Randomized phase II study of pemetrexed/cisplatin with or without axitinib for non-squamous non-small-cell lung cancer

Chandra P Belani, Nobuyuki Yamamoto, Igor M Bondarenko, Artem Poltoratskiy, Silvia Novello, Jie Tang, Paul Bycott, Andreas G Niethammer, Antonella Ingrosso, Sinil Kim, Giorgio V Scagliotti, Chandra P Belani, Nobuyuki Yamamoto, Igor M Bondarenko, Artem Poltoratskiy, Silvia Novello, Jie Tang, Paul Bycott, Andreas G Niethammer, Antonella Ingrosso, Sinil Kim, Giorgio V Scagliotti

Abstract

Background: The efficacy and safety of axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2, and 3 in combination with pemetrexed and cisplatin was evaluated in patients with advanced non-squamous non-small-cell lung cancer (NSCLC).

Methods: Overall, 170 patients were randomly assigned to receive axitinib at a starting dose of 5-mg twice daily continuously plus pemetrexed 500 mg/m(2) and cisplatin 75 mg/m(2) on day 1 of up to six 21-day cycles (arm I); axitinib on days 2 through 19 of each cycle plus pemetrexed/cisplatin (arm II); or pemetrexed/cisplatin alone (arm III). The primary endpoint was progression-free survival (PFS).

Results: Median PFS was 8.0, 7.9, and 7.1 months in arms I, II, and III, respectively (hazard ratio: arms I vs. III, 0.89 [P = 0.36] and arms II vs. III, 1.02 [P = 0.54]). Median overall survival was 17.0 months (arm I), 14.7 months (arm II), and 15.9 months (arm III). Objective response rates (ORRs) for axitinib-containing arms were 45.5% (arm I) and 39.7% (arm II) compared with 26.3% for pemetrexed/cisplatin alone (arm III). Gastrointestinal disorders and fatigue were frequently reported across all treatment arms. The most common all-causality grade ≥3 adverse events were hypertension in axitinib-containing arms (20% and 17%, arms I and II, respectively) and fatigue with pemetrexed/cisplatin alone (16%).

Conclusion: Axitinib in combination with pemetrexed/cisplatin was generally well tolerated. Axitinib combinations resulted in non-significant differences in PFS and numerically higher ORR compared with chemotherapy alone in advanced NSCLC.

Trial registration: ClinicalTrials.gov: NCT00768755 (October 7, 2008).

Figures

Figure 1
Figure 1
Summary of patient disposition. AE, adverse event.
Figure 2
Figure 2
Kaplan-Meier estimates for (a) progression-free survival and (b) overall survival.P values were based on one-sided log-rank test stratified by Eastern Cooperative Oncology Group performance status and gender. Progression-free survival was based on data cutoff date of December 21, 2011 and overall survival was based on the most recent data at the time of final database lock on May 18, 2012. CI, confidence interval; Cont, continuously; HR, hazard ratio; mod, modified schedule; mOS, median overall survival; mPFS, median progression-free survival.

References

    1. Cancer facts & figures 2012. Atlanta: American Cancer Society, 2012. [ ]
    1. Wang T, Nelson RA, Bogardus A, Grannis FW Jr. Five-year lung cancer survival: which advanced stage nonsmall cell lung cancer patients attain long-term survival? Cancer. 2010;116:1518–1525. doi: 10.1002/cncr.24871.
    1. Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH. Eastern Cooperative Oncology Group. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002;346:92–98. doi: 10.1056/NEJMoa011954.
    1. Xiao YY, Zhan P, Yuan DM, Liu HB, Lv TF, Song Y, Shi Y. Chemotherapy plus multitargeted antiangiogenic tyrosine kinase inhibitors or chemotherapy alone in advanced NSCLC: a meta-analysis of randomized controlled trials. Eur J Clin Pharmacol. 2013;69:151–159. doi: 10.1007/s00228-012-1333-3.
    1. Ellis PM, Al-Saleh K. Multitargeted anti-angiogenic agents and NSCLC: clinical update and future directions. Crit Rev Oncol Hematol. 2012;84:47–58. doi: 10.1016/j.critrevonc.2012.02.004.
    1. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355:2542–2550. doi: 10.1056/NEJMoa061884.
    1. Hu-Lowe DD, Zou HY, Grazzini ML, Hallin ME, Wickman GR, Amundson K, Chen JH, Rewolinski DA, Yamazaki S, Wu EY, McTigue MA, Murray BW, Kania RS, O’Connor P, Shalinsky DR, Bender SL. Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1, 2, 3. Clin Cancer Res. 2008;14:7272–7283. doi: 10.1158/1078-0432.CCR-08-0652.
    1. Schiller JH, Larson T, Ou SH, Limentani S, Sandler A, Vokes E, Kim S, Liau K, Bycott P, Olszanski AJ, von Pawel J. Efficacy and safety of axitinib in patients with advanced non-small-cell lung cancer: results from a phase II study. J Clin Oncol. 2009;27:3836–3841. doi: 10.1200/JCO.2008.20.8355.
    1. Kozloff MF, Martin LP, Krzakowski M, Samuel TA, Rado TA, Arriola E, De Castro Carpeño J, Herbst RS, Tarazi J, Kim S, Rosbrook B, Tortorici M, Olszanski AJ, Cohen RB. Phase I trial of axitinib combined with platinum doublets in patients with advanced non-small cell lung cancer and other solid tumours. Br J Cancer. 2012;107:1277–1285. doi: 10.1038/bjc.2012.406.
    1. Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, Lee JS, Mellemgaard A, Park K, Patil S, Rolski J, Goksel T, de Marinis F, Simms L, Sugarman KP, Gandara D. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008;26:3543–3551. doi: 10.1200/JCO.2007.15.0375.
    1. Tortorici MA, Iglesias L, Kozloff MF, Pithavala YK, Ingrosso A, Belani CP. Pharmacokinetic (PK) analysis of coadministration of axitinib and pemetrexed/cisplatin (pem/cis) in patients with non–small cell lung cancer (NSCLC) [abstract PI-69] Clin Pharmacol Ther. 2012;91(Suppl 1):S33.
    1. Cleeland CS. The M. D. Anderson Symptom Inventory User Guide [Draft]. Houston, Texas, University of Texas M. D. Anderson Cancer Center. Houston, TX: The University of Texas MD Anderson Cancer Center; 2010. [ ]
    1. Pirker R, Pereira JR, Szczesna A, von Pawel J, Krzakowski M, Ramlau R, Vynnychenko I, Park K, Eberhardt WE, de Marinis F, Heeger S, Goddemeier T, O’Byrne KJ, Gatzemeier U. Prognostic factors in patients with advanced non-small cell lung cancer: data from the phase III FLEX study. Lung Cancer. 2012;77:376–382. doi: 10.1016/j.lungcan.2012.03.010.
    1. Scagliotti G, Novello S, von Pawel J, Reck M, Pereira JR, Thomas M, Abrao Miziara JE, Balint B, de Marinis F, Keller A, Aren O, Csollak M, Albert I, Barrios CH, Grossi F, Krzakowski M, Cupit L, Cihon F, Dimatteo S, Hanna N. Phase III study of carboplatin and paclitaxel alone or with sorafenib in advanced non-small-cell lung cancer. J Clin Oncol. 2010;28:1835–1842. doi: 10.1200/JCO.2009.26.1321.
    1. Scagliotti GV, Vynnychenko I, Park K, Ichinose Y, Kubota K, Blackhall F, Pirker R, Galiulin R, Ciuleanu TE, Sydorenko O, Dediu M, Papai-Szekely Z, Banaclocha NM, McCoy S, Yao B, Hei YJ, Galimi F, Spigel DR. International, randomized, placebo-controlled, double-blind phase III study of motesanib plus carboplatin/paclitaxel in patients with advanced non-squamous non-small-cell lung cancer: MONET1. J Clin Oncol. 2012;30:2829–2836. doi: 10.1200/JCO.2011.41.4987.
