| Background and PurposeEsophageal cancer is one of the most common malignant tumors around all the world.In China,as a high-incidence disease,about 90%of the esophageal cancers are esophageal squamous cell carcinomas(ESCC).And the prognosis of patients with esophageal cancer are quit bad.So far,the main standard therapy for advanced ESCC is chemotherapy.However,chemotherapy alone exhibit low effective rate and unsatisfactory results and until now there is a lack of safe and effective second-line therapy plan.Anlotinib hydrochloride is a new class of multi-target tyrosine kinase inhibitor,which owns the effects of anti-tumor angiogenesis and inhibiting tumor growth.In the advanced ESCC phase II multi-center clinical trial ALTER1102,the single-agent therapy plan with anlotinib for second-line ESCC has confirmed efficacy and safety of anlotinib,which have been recommended by the 2019 Chinese Society of Clinical Oncology guidelines for advanced ESCC Second-line treatment options(2A recommendation).Anti-angiogenic drugs can induce the normalization of blood vessels inside the tumor,improve the hypoxia inside the tumor,promote autophagy,and enhance the sensitivity of the tumor to chemotherapy.Combination therapy of anti-angiogenic drugs and chemotherapy has become the standard therapy plan for many tumor types.Herein,the efficacy and safety of combination therapy by anlotinib and irinotecan for the second-line advanced ESCC were evaluated.Materials and MethodsThis study is a prospective,randomized,open phase Ⅱ clinical study conducted in 12 research centers in Henan Province,China.The eligible patients were adults aged 18-75,who histologically progressed or intolerated first-line chemotherapy of ESCC,and had a score of 0-1 from the Eastern Cooperative Oncology Group(ECOG).Patients were randomly divided(ratio,1:1)into the experimental group of combination therapy by anlotinib and irinotecan(anlotinib 12/10 mg po d1-d14 Q3W,irinotecan 65mg/m2 ivgtt d1,d8 Q3W)and single-drug control group of irinotecan(irinotecan 65mg/m2 ivgtt d1,d8 Q3W),The treatment endpoint was disease progression,toxicity intolerance,initiation of new anti-tumor therapy,withdrawal of informed consent,or the investigator’s judgment that the subject needs to withdraw from the therapy plan.The longest medication time of anlotinib and irinotecan were 2 years.The primary endpoints were the disease control rate(DCR)and progression-free survival(PFS)which were evaluated by the response evaluation criteria in solid tumors version 1.1(RECIST v1.1),and the secondary endpoints were the objective response rate(ORR),overall survival(OS)evaluated by RECIST v1.1,safety and drug tolerance.41 patients were planned to include in the experimental group and 41 patients in the control group.The research had been registered on the Clinical trial.gov website,registration number:NCT03387904.ResultsFrom January 2019 to December 2019,all 47 ESCC patients were recruited in 12 centers in Henan Province,in which 43 patients were successfully screened and randomly assigned to the experimental group(22 patients)and the control group(21 patients).There were no differences between the two groups of patients in terms of their age stratification,gender,ECOG score,degree of differentiation,lymph node metastasis,distant organ metastasis,concomitant disease and previous therapy history and other baseline characteristics(P>0.05).Until January 2021,the follow-up time was 2.3-23.6 months,and the median follow-up time was 10.3 months.32 patients were included in the efficacy analysis(16 patients in the experimental group and 16 patients in the control group).Compared with the control group,the experimental group increased the DCR(75%vs 50%,P=0.144).The PFS rates of the experimental group and the control group in 1-,2-and 4-month were 93.8%vs 87.5%,87.5%vs 50%,and 43.8%vs 8.3%,respectively.Compared with the control group,the experimental group significantly increased the median PFS by 2.04 months(3.78 months vs 1.74 months,P=0.012),and reduced the risk of disease progression by 65%(Hazard Ratio[HR]=0.35,95%Confidence Interval[CI]:0.15-0.83,P=0.017).The 6-month and 1-year OS rates of the experimental group and the control group were 93.8%vs 75%and 37.5%vs 37.5%,respectively.Compared with the control group,the experimental group prolonged the median OS(10.5 months vs 9.13 months,P=0.799),and reduced the risk of death by 9%(HR=0.91,95%CI:0.42-1.96,P=0.799).43 patients were included in the safety analysis(22 patients in the experimental group and 21 patients in the control group).The incidence of all grade adverse effects were 95.5%vs 95.2%for the experimental group and control group(P=0.744);the incidence of grade 3-4 adverse effects were 18.2%vs 4.8%for the experimental group and the control group(P=0.370).The most common adverse effects in the experimental group were fatigue(59.1%),nausea and vomiting(59.1%),hypertension(45.5%)and decreased appetite(45.5%).The most common adverse effects in the control group were fatigue(57.1%),nausea and vomiting(57.1%),decreased appetite(47.6%).The incidence of hypertension in the experimental group was higher(45.5%vs 14,3%P=0.026),but they were mostly 1-2 grade and controllable.There were no therapy-related death adverse events in the two groups.In the experimental group,14 patients were treated with the initial dose of anlotinib of 12 mg/d in which 10 patients were adjusted or stopped taking the medication(71.4%,10/14),and 8 patients was adjusted the initial dose of anlotinib to 10 mg/d due to the change of trial protocol in which 1 patient stopped the medication(12.5%,1/8).In the control group of 21 patients,7 patients were adjusted the dose or stopped the medication(33.3%,7/21).All patients in the trial did not undergo two dose adjustments.ConclusionThe combination therapy of anlotinib and irinotecan for the second-line advanced ESCC reached one of the main research endpoints of PFS.Compared to the control group,the experimental group significantly inc reased the median PFS by 2.04 months,and reduced the risk of disease progression by 65%.The enrollment has not terminated,and its other primary endpoint DCR and secondary endpoint OS both confirmed the advantages of combination therapy.In terms of adverse effects,the adverse effects of the experimental group were consistent with the previous single-agent data of anlotinib or irinotecan,in which there were no therapy-related deaths.Based on the result s of current samples and follow-up time,the combination therapy of anlotinib and irinotecan can be considered as a second-line treatment option for advanced ESCC. |
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