A randomized phase II trial of erlotinib vs. S-1 as a third- or fourth-line therapy for patients with wild-type EGFR non-small cell lung cancer (HOT1002)
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A high proportion of patients with wild-type EGFR non-small cell lung cancer (NSCLC) receive third-line therapy and beyond, with no prospective randomized trials addressing the issue. This study aimed to select the most suitable regimen as a third- or fourth-line therapy for wild-type EGFR NSCLC.
This multicenter, randomized phase II study in Japan included patients with recurrent or advanced NSCLC with wild-type or unknown EGFR, who progressed after two or three previous chemotherapies. The patients were randomly assigned to erlotinib (150 mg/day, days 1–21) or S-1 (80–120 mg/day, days 1–14) every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was disease control rate (DCR). The secondary endpoints included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), toxicity, and quality of life (QOL).
From 2011 to 2016, 37 patients were randomly assigned to receive erlotinib (E arm, n = 19) and S-1 (S arm, n = 18). This study was terminated prematurely because of poor patient accrual. DCR/ORR were 42.1%/15.8% in the E arm and 66.7%/16.7% in the S arm. Median PFS/OS were 1.6 months/8.0 months in the E arm and 3.3 months/12.2 months in the S arm. In both groups, the most commonly reported grade 3–4 toxicities were fatigue, anorexia, and nausea. One grade 5 pneumonitis occurred in the S arm. No significant difference was seen in QOL.
S-1 as a third- or fourth-line therapy for wild-type EGFR NSCLC showed numerically better clinical outcomes than erlotinib.
Clinical trial registration no.
KeywordsErlotinib S-1 Non-small cell lung cancer Third-line therapy Fourth-line therapy
Non-small cell lung cancer
Disease control rate
Objective response rate
Quality of life
Hokkaido oncology trial
- ECOG PS
Eastern cooperative oncology group performance status
Body surface area
Functional assessment of cancer therapy-lung
We thank the patients and their families as well as all of the investigators.
Compliance with ethical standards
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Conflict of interest
The all authors declare that they have no conflict of interest.
All procedures performed were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study was approved by the Institutional Review Board of all participating institutions (clinical trial registration no. UMIN000005308).
Informed consent was obtained from all individual participants included in the study.
- 2.Ohe Y, Ohashi Y, Kubota K, Tamura T, Nakagawa K, Negoro S, Nishiwaki Y, Saijo N, Ariyoshi Y, Fukuoka M (2007) Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: four-arm cooperative study in Japan. Ann Oncol 18:317–323CrossRefPubMedGoogle Scholar
- 3.Paz-Ares LG, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed S, John W, Chouaki N, Zimmermann AH, Visseren-Grul C, Gridelli C (2013) 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 31:2895–2902CrossRefPubMedGoogle Scholar
- 4.Shepherd FA, Dancey J, Ramlau R, Mattson K, Gralla R, O’Rourke M, Levitan N, Gressot L, Vincent M, Burkes R, Coughlin S, Kim Y, Berille J (2000) Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 18:2095–2103CrossRefPubMedGoogle Scholar
- 5.Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, Gatzemeier U, Tsao TC, Pless M, Muller T, Lim HL, Desch C, Szondy K, Gervais R, Shaharyar, Manegold C, Paul S, Paoletti P, Einhorn L, Bunn PA Jr (2004) Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 22:1589–1597CrossRefPubMedGoogle Scholar
