Who Should Receive Immunotherapy for Advanced Gastroesophageal Cancer?

go back to reference Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistiCS 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49.CrossRefPubMed Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistiCS 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49.CrossRefPubMed

go back to reference Paydary K, Reizine N, Catenacci DVT. Immune-checkpoint inhibition in the treatment of gastro-esophageal cancer: a closer look at the emerging evidence. Cancers. 2021;13:5929.CrossRefPubMedPubMedCentral Paydary K, Reizine N, Catenacci DVT. Immune-checkpoint inhibition in the treatment of gastro-esophageal cancer: a closer look at the emerging evidence. Cancers. 2021;13:5929.CrossRefPubMedPubMedCentral

go back to reference Shiravand Y, Khodadadi F, Kashani SMA, Hosseini-Fard SR, Hosseini S, Sadeghirad H, et al. Immune checkpoint inhibitors in cancer therapy. Curr Oncol. 2022;29:3044–60.CrossRefPubMedPubMedCentral Shiravand Y, Khodadadi F, Kashani SMA, Hosseini-Fard SR, Hosseini S, Sadeghirad H, et al. Immune checkpoint inhibitors in cancer therapy. Curr Oncol. 2022;29:3044–60.CrossRefPubMedPubMedCentral

go back to reference • Zhou KI, Peterson B, Serritella A, Thomas J, Reizine N, Moya S, et al. Spatial and temporal heterogeneity of PD-L1 expression and tumor mutational burden in gastroesophageal adenocarcinoma at baseline diagnosis and after chemotherapy. Clin Cancer Res. 2020;26:6453–63. This reference is of importance because it discusses the intricate challenges and complexities encountered with PD-L1 immunohistochemistry assays, notably issues related to reproducibility, heterogeneity, and subjectivity, in the context of gastroesophageal cancer. By highlighting the consistent correlation between higher CPS scores and an increased likelihood of clinical benefit, while also navigating through the debate on the efficacy of PD-L1 as a standalone biomarker, the reference provides a critical foundation. It thereby aids in exploring and validating alternative or complementary biomarkers, ensuring informed and nuanced discussions and investigations in future immunotherapy response studies across gastroesophageal cancer trials.CrossRefPubMedPubMedCentral • Zhou KI, Peterson B, Serritella A, Thomas J, Reizine N, Moya S, et al. Spatial and temporal heterogeneity of PD-L1 expression and tumor mutational burden in gastroesophageal adenocarcinoma at baseline diagnosis and after chemotherapy. Clin Cancer Res. 2020;26:6453–63. This reference is of importance because it discusses the intricate challenges and complexities encountered with PD-L1 immunohistochemistry assays, notably issues related to reproducibility, heterogeneity, and subjectivity, in the context of gastroesophageal cancer. By highlighting the consistent correlation between higher CPS scores and an increased likelihood of clinical benefit, while also navigating through the debate on the efficacy of PD-L1 as a standalone biomarker, the reference provides a critical foundation. It thereby aids in exploring and validating alternative or complementary biomarkers, ensuring informed and nuanced discussions and investigations in future immunotherapy response studies across gastroesophageal cancer trials.CrossRefPubMedPubMedCentral

go back to reference • Park R, Da Silva LL, Saeed A. Immunotherapy predictive molecular markers in advanced gastroesophageal cancer: MSI and beyond. Cancers. 2021;13:1715. This reference is of importance because it sheds light on the potential and early promise of various markers while emphasizing the necessity for their further prospective evaluations in the context of gastroesophageal cancer.CrossRefPubMedPubMedCentral • Park R, Da Silva LL, Saeed A. Immunotherapy predictive molecular markers in advanced gastroesophageal cancer: MSI and beyond. Cancers. 2021;13:1715. This reference is of importance because it sheds light on the potential and early promise of various markers while emphasizing the necessity for their further prospective evaluations in the context of gastroesophageal cancer.CrossRefPubMedPubMedCentral

go back to reference •• Janjigian YY, Shitara K, Moehler M, Garrido M, Salman P, Shen L, et al. 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. The Lancet. 2021;398:27–40. This reference is of outstanding importance because it is the phase III trial that demonstrated the superiority of first-line nivolumab plus chemotherapy to chemotherapy alone and it led to FDA approval.CrossRef •• Janjigian YY, Shitara K, Moehler M, Garrido M, Salman P, Shen L, et al. 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. The Lancet. 2021;398:27–40. This reference is of outstanding importance because it is the phase III trial that demonstrated the superiority of first-line nivolumab plus chemotherapy to chemotherapy alone and it led to FDA approval.CrossRef

go back to reference •• Sun J-M, Shen L, Shah MA, Enzinger P, Adenis A, Doi T, et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. The Lancet. 2021;398:759–71. This reference is of outstanding importance because is the phase III trial that demonstrated the superiority of pembrolizumab plus chemotherapy to chemotherapy alone and it led to FDA approval.CrossRef •• Sun J-M, Shen L, Shah MA, Enzinger P, Adenis A, Doi T, et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. The Lancet. 2021;398:759–71. This reference is of outstanding importance because is the phase III trial that demonstrated the superiority of pembrolizumab plus chemotherapy to chemotherapy alone and it led to FDA approval.CrossRef

go back to reference Shitara K, Ajani JA, Moehler M, Garrido M, Gallardo C, Shen L, et al. Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer. Nature. 2022;603:942–8.CrossRefPubMedPubMedCentral Shitara K, Ajani JA, Moehler M, Garrido M, Gallardo C, Shen L, et al. Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer. Nature. 2022;603:942–8.CrossRefPubMedPubMedCentral

go back to reference • Yap DWT, Leone AG, Wong NZH, Zhao JJ, Tey JCS, Sundar R, et al. Effectiveness of immune checkpoint inhibitors in patients with advanced esophageal squamous cell carcinoma: a meta-analysis including low PD-L1 subgroups. JAMA Oncol. 2023;9:215–24. This reference is of importance because it reveals insightful yet sobering findings regarding the efficacy of adding pembrolizumab to chemotherapy in low PD-L1–expressing gastric, esophageal, or GE cancers, specifically those with PD-L1 CPS 1 to 9. This metanalysis indicates no significant benefit of the addition of pembrolizumab in certain patient cohorts. Thus, it becomes a cornerstone for future research, guiding investigations and discussions toward understanding the varied impacts of immunotherapy across different PD-L1 expression levels and ensuring that subsequent trials and treatment strategies are sculpted with a more tailored approach.CrossRefPubMed • Yap DWT, Leone AG, Wong NZH, Zhao JJ, Tey JCS, Sundar R, et al. Effectiveness of immune checkpoint inhibitors in patients with advanced esophageal squamous cell carcinoma: a meta-analysis including low PD-L1 subgroups. JAMA Oncol. 2023;9:215–24. This reference is of importance because it reveals insightful yet sobering findings regarding the efficacy of adding pembrolizumab to chemotherapy in low PD-L1–expressing gastric, esophageal, or GE cancers, specifically those with PD-L1 CPS 1 to 9. This metanalysis indicates no significant benefit of the addition of pembrolizumab in certain patient cohorts. Thus, it becomes a cornerstone for future research, guiding investigations and discussions toward understanding the varied impacts of immunotherapy across different PD-L1 expression levels and ensuring that subsequent trials and treatment strategies are sculpted with a more tailored approach.CrossRefPubMed

go back to reference Park Y, Koh J, Na HY, Kwak Y, Lee K-W, Ahn S-H, et al. PD-L1 testing in gastric cancer by the combined positive score of the 22C3 PharmDx and SP263 assay with clinically relevant cut-offs. Cancer Res Treat. 2020;52:661–70.CrossRefPubMedPubMedCentral Park Y, Koh J, Na HY, Kwak Y, Lee K-W, Ahn S-H, et al. PD-L1 testing in gastric cancer by the combined positive score of the 22C3 PharmDx and SP263 assay with clinically relevant cut-offs. Cancer Res Treat. 2020;52:661–70.CrossRefPubMedPubMedCentral

go back to reference Sajjadi E, Venetis K, Scatena C, Fusco N. Biomarkers for precision immunotherapy in the metastatic setting: hope or reality? Ecancermedicalscience. 2020;14:1150.CrossRefPubMedPubMedCentral Sajjadi E, Venetis K, Scatena C, Fusco N. Biomarkers for precision immunotherapy in the metastatic setting: hope or reality? Ecancermedicalscience. 2020;14:1150.CrossRefPubMedPubMedCentral

