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Frontiers of Medicine

Front. Med.    2019, Vol. 13 Issue (1) : 12-23
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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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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Chenfei Zhou
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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
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
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
3 Perioperative Arm A: pembrolizumab+ XP; Arm B: placebo+ XP OS, pCR
Arm C: pembrolizumab+ FLOT; Arm D: placebo+ FLOT
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
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 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
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
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.
1 WChen, R Zheng, PDBaade, SZhang, HZeng, F Bray, AJemal, XQYu, J He. Cancer statistics in China, 2015. CA Cancer J Clin 2016; 66(2): 115–132
2 WChen, R Zheng, HZeng, SZhang, JHe. Annual report on status of cancer in China, 2011. Chin J Cancer Res 2015; 27(1): 2–12
3 VEStrong, AW Wu, LVSelby, MGonen, MHsu, KY Song, CHPark, DGCoit, JFJi, MF Brennan. Differences in gastric cancer survival between the U.S. and China. J Surg Oncol 2015; 112(1): 31–37
4 SYan, B Li, ZZBai, JQWu, DW Xie, YCMa, XXMa, JH Zhao, XJGuo. Clinical epidemiology of gastric cancer in Hehuang valley of China: a 10-year epidemiological study of gastric cancer. World J Gastroenterol 2014; 20(30): 10486–10494
5 YLiao, S Li, CChen, XHe, F Lin, JWang, ZYang, P Lan. Screening for colorectal cancer in Tianhe, Guangzhou: results of combining fecal immunochemical tests and risk factors for selecting patients requiring colonoscopy. Gastroenterol Rep (Oxf) 2018; 6(2): 132–136
6 ALopez, K Harada, DMizrak Kaya, JAAjani. Current therapeutic landscape for advanced gastroesophageal cancers. Ann Transl Med 2018; 6(4): 78
7 CMVeenstra, JC Krauss. Emerging systemic therapies for colorectal cancer. Clin Colon Rectal Surg 2018; 31(3): 179–191
8 AJiménez-Sánchez, DMemon, SPourpe, HVeeraraghavan, YLi, HA Vargas, M BGill, KJPark, OZivanovic, JKonner, JRicca, DZamarin, TWalther, CAghajanian, JDWolchok, ESala, T Merghoub, ASnyder, MLMiller. Heterogeneous tumor-immune microenvironments among differentially growing metastases in an ovarian cancer patient. Cell 2017; 170(5): 927–938.e920
9 KLee, H Hwang, KTNam. Immune response and the tumor microenvironment: how they communicate to regulate gastric cancer. Gut Liver 2014; 8(2): 131–139
10 EPérez-Ruiz, PBerraondo. Immunological landscape and clinical management of rectal cancer. Front Immunol 2016; 7: 61
11 MSanchez-Castañón, TKEr, L Bujanda, MHerreros-Villanueva. Immunotherapy in colorectal cancer: what have we learned so far? Clin Chim Acta 2016; 460: 78–87
12 DTLe, JN Durham, KNSmith, HWang, BR Bartlett, LKAulakh, SLu, H Kemberling, CWilt, BSLuber, FWong, NS Azad, AARucki, DLaheru, RDonehower, AZaheer, GAFisher, TSCrocenzi, JJLee, TF Greten, AGDuffy, KKCiombor, ADEyring, BHLam, A Joe, SPKang, MHoldhoff, LDanilova, LCope, C Meyer, SZhou, RMGoldberg, DKArmstrong, KMBever, ANFader, JTaube, FHousseau, DSpetzler, NXiao, DM Pardoll, NPapadopoulos, KWKinzler, JREshleman, BVogelstein, RAAnders, LADiaz Jr. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017; 357(6349): 409–413
13 RAnderson, BL Rapoport. Immune dysregulation in cancer patients undergoing immune checkpoint inhibitor treatment and potential predictive strategies for future clinical practice. Front Oncol 2018; 8: 80
14 CRobert, J Schachter, GVLong, AArance, JJGrob, LMortier, ADaud, MS Carlino, CMcNeil, MLotem, JLarkin, PLorigan, BNeyns, CUBlank, OHamid, CMateus, RShapira-Frommer, MKosh, H Zhou, NIbrahim, SEbbinghaus, A;Ribas the KEYNOTE-006 investigators. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 2015; 372(26): 2521–2532
15 HBorghaei, L Paz-Ares, LHorn, DRSpigel, MSteins, NEReady, LQChow, EEVokes, EFelip, EHolgado, FBarlesi, MKohlhaufl, OArrieta, MABurgio, JFayette, HLena, E Poddubskaya, DEGerber, SNGettinger, CMRudin, NRizvi, LCrino, GRBlumenschein Jr, SJAntonia, CDorange, CTHarbison, FGraf Finckenstein, JRBrahmer. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 2015; 373(17): 1627–1639
16 MJOverman, R McDermott, JLLeach, SLonardi, HJLenz, MAMorse, JDesai, AHill, M Axelson, RAMoss, MVGoldberg, ZACao, JM Ledeine, GAMaglinte, SKopetz, TAndre. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol 2017; 18(9): 1182–1191
17 CSFuchs, T Doi, RWJang, KMuro, T Satoh, MMachado, WSun, SI Jalal, MAShah, JPMetges, MGarrido, TGolan, MMandala, ZAWainberg, DVCatenacci, AOhtsu, KShitara, RGeva, J Bleeker, AHKo, GKu, P Philip, PCEnzinger, YJBang, DLevitan, JWang, M Rosales, RPDalal, HHYoon. Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: Phase 2 Clinical KEYNOTE-059 Trial. JAMA Oncol 2018; 4(5): e180013
18 YKKang, N Boku, TSatoh, MHRyu, Y Chao, KKato, HCChung, JSChen, KMuro, WK Kang, KHYeh, TYoshikawa, SCOh, LY Bai, TTamura, KWLee, Y Hamamoto, JGKim, KChin, DY Oh, KMinashi, JYCho, M Tsuda, LTChen. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538–12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017; 390(10111): 2461–2471
19 TKudo, Y Hamamoto, KKato, TUra, T Kojima, TTsushima, SHironaka, HHara, T Satoh, SIwasa, KMuro, H Yasui, KMinashi, KYamaguchi, AOhtsu, YDoki, Y Kitagawa. Nivolumab treatment for oesophageal squamous-cell carcinoma: an open-label, multicentre, phase 2 trial. Lancet Oncol 2017; 18(5): 631–639
20 PGotwals, S Cameron, DCipolletta, VCremasco, ACrystal, BHewes, BMueller, SQuaratino, CSabatos-Peyton, LPetruzzelli, JAEngelman, GDranoff. Prospects for combining targeted and conventional cancer therapy with immunotherapy. Nat Rev Cancer 2017; 17(5): 286–301
21 ABBlair, A Murphy. Immunotherapy as a treatment for biliary tract cancers: a review of approaches with an eye to the future. Curr Probl Cancer 2018; 42(1): 49–58
22 VLee, A Murphy, DTLe, LADiaz Jr. Mismatch repair deficiency and response to immune checkpoint blockade. Oncologist 2016; 21(10): 1200–1211
23 KKCiombor, T Bekaii-Saab. A comprehensive review of sequencing and combination strategies of targeted agents in metastatic colorectal cancer. Oncologist 2018; 23(1): 25–34
