A randomized phase II trial evaluating the addition of low dose, short course sunitinib to docetaxel in advanced solid tumours

Yvonne L E Ang, Gwo Fuang Ho, Ross A Soo, Raghav Sundar, Sing Huang Tan, Wei Peng Yong, Samuel G W Ow, Joline S J Lim, Wan Qin Chong, Phyu Pyar Soe, Bee Choo Tai, Lingzhi Wang, Boon Cher Goh, Soo-Chin Lee, Yvonne L E Ang, Gwo Fuang Ho, Ross A Soo, Raghav Sundar, Sing Huang Tan, Wei Peng Yong, Samuel G W Ow, Joline S J Lim, Wan Qin Chong, Phyu Pyar Soe, Bee Choo Tai, Lingzhi Wang, Boon Cher Goh, Soo-Chin Lee

Abstract

Background: We previously reported that low-dose, short-course sunitinib prior to neoadjuvant doxorubicin-cyclophosphamide (AC) normalised tumour vasculature and improved perfusion, but resulted in neutropenia and delayed subsequent cycles in breast cancer patients. This study combined sunitinib with docetaxel, which has an earlier neutrophil nadir than AC.

Methods: Patients with advanced solid cancers were randomized 1:1 to 3-weekly docetaxel 75 mg/m2, with or without sunitinib 12.5 mg daily for 7 days prior to docetaxel, stratified by primary tumour site. Primary endpoints were objective-response (ORR:CR + PR) and clinical-benefit rate (CBR:CR + PR + SD); secondary endpoints were toxicity and progression-free-survival (PFS).

Results: We enrolled 68 patients from 2 study sites; 33 received docetaxel-sunitinib and 35 docetaxel alone, with 33 breast, 25 lung and 10 patients with other cancers. There was no difference in ORR (30.3% vs 28.6%, p = 0.432, odds-ratio [OR] 1.10, 95% CI 0.38-3.18); CBR was lower in the docetaxel-sunitinib arm (48.5% vs 71.4%, p = 0.027 OR 0.37, 95% CI 0.14-1.01). Median PFS was shorter in the docetaxel-sunitinib arm (2.9 vs 4.9 months, hazard-ratio [HR] 2.00, 95% CI 1.15-3.48, p = 0.014) overall, as well as in breast (4.2 vs 5.6 months, p = 0.048) and other cancers (2.0 vs 5.3 months, p = 0.009), but not in lung cancers (2.9 vs 4.1 months, p = 0.597). Median OS was similar in both arms overall (9.9 vs 10.5 months, HR 0.92, 95% CI 0.51-1.67, p = 0.789), and in the breast (18.9 vs 25.8 months, p = 0.354), lung (7.0 vs 6.7 months, p = 0.970) and other cancers (4.5 vs 8.8 months, p = 0.449) subgroups. Grade 3/4 haematological toxicities were lower with docetaxel-sunitinib (18.2% vs 34.3%, p = 0.132), attributed to greater discretionary use of prophylactic G-CSF (90.9% vs 63.0%, p = 0.024). Grade 3/4 non-haematological toxicities were similar (12.1% vs 14.3%, p = 0.792).

Conclusions: The addition of sunitinib to docetaxel was well-tolerated but did not improve outcomes. The possible negative impact in metastatic breast cancer patients is contrary to results of adding sunitinib to neoadjuvant AC. These negative results suggest that the intermittent administration of sunitinib in the current dose and schedule with docetaxel in advanced solid tumours, particularly breast cancers, is not beneficial.

Trial registration: The study was registered ( NCT01803503 ) prospectively on clinicaltrials.gov on 4th March 2013.

Keywords: Advanced solid tumours; Anti-angiogenic; Docetaxel; Short-course sunitinib; Tumour vasculature.

Conflict of interest statement

RAS: Honoraria: Astra Zeneca, BMS, Boehringer Ingelheim, Eli-Lilly, Merck, Novartis, Pfizer, Roche and Taiho; Research grant: Astra-Zeneca.

RS: Advisory board: BMS, Merck, Eisai, Bayer, Taiho; honoraria for talks: MSD, Eli Lilly, BMS, Roche, Taiho; Travel funding: Roche, Astra Zeneca, Taiho, Eisai; Research funding: Paxman Coolers, MSD.

These are outside the submitted work.

SGWO: Honoraria: Pfizer, Astra Zeneca, Novartis, Eli Lily.

BCT: Honoraria for workshops: Boehringer Ingelheim; Royalty: Wiley-Blackwell.

SCL: Advisory board: Roche, MSD, Astra Zeneca, Pfizer, Novartis, Eli Lilly, ACT Genomics, Eisai; honoraria for talks: Astra Zeneca, Pfizer, Novartis, ACT Genomics, Eisai; Research Funding: Taiho, Eisai, Pfizer, ACT Genomics, ASLAN Pharmaceuticals Ltd.; Travel funding for conferences: Amgen, Pfizer.