go back to reference Bang Y-J, Cutsem EV, Feyereislova A, Chung HC, Shen L, Sawaki A, et al. 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;376:687–97.CrossRefPubMed Bang Y-J, Cutsem EV, Feyereislova A, Chung HC, Shen L, Sawaki A, et al. 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;376:687–97.CrossRefPubMed

go back to reference •• Janjigian YY, Kawazoe A, Yañez P, Li N, Lonardi S, Kolesnik O, et al. The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer. Nature. 2021;600:727–30. This reference is of outstanding importance because it clearly demonstrated the benefits of adding pembrolizumab to trastuzumab and chemotherapy which led to FDA approval.CrossRefPubMedPubMedCentral •• Janjigian YY, Kawazoe A, Yañez P, Li N, Lonardi S, Kolesnik O, et al. The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer. Nature. 2021;600:727–30. This reference is of outstanding importance because it clearly demonstrated the benefits of adding pembrolizumab to trastuzumab and chemotherapy which led to FDA approval.CrossRefPubMedPubMedCentral

go back to reference KEYTRUDA® (pembrolizumab) plus trastuzumab and chemotherapy met primary endpoint of progression-free survival as first-line treatment in patients with HER2-positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma [Internet]. Merck.com. [cited 2023 Oct 2]. Available from: https://www.merck.com/news/keytruda-pembrolizumab-plus-trastuzumab-and-chemotherapy-met-primary-endpoint-of-progression-free-survival-as-first-line-treatment-in-patients-with-her2-positive-advanced-gastric-or-gastroesop/ KEYTRUDA® (pembrolizumab) plus trastuzumab and chemotherapy met primary endpoint of progression-free survival as first-line treatment in patients with HER2-positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma [Internet]. Merck.com. [cited 2023 Oct 2]. Available from: https://​www.​merck.​com/​news/​keytruda-pembrolizumab-plus-trastuzumab-and-chemotherapy-met-primary-endpoint-of-progression-free-survival-as-first-line-treatment-in-patients-with-her2-positive-advanced-gastric-or-gastroesop/​

go back to reference •• Doki Y, Ajani JA, Kato K, Xu J, Wyrwicz L, Motoyama S, et al. Nivolumab combination therapy in advanced esophageal squamous-cell carcinoma. N Engl J Med. 2022;386:449–62. This reference is of outstanding importance because it is a phase III trial that underscored the pivotal role of nivolumab-based treatments, particularly in combination with chemotherapy, for advanced ESCC revealing a notable overall survival benefit compared to chemotherapy alone. Subgroup analyses illuminated that patients with a PD-L1 tumor proportion score (TPS) of ≥ 1% manifested pronounced survival advantages, thereby not only bolstering the FDA approval of Nivolumab but also emphasizing the significant impact of PD-L1 expression levels on treatment efficacy and survival outcomes in advanced ESCC.CrossRefPubMed •• Doki Y, Ajani JA, Kato K, Xu J, Wyrwicz L, Motoyama S, et al. Nivolumab combination therapy in advanced esophageal squamous-cell carcinoma. N Engl J Med. 2022;386:449–62. This reference is of outstanding importance because it is a phase III trial that underscored the pivotal role of nivolumab-based treatments, particularly in combination with chemotherapy, for advanced ESCC revealing a notable overall survival benefit compared to chemotherapy alone. Subgroup analyses illuminated that patients with a PD-L1 tumor proportion score (TPS) of ≥ 1% manifested pronounced survival advantages, thereby not only bolstering the FDA approval of Nivolumab but also emphasizing the significant impact of PD-L1 expression levels on treatment efficacy and survival outcomes in advanced ESCC.CrossRefPubMed

go back to reference Kang Y-K, Chen L-T, Ryu M-H, Oh D-Y, Oh SC, Chung HC, et al. Nivolumab plus chemotherapy versus placebo plus chemotherapy in patients with HER2-negative, untreated, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer (ATTRACTION-4): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2022;23:234–47.CrossRefPubMed Kang Y-K, Chen L-T, Ryu M-H, Oh D-Y, Oh SC, Chung HC, et al. Nivolumab plus chemotherapy versus placebo plus chemotherapy in patients with HER2-negative, untreated, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer (ATTRACTION-4): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2022;23:234–47.CrossRefPubMed

go back to reference •• Shitara K, Van Cutsem E, Bang Y-J, Fuchs C, Wyrwicz L, Lee K-W, et al. 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;6:1571–80. This reference is of outstanding importance because it is a phase III trial that illuminated the efficacy of pembrolizumab, especially within the MSI-H subgroup of advanced gastric cancer patients, showcasing a substantial survival benefit and reduced risk of death compared to chemotherapy alone. Particularly, it showed striking outcomes in patients with MSI-H tumors and a PD-L1 CPS of 1 or greater.CrossRefPubMed •• Shitara K, Van Cutsem E, Bang Y-J, Fuchs C, Wyrwicz L, Lee K-W, et al. 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;6:1571–80. This reference is of outstanding importance because it is a phase III trial that illuminated the efficacy of pembrolizumab, especially within the MSI-H subgroup of advanced gastric cancer patients, showcasing a substantial survival benefit and reduced risk of death compared to chemotherapy alone. Particularly, it showed striking outcomes in patients with MSI-H tumors and a PD-L1 CPS of 1 or greater.CrossRefPubMed

go back to reference Kojima T, Shah MA, Muro K, Francois E, Adenis A, Hsu C-H, et al. Randomized phase III KEYNOTE-181 study of pembrolizumab versus chemotherapy in advanced esophageal cancer. J Clin Oncol. 2020;38:4138–48.CrossRefPubMed Kojima T, Shah MA, Muro K, Francois E, Adenis A, Hsu C-H, et al. Randomized phase III KEYNOTE-181 study of pembrolizumab versus chemotherapy in advanced esophageal cancer. J Clin Oncol. 2020;38:4138–48.CrossRefPubMed

go back to reference Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372:2509–20.CrossRefPubMedPubMedCentral Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372:2509–20.CrossRefPubMedPubMedCentral

go back to reference •• Marabelle A, Le DT, Ascierto PA, Di Giacomo AM, De Jesus-Acosta A, Delord J-P, et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair–deficient cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol. 2020;38:1–10. This reference is of outstanding importance because of spotlights the significance of tumor mutation burden (TMB) in immunotherapy response across varied tumor types. Despite its foundational role, the trial prompts critical inquiries regarding the universal applicability of the TMB cutoff of 10 mutations per megabase across diverse GI malignancies and underscores the necessity for further exploration and validation in steering management strategies, especially in gastro-esophageal cancers.CrossRefPubMed •• Marabelle A, Le DT, Ascierto PA, Di Giacomo AM, De Jesus-Acosta A, Delord J-P, et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair–deficient cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol. 2020;38:1–10. This reference is of outstanding importance because of spotlights the significance of tumor mutation burden (TMB) in immunotherapy response across varied tumor types. Despite its foundational role, the trial prompts critical inquiries regarding the universal applicability of the TMB cutoff of 10 mutations per megabase across diverse GI malignancies and underscores the necessity for further exploration and validation in steering management strategies, especially in gastro-esophageal cancers.CrossRefPubMed

go back to reference Samstein RM, Lee C-H, Shoushtari AN, Hellmann MD, Shen R, Janjigian YY, et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat Genet. 2019;51:202–6.CrossRefPubMedPubMedCentral Samstein RM, Lee C-H, Shoushtari AN, Hellmann MD, Shen R, Janjigian YY, et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat Genet. 2019;51:202–6.CrossRefPubMedPubMedCentral

go back to reference Hsiehchen D, Hsieh A, Samstein RM, Lu T, Beg MS, Gerber DE, Wang T, Morris LGT, Zhu H. DNA repair gene mutations as predictors of immune checkpoint inhibitor response beyond tumor mutation burden. Cell reports medicine. 2020;1(3): 100034. https://doi.org/10.1016/j.xcrm.2020.100034.CrossRefPubMedPubMedCentral Hsiehchen D, Hsieh A, Samstein RM, Lu T, Beg MS, Gerber DE, Wang T, Morris LGT, Zhu H. DNA repair gene mutations as predictors of immune checkpoint inhibitor response beyond tumor mutation burden. Cell reports medicine. 2020;1(3): 100034. https://​doi.​org/​10.​1016/​j.​xcrm.​2020.​100034.CrossRefPubMedPubMedCentral

