A phase Ib study of anlotinib plus TQB2450 as second-line therapy for advanced biliary tract adenocarcinoma.

4075 Background: Although with modest efficacy, mFOLFOX is recommended as standard second-line chemotherapy for advanced biliary tract adenocarcinoma. Several clinical trials are exploring the combination treatment of anti-angiogenic drugs and immune checkpoint inhibitors. Anlotinib is an oral small molecule inhibitor of receptor tyrosine kinases, with inhibitory effects on tumor angiogenesis and growth. Anlotinib plus TQB2450,an anti-PD-L1 mAb, have shown anti-tumor activity in preclinical study and here we investigate the efficacy and safety of different dosage of this regimen as second-line treatment for advanced biliary tract adenocarcinoma. Methods: Patients with advanced biliary tract adenocarcinoma who had progressed after first-line treatment received anlotinib (once daily for 2 weeks on/1 week off) plus TQB2450 (1200mg once) every three weeks. The planned anlotinib dose levels to be explored were 10mg (starting) and 12mg daily. Dose expansion was performed after the determination of the maximum tolerable dose. Response to treatment was evaluated using the RECIST 1.1 criteria, supplemented by iRECIST. The primary endpoints were MTD, ORR, and the secondary endpoints were PFS, OS and safety. Results: Both 10mg and 12mg of anlotinib were tolerable after the initial safety observation of different doses from May 2019 to April 2020. 34 patients (8 cases of gallbladder cancer [GBC], 22 of intrahepatic cholangiocarcinoma [ICC] and 4 of extrahepatic cholangiocarcinoma [ECC]) were enrolled, 22 patients in the 10mg dose group and 12 in the 12mg dose group. The median age was 57 (37-72) years and 55.9% (19) of the patients were female. At the analysis cut-off date of 31 December 2020, the median follow-up duration was 14.9 months. Of the 34 patients, 4 patients had partial response (PR, 2 cases in the 10mg group and 2 in the 12mg group), including 2 cases with GBC and 2 with ICC, 17 had stable disease (SD, shrinkage, 12 in the 10mg group and 5 in the 12mg group) and 5 SD (enlargement, 4 in the 10mg group and 1 in the 12mg group), 7 had progression disease (PD, 5 in the 10mg group and 2 in the 12mg group) and 1 patient of ECC could not be evaluated. In the overall population, the median PFS (mPFS) was 5.95 (95%CI: 3.78-11.50) months. The mPFS was 5.29 (95%CI: 3.45-10.32) months in 10mg group and 12.98 (95%CI: 1.38-NR) in 12mg group. The median OS was not reached and the 12-month OS rate was 64.71% (60.87% in the 10mg group and 72.73% in the 12mg group). Grade 3 or higher toxicities were observed in 8 patients, with elevated transaminase (n = 4, 11.8%), elevated bilirubin (n = 3, 8.8%), fatigue (n = 1, 2.9%), hypertension (n = 1, 2.9%) and prolonged QTc (n = 1, 2.9%). Conclusions: Anlotinib plus TQB2450 as second-line therapy for advanced biliary tract adenocarcinoma was well tolerated and showed promising efficacy. No unexpected adverse events were observed in both drugs. This regimen is worthy of further exploration. Clinical trial information: NCT03825705.