24 PSharma, JP Allison. The future of immune checkpoint therapy. Science 2015; 348(6230): 56–61
25 DSChen, I Mellman. Oncology meets immunology: the cancer-immunity cycle. Immunity 2013; 39(1): 1–10
26 RKim, M Emi, KTanabe. Cancer immunoediting from immune surveillance to immune escape. Immunology 2007; 121(1): 1–14
27 GLBeatty, WL Gladney. Immune escape mechanisms as a guide for cancer immunotherapy. Clin Cancer Res 2015; 21(4): 687–692
28 SMuenst, H Laubli, SDSoysal, AZippelius, ATzankov, SHoeller. The immune system and cancer evasion strategies: therapeutic concepts. J Intern Med 2016; 279(6): 541–562
29 SMariathasan, SJ Turley, DNickles, ACastiglioni, KYuen, Y Wang, EEKadel III, HKoeppen, JLAstarita, RCubas, SJhunjhunwala, RBanchereau, YYang, Y Guan, CChalouni, JZiai, Y Senbabaoglu, SSantoro, DSheinson, JHung, JM Giltnane, AAPierce, KMesh, S Lianoglou, JRiegler, R A DCarano, PEriksson, MHoglund, LSomarriba, DLHalligan, MSvan der Heijden, YLoriot, JERosenberg, LFong, I Mellman, DSChen, MGreen, CDerleth, GDFine, PSHegde, RBourgon, TPowles. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 2018; 554(7693): 544–548
30 DVFTauriello, S Palomo-Ponce, DStork, ABerenguer-Llergo, JBadia-Ramentol, MIglesias, MSevillano, SIbiza, ACanellas, XHernando-Momblona, DByrom, JAMatarin, ACalon, EIRivas, ARNebreda, ARiera, CSAttolini, EBatlle. TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature 2018; 554(7693): 538–543
31 KAWard-Hartstonge, RAKemp. Regulatory T-cell heterogeneity and the cancer immune response. Clin Transl Immunology 2017; 6(9): e154
32 JSun, Y Zhang, MYang, YZhang, QXie, Z Li, ZDong, YYang, B Deng, AFeng, WHu, H Mao, XQu. Hypoxia induces T-cell apoptosis by inhibiting chemokine C receptor 7 expression: the role of adenosine receptor A(2). Cell Mol Immunol 2010; 7(1): 77–82
33 CERudd, A Taylor, HSchneider. CD28 and CTLA-4 coreceptor expression and signal transduction. Immunol Rev 2009; 229(1): 12–26
34 DMPardoll. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12(4): 252–264
35 CBoutros, A Tarhini, ERoutier, OLambotte, FLLadurie, FCarbonnel, HIzzeddine, AMarabelle, SChampiat, ABerdelou, ELanoy, MTexier, CLibenciuc, AMEggermont, JCSoria, CMateus, CRobert. Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. Nat Rev Clin Oncol 2016; 13(8): 473–486
36 EMaj, D Papiernik, JWietrzyk. Antiangiogenic cancer treatment: the great discovery and greater complexity. Int J Oncol 2016; 49(5): 1773–1784
37 JJWallin, JC Bendell, RFunke, MSznol, KKorski, SJones, GHernandez, JMier, X He, FSHodi, MDenker, VLeveque, MCanamero, GBabitski, HKoeppen, JZiai, N Sharma, FGaire, DSChen, DWaterkamp, PSHegde, DFMcDermott. Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma. Nat Commun 2016; 7(1): 12624
38 DFukumura, J Kloepper, ZAmoozgar, DGDuda, RKJain. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat Rev Clin Oncol 2018; 15(5): 325–340
39 PAOtt, FS Hodi, EIBuchbinder. Inhibition of immune checkpoints and vascular endothelial growth factor as combination therapy for metastatic melanoma: an overview of rationale, preclinical evidence, and initial clinical data. Front Oncol 2015; 5: 202
