Abstract
Gastric cancer (GC) is the fifth most common malignancy and the third cause of cancer-related deaths worldwide. Currently, surgery and chemotherapy remain the main therapeutic options and the prognosis of the disease is still poor in the metastatic setting. Avelumab is a human IgG1 antibody directed against PD-L1 approved for Merkel cell carcinoma and urothelial carcinoma that could be useful also for the treatment of GC. This review describes the chemical structure, the pharmacologic properties and the current knowledge of the efficacy of avelumab in the treatment of GC from the data available on the first and later phase clinical trials. The ongoing studies testing this drug either alone or in combination with other drugs are also described.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1 . Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68(6), 394–424 (2018). • It shows the impact the disease has in the clinical world and how important it is to find an alternative way to better treat the disease.
- 2 . Gastric cancer and the epoch of immunotherapy approaches. World J. Gastroenterol. 21, 5778–5793 (2015).
- 3 Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised Phase III noninferiority trial. Ann. Oncol. 20, 666–673 (2009).
- 4 Capecitabine and oxaliplatin for advanced esophagogastric cancer. N. Engl. J. Med. 358, 36–46 (2008).
- 5 Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer – a randomised Phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Eur. J. Cancer 47, 2306–2314 (2011).
- 6 Salvage chemotherapy for pretreated gastric cancer: a randomized Phase III trial comparing chemotherapy plus best supportive care with best supportive care alone. J. Clin. Oncol. 30, 1513–1518 (2012).
- 7 Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02): an open-label, Phase 3 randomised controlled trial. Lancet. Oncol. 15, 78–86 (2014).
- 8 Apatinib for the treatment of gastric cancer. Expert Rev. Gastroenterol. Hepatol. 10, 1–6 (2016).
- 9 Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): a randomised, double-blind, placebo-controlled, Phase III trial. Lancet Oncol. 19, 1437–1448 (2018).
- 10 KEYNOTE-059 cohort 1: efficacy and safety of pembrolizumab (pembro) monotherapy in patients with previously treated advanced gastric cancer. J. Clin. Oncol. 35, 4003–4003 (2017).
- 11 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 390, 2461–2471 (2017).
- 12 Updated efficacy of avelumab in patients with previously treated metastatic Merkel cell carcinoma after ≥1 year of follow-up: JAVELIN Merkel 200, a phase 2 clinical trial. J. Immunother. Cancer 6, 7 (2018). •• Data from JAVELIN Merkel 200, which is a Phase II clinical trial on the Merkel cell carcinoma that brought to the US FDA approval of avelumab for Merkel cell carcinoma.
- 13 . Cancer immunoediting: from immunosurveillance to tumor escape. Nat. Immunol. 3, 991–998 (2002).
- 14 Expression of Tim-3 in gastric cancer tissue and its relationship with prognosis. Int. J. Clin. Exp. Pathol. 8, 9452–9457 (2015).
- 15 . Upregulation of immune checkpoint molecules, PD-1 and LAG-3, on CD4+ and CD8+ T cells after gastric cancer surgery. Yonago Acta Med. 58, 39–44 (2015).
- 16 Prognostic implications of immunosuppressive protein expression in tumors as well as immune cell infiltration within the tumor microenvironment in gastric cancer. Gastric Cancer 19, 42–52 (2016).
- 17 . T-cell exhaustion: characteristics, causes and conversion. Immunology 129, 474–481 (2010).
- 18 Prognostic and predictive values of PD-L1 expression in patients with digestive system cancer: a meta-analysis. Onco. Targets. Ther. 10, 3625–3634 (2017).
- 19 . PD-L1 and survival in solid tumors: a meta-analysis. PLoS ONE 10, e0131403 (2015).
- 20 . Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr. Opin. Immunol. 24, 207–212 (2012).
- 21 . Immune checkpoint blockade in cancer therapy. J. Clin. Oncol. 33, 1974–1982 (2015).
- 22 . CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am. J. Clin. Oncol. 39, 98–106 (2016).
- 23 Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513, 202–209 (2014).
- 24 Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic. Ann. Oncol. 30(1), 44–56 (2018).
- 25 . Immunotherapy for advanced gastric and esophageal cancer: preclinical rationale and ongoing clinical investigations. J. Gastrointest. Oncol. 6, 561–569 (2015).
- 26 . Molecular pathways: the immunogenic effects of platinum-based chemotherapeutics. Clin. Cancer Res. 20, 2831–2837 (2014).
- 27 Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513, 202–209 (2014).
- 28 . Clinical efficacy of immune checkpoint inhibitors in the treatment of unresectable advanced or recurrent gastric cancer: an evidence-based review of therapies. Onco. Targets. Ther. 11, 8239–8250 (2018).
- 29 Antibody-dependent cellular cytotoxicity activity of a novel anti-PD-L1 antibody avelumab (MSB0010718C) on human tumor cells. Cancer Immunol. Res. 3, 1148–1157 (2015).
- 30 . A fully human IgG1 anti-PD-L1 MAb in an in vitro assay enhances antigen-specific T-cell responses. Clin. Transl. Immunol. 5, e83 (2016).
- 31 Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science 350, 207–211 (2015).
- 32 . Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity 27, 111–122 (2007).
- 33 Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production. J. Immunol. 170, 1257–1266 (2003).
- 34 . Mechanism of FGF receptor dimerization and activation. Nat. Commun. 7, 10262 (2016).
- 35 Structural basis of anti-PD-L1 monoclonal antibody avelumab for tumor therapy. Cell Res. 27, 151–153 (2017).
- 36 . Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 11, 3887–3895 (1992).
- 37 . B7 family checkpoint regulators in immune regulation and disease. Trends Immunol. 34, 556–563 (2013).
