled in this study are ongoing. This study has been conducted in compliance with the principles of the Declaration of Helsinki, and is registered in the University Hospital Medical Information Network database (UMIN000006737).
Key Eligibility Criteria Key eligibility criteria are patients aged 20 to 75 years, histologically confirmed pathological stage II or IIIA nonsquamous NSCLC (Union for International Cancer Control Tumor, Node, Metastases classification, seventh edition), proven mutation of the EGFR gene, Eastern Cooperative Oncology Group performance status of 0 or 1, as well as adequate hematologic and organ function. Each patient receives complete resections using lobectomy or pneumonectomy with resection of any involved N1 lymph nodes within 3 to 8 weeks before patient enrollment. All patients must sign informed consent forms approved by the review board of each institution. Key exclusion criteria are severe postoperative complications, interstitial pneumonia on computed tomography of the chest, currently pregnant women, and other severe complications.
Treatment Plan Patients enrolled in this study will be randomized to receive pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) by intravenous infusion on the first day, or vinorelbine (25 mg/m2) on the first and eighth days and cisplatin (80 mg/m2) on the first day by intravenous infusion. This treatment, defined as “1 cycle,” will be repeated every 3 weeks until 4 cycles have been completed.
Statistical Design The primary endpoint of this study is OS, defined as the duration from patient enrollment to the date of death or the patient’s last visit. The 5-year survival rate of patients treated with vinorelbine with cisplatin as the control arm is estimated to be 50% on the basis of previous reports.
Nobuyuki Yamamoto et al Figure 1 Japan Intergroup Trial of Pemetrexed Adjuvant Chemotherapy for Completely Resected Nonsquamous NoneSmall-Cell Lung Cancer (JIPANG) Study Design
Randomize
p-Stage II-IIIA, completely resected nonsquamous NSCLC PS: 0-1 Age: 20–75 years
Cisplatin (75 mg/m2 , day 1) with Pemetrxed (500 mg/m2 , day 1) Every 3 weeks for 4 cycles (n = 400)
Cisplatin (80 mg/m2 , day 1) with Vinorelbine (25 mg/m2 , day 1 and 8) Every 3 weeks for 4 cycles (n = 400)
Abbreviations: NSCLC ¼ nonesmall-cell lung cancer; PS ¼ performance status.
In this study, the 5-year survival rate is expected to be improved by approximately 8%. To carry out the log rank test under the chosen condition (a ¼ 1-sided 0.05; 1-b ¼ 0.8; 3-year registration period and 5-year follow-up after registration of the last patient), 426 events and 777 patients are required. After allowance for exclusion of some patients from analyses, the sample size is planned at 400 patients per arm (a total of 800 patients). A total of 804 patients with pathological stage II to IIIA completely resected nonsquamous NSCLC were enrolled in this study between March 2012 and August 2016.
Discussion A study on the basis of a Japanese lung cancer registry showed that stage-specific prognoses improved over 1 decade.11 In addition, some Japanese phase II studies have reported that the 5-year OS rate was approximately 70% in patients with stage II to IIIA NSCLC who underwent postoperative adjuvant chemotherapy.12,13 This phenomenon might be influenced by recent advances in diagnostic and surgical procedures and the improved efficacy of chemotherapy, including molecular targeted therapies. Therefore, it might be acceptable to change the primary endpoint from OS to disease-free survival in this study. This JIPANG study is ongoing as an intergroup study among 7 clinical study groups in Japan14: Lung Oncology Group in Kyushu, Setouchi Lung Cancer Group, Japan Multinational Trial Organization, West Japan Oncology Group (WJOG), Central Japan Lung Study Group, Tokyo Cooperative Oncology Group, and the Thoracic Oncology Research Group.
Conclusion Cisplatin-based chemotherapy remains standard treatment for patients who have undergone complete resection of stage II to III NSCLC. The JIPANG study will show the optimal chemotherapy regimen for completely resected nonsquamous NSCLC.
Acknowledgments We thank the patients, their families, and all of the JIPANG investigators who are participating in this study. This study is
supported by Seiko Tanaka and other staff members of the WJOG Data Center (data management) and the Pharma-Valley Center, Shizuoka Industrial Foundation (study management). Pemetrexed for this study was provided by Eli Lilly (Tokyo, Japan). This study was funded by the Japan Agency for Medical Research and Development (grant number 16lk0201005h0005).
References 1. Arriagada R, Bergman B, Dunant A, et al. Cisplatin-based adjuvant chemotherapy in patients with completely resected nonesmall-cell lung cancer. N Engl J Med 2004; 350:351-60. 2. Winton T, Livingston R, Johnson D, et al. Vinorelbine plus cisplatin vs. observation in resected nonesmall-cell lung cancer. N Engl J Med 2005; 352:2589-97. 3. Douillard JY, Rosell R, De Lena M, et al. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA nonesmallcell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol 2006; 7:719-27. 4. Pignon JP, Tribodet H, Scagliotti GV, et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol 2008; 26:3552-9. 5. Douillard JY, Tribodet H, Aubert D, et al. Adjuvant cisplatin and vinorelbine for completely resected nonesmall-cell lung cancer: subgroup analysis of the Lung Adjuvant Cisplatin Evaluation. J Thorac Oncol 2010; 5:220-8. 6. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage nonesmall-cell lung cancer. J Clin Oncol 2008; 26:3543-51. 7. Scagliotti G, Hanna N, Fossella F, et al. The differential efficacy of pemetrexed according to NSCLC histology: a review of two phase III studies. Oncologist 2009; 14:253-63. 8. Kreuter M, Vansteenkiste J, Fischer JR, et al. Randomized phase 2 trial on refinement of early-stage NSCLC adjuvant chemotherapy with cisplatin and pemetrexed versus cisplatin and vinorelbine: the TREAT study. Ann Oncol 2013; 24:986-92. 9. Kreuter M, Vansteenkiste J, Fischer JR, et al. Three-year follow-up of a randomized phase II trial on refinement of early-stage NSCLC adjuvant chemotherapy with cisplatin and pemetrexed versus cisplatin and vinorelbine (the TREAT study). J Thorac Oncol 2016; 11:85-93. 10. Schmid-Bindert G, Engel-Riedel W, Reck M, et al. A randomized phase 2 study of pemetrexed in combination with cisplatin or carboplatin as adjuvant chemotherapy in patients with completely resected stage IB or II nonesmall-cell lung cancer. Lung Cancer 2015; 90:397-404. 11. Sawabata N, Miyaoka E, Asamura H, et al. Japanese lung cancer registry study of 11,663 surgical cases in 2004: demographic and prognosis changes over decade. J Thorac Oncol 2011; 6:1229-35. 12. Iwamoto Y, Mitsudomi T, Sakai K, et al. Randomized phase II study of adjuvant chemotherapy with long-term S-1 versus cisplatinþS-1 in completely resected stage II-IIIA nonesmall-cell lung cancer. Clin Cancer Res 2015; 21:5245-52. 13. Sonobe M, Okubo K, Teramukai S, et al. Phase II study of adjuvant vinorelbine and cisplatin in Japanese patients with completely resected stage II and III nonesmall-cell lung cancer. Cancer Chemother Pharmacol 2014; 74:1199-206. 14. Kawano Y, Okamoto I, Fukuda H, et al. Current status and future perspectives of cooperative study groups for lung cancer in Japan. Respir Investig 2014; 52:339-47.
Clinical Lung Cancer Month 2017
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