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.
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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
Fig.1
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