- 38 . PD-1 and its ligands in tolerance and immunity. Annu. Rev. Immunol. 26, 677–704 (2008).
- 39 . Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27, 450–461 (2015).
- 40 . PD-1 signaling in primary T cells. Immunol. Rev. 229, 114–125 (2009).
- 41 Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat. Med. 8, 793–800 (2002).
- 42 . Cancer immunotherapy using checkpoint blockade. Science 359, 1350–1355 (2018).
- 43 . Predictive factors of activity of anti-programmed death-1/programmed death ligand-1 drugs: immunohistochemistry analysis. Transl. lung cancer Res. 4, 743–751 (2015).
- 44 PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat. Immunol. 2, 261–268 (2001).
- 45 B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells. J. Exp. Med. 193, 839–846 (2001).
- 46 . Coinhibitory pathways in immunotherapy for cancer. Annu. Rev. Immunol. 34, 539–573 (2016).
- 47 . Adaptive immune resistance: how cancer protects from immune attack. Cancer Discov. 5, 915–919 (2015).
- 48 . The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012).
- 49 . The role of the PD-1 pathway in autoimmunity and peripheral tolerance. Ann. NY Acad. Sci. 1217, 45–59 (2011).
- 50 . The PD-1 pathway in tolerance and autoimmunity. Immunol. Rev. 236, 219–242 (2010).
- 51 . PD-1 and PD-1 ligands: from discovery to clinical application. Int. Immunol. 19, 813–824 (2007).
- 52 A mini-review for cancer immunotherapy: molecular understanding of PD-1/PD-L1 pathway & translational blockade of immune checkpoints. Int. J. Mol. Sci. 17, 1151 (2016).
- 53 . Inhibitory B7-family molecules in the tumour microenvironment. Nat. Rev. Immunol. 8, 467–477 (2008).
- 54 Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood 114, 1537–1544 (2009).
- 55 PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J. Exp. Med. 206, 3015–3029 (2009).
- 56 PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3ζ signalosome and downstream signaling to PKCθ. FEBS Lett. 574, 37–41 (2004).
- 57 . Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science 331, 1565–1570 (2011).
- 58 . The B7 family revisited. Annu. Rev. Immunol. 23, 515–548 (2005).
- 59 . Hallmarks of Cancer: The Next Generation Cell. 4 144(5), 646–674 (2011).
- 60 . Monoclonal antibodies: versatile platforms for cancer immunotherapy. Nat. Rev. Immunol. 10, 317–327 (2010).
- 61 . B7-H1/PD-1 blockade therapy in non-small cell lung cancer. Cancer J. 20, 281–289 (2014).
- 62 Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515, 563–567 (2014).
- 63 Analyses of the peripheral immunome following multiple administrations of avelumab, a human IgG1 anti-PD-L1 monoclonal antibody. J. Immunother. Cancer 5, 20 (2017).
- 64 . PD-L1 inhibition with avelumab for metastatic Merkel cell carcinoma. Expert Rev. Clin. Pharmacol. 11, 345–359 (2018).
- 65 US FDA. Information., E.S.I. and P.I.B. (avelumab) injection: U. (2017). www.fda.gov
- 66 Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN solid tumor): a phase 1a, multicohort, dose-escalation trial. Lancet Oncol. 18, 587–598 (2017). •• Results from the JAVELIN in Solid Tumors Phase Ia dose-escalation clinical trial.
- 67 Avelumab (anti–PD-L1) as first-line switch-maintenance or second-line therapy in patients with advanced gastric or gastroesophageal junction cancer: phase 1b results from the JAVELIN Solid Tumor trial. J. Immunother. Cancer 7, 30 (2019).
- 68 Phase 1 trial of avelumab (anti-PD-L1) in Japanese patients with advanced solid tumors, including dose expansion in patients with gastric or gastroesophageal junction cancer: the JAVELIN Solid Tumor JPN trial. Gastric Cancer (2018). (Epub ahead of print). •• Results of avelumab in Japanese patients with advanced gastric cancer Phase Ib clinical trial.
- 69 Phase III, randomised trial of avelumab versus physician's choice of chemotherapy as third-line treatment of patients with advanced gastric or gastro-oesophageal junction cancer: primary analysis of JAVELIN Gastric 300. Ann. Oncol. 29, 2052–2060 (2018). •• Results of the JAVELIN Gastric 300.
- 70 Maintenance avelumab versus continuation of first-line chemotherapy in gastric cancer: JAVELIN Gastric 100 study design. Future Oncol. fon-2018-0668 (2018). •• The design of the latest large clinical trial testing avelubam maintenance therapy versus continuation of first-line chemotherapy.
- 71 Safety profile of avelumab in patients with advanced solid tumors: a pooled analysis of data from the phase 1 JAVELIN solid tumor and phase 2 JAVELIN Merkel 200 clinical trials. Cancer 124, 2010–2017 (2018).
- 72 . Advancing a framework for regulatory use of real-world evidence. Ther. Innov. Regul. Sci. 52, 362–368 (2018). •• The safety profile of avelumab in patients with advanced solid tumors.
- 73 . Avelumab in locally advanced or metastatic urothelial carcinoma – the ASCO Post. (2018). www.ascopost.com/issues/october-10-2017/avelumab-in-locally-advanced-or-metastatic-urothelial-carcinoma/
- 74 FDA; CDER. Highlights of prescribing information. www.fda.gov/Drugs/default.htm
- 75 The lipoprotein HP1454 of Helicobacter pylori regulates T-cell response by shaping T-cell receptor signalling. Cell. Microbiol. e13006 (2019).
- 76 Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N. Engl. J. Med. 378, 2093–2104 (2018).