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Safety and Efficacy of Anlotinib, a Multikinase Angiogenesis Inhibitor, in Patients with Refractory Metastatic Soft-Tissue Sarcoma

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Safety and Efficacy of Anlotinib, a Multikinase Angiogenesis Inhibitor, in Patients with Refractory Metastatic Soft-Tissue Sarcoma Published OnlineFirst June 12, 2018; DOI: 10.1158/1078-0432.CCR-17-3766 Cancer Therapy: Clinical Clinical Cancer Research Safety and Efficacy of Anlotinib, a Multikinase Angiogenesis Inhibitor, in Patients with Refractory Metastatic Soft-Tissue Sarcoma Yihebali Chi1, Zhiwei Fang2, Xiaonan Hong3, Yang Yao4, Ping Sun5, Guowen Wang6, Feng Du7, Yongkun Sun1, Qiong Wu8, Guofan Qu9, Shusen Wang10, Jianmin Song11, Jianchun Yu12, Yongkui Lu13, Xia Zhu14, Xiaohui Niu15, Zhiyong He16, Jinwan Wang1, Hao Yu17, and Jianqiang Cai1 Abstract Purpose: The prognosis for patients with refractory soft- response rate was 13% (95% confidence interval, 7.6%– tissue sarcoma (STS) is dismal. Anlotinib has previously 18%). The median progression-free survival (PFS) and overall shown antitumor activity on STS in preclinical and phase I survival (OS) were 5.6 and 12 months, respectively. The studies. PFR12 weeks, median PFS and OS were: 58%, 4.1 and 11 months Experimental Design: Patients 18 years and older, progres- for UPS (n ¼ 19); 63%, 5.6 and 13 months for LPS (n ¼ 13); sing after anthracycline-based chemotherapy, na€ve from 75%, 11 and 15 months for LMS (n ¼ 26); 75%, 7.7 and 12 angiogenesis inhibitors, with at least one measurable lesion months for SS (n ¼ 47); 81%, 5.6 and 12 months for FS according to RECIST 1.1, were enrolled. The main subtypes (n ¼ 18); 77%, 21 and not reached for ASPS (n ¼ 13); 54%, 11 eligible were undifferentiated pleomorphic sarcoma (UPS), and 16 months for CCS (n ¼ 7); and 44%, 2.8 and 8.8 months liposarcoma (LPS), leiomyosarcoma (LMS), synovial sarcoma for other sarcoma (n ¼ 23), respectively. The most common (SS), fibrosarcoma (FS), alveolar soft-part sarcoma (ASPS), clinically significant grade 3 or higher adverse events were and clear cell sarcoma (CCS). Participants were treated with hypertension (4.8%), triglyceride elevation (3.6%), and pneu- anlotinib. The primary endpoint was progression-free rate at mothorax (2.4%). No treatment-related death occurred. 12 weeks (PFR12 weeks). Conclusions: Anlotinib showed antitumor activity Results: A total of 166 patients were included in the final in several STS entities. The toxicity was manageable. Clin analysis. Overall, the PFR12 weeks was 68%, and objective Cancer Res; 1–6. Ó2018 AACR. Introduction 1National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences 2 Soft-tissue sarcoma (STS) represents a heterogeneous malig- and Peking Union Medical College, Beijing, China. Peking University Cancer nant tumor category comprising over 50 different entities that Hospital, Beijing, China. 3Fudan University Shanghai Cancer Center, Shanghai, China. 4Sixth People's Hospital, Shanghai, China. 5Liaoning Cancer Hospital and associated with distinct morbidity and mortality (1). For patients Institute, Shenyang, China. 6Tianjin Medical University Cancer Institute and diagnosed with advanced or metastatic STS, doxorubicin alone or Hospital, Tianjin, China. 7Key Laboratory of Carcinogenesis and Translational in combination with other cytotoxic agents has been typically Research (Ministry of Education/Beijing), the VIPII Gastrointestinal Cancer recommended as the first-line treatment in the past four decades Division of Medical Department, Peking University Cancer Hospital and Institute, – 8 (2 6). Olaratumab, a recombinant monoclonal antibody against Beijing, China. The first Affiliated Hospital of Bengbu Medical College, Bengbu, a a 9 10 platelet-derived growth factor receptor (PDGFR ), showed a China. Harbin Medical University Cancer Hospital, Harbin, China. Sun Yat-sen fi University Cancer Center, Guangzhou, China. 11Gansu Provincial Cancer Hospital, highly signi cant improvement of OS when combined with Lanzhou, China. 12Peking Union Medical College Hospital, Beijing, China. 13Affil- doxorubicin, highlighting the potential of PDGFRa as a thera- iated Cancer Hospital of Guangxi Medical University, Nanning, China. 14First peutic target for STS (7). Also, several novel agents have been Affiliated Hospital of Fujian Medical University, Fuzhou, China. 15Beijing Jishuitan approved for the treatment of STS after failure of standard che- Hospital, Beijing, China. 16Fujian Provincial Cancer Hospital, Fuzhou, China. 