Abstract 944: Analysis of efficacy of receptor tyrosine kinase and immune checkpoint inhibitors and insights to potential combinatorial treatment strategies in cholangiocarcinomas
Authors: Liu Jun , Cao Junning , Wang Guan , Hu Bingyang , Dai Chun , Wang Shengzhou , Xu Fei , Xu Qiang , Lu Shichun 
Published: July 2021

Introduction: Cholangiocarcinomas (CCA) are aggressive tumors with poor prognosis. A large number of CCA patients are already in late stage at diagnosis so are only amenable to systematic therapies. Traditional systematic therapies are often associated with high toxicity and low efficacy. Several advanced therapies, including immune checkpoint inhibitors (ICI) and tyrosine kinase inhibitors (TKI) are under testing against CCA. These efforts are highlighted by the recent FDA approval of pemigatinib, which blocks FGFR2 activation. Combination use of anti-angiogenesis agents with ICI or TKI are also hot research areas. However, data are lacking to demonstrate the real-world value of the above advanced or testing therapies. Here we aim to use a real-world CCA patient set to explore the clinic value and best strategy of combination therapy in CCA.

Methods: We retrospectively enrolled 286 CCA patients with a majority (219) of intrahepatic CCA. In total, 73 patients received anti-PD-1/L1 therapies, including mono-use of pembrolizumab (19), camelizumab (12), nivolumab (11), toripalimab (7), and sintilimab (4), and mixed-use (8) or unspecified (12) of the above anti-PD-1/L1 agents. On the other hand, 68 patients received one or more treatment of anlotinib, apatinib, regorafenib, and sorafenib/sorafenib tosylate TKIs. We performed whole-exome sequencing (WES) (all 286 patients) and RNA-seq (200 patients) to analyze the patients' somatic mutation profiles and tumor microenvironment (TME). We also analyzed their survival benefits stratified by TME, treatment, and gene mutation/fusion status.

Results: We identified 59 patients with FGFR family gene copy number (CNV) gain or gene fusion (9 in FGFR2). Treatment with the above five mentioned TKIs show good prognosis (2-year survival rate 100% vs. 60% in un-treated, p=0.057). However, lenvatinib, an anti-VEGF angiogenesis inhibitor, showed no survival benefit in the 59 patients (HR 0.879, p=0.837). This conclusion was largely recapitulated in 114 patients who had higher transcription (top quartile) of FGFR family genes. Treatment with the first 5 TKIs (counted together) gave HR 0.395 (treated vs. non-treated, p=0.041), while lenvatinib gave HR 0.586 (p=0.164). For the 184 patients with survival data, the above mentioned anti-PD-1/L1 treatments gave HR 0.667 (treated vs. un-treated, p=0.073). Among these who received anti-PD-1/L1 treatment, 64 also received lenvatinib treatment and they gave HR 0.647 (treated vs. non-treated, p=0.265).

Conclusion: Multi-TKIs and ICIs treatment are effective in prolonging patient lives in CCA. The combination use of lenvatinib with other TKIs has limited survival benefit. However, it has a trend of giving some additional benefit when in combination with anti-PD-1/L1 therapies. However, more testings are needed to confirm this.

Citation Format: Jun Liu, Junning Cao, Guan Wang, Bingyang Hu, Chun Dai, Shengzhou Wang, Fei Xu, Qiang Xu, Shichun Lu. Analysis of efficacy of receptor tyrosine kinase and immune checkpoint inhibitors and insights to potential combinatorial treatment strategies in cholangiocarcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 944.