Preliminary results of the ALTER-E009 study: Efficacy and safety of anlotinib combined with radiotherapy in patients with locally advanced or metastatic esophageal squamous cell carcinoma (ESCC)—A multicenter, multi-cohort retrospective exploratory study.
Authors: Wang Xin , Feng Guojie , Fu Chengrui , Wang Fan , Wang Xinyi , Li Jiancheng , Yang Baihua , Jiang Yue , Xu Wencai , Zhang Yaowen , Cheng Xinyu , Ge Xiaolin , Xia Xiaojie , Xi Heming , Zhao Xuesong , Ma Hongbing , Zhao Xixi , Li Baosheng 
Published: January 2025

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Background:
Therapeutic options for metastatic esophageal squamous cell carcinoma (ESCC) primarily involve immunotherapy combined with chemotherapy. For locally advanced ESCC, concurrent chemoradiotherapy (CRT) or radiotherapy is the standard, though outcomes remain suboptimal. Targeted therapies, particularly anti-angiogenic agents, hold promise to enhance CRT efficacy. Anlotinib, a multi-target anti-angiogenic agent inhibiting VEGFR, PDGFR, FGFR, and c-KIT, has shown potential to enhance radiotherapy by alleviating tumor hypoxia. This multicenter, retrospective study evaluates the efficacy and safety of anlotinib combined with radiotherapy in locally advanced or metastatic ESCC.
Methods:
This study screened patients (pts) with locally advanced or metastatic ESCC treated with anlotinib (8-12 mg, p.o., qd, d1-14, q3w) and radiotherapy from June 2018 to June 2024. Two cohorts were included: Cohort 1 (metastatic ESCC) and Cohort 2 (locally advanced ESCC). Cohort 2 was divided into an observational group (OG, anlotinib + radiotherapy ± chemotherapy) and a control group (CG, radiotherapy ± chemotherapy). Radiotherapy doses for primary lesions were 45-60 Gy (1.8-2.2 Gy per fraction), while metastatic lesions received either standard fractionation (≥45 Gy) or stereotactic body radiotherapy (SBRT, ≥3 Gy per fraction, total dose ≥30 Gy). Chemotherapy regimens were not restricted. Cohort 1 aimed to enroll 50 pts, while Cohort 2 included 100 in the OG and 200 in the CG. The primary endpoint was overall survival (OS), with secondary endpoints including objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of response (DoR), and safety.
Results:
By September 10, 2024, 128 pts had been enrolled: 34 in Cohort 1 and 94 in the OG of Cohort 2. In Cohort 1, all 34 pts (100%) were stage IVB, with a median OS of 24.0 months (95% CI: 12.44-35.60) and a median PFS of 9.2 months (95% CI: 7.60-10.80). The 24-month OS and PFS rates were 54.0% (95% CI: 27.20-74.73) and 30.8% (95% CI: 10.21-54.53), respectively. ORR was 52.9% (95% CI: 35.1-70.2), with 1 complete response (CR) and 17 partial responses (PR), DCR was 88.2% (95% CI: 72.5-96.7). In Cohort 2, 50 pts (53.2%) were stage III, and 28 (29.8%) were stage IVA. The median OS is not yet mature, but the median PFS was 20.1 months. The 36-month OS and PFS rates were 61.9% (95% CI: 46.12-74.34) and 48.4% (95% CI: 29.58-64.87). ORR was 46.8% (95% CI: 36.4-57.4), with 6 CRs and 38 PRs, DCR was 95.7% (95% CI: 89.5-98.8). Safety data collection is ongoing.
Conclusions:
Anlotinib combined with radiotherapy exhibited promising efficacy in locally advanced or metastatic ESCC, though further data are needed to confirm these preliminary findings.