17 motherapy, including trabectedin for leiomyosarcoma (LMS) and School of Public Health Nanjing Medical University, Nanjing, China. liposarcoma (LPS; refs. 8, 9), eribulin for LPS (10), and pazopanib Note: Supplementary data for this article are available at Clinical Cancer for nonadipocytic and nongastrointestinal stromal tumor (GIST) Research Online (http://clincancerres.aacrjournals.org/). STS (11). However, the prognosis of patients with metastatic STS Corresponding Author: Jianqiang Cai, National Cancer Center/Cancer Hospital, remains dismal, with a median OS barely exceeding 1 year (5, 12). Chinese Academy of Medical Sciences and Peking Union Medical College, PO This highlights an ongoing challenge with the relatively small Box 2258, 17 Panjiayuan Nanli, Beijing 100021, China. Phone: 86-010-67781331; increments of effective treatment and represents an unmet med- E-mail: [email protected] ical need warranting further investigation. doi: 10.1158/1078-0432.CCR-17-3766 A number of comprehensive genomic analyses have identified Ó2018 American Association for Cancer Research. specific molecular alterations in STS (13, 14). VEGF is one of the www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst June 12, 2018; DOI: 10.1158/1078-0432.CCR-17-3766 Chi et al. fibrosarcoma (FS), alveolar soft-part sarcoma (ASPS), clear cell Translational Relevance sarcoma (CCS), malignant peripheral nerve sheath tumor Currently, pazopanib is the only tyrosine kinase inhibitor (MPNST), angiosarcoma, and epithelioid sarcoma. Patients (TKI) approved by FDA for nongastrointestinal stromal tumor with the following entities were excluded: GIST, rhabdomyo- and nonadipocytic soft-tissue sarcoma (STS) that progressed sarcoma, chondrosarcoma, osteosarcoma, dermatofibrosar- after standard chemotherapy. For Chinese STS patients who coma protuberans, Ewing sarcoma, primitive neuroectodermal failed chemotherapy, there is no available standard drug as tumor, inflammatory myofibroblastic tumor, and malignant pazopanib has not been approved for treating STS in China. mesothelioma. Pathology materials(tumorblocksorrepresen- Anlotinib is a new TKI, inhibiting kinases involved in angio- tative slides) were centrally reviewed. genesis and tumor proliferation. In this phase II study, anlo- The main exclusion criteria included prior treatment with tinib showed antitumor activity in several STS subtypes that antiangiogenic agents such as sunitinib, sorafenib, and bevacizu- progressed after previous anthracycline-based chemotherapy. mab, known history of or concomitant malignancy likely to affect In contrast to pazopanib and regorafenib, anlotinib has shown life expectancy except curative skin basal cell carcinoma and clinical activity in liposarcoma highlighting the uniqueness of cervical carcinoma in situ, chemotherapy or radiotherapy within anlotinib. The toxicity was manageable and acceptable. 28 days before start study entry, taken part in other clinical trial within 28 days before study entry, ongoing toxicity > grade 2 according to Common Terminology Criteria for Adverse Events v4.0 (CTCAE), inability to swallow oral medications, known main drivers for angiogenesis, which plays a crucial role in tumor history of brain or meningeal metastasis, and spinal compression. growth, invasion, and metastasis (15, 16). Besides, the dysregula- The complete inclusion and exclusion criteria were in Supple- tion of FGF/FGFR axis promotes cancer progression and enhances mentary Methods S1. The trial was registered at ClinicalTrials.gov the angiogenic potential of tumor microenvironment (17, 18). In (NCT01878448). addition to the angiogenic pathway, factors in proliferative path- The protocol was approved by the Institutional Review Board at way, such as PDGF and c-Kit, are also likely to contribute to the each participating institution center and complied with good highly malignant phenotype of STS (19, 20). Taken together, these clinical practice guidelines, as well as the Declaration of Helsinki. findings provide a rationale for proangiogenic and proliferative All patients provided written informed consent to participate in factors to serve as the potential targets for treatment of STS. the study. Anlotinib is a novel tyrosine kinase inhibitor targeting multiple factors involving tumor proliferation, vasculature, and tumor Procedures microenvironment (21). Anlotinib inhibits VEGF/VEGFR signal- After verification of eligibility criteria, patients would receive ing by selectively targeting VEGFR-2,-3 and FGFR-1,-2,-3,-4 with oral anlotinib 12 mg, once daily, 2-week on/1-week off, until high affinity. Anlotinib also suppresses the activity of PDGFRa/b, disease progression according to RECIST 1.1, death, unacceptable c-Kit, Ret, Aurora-B, c-FMS, and discoidin domain receptor 1 toxicity, or withdrawal of consent for any reasons. A cycle was (DDR1), leading to significant inhibition of tumor proliferation considered to be 3 weeks. During the treatment period, the tumor (21). In the preclinical stage, anlotinib showed broad antitumor assessment would be done every 6 weeks. Dose modifications for activity against a variety of xenograft models (21). adverse events were done according to the protocol. Clinical In phase I study,
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