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Camrelizumab in Combination with Apatinib in Second-Line Or Above Therapy for Advanced Primary Liver Cancer

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Camrelizumab in Combination with Apatinib in Second-Line Or Above Therapy for Advanced Primary Liver Cancer Open access Original research J Immunother Cancer: first published as 10.1136/jitc-2020-002191 on 19 March 2021. Downloaded from Camrelizumab in combination with apatinib in second-line or above therapy for advanced primary liver cancer: cohort A report in a multicenter phase Ib/II trial Kuimin Mei,1 Shukui Qin,1 Zhendong Chen,2 Ying Liu,3 Linna Wang,4 Jianjun Zou4 To cite: Mei K, Qin S, Chen Z, ABSTRACT China is an area with a high PLC incidence, et al. Camrelizumab in Background Emerging clinical data suggest that contributing to >50% of the new cases and combination with apatinib in an immune checkpoint inhibitor in combination with deaths globally.1 2 Patients with PLC are often second- line or above therapy for an antiangiogenic agent is a reasonable strategy for advanced primary liver cancer: diagnosed at the locally advanced stage or on multiple malignancies. We assessed the combination cohort A report in a multicenter developing distant metastasis, which is not of camrelizumab with apatinib in pretreated advanced phase Ib/II trial. Journal for suitable for surgery or other local treatment, primary liver cancer (PLC, cohort A) from a multicohort ImmunoTherapy of Cancer thereby leading to poor prognosis with a 2021;9:e002191. doi:10.1136/ phase Ib/II trial. 3 jitc-2020-002191 Methods Patients with PLC after prior systemic 5-year survival rate of only 10%–20%. treatment(s) were administered camrelizumab (3 mg/kg, Since the development of sorafenib and ► Additional material is once every 2 weeks) plus apatinib (125, 250, 375, or 500 systematic chemotherapy containing oxal- published online only. To view, mg; once per day) in a 3+3 dose-escala tion stage and iplatin in recent years, the progress of systemic please visit the journal online subsequent expansion stage. The primary endpoints were therapy for advanced PLC mainly came from (http:// dx. doi. org/ 10. 1136/ jitc- tolerability and safety of study treatment. antiangiogenic molecular target drugs and 2020- 002191). Results From April 2017 to July 2019, 28 patients (21 immune checkpoint inhibitors (ICIs).4 The with hepatocellular carcinoma and 7 with intrahepatic median overall survival (mOS) for sorafenib, cholangiocarcinoma) received camrelizumab plus apatinib. KM and SQ are joint first lenvatinib, regorafenib, cabozantinib, ramu- authors. Two dose- limiting toxicities (both grade 3 diarrhea) were reported in the 500 mg cohort. Therefore, the 375 mg cirumab, and donafenib as first- line or http://jitc.bmj.com/ Accepted 14 February 2021 cohort was expanded. Of the 19 patients in the 375 mg second- line therapy for advanced PLC is cohort, dose reduction to 250 mg occurred in 8 patients between 6.5 months and 13.6 months, and within 2 months after treatment initiation. Of the 28 most objective response rates (ORRs) are patients with PLC, 26 had grade ≥3 treatment- related <10%.4–6 Compared with traditional molec- adverse events, with hypertension being the most ular target drugs and systemic chemotherapy, common (9/28). One treatment-rela ted death occurred. ICIs, represented by programmed death-1 The objective response rate was 10.7% (95% CI 2.3% (PD-1)/programmed death ligand-1 (PD- L1) on September 28, 2021 by guest. Protected copyright. to 28.2%). Median progression-free survival and overall inhibitors (such as nivolumab and pembroli- survival were 3.7 months (95% CI 2.0 to 5.8) and 13.2 months (95% CI 8.9 to not reached), respectively. zumab), have significantly improved the effec- Conclusion The combination of camrelizumab with tiveness in the treatment of advanced PLC, 7 8 apatinib had a manageable toxicity and promising with the ORR being up to 15%–20% ; never- antitumor activity in patients with advanced PLC. Apatinib theless, the overall effect remains limited. at a dose of 250 mg is recommended as a combination PLC has the dual characteristics of a rich therapy for further studies of advanced PLC treatment. blood supply and innate immune tolerance. © Author(s) (or their Trial registration numbers NCT03092895. Previous studies have shown that antiangio- employer(s)) 2021. Re- use genic drugs can reverse the immunosuppres- permitted under CC BY-NC. No 9 commercial re- use. See rights sive status of the tumor microenvironment, and permissions. Published by INTRODUCTION and in combination with ICIs they can be BMJ. Primary liver cancer (PLC) consists mainly synergistic, which is a promising therapeutic For numbered affiliations see of hepatocellular carcinoma (HCC), intra- strategy to improve the efficacy of treatment end of article. hepatic cholangiocarcinoma (ICC), and for advanced PLC. mixed HCC–ICC type, of which about 90% Camrelizumab is a humanized PD-1 mono- Correspondence to 1 Professor Shukui Qin; are HCC. In 2018, there were 841 000 new