go back to reference Nishikawa J, Iizasa H, Yoshiyama H, Shimokuri K, Kobayashi Y, Sasaki S, et al. Clinical importance of Epstein-Barr virus-associated gastric cancer. Cancers (Basel). 2018;10:167.CrossRefPubMedPubMedCentral Nishikawa J, Iizasa H, Yoshiyama H, Shimokuri K, Kobayashi Y, Sasaki S, et al. Clinical importance of Epstein-Barr virus-associated gastric cancer. Cancers (Basel). 2018;10:167.CrossRefPubMedPubMedCentral

go back to reference Kim ST, Cristescu R, Bass AJ, Kim K-M, Odegaard JI, Kim K, et al. Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer. Nat Med. 2018;24:1449–58.CrossRefPubMed Kim ST, Cristescu R, Bass AJ, Kim K-M, Odegaard JI, Kim K, et al. Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer. Nat Med. 2018;24:1449–58.CrossRefPubMed

go back to reference Saeed A, Park R, Dai J, Al-Rajabi R, Kasi A, Baranda J, et al. Cabozantinib plus durvalumab in advanced gastroesophageal cancer and other gastrointestinal malignancies: phase Ib CAMILLA trial results. Cell Rep Med. 2023;4(2):100916. https://doi.org/10.1016/j.xcrm.2023.100916.CrossRefPubMedPubMedCentral Saeed A, Park R, Dai J, Al-Rajabi R, Kasi A, Baranda J, et al. Cabozantinib plus durvalumab in advanced gastroesophageal cancer and other gastrointestinal malignancies: phase Ib CAMILLA trial results. Cell Rep Med. 2023;4(2):100916. https://​doi.​org/​10.​1016/​j.​xcrm.​2023.​100916.CrossRefPubMedPubMedCentral

go back to reference Saeed A, Park R, Sun W. The integration of immune checkpoint inhibitors with VEGF targeted agents in advanced gastric and gastroesophageal adenocarcinoma: a review on the rationale and results of early phase trials. J Hematol Oncol. 2021;14:13.CrossRefPubMedPubMedCentral Saeed A, Park R, Sun W. The integration of immune checkpoint inhibitors with VEGF targeted agents in advanced gastric and gastroesophageal adenocarcinoma: a review on the rationale and results of early phase trials. J Hematol Oncol. 2021;14:13.CrossRefPubMedPubMedCentral

go back to reference Cutsem EV, di Bartolomeo M, Smyth E, Chau I, Park H, Siena S, et al. Trastuzumab deruxtecan in patients in the USA and Europe with HER2-positive advanced gastric or gastroesophageal junction cancer with disease progression on or after a trastuzumab-containing regimen (DESTINY-Gastric02): primary and updated analyses from a single-arm, phase 2 study. Lancet Oncol. 2023;24:744–56.CrossRefPubMed Cutsem EV, di Bartolomeo M, Smyth E, Chau I, Park H, Siena S, et al. Trastuzumab deruxtecan in patients in the USA and Europe with HER2-positive advanced gastric or gastroesophageal junction cancer with disease progression on or after a trastuzumab-containing regimen (DESTINY-Gastric02): primary and updated analyses from a single-arm, phase 2 study. Lancet Oncol. 2023;24:744–56.CrossRefPubMed

go back to reference Qi C, Gong J, Li J, Liu D, Qin Y, Ge S, et al. Claudin18.2-specific CAR T cells in gastrointestinal cancers: phase 1 trial interim results. Nat Med. 2022;28:1189–98. Qi C, Gong J, Li J, Liu D, Qin Y, Ge S, et al. Claudin18.2-specific CAR T cells in gastrointestinal cancers: phase 1 trial interim results. Nat Med. 2022;28:1189–98.

go back to reference Lu Z, Chen H, Jiao X, Zhou W, Han W, Li S, et al. Prediction of immune checkpoint inhibition with immune oncology-related gene expression in gastrointestinal cancer using a machine learning classifier. J Immunother Cancer. 2020;8:e000631.CrossRefPubMedPubMedCentral Lu Z, Chen H, Jiao X, Zhou W, Han W, Li S, et al. Prediction of immune checkpoint inhibition with immune oncology-related gene expression in gastrointestinal cancer using a machine learning classifier. J Immunother Cancer. 2020;8:e000631.CrossRefPubMedPubMedCentral