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Frontiers of Medicine

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 Authors: 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.
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http://journal.hep.com.cn/fmd/EN/10.1007/s11684-019-0685-9
http://journal.hep.com.cn/fmd/EN/Y2019/V13/I1/12
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Chenfei Zhou
Jun Zhang
Trial Phase Line Treatment No. Efficacy Adverse events
Anti-angiogenesis agents
Colorectal cancer
Abstract 2651 [55] 2 1st B+ A+ FOLFOX 23 ORR 52%
PFS 14.1 m, DOR 11.4 m
NR
NCT01633970 [54] 1b ≥3rd, dMMR B+ A 10 ORR 30% G3/4 40%; all-grade 80%
Gastric cancer
NCT02999295 1/2 2nd Ram+ N 46 PR 22%, DCR 59% G3/4 13%; all-grade 87%
NCT02572687 [58] 1a/b ≥2nd Ram+ D 29 ORR 17%
PFS 2.6 m, OS 6.4 m
G3/4 72%; all-grade 100%
Hepatocellular cancer
NCT03006926 [59] 1b 1st L+ P 18 PR 46%, SD 46% All-grade 94%
NCT02715531 [60] 1b 1st B+ A 26 PR 62% G3/4 35%; all-grade 81%
Other targeted agents
Colorectal cancer
NCT02437136 [72] 2 ≥2nd Entinostat+ P 16 1PR, 5SD G3/4 50%; all-grade 100%
NCT01988896 [73] 1 ≥3rd C+ A 23 ORR 17% G3/4 34.8%;
NCT02788279 [74] 3 ≥3rd C+ A /A/ Reg 363 OS 8.9 m /7.1 m/8.5 m
ORR 2.7%/2.2%/2.2%
G3/4 45%/10%/49%
Gastric cancer
NCT02689284 [69] 2 2nd, HER2 ( + ) M+ P 60 ORR 16%, DCR 54% G3/4 16%
Chemotherapy or radiotherapy
Colorectal cancer
Abstract 3541 [11] 2 1st FOLFOX6+ P 30 ORR 53%
8 w DCR 100%
G3/4 36.7%
NCT02437071 [85] 2 ≥3rd Radiation/ablation+ P 19 ORR 9% All-grade 73%
Gastric cancer
NCT02335411
KEYNOTE-059
Cohort 2 [83]
2 1st, HER2 (-) CF+ P 25 ORR 60%
PFS 6.6 m
OS 13.8 m
G3/4 76%
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
Arm B: chemoradiation+ nivolumab+ ipilimumab
Gastric cancer
NCT03006705 3 Adjuvant
pStage III (D2)
Arm A: nivolumab+ S-1 or CapeOX RFS
Arm B: placebo+ S-1 or CapeOX
NCT03221426
KEYNOTE-585
3 Perioperative Arm A: pembrolizumab+ XP; Arm B: placebo+ XP OS, pCR
Arm C: pembrolizumab+ FLOT; Arm D: placebo+ FLOT
NCT03382600
KEYNOTE-659
2b 1st-line Arm A: pembrolizumab+ oxaliplatin+ S-1 ORR
Arm B: pembrolizumab+ cisplatin+ S-1
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
Arm B: trastuzumab+ nivolumab+ mFOLFOX6
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
Arm B: chemotherapy
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
Arm B: FOLFOX+ bevacizumab
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
Sorafenib
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
Nivolumab+ ipilimumab
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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