Phase II study of continuous daily sunitinib dosing in patients with previously treated advanced non-small cell lung cancer

S Novello, G V Scagliotti, R Rosell, M A Socinski, J Brahmer, J Atkins, C Pallares, R Burgess, L Tye, P Selaru, E Wang, R Chao, R Govindan, S Novello, G V Scagliotti, R Rosell, M A Socinski, J Brahmer, J Atkins, C Pallares, R Burgess, L Tye, P Selaru, E Wang, R Chao, R Govindan

Abstract

Background: Sunitinib malate (SUTENT) has promising single-agent activity given on Schedule 4/2 (4 weeks on treatment followed by 2 weeks off treatment) in advanced non-small cell lung cancer (NSCLC).

Methods: We examined the activity of sunitinib on a continuous daily dosing (CDD) schedule in an open-label, multicentre phase II study in patients with previously treated, advanced NSCLC. Patients > or =18 years with stage IIIB/IV NSCLC after failure with platinum-based chemotherapy, received sunitinib 37.5 mg per day. The primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS), overall survival (OS), 1-year survival rate, and safety.

Results: Of 47 patients receiving sunitinib, one patient achieved a confirmed partial response (ORR 2.1% (95% confidence interval (CI) 0.1, 11.3)) and 11 (23.4%) had stable disease (SD) > or =8 weeks. Five patients had SD>6 months. Median PFS was 11.9 weeks (95% CI 8.6, 14.1) and median OS was 37.1 weeks (95% CI 31.1, 69.7). The 1-year survival probability was 38.4% (95% CI 24.2, 52.5). Treatment was generally well tolerated.

Conclusions: The safety profile and time-to-event analyses, albeit relatively low response rate of 2%, suggest single-agent sunitinib on a CDD schedule may be a potential therapeutic agent for patients with advanced, refractory NSCLC.

Figures

Figure 1
Figure 1
Best response for target lesions by patient, based on maximal percentage of tumour reduction.
Figure 2
Figure 2
(A) Progression-free survival (PFS) and (B) overall survival (OS) Kaplan–Meier plots. Probability of survival at 1 year was 38.4% (95% CI 24.2, 52.5).

References

    1. Abrams TJ, Lee LB, Murray LJ, Pryer NK, Cherrington JM (2003) SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. Mol Cancer Ther 2: 471–478
    1. Burstein HJ, Elias AD, Rugo HS, Cobleigh MA, Wolff AC, Eisenberg PD, Lehman M, Adams BJ, Bello CL, DePrimo SE, Baum CM, Miller KD (2008) Phase II study of sunitinib malate, an oral multitargeted tyrosine kinase inhibitor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol 26: 1810–1816
    1. Christensen JG (2008) Antitumor efficacy of sunitinib malate in concurrent and sequential combinations with standard chemotherapeutic agents in non-small cell lung cancer (NSCLC) nonclinical models. Proceedings of the 99th Annual Meeting of the American Association for Cancer Research: San Diego, CA, USA (abstr. 1433)
    1. Escudier B, Roigas J, Gillessen S, Harmenberg U, Srinivas S, Mulder SF, Fountzilas G, Peschel C, Flodgren P, Maneval EC, Chen I, Vogelzang NJ (2009) Phase II study of sunitinib administered in a continuous once-daily dosing regimen in patients with cytokine-refractory metastatic renal cell carcinoma. J Clin Oncol 27: 4068–4075
    1. Gatzemeier U, Blumenschein G, Fossella F, Simantov R, Elting J, Bigwood D, Cihon F, Reck M (2006) Phase II trial of single-agent sorafenib in patients with advanced non-small cell lung carcinoma. J Clin Oncol 24(18S): 364a (abstr. 7002)
    1. George S, Blay JY, Casali PG, Le Cesne A, Morgan JA, Poleka J, Quigley MT (2007) Continuous daily dosing (CDD) of sunitinib malate compares favourably with intermittent dosing in pts with advanced GIST. J Clin Oncol 25(18S): 548S (abstr. 10015)
    1. George S, Blay JY, Casali PG, Le CA, Stephenson P, DePrimo SE, Harmon CS, Law CN, Morgan JA, Ray-Coquard I, Tassell V, Cohen DP, Demetri GD (2009) Clinical evaluation of continuous daily dosing of sunitinib malate in patients with advanced gastrointestinal stromal tumour after imatinib failure. Eur J Cancer 45: 1959–1968
    1. Hanna N, Shepherd FA, Fossella FV, Pereira JR, De MF, von PJ, 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 Jr PA (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: 1589–1597
    1. Hasumi Y, Klosowska-Wardega A, Furuhashi M, Ostman A, Heldin CH, Hellberg C (2007) Identification of a subset of pericytes that respond to combination therapy targeting PDGF and VEGF signaling. Int J Cancer 121: 2606–2614
    1. Kim DW, Jo YS, Jung HS, Chung HK, Song JH, Park KC, Park SH, Hwang JH, Rha SY, Kweon GR, Lee SJ, Jo KW, Shong M (2006) An orally administered multitarget tyrosine kinase inhibitor, SU11248, is a novel potent inhibitor of thyroid oncogenic RET/papillary thyroid cancer kinases. J Clin Endocrinol Metab 91: 4070–4076
    1. Koukourakis MI, Giatromanolaki A, O'Byrne KJ, Comley M, Whitehouse RM, Talbot DC, Gatter KC, Harris AL (1997) Platelet-derived endothelial cell growth factor expression correlates with tumour angiogenesis and prognosis in non-small-cell lung cancer. Br J Cancer 75: 477–481
    1. Manegold C, Von Pawel J, Zatloukal P, Ramlau R, Gorbunova V, Hirsh V, Leighl N, Mezger J, Archer V, Reck M (2008) BO17704 (AVAIL): a phase III randomised study of first-line bevacizumab combined with cisplatin/gemcitabine (CG) in patients (pts) with advanced or recurrent non-squamous, non-small cell lung cancer (NSCLC). Ann Oncol 19: LBA1
    1. Manegold C, Von Pawel J, Zatloukal P, Ramlau R, Gorbunova V, Hirsh V, Leighl N, Mezger J, Moore N, Reck M (2007) Efficacy and safety results from BO17704, a randomised, placebo-controlled phase III study of bevacizumab in combination with cisplatin and gemcitabine in patients with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC). Eur J Cancer Suppl 5: 356 (abstract)
    1. Mendel DB, Laird AD, Xin X, Louie SG, Christensen JG, Li G, Schreck RE, Abrams TJ, Ngai TJ, Lee LB, Murray LJ, Carver J, Chan E, Moss KG, Haznedar JO, Sukbuntherng J, Blake RA, Sun L, Tang C, Miller T, Shirazian S, McMahon G, Cherrington JM (2003) In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 9: 327–337
    1. Motzer RJ, Michaelson MD, Rosenberg J, Bukowski RM, Curti BD, George DJ, Hudes GR, Redman BG, Margolin KA, Wilding G (2007) Sunitinib efficacy against advanced renal cell carcinoma. J Urol 178: 1883–1887
    1. Motzer RJ, Rini BI, Bukowski RM, Curti BD, George DJ, Hudes GR, Redman BG, Margolin KA, Merchan JR, Wilding G, Ginsberg MS, Bacik J, Kim ST, Baum CM, Michaelson MD (2006) Sunitinib in patients with metastatic renal cell carcinoma. JAMA 295: 2516–2524
    1. Murray LJ, Abrams TJ, Long KR, Ngai TJ, Olson LM, Hong W, Keast PK, Brassard JA, O'Farrell AM, Cherrington JM, Pryer NK (2003) SU11248 inhibits tumor growth and CSF-1R-dependent osteolysis in an experimental breast cancer bone metastasis model. Clin Exp Metastasis 20: 757–766
    1. O'Farrell AM, Abrams TJ, Yuen HA, Ngai TJ, Louie SG, Yee KW, Wong LM, Hong W, Lee LB, Town A, Smolich BD, Manning WC, Murray LJ, Heinrich MC, Cherrington JM (2003) SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood 101: 3597–3605
    1. Potapova O, Laird AD, Nannini MA, Barone A, Li G, Moss KG, Cherrington JM, Mendel DB (2006) Contribution of individual targets to the antitumor efficacy of the multitargeted receptor tyrosine kinase inhibitor SU11248. Mol Cancer Ther 5: 1280–1289
    1. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355: 2542–2550
    1. 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: 2095–2103
    1. Shepherd FA, Rodrigues PJ, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, Campos D, Maoleekoonpiroj S, Smylie M, Martins R, van KM, Dediu M, Findlay B, Tu D, Johnston D, Bezjak A, Clark G, Santabarbara P, Seymour L (2005) Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353: 123–132
    1. Shikada Y, Yonemitsu Y, Koga T, Onimaru M, Nakano T, Okano S, Sata S, Nakagawa K, Yoshino I, Maehara Y, Sueishi K (2005) Platelet-derived growth factor-AA is an essential and autocrine regulator of vascular endothelial growth factor expression in non-small cell lung carcinomas. Cancer Res 65: 7241–7248
    1. Socinski MA, Novello S, Brahmer JR, Rosell R, Sanchez JM, Belani CP, Govindan R, Atkins JN, Gillenwater HH, Pallares C, Tye L, Selaru P, Chao RC, Scagliotti GV (2008) Multicenter, phase II trial of sunitinib in previously treated, advanced non-small-cell lung cancer. J Clin Oncol 26: 650–656
    1. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92: 205–216
    1. Yuan A, Yu CJ, Kuo SH, Chen WJ, Lin FY, Luh KT, Yang PC, Lee YC (2001) Vascular endothelial growth factor 189 mRNA isoform expression specifically correlates with tumor angiogenesis, patient survival, and postoperative relapse in non-small-cell lung cancer. J Clin Oncol 19: 432–441

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere