Highlights
- •Newly approved immune checkpoint inhibitors (ICI) enrich options for GEJ/GC therapies.
- •Relevant phase II/III trials focus on important biomarkers including PD-L1 assessment.
- •Next research may clarify ICI resistance mechanisms and varied gender responses.
Abstract
The new era of immunotherapy is successfully implemented in the treatment of metastatic/locally
advanced esophagogastric adenocarcinoma (EGAC), as it has been investigated in combinations
with/without chemotherapy in human epidermal growth factor receptor 2 (Her2)-positive
and Her2-negative tumors. Recent approvals of immune checkpoint inhibitors (ICI) enrich
the therapeutic landscape in nearly every therapeutic line. Based on CHECKMATE-649,
the combination of nivolumab and chemotherapy in first-line therapy of programmed
cell death protein 1 (PD-L1)-positive patients with advanced gastroesophageal junction
cancer (GEJC), esophageal cancer (EC), and gastric cancer (GC) was approved in Europe
for PD-L1 combined positivity score (CPS) ≥ 5 patients and independently from PD-L1
score in the USA and Asia. Based on KEYNOTE-590, patients with advanced GEJC and EC
qualify for the combination of pembrolizumab plus chemotherapy in Europe (CPS ≥ 10)
and the USA. For Her2-positive patients, trastuzumab with first-line chemotherapy
plus pembrolizumab has beneficial response rates and resulted in approval in the USA
(KEYNOTE-811). In third-line therapy, superior overall survival (OS) was achieved
by the administration of nivolumab (approval in Japan, ATTRACTION-02), and pembrolizumab
shows a positive effect on the duration of response (KEYNOTE-059). Questions of resistance
to immunotherapy or the role of gender in response to ICI need to be clarified. This
review provides an overview of the current approvals of ICI in advanced EGAC and reflects
results of relevant phase II/III trials with focus on possible biomarkers, including
PD-L1 CPS and microsatellite-instability (MSI) status.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to European Journal of CancerAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Cancer incidence and mortality patterns in Europe: estimates for 40 countries and 25 major cancers in 2018.Eur J Cancer. 2018; 103: 356-387https://doi.org/10.1016/j.ejca.2018.07.005
- Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial.Lancet. 2010; 376: 687-697https://doi.org/10.1016/S0140-6736(10)61121-X
- Novel HER2-directed treatments in advanced gastric carcinoma: AnotHER paradigm shift?.Cancers. 2021; 13: 1664https://doi.org/10.3390/cancers13071664
- Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive gastric cancer: a dose-expansion, phase 1 study.Lancet Oncol. 2019; 20: 827-836https://doi.org/10.1016/S1470-2045(19)30088-9
- Dose-escalation and dose-expansion study of trastuzumab deruxtecan (T-DXd) monotherapy and combinations in patients (Pts) with advanced/metastatic HER2+ gastric cancer (GC)/Gastroesophageal junction adenocarcinoma (GEJA): DESTINY-Gastric03.J Clin Orthod. 2022; 40 (295–295)https://doi.org/10.1200/JCO.2022.40.4_suppl.295
- Margetuximab plus pembrolizumab in patients with previously treated, HER2-positive gastro-oesophageal adenocarcinoma (CP-MGAH22-05): a single-arm, phase 1b-2 trial.Lancet Oncol. 2020; 21: 1066-1076https://doi.org/10.1016/S1470-2045(20)30326-0
- Margetuximab (M) combined with anti-PD-1 (retifanlimab) or anti-PD-1/LAG-3 (tebotelimab) +/− chemotherapy (CTX) in first-line therapy of advanced/metastatic HER2+ gastroesophageal junction (GEJ) or gastric cancer (GC).J Clin Orthod. 2021; 39 (TPS264–TPS264)https://doi.org/10.1200/JCO.2021.39.3_suppl.TPS264
- First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial.Lancet. 2021; 398: 27-40https://doi.org/10.1016/S0140-6736(21)00797-2
- Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer.Nature. 2022; 603: 942-948https://doi.org/10.1038/s41586-022-04508-4
- Sex differences in immune responses.Nat Rev Immunol. 2016; 16: 626-638https://doi.org/10.1038/nri.2016.90
- Gender medicine and oncology: report and consensus of an ESMO workshop.Ann Oncol. 2019; 30: 1914-1924https://doi.org/10.1093/annonc/mdz414
- ATTRACTION-04 (ONO-4538-37): a randomized, multicenter, phase 2/3 study of nivolumab (Nivo) plus chemotherapy in patients (Pts) with previously untreated advanced or recurrent gastric (G) or gastroesophageal junction (GEJ) cancer.Ann Oncol. 2017; 28: v266https://doi.org/10.1093/annonc/mdx369.159
- Safety and efficacy of nivolumab in combination with S-1/capecitabine plus oxaliplatin in patients with previously untreated, unresectable, advanced, or recurrent gastric/gastroesophageal junction cancer: interim results of a randomized, phase II trial (ATTRACTION-4).Ann Oncol. 2019; 30: 250-258https://doi.org/10.1093/annonc/mdy540
- Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study.Lancet. 2021; 398: 759-771https://doi.org/10.1016/S0140-6736(21)01234-4
- Efficacy and safety of pembrolizumab or pembrolizumab plus chemotherapy vs chemotherapy alone for patients with first-line, advanced gastric cancer: the KEYNOTE-062 phase 3 randomized clinical trial.JAMA Oncol. 2020; 6: 1571-1580https://doi.org/10.1001/jamaoncol.2020.3370
- Pembrolizumab with or without chemotherapy versus chemotherapy alone for patients with PD-L1–positive advanced gastric or gastroesophageal junction adenocarcinoma: update from the phase 3 KEYNOTE-062 trial.J Clin Orthod. 2022; 40 (243–243)
- KEYNOTE-859: a phase III study of pembrolizumab plus chemotherapy in gastric/gastroesophageal junction adenocarcinoma.Future Oncol. 2021; 17: 2847-2855https://doi.org/10.2217/fon-2021-0176
- Results of the JAVELIN gastric 100 phase 3 trial: avelumab maintenance following first-line (1L) chemotherapy (CTx) vs continuation of CTx for HER2− advanced gastric or gastroesophageal junction cancer (GC/GEJC).J Clin Orthod. 2020; 38 (278–278)https://doi.org/10.1200/JCO.2020.38.4_suppl.278
- LBA53 sintilimab plus chemotherapy (chemo) versus chemo as first-line treatment for advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma (ORIENT-16): first results of a randomized, double-blind, phase III study.Ann Oncol. 2021; 32: S1331https://doi.org/10.1016/j.annonc.2021.08.2133
BeiGene announces positive findings from phase 3 trial of tislelizumab in combination with chemotherapy in first-line gastric or gastroesophageal junction cancer. Available online: https://www.businesswire.com/news/home/20220124005223/en/BeiGene-Announces-Positive-Findings-from-Phase-3-Trial-of-Tislelizumab-in-Combination-with-Chemotherapy-in-First-Line-Gastric-or-Gastroesophageal-Junction-Cancer [accessed on 08.08.22].
- Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial.Lancet. 2018; 392: 123-133https://doi.org/10.1016/S0140-6736(18)31257-1
- Ramucirumab plus pembrolizumab in patients with previously treated advanced non-small-cell lung cancer, gastro-oesophageal cancer, or urothelial carcinomas (JVDF): a multicohort, non-randomised, open-label, phase 1a/b trial.Lancet Oncol. 2019; 20: 1109-1123https://doi.org/10.1016/S1470-2045(19)30458-9
- RAP: a phase II trial with ramucirumab, avelumab, and paclitaxel as second line treatment in gastro-esophageal adenocarcinoma of the Arbeitsgemeinschaft Internistische Onkologie (AIO).J Clin Orthod. 2019; 37 (TPS4148–TPS4148. https://doi.org/10.1200/JCO.2019.37.15_suppl.TPS4148)
- Ramucirumab, avelumab, and paclitaxel (RAP) as second-line treatment in gastro-esophageal adenocarcinoma, a phase II trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO).J Clin Orthod. 2022; 40 (4051–4051. https://doi.org/10.1200/JCO.2022.40.16_suppl.4051)
- PRODIGE 59-DURIGAST trial: a randomised phase II study evaluating FOLFIRI + durvalumab ± tremelimumab in second-line of patients with advanced gastric cancer.Dig Liver Dis. 2021; 53: 420-426https://doi.org/10.1016/j.dld.2020.11.036
- The PRODIGE 59-DURIGAST trial: a randomized phase II study evaluating FOLFIRI plus durvalumab and FOLFIRI plus durvalumab plus tremelimumab in second-line treatment of patients with advanced gastric or gastro-esophageal junction adenocarcinoma.J Clin Orthod. 2022; 40 (4036–4036. https://doi.org/10.1200/JCO.2022.40.16_suppl.4036)
- KEYNOTE-059 cohort 1: efficacy and safety of pembrolizumab (Pembro) monotherapy in patients with previously treated advanced gastric cancer.J Clin Orthod. 2017; 35 (4003–4003. https://doi.org/10.1200/JCO.2017.35.15_suppl.4003)
- 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: 2461-2471https://doi.org/10.1016/S0140-6736(17)31827-5
- 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. 2018; 29: 2052-2060https://doi.org/10.1093/annonc/mdy264
- INTEGRATE IIb: a randomized phase III open label study of regorafenib + nivolumab versus standard chemotherapy in refractory advanced gastroesophageal cancer (AGOC).J Clin Orthod. 2022; 40 (TPS366–TPS366)https://doi.org/10.1200/JCO.2022.40.4_suppl.TPS366
- CheckMate-032 study: efficacy and safety of nivolumab and nivolumab plus ipilimumab in patients with metastatic esophagogastric cancer.J Clin Oncol. 2018; 36: 2836-2844https://doi.org/10.1200/JCO.2017.76.6212
- Oligometastases.J Clin Oncol. 1995; 13: 8-10https://doi.org/10.1200/JCO.1995.13.1.8
- Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer.N Engl J Med. 2021; 384: 1191-1203https://doi.org/10.1056/NEJMoa2032125
- Definitions and treatment of oligometastatic oesophagogastric cancer according to multidisciplinary tumour boards in Europe.Eur J Cancer. 2022; 164: 18-29https://doi.org/10.1016/j.ejca.2021.11.032
- First-line pembrolizumab and trastuzumab in HER2-positive oesophageal, gastric, or gastro-oesophageal junction cancer: an open-label, single-arm, phase 2 trial.Lancet Oncol. 2020; 21: 821-831https://doi.org/10.1016/S1470-2045(20)30169-8
- Pembrolizumab plus trastuzumab and chemotherapy for HER2+ metastatic gastric or gastroesophageal junction (G/GEJ) cancer: initial findings of the global phase 3 KEYNOTE-811 study.J Clin Orthod. 2021; 39 (4013–4013)https://doi.org/10.1200/JCO.2021.39.15_suppl.4013
- Ipilimumab or FOLFOX with nivolumab and trastuzumab in previously untreated HER2-positive locally advanced or metastatic EsophagoGastric adenocarcinoma – the randomized phase 2 INTEGA trial (AIO STO 0217).BMC Cancer. 2020; : 20https://doi.org/10.1186/s12885-020-06958-3
- Efficacy of ipilimumab vs FOLFOX in combination with nivolumab and trastuzumab in patients with previously untreated ERBB2-positive esophagogastric adenocarcinoma: the AIO INTEGA randomized clinical trial.JAMA Oncol. 2022; https://doi.org/10.1001/jamaoncol.2022.2228
- A phase Ib/II, multicenter, open-label, dose-escalation, and dose-expansion study evaluating trastuzumab deruxtecan (T-DXd, DS-8201) monotherapy and combinations in patients with HER2-overexpressing gastric cancer (DESTINY-Gastric03).J Clin Orthod. 2021; 39 (TPS261–TPS261. https://doi.org/10.1200/JCO.2021.39.3_suppl.TPS261)
- 1379P margetuximab (M) with retifanlimab (R) in HER2+, PD-L1+ 1st-line unresectable/metastatic gastroesophageal adenocarcinoma (GEA): MAHOGANY cohort A.Ann Oncol. 2021; 32: S1043-S1044https://doi.org/10.1016/j.annonc.2021.08.1488
A Phase 1 clinical study to investigate the safety and pharmacokinetics of tucatinib (MK-7119) in China participants with HER2+ advanced breast cancer, gastric or gastroesophageal junction adenocarcinoma and colorectal cancer – AdisInsight Available online: https://adisinsight.springer.com/trials/700352320 [accessed on 31.07.22].
- P-26 HERIZON-GEA-01: a phase 3 study of zanidatamab in combination with chemotherapy with or without tislelizumab in first-line human epidermal growth factor receptor 2 positive (HER2+) advanced/metastatic gastroesophageal adenocarcinoma (GEA).Ann Oncol. 2022; 33: S256https://doi.org/10.1016/j.annonc.2022.04.117
- Re-evaluation of HER2 status in patients with HER2-positive advanced or recurrent gastric cancer refractory to trastuzumab (KSCC1604).Eur J Cancer. 2018; 105: 41-49https://doi.org/10.1016/j.ejca.2018.09.024
- ESMO guidelines committee gastric cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2016; 27: v38-v49https://doi.org/10.1093/annonc/mdw350
- Oesophageal cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2016; 27: v50-v57https://doi.org/10.1093/annonc/mdw329
- de ESMO-Magnitude of clinical benefit scale Version 1.1.Ann Oncol. 2017; 28: 2340-2366https://doi.org/10.1093/annonc/mdx310
- The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer.Nature. 2021; 600: 727-730https://doi.org/10.1038/s41586-021-04161-3
- Comprehensive molecular characterization of gastric adenocarcinoma.Nature. 2014; 513: 202-209https://doi.org/10.1038/nature13480
- Claudin 18.2 expression in esophageal adenocarcinoma and its potential impact on future treatment strategies.Oncol Lett. 2020; 19: 3665-3670https://doi.org/10.3892/ol.2020.11520
- FAST: a randomised phase II study of zolbetuximab (IMAB362) plus EOX versus EOX alone for first-line treatment of advanced CLDN18.2-positive gastric and gastro-oesophageal adenocarcinoma.Ann Oncol. 2021; 32: 609-619https://doi.org/10.1016/j.annonc.2021.02.005
- GLOW: randomized phase III study of zolbetuximab + CAPOX compared with placebo + CAPOX as first-line treatment of patients with CLD18.2+/HER2− locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma.Ann Oncol. 2019; 30: v322https://doi.org/10.1093/annonc/mdz247.162
- SPOTLIGHT: comparison of zolbetuximab or placebo + MFOLFOX6 as first-line treatment in patients with claudin18.2+/HER2− locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma (GEJ): a randomized phase III study.Ann Oncol. 2019; 30: ix66-ix67https://doi.org/10.1093/annonc/mdz422.074
- Trial in progress: phase 3 study of bemarituzumab + MFOLFOX6 versus placebo + MFOLFOX6 in previously untreated advanced gastric or gastroesophageal junction (GEJ) cancer with FGFR2b overexpression (FORTITUDE-101).J Clin Orthod. 2022; 40 (TPS4164–TPS4164. https://doi.org/10.1200/JCO.2022.40.16_suppl.TPS4164)
- Trial in progress: phase 1b/3 study of bemarituzumab + MFOLFOX6 + nivolumab versus MFOLFOX6 + nivolumab in previously untreated advanced gastric and gastroesophageal junction (GEJ) cancer with FGFR2b overexpression (FORTITUDE-102).J Clin Orthod. 2022; 40 (TPS4165–TPS4165. https://doi.org/10.1200/JCO.2022.40.16_suppl.TPS4165)
- Overview of Epstein-Barr-virus-associated gastric cancer correlated with prognostic classification and development of therapeutic options.Int J Mol Sci. 2020; 21: E9400https://doi.org/10.3390/ijms21249400
- Immune activation and benefit from avelumab in EBV-positive gastric cancer.J Natl Cancer Inst. 2017; 110: 316-320https://doi.org/10.1093/jnci/djx213
- High PD-L1 expression in gastric cancer (GC) patients and correlation with molecular features.Pathol Res Pract. 2020; 216152881https://doi.org/10.1016/j.prp.2020.152881
- Helicobacter pylori in gastric cancer: features of infection and their correlations with long-term results of treatment.World J Gastroenterol. 2021; 27: 6290-6305https://doi.org/10.3748/wjg.v27.i37.6290
- Global burden of gastric cancer attributable to Helicobacter pylori.Int J Cancer. 2015; 136https://doi.org/10.1002/ijc.28999
- Helicobacter pylori and gastric cancer: a state of the art review.Gastroenterol Hepatol Bed Bench. 2015; 8: S6-S14
- Effects of Helicobacter pylori on tumor microenvironment and immunotherapy responses.Front Immunol. 2022; 13
- Efficacy of pembrolizumab monotherapy for advanced gastric/gastroesophageal junction cancer with programmed death ligand 1 combined positive score ≥10.Clin Cancer Res. 2021; 27: 1923-1931https://doi.org/10.1158/1078-0432.CCR-20-2980
- Low programmed death-ligand 1–expressing subgroup outcomes of first-line immune checkpoint inhibitors in gastric or esophageal adenocarcinoma.J Clin Orthod. 2022; 40: 392-402https://doi.org/10.1200/JCO.21.01862
- Association of magnitude and consistency of PD-L1 expression and other variables associated with benefit from immune checkpoint inhibition (ICI): systematic review and meta-analysis of 14 phase 3 trials in advanced gastroesophageal cancer (GEC).J Clin Orthod. 2022; 40 (344–344. https://doi.org/10.1200/JCO.2022.40.4_suppl.344)
- Predictive value of PD-L1 diagnostics.Pathologe. 2018; 39: 498-519https://doi.org/10.1007/s00292-018-0507-x
- Predictive role of microsatellite instability for PD-1 blockade in patients with advanced gastric cancer: a meta-analysis of randomized clinical trials.ESMO Open. 2021; 6https://doi.org/10.1016/j.esmoop.2020.100036
- MSI-GC-01: individual patient data (IPD) meta-analysis of microsatellite instability (MSI) and gastric cancer (GC) from four randomized clinical trials (RCTs).J Clin Orthod. 2019; 37 (66–66. https://doi.org/10.1200/JCO.2019.37.4_suppl.66)
- 1429P pathological regression in patients with microsatellite instability (MSI) receiving perioperative atezolizumab in combination with FLOT vs. FLOT alone for resectable esophagogastric adenocarcinoma: results from the DANTE trial of the German gastric group at the AIO and SAKK.Ann Oncol. 2021; 32: S1069https://doi.org/10.1016/j.annonc.2021.08.1538
- Neoadjuvant nivolumab plus ipilimumab and adjuvant nivolumab in patients (Pts) with localized microsatellite instability-high (MSI)/mismatch repair deficient (DMMR) oeso-gastric adenocarcinoma (OGA): the GERCOR NEONIPIGA phase II study.J Clin Orthod. 2022; 40 (244–244 https://doi.org/10.1200/JCO.2022.40.4_suppl.244)
- Tumor mutation burden as a biomarker in resected gastric cancer via its association with immune infiltration and hypoxia.Gastric Cancer. 2021; 24: 823-834https://doi.org/10.1007/s10120-021-01175-8
- The association of tissue tumor mutational burden (TTMB) using the foundation medicine genomic platform with efficacy of pembrolizumab versus paclitaxel in patients (Pts) with gastric cancer (GC) from KEYNOTE-061.J Clin Orthod. 2020; 38 (4537–4537. https://doi.org/10.1200/JCO.2020.38.15_suppl.4537)
- Pembrolizumab (Pembro) versus standard of care chemotherapy (chemo) in patients with advanced gastric or gastroesophageal junction adenocarcinoma: Asian subgroup analysis of KEYNOTE-062.J Clin Orthod. 2020; 38 (4523–4523 https://doi.org/10.1200/JCO.2020.38.15_suppl.4523)
- 1443P modified FOLFOX versus modified FOLFOX plus nivolumab and ipilimumab in patients with previously untreated advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction – safety results from AIO-STO-0417: a randomized phase II trial of the German gastric group of the AIO.Ann Oncol. 2020; 31: S908https://doi.org/10.1016/j.annonc.2020.08.1949
- Assessment of POLE and POLD1 mutations as prognosis and immunotherapy biomarkers for stomach adenocarcinoma.Transl Cancer Res. 2022; 11: 193-205https://doi.org/10.21037/tcr-21-1601
- CD155T/TIGIT signaling regulates CD8+ T-cell metabolism and promotes tumor progression in human gastric cancer.Cancer Res. 2017; 77: 6375-6388https://doi.org/10.1158/0008-5472.CAN-17-0381
- CD155 on tumor cells drives resistance to immunotherapy by inducing the degradation of the activating receptor CD226 in CD8+ T cells.Immunity. 2020; 53: 805-823.e15https://doi.org/10.1016/j.immuni.2020.09.010
- Phase I trial of claudin 18.2-specific chimeric antigen receptor T cells for advanced gastric and pancreatic adenocarcinoma.J Clin Orthod. 2019; 37 (2509–2509. https://doi.org/10.1200/JCO.2020.38.15_suppl.4523)
- Claudin18.2-Specific CAR T cells in gastrointestinal cancers: phase 1 trial interim results.Nat Med. 2022; 28: 1189-1198https://doi.org/10.1038/s41591-022-01800-8
Article Info
Publication History
Published online: September 29, 2022
Accepted:
August 22,
2022
Received in revised form:
August 12,
2022
Received:
April 16,
2022
Identification
Copyright
© 2022 Elsevier Ltd. All rights reserved.