40 FGhiringhelli, PE Puig, SRoux, AParcellier, ESchmitt, ESolary, GKroemer, FMartin, BChauffert, LZitvogel. Tumor cells convert immature myeloid dendritic cells into TGF-β-secreting cells inducing CD4+CD25+ regulatory T cell proliferation. J Exp Med 2005; 202(7): 919–929
41 MTerme, S Pernot, EMarcheteau, FSandoval, NBenhamouda, OColussi, ODubreuil, AFCarpentier, ETartour, JTaieb. VEGFA-VEGFR pathway blockade inhibits tumor-induced regulatory T-cell proliferation in colorectal cancer. Cancer Res 2013; 73(2): 539–549
42 DGabrilovich, T Ishida, TOyama, SRan, V Kravtsov, SNadaf, DPCarbone. Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood 1998; 92(11): 4150–4166
43 MMDikov, JE Ohm, NRay, EETchekneva, JBurlison, DMoghanaki, SNadaf, DPCarbone. Differential roles of vascular endothelial growth factor receptors 1 and 2 in dendritic cell differentiation. J Immunol 2005; 174(1): 215–222
44 TOsada, G Chong, RTansik, THong, N Spector, RKumar, HIHurwitz, IDev, AB Nixon, HKLyerly, TClay, MA Morse. The effect of anti-VEGF therapy on immature myeloid cell and dendritic cells in cancer patients. Cancer Immunol Immunother 2008; 57(8): 1115–1124
45 YHuang, S Goel, DGDuda, DFukumura, RKJain. Vascular normalization as an emerging strategy to enhance cancer immunotherapy. Cancer Res 2013; 73(10): 2943–2948
46 RKShrimali, Z Yu, MRTheoret, DChinnasamy, NPRestifo, SARosenberg. Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer. Cancer Res 2010; 70(15): 6171–6180
47 JHStrickler, HI Hurwitz. Bevacizumab-based therapies in the first-line treatment of metastatic colorectal cancer. Oncologist 2012; 17(4): 513–524
48 JLi, S Qin, RXu, TCYau, B Ma, HPan, JXu, Y Bai, YChi, LWang, KH Yeh, FBi, YCheng, ATLe, JK Lin, TLiu, DMa, C Kappeler, JKalmus, TW;Kim the CONCUR Investigators. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2015; 16(6): 619–629
49 JMLlovet, S Ricci, VMazzaferro, PHilgard, EGane, JF Blanc, ACde Oliveira, ASantoro, JLRaoul, AForner, MSchwartz, CPorta, SZeuzem, LBolondi, TFGreten, PRGalle, JFSeitz, IBorbath, DHaussinger, TGiannaris, MShan, M Moscovici, DVoliotis, JBruix; the SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359(4): 378–390
50 JMLlovet, R Montal, DSia, RSFinn. Molecular therapies and precision medicine for hepatocellular carcinoma. Nat Rev Clin Oncol 2018; 15(10): 599–616
51 CSFuchs, J Tomasek, CJYong, FDumitru, RPassalacqua, CGoswami, HSafran, LVDos Santos, GAprile, DRFerry, BMelichar, MTehfe, ETopuzov, JRZalcberg, IChau, W Campbell, CSivanandan, JPikiel, MKoshiji, YHsu, AM Liepa, LGao, JDSchwartz, J;Tabernero the REGARD Trial Investigators. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 2014; 383(9911): 31–39
52 SYasuda, M Sho, IYamato, HYoshiji, KWakatsuki, SNishiwada, HYagita, YNakajima. Simultaneous blockade of programmed death 1 and vascular endothelial growth factor receptor 2 (VEGFR2) induces synergistic anti-tumour effect in vivo. Clin Exp Immunol 2013; 172(3): 500–506
53 RKJain. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 2005; 307(5706): 58–62
54 HSHochster, JC Bendell, JMCleary, PFoster, WZhang, XHe, G Hernandez, KIizuka. Efficacy and safety of atezolizumab (atezo) and bevacizumab (bev) in a phase Ib study of microsatellite instability (MSI)-high metastatic colorectal cancer (mCRC). J Clin Oncol 2017; 35(4_suppl): 673
55 JWallin, MJ Pishvaian, GHernandez, MYadav, SJhunjhunwala, LDelamarre, XHe, J Powderly, CLieu, SGEckhardt, HHurwitz, HSHochster, JMurphy, VLeveque, ECha, R Funke, DWaterkamp, PHegde J, Bendell . Clinical activity and immune correlates from a phase Ib study evaluating atezolizumab (anti-PDL1) in combination with FOLFOX and bevacizumab (anti-VEGF) in metastatic colorectal carcinoma. Cancer Res, 2016, 76(14_suppl): 2651
56 LBSaltz, S Clarke, EDiaz-Rubio, WScheithauer, AFiger, RWong, S Koski, MLichinitser, TSYang, FRivera, FCouture, FSirzen, JCassidy. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 2008; 26(12): 2013–2019
57 ESmyth, PC Thuss-Patience. Immune checkpoint inhibition in gastro-oesophageal cancer. Oncol Res Treat 2018; 41(5): 272–280
58 YJBang , T Golan , CCLin, YKKang, Z,Wainberg HWasserstrom, J Jin, GMi , SMcNeely, NLaing, LWGoff, SFu. Interim safety and clinical activity in patients (pts) with locally advanced and unresectable or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma from a multicohort phase I study of ramucirumab (R) plus durvalumab (D). J Clin Oncol 2018; 36(4_suppl): 92
59 MIkeda, M W Sung, M. Kudo A phase 1b trial of lenvatinib (LEN) plus pembrolizumab (PEM) in patients (pts) with unresectable hepatocellular carcinoma (uHCC). J Clin Oncol 2018; 36(suppl): abstr 4076
60 SStein, M J Pishvaian, M S Lee. Safety and clinical activity of 1L atezolizumab+ bevacizumab in a phase Ib study in hepatocellular carcinoma (HCC). J Clin Oncol 2018; 36(suppl): abstr 4074
61 ICorraliza-Gorjón , BSomovilla-Crespo, SSantamaria, JAGarcia-Sanz, LKremer. New strategies using antibody combinations to increase cancer treatment effectiveness. Front Immunol 2017; 8: 1804
62 RLFerris, HJ Lenz, AMTrotta, JGarcia-Foncillas, JSchulten, FAudhuy, MMerlano, GMilano. Rationale for combination of therapeutic antibodies targeting tumor cells and immune checkpoint receptors: harnessing innate and adaptive immunity through IgG1 isotype immune effector stimulation. Cancer Treat Rev 2018; 63: 48–60
63 YInoue, S Hazama, NSuzuki, YTokumitsu, SKanekiyo, STomochika, RTsunedomi, YTokuhisa, MIida, K Sakamoto, STakeda, TUeno, S Yoshino, HNagano. Cetuximab strongly enhances immune cell infiltration into liver metastatic sites in colorectal cancer. Cancer Sci 2017; 108(3): 455–460
64 SChen, X Li, RChen, MYin, Q Zheng. Cetuximab intensifies the ADCC activity of adoptive NK cells in a nude mouse colorectal cancer xenograft model. Oncol Lett 2016; 12(3): 1868–1876
65 HBJie, PJ Schuler, SCLee, RMSrivastava, AArgiris, SFerrone, TLWhiteside, RLFerris. CTLA-4(+) regulatory t cells increased in cetuximab-treated head and neck cancer patients suppress NK cell cytotoxicity and correlate with poor prognosis. Cancer Res 2015; 75(11): 2200–2210
66 HBJie, RM Srivastava, AArgiris, JEBauman, LPKane, RLFerris. Increased PD-1(+) and TIM-3(+) TILs during cetuximab therapy inversely correlate with response in head and neck cancer patients. Cancer Immunol Res 2017; 5(5): 408–416
67 HInoue, R Horii, YIto, TIwase, SOhno, F Akiyama. Tumor-infiltrating lymphocytes affect the efficacy of trastuzumab-based treatment in human epidermal growth factor receptor 2-positive breast cancer. Breast Cancer 2018; 25(3): 268–274
68 BKRChaganty, S Qiu, AGest, YLu, C Ivan, GACalin, LMWeiner, ZFan. Trastuzumab upregulates PD-L1 as a potential mechanism of trastuzumab resistance through engagement of immune effector cells and stimulation of IFNγ secretion. Cancer Lett 2018; 430: 47–56
69 D VCatenacci, HPark, H E Uronis, Y Kang, JLacy, P CEnzinger, S HPark, K WLee. Margetuximab plus pembrolizumab in ERBB2-amplified PD-L1+ gastroesophageal adenocarcinoma post trastuzumab. J Clin Oncol 2018; 36(suppl): abstr 4030
70 LRobert, A Ribas, SHu-Lieskovan. Combining targeted therapy with immunotherapy. Can 1+1 equal more than 2? Semin Immunol 2016; 28(1): 73–80
71 SAPatel, AJ Minn. Combination cancer therapy with immune checkpoint blockade: mechanisms and strategies. Immunity 2018; 48(3): 417–433
72 N SAzad, K Shirai, A JMcRee, MOpyrchal, D BJohnson, POrdentlich, SBrouwer, SSankoh, E VSchmidt, M LMeyers, M LJohnson. ENCORE 601: a phase 2 study of entinostat in combinationwith pembrolizumab in patients with microsatellite stable metastatic colorectal cancer. J Clin Oncol 2018; 36(suppl): abstr 3557
73 JBendell, TW Kim, BGoh, JWallin, DYOh, SW Han, CLee, MDHellmann, JDesai, JHLewin, BSolomon, QMChow, WMiller, JGainor, KFlaherty, JInfante, MDas-Thakur, PFoster, ECha, YJ Bang. Clinical activity and safety of cobimetinib (cobi) and atezolizumab in colorectal cancer (CRC). J Clin Oncol 2016; 34(5_suppl): 3502
74 JBendell, F Ciardiello, JTabernero, NTebbutt, CEng, M Di Bartolomeo, A Falcone, MFakih, MKozloff, NSegal, ASobrero, YShi, L Roberts, YYan, IChang, AUyei, T Kim. Efficacy and safety results from IMblaze370, a randomised phase III study comparing atezolizumab1cobimetinib and atezolizumab monotherapy vs. regorafenib in chemotherapy-refractory metastatic colorectal cancer. Ann Oncol 2018; 29(suppl_5): LBA-004
75 PSharma, JP Allison. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell 2015; 161(2): 205–214
76 EAReits, JW Hodge, CAHerberts, TAGroothuis, MChakraborty, EKWansley, KCamphausen, RMLuiten, AHde Ru, JNeijssen, AGriekspoor, EMesman, FAVerreck, HSpits, JSchlom, Pvan Veelen, JJNeefjes. Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J Exp Med 2006; 203(5): 1259–1271
77 KHYoung, JR Baird, TSavage, BCottam, DFriedman, SBambina, DJMessenheimer, BFox, P Newell, KSBahjat, MJGough, MRCrittenden. Optimizing timing of immunotherapy improves control of tumors by hypofractionated radiation therapy. PLoS One 2016; 11(6): e0157164
78 SDemaria, CN Coleman, SCFormenti. Radiotherapy: changing the game in immunotherapy. Trends Cancer 2016; 2(6): 286–294
79 YPico de Coaña, AChoudhury, RKiessling. Checkpoint blockade for cancer therapy: revitalizing a suppressed immune system. Trends Mol Med 2015; 21(8): 482–491
80 XXu, Z Huang, LZheng, YFan. The efficacy and safety of anti-PD-1/PD-L1 antibodies combined with chemotherapy or CTLA4 antibody as a first-line treatment for advanced lung cancer. Int J Cancer 2018; 142(11): 2344–2354
81 GMBlumenthal, L Zhang, HZhang, DKazandjian, SKhozin, STang, K Goldberg, RSridhara, PKeegan, RPazdur. Milestone analyses of immune checkpoint inhibitors, targeted therapy, and conventional therapy in metastatic non-small cell lung cancer trials: a meta-analysis. JAMA Oncol 2017; 3(8): e171029
82 LGandhi, D Rodriguez-Abreu, SGadgeel, EEsteban, EFelip, FDe Angelis, MDomine, PClingan, MJHochmair, SFPowell, SYCheng, HGBischoff, NPeled, FGrossi, RRJennens, MReck, R Hui, EBGaron, MBoyer, BRubio-Viqueira, SNovello, TKurata, JEGray, JVida, Z Wei, JYang, HRaftopoulos, MCPietanza, MCGarassino; the KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med 2018; 378(22): 2078–2092
83 YJBang , K Muro, CFuchs, TGolan, RGeva, H Hara, SIJalal, CBorg, T Doi, ZWainberg, JDWang, MKoshiji, RDalal, HCChung. KEYNOTE-059 cohort 2: safety and efficacy of pembrolizumab (pembro) plus 5-fluorouracil (5-FU) and cisplatin for first-line (1L) treatment of advanced gastric cancer. J Clin Oncol 2017; 35(15_suppl): 4012
84 FGHerrera, J Bourhis, GCoukos. Radiotherapy combination opportunities leveraging immunity for the next oncology practice. CA Cancer J Clin 2017; 67(1): 65–85
85 MSBeg, J Meyer. Developing rational combinations of immune checkpoint inhibitors and radiation therapy for gastrointestinal cancers. J Gastrointest Oncol 2018; 9(1): 225–230
86 FFiorica, L Belluomini, AStefanelli, ASantini, BUrbini, CGiorgi, AFrassoldati. Immune checkpoint inhibitor nivolumab and radiotherapy in pretreated lung cancer patients: efficacy and safety of combination. Am J Clin Oncol 2018; 1 Jan 31. [Epub ahead of print] doi: 10.1097/COC.0000000000000428
87 MHilmi, L Bartholin, CNeuzillet. Immune therapies in pancreatic ductal adenocarcinoma: where are we now? World J Gastroenterol 2018; 24(20): 2137–2151
88 YJBang, T Doi, FDe Broud, SPiha-Paul, AHollebecque, ARRazak. Safety and efficacy of pembrolizumab (MK-3475) in patients (pts) with advanced biliary tract cancer: interim results of KEYNOTE-028. Eur J Cancer 2015; 51(3): s112
89 BAWeinberg, J Xiu, JJHwang, AFShields, MESalem, JLMarshall. Immuno-oncology biomarkers for gastric and gastroesophageal junction adenocarcinoma: why PD-L1 testing may not be enough. Oncologist 2018; 23(10): 1171–1177
90 GDeslypere, D Gullentops, EWauters, JVansteenkiste. Immunotherapy in non-metastatic non-small cell lung cancer: can the benefits of stage IV therapy be translated into earlier stages? Ther Adv Med Oncol 2018; 10: 1758835918772810
91 PMForde, JE Chaft, KNSmith, VAnagnostou, TRCottrell, MDHellmann, MZahurak, SCYang, DRJones, SBroderick, RJBattafarano, MJVelez, NRekhtman, ZOlah, J Naidoo, KAMarrone, FVerde, HGuo, J Zhang, JXCaushi, HYChan, JWSidhom, RBScharpf, JWhite, EGabrielson, HWang, GL Rosner, VRusch, JDWolchok, TMerghoub, JMTaube, VEVelculescu, SLTopalian, JRBrahmer, DMPardoll. Neoadjuvant PD-1 blockade in resectable lung cancer. N Engl J Med 2018; 378(21): 1976–1986
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