Subgroup Analysis by Liver Metastasis in the FRESCO Trial Comparing Fruquintinib versus Placebo Plus Best Supportive Care in Chinese Patients with Metastatic Colorectal Cancer

Shukui Qin, Rui-Hua Xu, Lin Shen, Jianming Xu, Yuxian Bai, Lei Yang, Yanhong Deng, Zhen-Dong Chen, Haijun Zhong, Hongming Pan, Weijian Guo, Yongqian Shu, Ying Yuan, Jianfeng Zhou, Nong Xu, Tianshu Liu, Dong Ma, Changping Wu, Ying Cheng, Donghui Chen, Wei Li, Sanyuan Sun, Zhuang Yu, Peiguo Cao, Haihui Chen, Jiejun Wang, Shubin Wang, Hongbing Wang, Ning Wang, Bin Zhang, Qiang Zhang, Weiguo Su, Xiaojun Guo, Jin Li, Shukui Qin, Rui-Hua Xu, Lin Shen, Jianming Xu, Yuxian Bai, Lei Yang, Yanhong Deng, Zhen-Dong Chen, Haijun Zhong, Hongming Pan, Weijian Guo, Yongqian Shu, Ying Yuan, Jianfeng Zhou, Nong Xu, Tianshu Liu, Dong Ma, Changping Wu, Ying Cheng, Donghui Chen, Wei Li, Sanyuan Sun, Zhuang Yu, Peiguo Cao, Haihui Chen, Jiejun Wang, Shubin Wang, Hongbing Wang, Ning Wang, Bin Zhang, Qiang Zhang, Weiguo Su, Xiaojun Guo, Jin Li

Abstract

Objective: The aim of the present subgroup analysis of the FRESCO trial is to determine the efficacy and hepatotoxicity of fruquintinib in Chinese patients with metastatic CRC with liver metastasis (CRLM) who were receiving third-line or posterior-line therapy.

Methods: Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier method. Hazard ratio (HR) was estimated through Cox proportional hazards model. Hepatotoxicity was coded using the standardized MedDRA queries of hepatic failure, fibrosis, cirrhosis, and other liver injury-related conditions and graded using the Common Terminology Criteria Adverse Events grades. The efficacy of fruquintinib in patients with CRLM was evaluated in various subgroups.

Results: A total of 287 (69.0%) patients with metastatic CRC had liver metastasis (LM, fruquintinib: 185 and placebo: 102). Median OS in patients with CRLM was significantly prolonged with fruquintinib compared with placebo (8.61 months vs 5.98 months; HR=0.59, 95% CI, 0.45-0.77, P<0.001). In patients with CRLM, the incremental median PFS for patients in the fruquintinib-treated group was significantly higher than in the placebo group (median PFS: 3.71 vs.1.84 months; HR=0.22, 95% CI: 0.17-0.30; P<0.001). Compared with placebo, significant improvements in OS were observed with fruquintinib in LM patients regardless of lung metastasis, prior target therapy, and K-RAS status. In patients with CRLM, treatment-emergent hepatotoxicities of any grade occurred in 7 (3.8%) patients in the fruquintinib group vs 2 (2.0%) in the placebo group.

Conclusion: Fruquintinib demonstrated a statistically significant increase in OS and PFS as compared with placebo in Chinese patients with CRLM. The hepatotoxicity of fruquintinib was less reported, and comparable with placebo in patients with CRLM.

Clinicaltrialsgov identifier: NCT02314819.

Keywords: FRESCO trial; colorectal cancer; fruquintinib; liver metastasis.

Conflict of interest statement

Ning Wang, Bin Zhang, and Qiang Zhang are employees of Eli Lilly and Company. Weiguo Su and Xiaojun Guo are employees of Hutchison MediPharma Limited. Dr Lin Shen reports non-financial support from Lilly, non-financial support from HMPL, during the conduct of the study; grants from Beijing Xiantong Biomedical Technology, grants from Qilu Pharmaceutical, grants from ZaiLab Pharmaceutical, grants from Beihai Kangcheng (Beijing) Medical Technology, grants from Jacobio Pharmaceuticals; received consulting fees from MSD, Merck, Mingji Biopharmaceutical, Haichuang pharmaceutical, Harbour Biomed, and BI; also received fees for speakers Bureaus from Hutchison Whampoa, Hengrui, ZaiLab, CSTONE pharmaceutical; and a member of Advisory Board of Rongchang Pharmaceutical, ZaiLab, CSTONE Pharmaceutical, BMS, outside the submitted work. The other authors have nothing to disclose.

© 2021 Qin et al.

Figures

Figure 1
Figure 1
Comparison of overall survival in mCRC patients with liver metastasis (A) and without liver metastasis (B).
Figure 2
Figure 2
Comparison of progression-free survival in mCRC patients with liver metastasis (A) and without liver metastasis (B).
Figure 3
Figure 3
Comparison of overall survival for subgroup analysis of CRLM patients.
Figure 4
Figure 4
Comparison of progression free survival for subgroup analysis of CRLM patients.

References

    1. Rawla P, Sunkara T, Barsouk A. Epidemiology of colorectal cancer: incidence, mortality, survival, and risk factors. Prz Gastroenterol. 2019;14(2):89–103. doi:10.5114/pg.2018.81072
    1. Haggar FA, Boushey RP. Colorectal cancer epidemiology: incidence, mortality, survival, and risk factors. Clin Colon Rectal Surg. 2009;22(4):191–197. doi:10.1055/s-0029-1242458
    1. Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66(2):115–132. doi:10.3322/caac.21338
    1. Pourhoseingholi MA. Increased burden of colorectal cancer in Asia. World J Gastrointest Oncol. 2012;4(4):68–70. doi:10.4251/wjgo.v4.i4.68
    1. Van de Velde CJH. Treatment of liver metastases of colorectal cancer. Ann Oncol. 2005;16(Suppl 2):ii144–ii149. doi:10.1093/annonc/mdi702
    1. Welch JP, Donaldson GA. The clinical correlation of an autopsy study of recurrent colorectal cancer. Ann Surg. 1979;189(4):496–502. doi:10.1097/00000658-197904000-00027
    1. Xu R, Wang W, Zhu B, et al. Disease characteristics and treatment patterns of Chinese patients with colorectal cancer: a retrospective study using medical records from China. BMC Cancer. 2020;131(20). doi:10.1186/s12885-020-6557-5
    1. Chow FC, Chok KS. Colorectal liver metastases: an update on multidisciplinary approach. World J Hepatol. 2019;11(2):150–172. doi:10.4254/wjh.v11.i2.150
    1. Blackham AU, Swett K, Levine EA, Shen P. Surgical management of colorectal cancer metastases to the liver: multimodality approach and a single institutional experience. Colorectal Cancer. 2013;2(1):73–88. doi:10.2217/crc.12.80
    1. Xu F, Tang B, Jin TQ, Dai CL. Current status of surgical treatment of colorectal liver metastases. World J Clin Cases. 2018;6(14):716–734. doi:10.12998/wjcc.v6.i14.716
    1. Aparicio J, Fernandez-Martos C, Vincent JM, et al. FOLFOX alternated with FOLFIRI as first-line chemotherapy for metastatic colorectal cancer. Clin Colorectal Cancer. 2005;5(4):263–267. doi:10.3816/CCC.2005.n.037
    1. Jonker D, Rumble RB, Maroun J; Gastrointestinal Cancer Disease Site Group of Cancer Care Ontario’s Program in Evidence-Based Care. Role of oxaliplatin combined with 5-fluorouracil and folinic acid in the first- and second-line treatment of advanced colorectal cancer. Curr Oncol. 2006;13(5):173–184. doi:10.3747/co.v13i5.99
    1. Limaiem F, Bouraoui S. Chemotherapy-induced liver injury in metastatic colorectal cancer: about 48 cases. Pan Afr Med J. 2018;30:198. doi:10.11604/pamj.2018.30.198.15548
    1. Maor Y, Malnick S. Liver injury induced by anticancer chemotherapy and radiation therapy. Int J Hepatol. 2013;2013:815105. doi:10.1155/2013/815105
    1. Choti MA. Chemotherapy-associated hepatotoxicity: do we need to be concerned? Ann Surg Oncol. 2009;16(9):2391–2394. doi:10.1245/s10434-009-0512-7
    1. Chen D, Gu K, Wang H. Optimizing sequential treatment with anti-EGFR and VEGF mAb in metastatic colorectal cancer: current results and controversies. Cancer Manag Res. 2019;11:1705–1716. doi:10.2147/CMAR.S196170
    1. Schirripa M, Lenz HJ. Colorectal cancer: overcoming resistance to anti-EGFR therapy-where do we stand? Nat Rev Gastroenterol Hepatol. 2016;13(5):258–259. doi:10.1038/nrgastro.2016.52
    1. De Mattia E, Cecchin E, Toffoli G. Pharmacogenomics of intrinsic and acquired pharmacoresistance in colorectal cancer: toward targeted personalized therapy. Drug Resist Updat. 2015;20:39–70.
    1. Zhang Y, Zou JY, Wang Z, Wang Y. Fruquintinib: a novel antivascular endothelial growth factor receptor tyrosine kinase inhibitor for the treatment of metastatic colorectal cancer. Cancer Manag Res. 2019;11:7787–7803. doi:10.2147/CMAR.S215533
    1. Li J, Qin S, Xu RH, et al. Effect of fruquintinib vs placebo on overall survival in patients with previously treated metastatic colorectal cancer: the FRESCO randomized clinical trial. JAMA. 2018;319(24):2486–2496. doi:10.1001/jama.2018.7855
    1. V T Broadbridge, C S Karapetis, C Beeke et al. Do Metastatic Colorectal Cancer Patients Who Present With Late Relapse After Curative Surgery Have a Better Survival?. Br J Cancer. 2013;109(5):1138–43.
    1. Kanas G, Aliki T, Primrose J et al. Survival after liver resection in metastatic colorectal cancer: review and meta-analysis of prognostic factors. Clin Epidemiol. 2012;4:283–301.
    1. F. Jones, D. Edelstein, K. Wichner, C. Ross, F. Holtrup. 2012 Concordance of RAS mutation status in metastatic CRC patients bycomparison of results from circulating tumor DNA and tissue-based RAS testing. European Journal of Cancer. 2015;51(3):S331–S332.

Source: PubMed

スポンサーと協力者

医学的状態

薬物療法

3
購読する