    1. Paz-Ares LG, Biesma B, Heigener D, von Pawel J, Eisen T, Bennouna J, Zhang L, Liao M, Sun Y, Gans S, Syrigos K, Le Marie E, Gottfried M, Vansteenkiste J, Alberola V, Strauss UP, Montegriffo E, Ong TJ, Santoro A. NSCLC [non-small-cell lung cancer] Research Experience Utilizing Sorafenib (NExUS) Investigators Study Group. Phase III, randomized, double-blind, placebo-controlled trial of gemcitabine/cisplatin alone or with sorafenib for the first-line treatment of advanced, non-squamous non-small-cell lung cancer. J Clin Oncol. 2012;30:3084–3092. doi: 10.1200/JCO.2011.39.7646.
    1. Dickson PV, Hamner JB, Sims TL, Fraga CH, Ng CY, Rajasekeran S, Hagedorn NL, McCarville MB, Stewart CF, Davidoff AM. Bevacizumab-induced transient remodeling of the vasculature in neuroblastoma xenografts results in improved delivery and efficacy of systemically administered chemotherapy. Clin Cancer Res. 2007;13:3942–3950. doi: 10.1158/1078-0432.CCR-07-0278.
    1. Goel S, Duda DG, Xu L, Munn LL, Boucher Y, Fukumura D, Jain RK. Normalization of the vasculature for treatment of cancer and other diseases. Physiol Rev. 2011;91:1071–1121. doi: 10.1152/physrev.00038.2010.
    1. Ma J, Waxman DJ. Modulation of the antitumor activity of metronomic cyclophosphamide by the angiogenesis inhibitor axitinib. Mol Cancer Ther. 2008;7:79–89.
    1. Hoh C, Infante JR, Burris HA, Tarazi JC, Kim S, Rosbrook B, Reid TR. Axitinib inhibition of [18F] fluorothymidine (FLT) uptake in patients (pts) with colorectal cancer (CRC): implications for cytotoxic chemotherapy combinations [abstract 3591] J Clin Oncol. 2011;29(Suppl):15s.
    1. Jeraj R, Liu G, Simoncic U, Vanderhoek M, Perlman S, Alberti DB, Harrison MR, Wilding G. Concurrent assessment of vasculature and proliferative pharmacodynamics in patients treated with VEGFR TKI [abstract 3050] J Clin Oncol. 2010;28(Suppl):15s.
    1. Joyce JA. Therapeutic targeting of the tumor microenvironment. Cancer Cell. 2005;7:513–520. doi: 10.1016/j.ccr.2005.05.024.
    1. Dahlberg SE, Sandler AB, Brahmer JR, Schiller JH, Johnson DH. Clinical course of advanced non-small-cell lung cancer patients experiencing hypertension during treatment with bevacizumab in combination with carboplatin and paclitaxel on ECOG 4599. J Clin Oncol. 2010;28:949–954. doi: 10.1200/JCO.2009.25.4482.
    1. Rini BI, Schiller JH, Fruehauf JP, Cohen EE, Tarazi JC, Rosbrook B, Bair AH, Ricart AD, Olszanski AJ, Letrent KJ, Kim S, Rixe O. Diastolic blood pressure as a biomarker of axitinib efficacy in solid tumors. Clin Cancer Res. 2011;17:3841–3849. doi: 10.1158/1078-0432.CCR-10-2806.
    1. Mok TSK, Paz-Ares L, Wu Y-L, Novello S, Juhasz E, Aren O, Sun Y, Hirsh V, Smit EF, Lathia C, Ong TJ, Pena C. Association between tumor EGFR and KRas mutation status and clinical outcomes in NSCLC patients randomized to sorafenib plus best supportive care (BSC) or BSC alone: subanalysis of the phase III MISSION trial [abstract LBA9_PR] Ann Oncol. 2012;23(Suppl 9):ixe1.
    1. Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson M. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304:1497–1500. doi: 10.1126/science.1099314.
    1. Cappuzzo F, Ciuleanu T, Stelmakh L, Cicenas S, Szczesna A, Juhasz E, Esteban E, Molinier O, Brugger W, Melezinek I, Klingelschmitt G, Klughammer B, Giaccone G. SATURN investigators. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol. 2010;11:521–529. doi: 10.1016/S1470-2045(10)70112-1.
    1. Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG, Ou SH, Dezube BJ, Janne PA, Costa DB, Varella-Garcia M, Kim WH, Lynch TJ, Fidias P, Stubbs H, Engelman JA, Sequist LV, Tan W, Gandhi L, Mino-Kenudson M, Wei GC, Shreeve SM, Ratain MJ, Settleman J, Christensen JG, Haber DA, Wilner K, Salgia R, Shapiro GI, Clark JW. et al.Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010;363:1693–1703. doi: 10.1056/NEJMoa1006448.
    1. Jeong WJ, Mo JH, Park MW, Choi IJ, An SY, Jeon EH, Ahn SH. Sunitinib inhibits papillary thyroid carcinoma with RET/PTC rearrangement but not BRAF mutation. Cancer Biol Ther. 2011;12:458–465. doi: 10.4161/cbt.12.5.16303.
    1. Henderson YC, Ahn SH, Kang Y, Clayman GL. Sorafenib potently inhibits papillary thyroid carcinomas harboring RET/PTC1 rearrangement. Clin Cancer Res. 2008;14:4908–4914. doi: 10.1158/1078-0432.CCR-07-1772.

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