Immunotherapy-based combination strategies for treatment of gastrointestinal cancers: current status and future prospects

doi:10.1007/s11684-019-0685-9

Front. Med.

2019, Vol. 13

Issue (1) : 12-23 https://doi.org/10.1007/s11684-019-0685-9

REVIEW

Immunotherapy-based combination strategies for treatment of gastrointestinal cancers: current status and future prospects

Chenfei Zhou, Jun Zhang(

)

Department of Oncology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China

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Abstract

Strategies in comprehensive therapy for gastrointestinal (GI) cancer have been optimized in the last decades to improve patients’ outcomes. However, treatment options remain limited for late-stage or refractory diseases. The efficacy of immune checkpoint inhibitors (ICIs) for treatment of refractory GI cancer has been confirmed by randomized clinical trials. In 2017, pembrolizumab was approved by the US Food and Drug Administration as the first agent for treatment of metastatic solid tumors with mismatch repair deficiency, especially for colorectal cancer. Given the different mechanisms, oncologists have focused on determining whether ICIs-based combination strategies could achieve higher efficacy than conventional therapy alone in late-stage or even front-line treatment of GI cancer. This review discusses the current status of combining immune checkpoint inhibitors with molecular targeted therapy, chemotherapy, or radiotherapy in GI cancer in terms of mechanisms, safety, and efficacy to provide basis for future research.

Keywords gastrointestinal cancer immune checkpoint inhibitor combination therapy

Corresponding Author(s): Jun Zhang

Just Accepted Date: 16 January 2019 Online First Date: 22 February 2019 Issue Date: 12 March 2019

Cite this article:

Chenfei Zhou,Jun Zhang. Immunotherapy-based combination strategies for treatment of gastrointestinal cancers: current status and future prospects[J]. Front. Med., 2019, 13(1): 12-23.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-019-0685-9
https://academic.hep.com.cn/fmd/EN/Y2019/V13/I1/12

Tab.1 Current data on combining ICIs with other therapies for GI cancer

Trial	Phase	Patients	Treatment	End point
Esophageal cancer
NCT03044613	2	Neoadjuvant cStage II/III	Nivolumab±ipilimumab followed by carboplatin+ paclitaxel+ RT+ nivolumab	Safety
NCT03377400	2	1st-line, SCC	Durvalumab or tremelimumab+ CCRT	PFS
NCT03437200	2	1st-line	Arm A: chemoradiation+ nivolumab	12 m PFS
NCT03437200	2	1st-line	Arm B: chemoradiation+ nivolumab+ ipilimumab	12 m PFS
Gastric cancer
NCT03006705	3	Adjuvant pStage III (D2)	Arm A: nivolumab+ S-1 or CapeOX	RFS
NCT03006705	3	Adjuvant pStage III (D2)	Arm B: placebo+ S-1 or CapeOX	RFS
NCT03221426 KEYNOTE-585	3	Perioperative	Arm A: pembrolizumab+ XP; Arm B: placebo+ XP	OS, pCR
NCT03221426 KEYNOTE-585	3	Perioperative	Arm C: pembrolizumab+ FLOT; Arm D: placebo+ FLOT	OS, pCR
NCT03382600 KEYNOTE-659	2b	1st-line	Arm A: pembrolizumab+ oxaliplatin+ S-1	ORR
NCT03382600 KEYNOTE-659	2b	1st-line	Arm B: pembrolizumab+ cisplatin+ S-1	ORR
NCT03488667	2	Perioperative	Pembrolizumab+ mFOLFOX6 before and after surgery	ypRR
NCT02918162	2	Perioperative	Chemotherapy+ pembrolizumab before and after surgery Pembrolizumab maintenance	24 m DFS
NCT03257163	2	Perioperative	Pembrolizumab before surgery Pembrolizumab+ capecitabine after surgery	RFS
NCT03409848	2	1st-line, HER2 (+)	Arm A: trastuzumab+ nivolumab+ ipilimumab	OS
NCT03409848	2	1st-line, HER2 (+)	Arm B: trastuzumab+ nivolumab+ mFOLFOX6	OS
NCT02872116		1st-line	Arm A: nivolumab+ ipilimumab followed by nivolumab	OS: A vs. B+ C; D+ E vs. B+ C
			Arm B: XELOX
			Arm C: FOLFOX
			Arm D: nivolumab+ XELOX
			Arm E: nivolumab+ FOLFOX
NCT03342937	2	1st-line	Pembrolizumab+ CapeOx	PFS
NCT03413397	2	≥2nd-line	Pembrolizumab+ lenvatinib	ORR
NCT03453164	1/2	≥2nd-line	Nivolumab+ radiotherapy	DCR
NCT02999295	1/2	≥2nd-line	Nivolumab+ ramucirumab	6 m PFS
Colorectal cancer
NCT02563002 KEYNOTE-177	3	1st-line, dMMR	Arm A: pembrolizumab	PFS, OS
NCT02563002 KEYNOTE-177	3	1st-line, dMMR	Arm B: chemotherapy	PFS, OS
			Arm A: atezolizumab
NCT02788279	3	≥3rd-line	Arm B: cobimetinib+ atezolizumab	OS
			Arm C: regorafenib
NCT03414983	2/3	1st-line	Arm A: nivolumab+ FOLFOX+ bevacizumab	PFS
NCT03414983	2/3	1st-line	Arm B: FOLFOX+ bevacizumab	PFS
NCT03174405	2	1st-line	Avelumab+ cetuximab+ FOLFOX	12 m PFS
NCT03202758	1/2	1st-line, Kras MT	Durvalumab+ tremelimumab+ FOLFOX	Safety
NCT03475004	1/2	3rd-line	Pembrolizumab+ bevacizumab+ binimetinib	ORR
NCT03332498	1/2	>3rd-line	Pembrolizumab+ ibrutinib	4 m DCR
Hepatocellular cancer
NCT03434379	3	1st-line	Atezolizumab+ bevacizumab	ORR/OS
NCT03434379	3	1st-line	Sorafenib	ORR/OS
NCT03439891	2	1st-line	Nivolumab+ sorafenib	Safety/ORR
NCT01658878	1/2	1st-line	Nivolumab+ cabozantinib	Safety/ORR
NCT03382886	1	≥2nd-line	Nivolumab+ bevacizumab	Safety
Biliary tract cancer
NCT03101566	2	1st-line	Nivolumab+ gemcitabine+ cisplatin	6 m PFS
NCT03101566	2	1st-line	Nivolumab+ ipilimumab	6 m PFS
NCT03111732	2	≥2nd-line	Pembrolizumab+ oxaliplatin+ capecitabine	5 m PFS
Pancreatic cancer
NCT02620423	1	2nd-line	Pembrolizumab+ chemotherapy	Safety
NCT03250273	2	≥2nd-line	Nivolumab+ entinostat	ORR
NCT02879318	2	1st-line	Tremelimumab+ durvalumab+ G+ nab-paclitaxel	OS
			Gemcitabine+ nab-paclitaxel

Tab.2 Ongoing clinical trials on combining ICIs with other therapies for GI cancer

Fig.1 Mechanisms of ICI interaction with conventional therapies against tumor cells.

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[1]	Yong Fan, Yan Geng, Lin Shen, Zhuoli Zhang. Advances on immune-related adverse events associated with immune checkpoint inhibitors[J]. Front. Med., 2021, 15(1): 33-42.
[2]	Fang Fang, Weihua Xiao, Zhigang Tian. Challenges of NK cell-based immunotherapy in the new era[J]. Front. Med., 2018, 12(4): 440-450.

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