The other authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Consort diagram
Fig. 2
Fig. 2
Progression-free survival 2a Progression-free survival in the overall patient population 2b Progression-free survival in the breast cancer subgroup 2c Progression-free survival in the lung cancer subgroup 2d Progression-free survival in the other cancers subgroup
Fig. 3
Fig. 3
Overall Survival 3a Overall survival in the overall patient population 3b Overall survival in the breast cancer subgroup 3c Overall survival in the lung cancer subgroup 3d Overall survival in the other cancers subgroup

References

    1. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–2342. doi: 10.1056/NEJMoa032691.
    1. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. 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. Carrato A, Swieboda-Sadlej A, Staszewska-Skurczynska M, Lim R, Roman L, Shparyk Y, et al. Fluorouracil, leucovorin, and irinotecan plus either sunitinib or placebo in metastatic colorectal cancer: a randomized, phase III trial. J Clin Oncol. 2013;31(10):1341–1347. doi: 10.1200/JCO.2012.45.1930.
    1. Bergh J, Bondarenko IM, Lichinitser MR, Liljegren A, Greil R, Voytko NL, et al. First-line treatment of advanced breast cancer with sunitinib in combination with docetaxel versus docetaxel alone: results of a prospective, randomized phase III study. J Clin Oncol. 2012;30(9):921–929. doi: 10.1200/JCO.2011.35.7376.
    1. Paz-Ares LG, Biesma B, Heigener D, von Pawel J, Eisen T, Bennouna J, et al. Phase III, randomized, double-blind, placebo-controlled trial of gemcitabine/cisplatin alone or with sorafenib for the first-line treatment of advanced, nonsquamous non-small-cell lung cancer. J Clin Oncol. 2012;30(25):3084–3092. doi: 10.1200/JCO.2011.39.7646.
    1. Duda DG, Batchelor TT, Willett CG, Jain RK. VEGF-targeted cancer therapy strategies: current progress, hurdles and future prospects. Trends Mol Med. 2007;13(6):223–230. doi: 10.1016/j.molmed.2007.04.001.
    1. Willett CG, Boucher Y, di Tomaso R, Duda DG, Munn LL, Tong RT, et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med. 2004;10(2):145–147. doi: 10.1038/nm988.
    1. Gradishar WJ, Kaklamani V, Sahoo TP, Lokanatha D, Raina V, Bondarde S, et al. A double-blind, randomised, placebo-controlled, phase 2b study evaluating sorafenib in combination with paclitaxel as a first-line therapy in patients with HER2-negative advanced breast cancer. Eur J Cancer. 2013;49(2):312–322. doi: 10.1016/j.ejca.2012.08.005.
    1. Baselga J, Roche H, Costa F, Getulio Martins Segalla J, Pinczowski H, Ma Ciruelos E, et al. SOLTI-0701: A multinational double-blind, randomized Phase 2b study evaluating the efficacy and safety of sorafenib compared to placebo when administered in combination with capecitabine in patients with locally advanced or metastatic breast cancer (BC) Cancer Res. 2009;69(24 Suppl):Abstract nr 45.
    1. Winkler F, Kozin SV, Tong RT, Chae SS, Booth MF, Garkavtsev I, et al. Kinetics of vascular normalization by VEGFR2 blockage governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteases. Cancer Cell. 2004;6(6):553–563.
    1. Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005;307(5706):58–62. doi: 10.1126/science.1104819.
    1. Wong ALA, Sundar R, Wang T-T, Ng T-C, Zhang B, Tan S-H, et al. Phase Ib/II randomized, open-label study of doxorubicin and cyclophosphamide with or without low-dose, short-course sunitinib in the pre-operative treatment of breast cancer. Oncotarget. 2016;7(39):64089–64099. doi: 10.18632/oncotarget.11596.
    1. Schulz KF, Altman DG, Moher D. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. BMC Med. 2010;8:18. doi: 10.1186/1741-7015-8-18.
    1. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer. 2009;45:228–247. doi: 10.1016/j.ejca.2008.10.026.
    1. Goh BC, Lee SC, Wang LZ, Fan L, Guo JY, Lamba J, et al. Explaining interindividual variability of docetaxel pharmacokinetics and pharmacodynamics in Asians through phenotyping and genotyping strategies. J Clin Oncol. 2002;20(17):3683–3690. doi: 10.1200/JCO.2002.01.025.
    1. Nabholtz JM, Senn HJ, Bezwoda WR, Melnychuk D, Deschenes L, Douma J, et al. Prospective randomized trial of docetaxel versus mitomycin plus vinblastine in patients with metastatic breast cancer progressing despite previous anthracycline-containing chemotherapy. 304 study group. J Clin Oncol. 1999;17(5):1413–1424. doi: 10.1200/JCO.1999.17.5.1413.
    1. Fossella FV, DeVore R, Kerr RN, Crawford J, Natale RR, Dunphy F, et al. 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. 2000;18(12):2354–2362. doi: 10.1200/JCO.2000.18.12.2354.
    1. Heist RS, Wang X, Hodgson L, Otterson GA, Stinchcombe TE, Gandhi L, et al. CALGB 30704 (Alliance): a randomized phase II study to assess the efficacy of pemetrexed or sunitinib or pemetrexed plus sunitinib in the second-line treatment of advanced non small-cell lung cancer. J Thorac Oncol. 2014;9(2):214–221. doi: 10.1097/JTO.0000000000000071.
    1. Reck M, Kaiser R, Mellemgaard A, Douillard J-Y, Orlov S, Krzakowski M, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol. 2014;15(2):143–155. doi: 10.1016/S1470-2045(13)70586-2.
    1. Garon EB, Ciuleani T-E, Arrieta O, Prabhash K, Syrigos KN, Goksel T, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum based therapy (REVEL): a multicenter, double-blind, randomised phase 3 trial. Lancet. 2014;384(9944):665–673. doi: 10.1016/S0140-6736(14)60845-X.
    1. Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357:2666–2676. doi: 10.1056/NEJMoa072113.
    1. Robert NJ, Dieras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, et al. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011;29(10):1252–60.

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться