Immunotherapy in biliary tract cancers: Current evidence and future perspectives

Table 1 Immunotherapy studies including biliary cancer patients, biomarkers, response rate and Food and Drug Administration approvals

Ref.	Patients	n	Biomarker	RR	Drug	FDA approval
Lemery et al[26], 2017	Previously treated	11	MSI-H	27%	Pembrolizumab	5/23/2017
Marabelle et al[27], 2020 (KN158)	Previously treated	22	MSI-H	40.9%	Pembrolizumab	5/23/2017
Marabelle et al[31], 2020 (KN158)	No TMB-H in cholangiocarcinoma cohort	0	TMB-H (≥ 10 mut/Mb)	?	Pembrolizumab	6/16/2020
Ueno et al[32], 2018 (KN158)	Previously treated	104	PD-L1 (CPS ≥ 1)	CPS ≥ 1: 6.6%CPS < 1: 2.9%	Pembrolizumab	-
Bang et al[33], 2019 (KN028)	Previously treated	24	PD-L1 ≥ 1	13%	Pembrolizumab	-
Kim et al[35], 2020	Previously treated	54	-	IA: 22%CIR: 11%	Nivolumab	-
Klein et al[40], 2020 (CA 209-538)	Previously treated	39	-	24%	Nivolumab + Ipilimumab	-
Oh et al[42], 2020	Chemo-naïve	121	-	50%-73%	Gem + Cis + Durvalumab ± Tremelimumab	-
Oh et al[19], 2022 (TOPAZ-1)	Chemo-naive	344	PD-L1 (TAP)	18.7%	Gem + Cis	-
		341		26.7%	Gem + Cis + Durvalumab

KN: Keynote; RR: Response rate; MSI-H: Microsatellite instability-high; TMB-H: Tumor mutational burden-high; mut/Mb: Mutations/megabase; PD-L1: Programmed death-ligand 1; CPS: Combined positive score; IA: Investigator-assessed; CIR: Central independent review; Gem: Gemcitabine; Cis: Cisplatin; TAP: Tumor area positivity.

Table 2 Recruiting trials with checkpoint inhibitors in biliary tract cancers

ClinicalTrials.gov identifier	Study	Intervention	Patients included	State
Immune checkpoint inhibitors combined with chemotherapy
NCT03796429	Phase II	Gemcitabine + S1 + Toripalimab	Chemo naïve	Recruiting
NCT04172402	Phase II	Gemcitabine + TS-1 + Nivolumab	Chemo naïve	Recruiting
NCT04027764	Phase II	Nab-paclitaxel + S1 + Toripalimab	Chemo naïve	Recruiting
NCT04300959	Phase II	Gemcitabine + Cisplatin + Anlotinib + Sintilimab	Chemo naïve	Recruiting
NCT03785873	Phase Ib/II	Nanoliposomal-irinotecan + 5-Fluorouracil + Nivolumab	Advanced disease	Recruiting
NCT04066491	Phase II/III	Gemcitabine + Cisplatin + Bintrafusp alfa	Chemo naïve	Recruiting
NCT04004234	Phase I/II	Gemcitabine + Nab-paclitaxel + Manganese primed anti-PD-1 antibody	Advanced disease	Recruiting
NCT04308174	Phase II	Gemcitabine + Cisplatin + Durvalumab	Resectable disease	Recruiting
NCT03875235	Phase III	Gemcitabine + Cisplatin + Durvalumab	Chemo naïve	Recruiting
NCT03046862	Phase II	Gemcitabine + Cisplatin + Durvalumab + Tremelimumab	Chemo naïve	Recruiting
NCT03478488	Phase III	Gemcitabine + Cisplatin + KN035	Chemo naïve	Recruiting
NCT04191343	Phase II	Gemcitabine + Oxaliplatin + Toripalimab	Chemo naïve	Recruiting
NCT03111732	Phase II	Capecitabine + Oxaliplatin + Pembrolizumab	Advanced disease	Recruiting
NCT03704480	Phase II	Durvalumab + Tremelimumab + Paclitaxel	Second-line systemic treatment	Recruiting
NCT03260712	Phase II	Gemcitabine + Cisplatin + Pembrolizumab	Chemo naïve	Recruiting
Immune checkpoint inhibitors combined with targeted therapy
NCT03639935	Phase II	Rucaparib + Nivolumab	Advanced disease	Recruiting
NCT04211168	Phase II	Toripalimab + Lenvatinib	Second-line systemic treatment	Not yet recruiting
NCT04057365	Phase II	Nivolumab + DKN-01	Advanced disease	Recruiting
NCT04298008	Phase II	Durvalumab + AZD6738	Advanced disease	Recruiting
NCT04298021	Phase II	Durvalumab + AZD6738 + Olaparib	Second-line systemic treatment	Recruiting
NCT03475953	Phase I/II	Regorafenib + Avelumab	Advanced disease	Recruiting
NCT04234113	Phase I	SO-C101 + Pembrolizumab	Advanced disease	Recruiting
NCT04010071	Phase II	Toripalimab + Axitinib	Advanced disease	Not yet recruiting
NCT03829436	Phase I	TPST-1120 + Nivolumab	Advanced disease	Recruiting
NCT03095781	Phase I	Pembrolizumab + XL888	Advanced disease	Recruiting
NCT03250273	Phase II	Entinostat + Pembrolizumab	Advanced disease	Recruiting
NCT03895970	Phase II	Lenvatinib + Pembrolizumab	Advanced disease	Recruiting
NCT03825705	Phase Ib/II	Anlotinib + TQB2450	Advanced disease	Recruiting
Immune checkpoint inhibitors combined with local therapy
NCT03482102	Phase II	Durvalumab + Tremelimumab + Radiotherapy	Advanced disease	Recruiting
NCT02866383	Phase II	Nivolumab + Ipilimumab + Radiotherapy	Second-line systemic treatment	Recruiting
NCT04238637	Phase II	Durvalumab + Tremelimumab + Y-90 SIRT	Intrahepatic biliary cancer	Recruiting
NCT02821754	Phase II	Durvalumab + Tremelimumab + Ablative therapies	Advanced disease	Recruiting
NCT03898895	Phase II	Camrelizumab + Radiotherapy	Unresectable disease	Recruiting
Immune checkpoint inhibitors combined with cell therapy
NCT03937895	Phase I/IIa	Allogeneic NK cell (SMT-NK) + Pembrolizumab	Advanced disease	Recruiting

Ongoing clinical trials identified in ClinicalTrials.gov using the term “Biliar”.