- 6.Fossella FV, DeVore R, Kerr RN, Crawford J, Natale RR, Dunphy F, Kalman L, Miller V, Lee JS, Moore M, Gandara D, Karp D, Vokes E, Kris M, Kim Y, Gamza F, Hammershaimb L (2000) Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol 18:2354–2362CrossRefPubMedGoogle Scholar
- 7.Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Arén Frontera O, Havel L, Steins M, Garassino MC, Aerts JG, Domine M, Paz-Ares L, Reck M, Baudelet C, Harbison CT, Lestini B, Spigel DR (2015) Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 373:123–135CrossRefPubMedPubMedCentralGoogle Scholar
- 8.Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhäufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crinò L, Blumenschein GR Jr, Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR (2015) Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 373:1627–1639CrossRefPubMedGoogle Scholar
- 9.Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O’Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR, KEYNOTE-024 Investigators (2016) Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 375:1823–1833CrossRefPubMedGoogle Scholar
- 10.Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, Gadgeel SM, Hida T, Kowalski DM, Dols MC, Cortinovis DL, Leach J, Polikoff J, Barrios C, Kabbinavar F, Frontera OA, De Marinis F, Turna H, Lee JS, Ballinger M, Kowanetz M, He P, Chen DS, Sandler A, Gandara DR; OAK Study Group (2017) Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 389:255–265CrossRefPubMedGoogle Scholar
- 11.Kim ES, Hirsh V, Mok T, Socinski MA, Gervais R, Wu YL, Li LY, Watkins CL, Sellers MV, Lowe ES, Sun Y, Liao ML, Osterlind K, Reck M, Armour AA, Shepherd FA, Lippman SM, Douillard JY (2008) Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet 372:1809–1818CrossRefPubMedGoogle Scholar
- 13.Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, Campos D, Maoleekoonpiroj S, Smylie M, Martins R, van Kooten M, Dediu M, Findlay B, Tu D, Johnston D, Bezjak A, Clark G, Santabárbara P, Seymour L, National Cancer Institute of Canada Clinical Trials Group (2005) Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353:123–132CrossRefPubMedGoogle Scholar
- 14.Azzoli CG, Baker S Jr, Temin S, Pao W, Aliff T, Brahmer J, Johnson DH, Laskin JL, Masters G, Milton D, Nordquist L, Pfister DG, Piantadosi S, Schiller JH, Smith R, Smith TJ, Strawn JR, Trent D, Giaccone G, American Society of Clinical Oncology (2009) American Society of Clinical Oncology Clinical Practice Guideline update on chemotherapy for stage IV non-small-cell lung cancer. J Clin Oncol 27:6251–6266CrossRefPubMedPubMedCentralGoogle Scholar
- 15.Okamoto I, Yoshioka H, Morita S, Ando M, Takeda K, Seto T, Yamamoto N, Saka H, Asami K, Hirashima T, Kudoh S, Satouchi M, Ikeda N, Iwamoto Y, Sawa T, Miyazaki M, Tamura K, Kurata T, Fukuoka M, Nakagawa K (2010) Phase III trial comparing oral S-1 plus carboplatin with paclitaxel plus carboplatin in chemotherapy-naive patients with advanced non-small-cell lung cancer: results of a west Japan oncology group study. J Clin Oncol 28:5240–5246CrossRefPubMedGoogle Scholar
- 16.Totani Y, Saito Y, Hayashi M, Tada T, Kohashi Y, Mieno Y, Kato A, Imizu H, Yoneda Y, Hoshino T, Uchiyama Y, Takeuchi Y, Okazawa M, Sakakibara H (2009) A phase II study of S-1 monotherapy as second-line treatment for advanced non-small cell lung cancer. Cancer Chemother Pharmacol 64:1181–1185CrossRefPubMedGoogle Scholar