clonal antibody that has a high affinity qinsk@ csco. org. cn cases of PLC worldwide, with 782 000 deaths. (KD=3.31 nmol/L) with PD-1, a high Mei K, et al. J Immunother Cancer 2021;9:e002191. doi:10.1136/jitc-2020-002191 1 Open access J Immunother Cancer: first published as 10.1136/jitc-2020-002191 on 19 March 2021. Downloaded from occupancy of circulating T-lymphocyte receptors (85% dose- escalation stage, and the second stage was the dose- at a dose of 200 mg),10 and a good tolerance and cura- expansion stage. tive effect on a variety of solid tumors, including PLC.11 In the dose- escalation stage, the camrelizumab dose On the other hand, apatinib is a highly selective small- was set to 3 mg/kg, intravenously, once every 2 weeks. molecule tyrosine kinase inhibitor of vascular endothe- The initial dose of apatinib was 125 mg, oral, once per day lial growth factor receptor 2 (VEGFR-2). Results from (QD), which was then increased stepwise to 250 mg QD, phase II clinical trials have shown that apatinib as a first- 375 mg QD, and 500 mg QD. Three to six patients were line treatment has potential survival benefits for Chinese included in each dose group. The observation period patients with advanced HCC.12 for the dose- limiting toxicity (DLT) was the first cycle of Based on these theoretical bases and clinical data, we continuous administration (28 days). If DLT occurred in conducted a clinical trial on camrelizumab in combi- two patients in a certain dose group, the dose escalation nation with apatinib for the treatment of patients with was stopped. The prior dose would be considered as the advanced PLC. The patients enrolled in this study were MTD. Afterwards, a total of 12 patients were entered into from cohort A in a phase Ib/II trial of camrelizumab in the dose- expansion stage. combination with apatinib or chemotherapy in advanced The patients were administered with camrelizumab PLC or biliary- tract cancer (BTC). The treatment results in combination with apatinib until investigator-assessed of this cohort are reported herein. disease progression (according to RECIST V.1.1), unac- ceptable toxicity, withdrawal of consent, investigator decision, or study completion. For patients with radio- METHODS logical disease progression, if the investigator judged Study design and subjects that the patients would benefit from and were tolerant Patients were from cohort A of an open, multicenter, of continued treatment, and if the patient had been multicohort phase Ib/II clinical trial of camrelizumab in informed and provided voluntary consent, the combi- combination with apatinib or chemotherapy in the treat- nation treatment was allowed to continue. During treat- ment of advanced PLC or BTC. Patients with advanced ment, camrelizumab could be suspended for <6 weeks PLC who failed or could not tolerate systematic therapy to manage adverse events (AEs), although the camreli- were enrolled in this study. Eligible patients were 18–70 zumab dose was not allowed to be adjusted. On the other years old, had a histologically or cytologically confirmed hand, apatinib could be suspended for <28 days, and the diagnosis of advanced PLC, were unsuitable for surgery dose was allowed to be reduced (except in the 125 mg or local treatment, had at least one measurable lesion group). as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1, had a Child- Pugh score of ≤7, Outcomes had an Eastern Cooperative Oncology Group (ECOG) The primary endpoints of this study were the safety and tolerance of camrelizumab in combination with apatinib performance score of 0 or 1, had a predicted life expec- http://jitc.bmj.com/ tancy of greater than 12 weeks and had adequate organ in the treatment of advanced PLC. The secondary function. Patients with chronic hepatitis B virus (HBV) endpoints included ORR, duration of response (DoR), infections with a viral load of <500 IU/mL were permitted progression- free survival, time to progression, disease to enroll, and those infected with HBV and hepatitis C control rate (DCR), and OS. virus were required to receive standardized antiviral treat- During the study, any AEs and laboratory abnormalities were monitored and recorded from the time of informed ment. The main exclusion criteria were as follows: current on September 28, 2021 by guest. Protected copyright. or previous pulmonary fibrosis; interstitial pneumonia; consent until 90 days after the last administration, and active or prior autoimmune disease; previous abdominal were graded according to the National Cancer Institute fistula, gastrointestinal perforation, or abdominal abscess Common Terminology Criteria for Adverse Events V.4.03. in the past 2 months; previous gastrointestinal bleeding Tumor imaging evaluation was performed every 8 or clear tendency of gastrointestinal bleeding in the past weeks (±7 days) during the study period, and the tumor 6 months; current or previous central nervous system responses were evaluated according to the RECIST V.1.1 metastasis; local treatment for the liver (including but criteria.
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