- 20.Harada T, Oizumi S, Ito K, Takamura K, Kikuchi E, Kuda T, Sugawara S, Suzuki A, Maemondo M, Fujita Y, Kinoshita I, Inoue A, Hommura F, Katsuura Y, Dosaka-Akita H, Isobe H, Nishimura M, Hokkaido Lung Cancer Clinical Study Group (2013) A phase II study of amrubicin as a third-line or fourth-line chemotherapy for patients with non-small cell lung cancer: Hokkaido Lung Cancer Clinical Study Group Trial (HOT) 0901. Oncologist 18:439–445CrossRefPubMedPubMedCentralGoogle Scholar
- 21.Matsubara N, Maemondo M, Inoue A, Ishimoto O, Watanabe K, Sakakibara T, Fukuhara T, Morikawa N, Tanaka M, Sugawara S, Nukiwa T (2013) Phase II study of irinotecan as a third- or fourth-line treatment for advanced non-small cell lung cancer: NJLCG0703. Respir Investig 51:28–34CrossRefPubMedGoogle Scholar
- 22.Cella D, Eton DT, Fairclough DL, Bonomi P, Heyes AE, Silberman C, Wolf MK, Johnson DH (2002) What is a clinically meaningful change on the Functional Assessment of Cancer Therapy-Lung (FACT-L) Questionnaire? Results from Eastern Cooperative Oncology Group (ECOG) Study 5592. J Clin Epidemiol 55:285–295CrossRefPubMedGoogle Scholar
- 23.Garassino MC, Martelli O, Broggini M, Farina G, Veronese S, Rulli E, Bianchi F, Bettini A, Longo F, Moscetti L, Tomirotti M, Marabese M, Ganzinelli M, Lauricella C, Labianca R, Floriani I, Giaccone G, Torri V, Scanni A, Marsoni S, TAILOR trialists (2013) Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): a randomised controlled trial. Lancet Oncol 14:981–988CrossRefPubMedGoogle Scholar
- 24.Kawaguchi T, Ando M, Asami K, Okano Y, Fukuda M, Nakagawa H, Ibata H, Kozuki T, Endo T, Tamura A, Kamimura M, Sakamoto K, Yoshimi M, Soejima Y, Tomizawa Y, Isa S, Takada M, Saka H, Kubo A (2014) 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). J Clin Oncol 32:1902–1908CrossRefPubMedGoogle Scholar
- 25.Nishio M, Mok TSK, Nakagawa K, Yamamoto N, Shi Y, Zhang L, Lu S, Soo R, Yang J, Morita S, Sugawara S, Nokihara H, Takahashi T, Goto K, Chang J, Maemondo M, Ichinose Y, Cheng Y, Lim WT, Tamura T (2016) EAST-LC: randomized controlled phase III trial of S-1 versus docetaxel in patients with non-small-cell lung cancer who had received a platinum-based treatment. Ann Oncol 27:1218PDGoogle Scholar
- 27.Wada M, Yamamoto M, Ryuge S, Nagashima Y, Hayashi N, Maki S, Otani S, Katono K, Takakura A, Yanaihara T, Igawa S, Yokoba M, Mitsufuji H, Kubota M, Katagiri M, Masuda N (2012) Phase II study of S-1 monotherapy in patients with previously treated, advanced non-small-cell lung cancer. Cancer Chemother Pharmacol 69:1005–1011CrossRefPubMedGoogle Scholar
- 29.Yoshioka H, Hotta K, Kiura K, Takigawa N, Hayashi H, Harita S, Kuyama S, Segawa Y, Kamei H, Umemura S, Bessho A, Tabata M, Tanimoto M, Okayama Lung Cancer Study Group (2010) A phase II trial of erlotinib monotherapy in pretreated patients with advanced non-small cell lung cancer who do not possess active EGFR mutations: Okayama Lung Cancer Study Group trial 0705. J Thorac Oncol 5:99–104CrossRefPubMedGoogle Scholar
- 30.Minemura H, Yokouchi H, Azuma K, Hirai K, Sekine S, Oshima K, Kanazawa K, Tanino Y, Inokoshi Y, Ishii T, Katsuura Y, Oishi A, Ishida T, Munakata M (2015) A phase II trial of erlotinib monotherapy for pretreated elderly patients with advanced EGFR wild-type non-small cell lung cancer. BMC Res Notes 8:220CrossRefPubMedPubMedCentralGoogle Scholar
- 31.Gallant JN, Sheehan JH, Shaver TM, Bailey M, Lipson D, Chandramohan R, Red Brewer M, York SJ, Kris MG, Pietenpol JA, Ladanyi M, Miller VA, Ali SM, Meiler J, Lovly CM (2015) EGFR kinase domain duplication (EGFR-KDD) is a novel oncogenic driver in lung cancer that is clinically responsive to afatinib. Cancer Discov 5:1155–1163CrossRefPubMedPubMedCentralGoogle Scholar