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Innovative strategies in metastatic gastric cancer: a short review

Innovative strategies in metastatic gastric cancer: a short review short review memo (2022) 15:29–34 https://doi.org/10.1007/s12254-021-00762-w Innovative strategies in metastatic gastric cancer: a short review Hannah Christina Puhr · Aysegul Ilhan-Mutlu Received: 6 July 2021 / Accepted: 22 September 2021 / Published online: 19 October 2021 © The Author(s) 2021 Summary Recent innovative advances, especially MSI-H High microsatellite instability concerning immunotherapeutic agents and targeted n.r. Not reached therapies, have changed the face of modern oncol- ORR Overall response rate ogy. The year 2020 represents a milestone in the OS Overall survival treatment of gastroesophageal cancer because sev- PD-(L)1 Programmed cell death receptor (ligand) 1 eral trials showed promising survival benefits, at least PFS Progression-free survival for a specific subgroup of patients. Not only im- TMB-H High tumor mutational burden munotherapeutic agents, but also targeted therapies seem to be beneficial, particularly when the target Introduction is well defined and the threshold value is selected appropriately. Thus, many new innovative treatment Gastric cancer is a major contributor to global dis- strategies are underway and might lead to a further ease burden and, thus, new treatment options are des- paradigm change in the therapy of patients with ad- perately needed to improve the outcome of patients vanced gastric tumors. This review gives a concise suffering from this devastating disease [1]. Although overview of these new therapeutic options and re- advances in immunotherapy as well as targeted ther- cently approved strategies as well as ongoing studies. apy at the beginning of the 21st century have led to major breakthroughs in various types of cancer, these Keywords Gastroesophageal cancer · Gastric cancer · high expectations could only recently be met in trials Immunotherapy · Targeted therapy · Upper concerning gastric cancer [2]. Thus, new innovative gastrointestinal cancer · Advanced cancer targets and drugs are underway to improve the care of patients with gastric cancer. The aim of this mini- Abbreviations review is to concisely highlight some promising new CI Confidence interval treatment approaches of metastatic gastric cancer and CPS Combined Positive Score their clinical relevance. Trials, which showed clini- DoR Duration of response cal and statistical relevant data leading to approval of EMA European Medicines Agency new therapeutic strategies by appropriate authorities FDA Food and Drug Administration for advanced gastric cancer patients in recent years, FGFR2b Fibroblast growth factor receptor 2b are listed in Table 1. GEJ Gastroesophageal junction HER2 Human epidermal growth factor receptor 2 Immunotherapy for gastric cancer HR Hazard ratio Current treatment landscape with H. C. Puhr, MD · A. Ilhan-Mutlu, MD PhD () immunotherapeutic agents Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria So far, the most promising immunotherapeutic tar- aysegul.ilhan@meduniwien.ac.at get in gastric cancer patients was the programmed cell death receptor 1 (PD-1)/programmed cell death H. C. Puhr, MD hannah.puhr@meduniwien.ac.at ligand 1 (PD-L1) checkpoint axis [3]. Although some K Innovative strategies in advanced gastric cancer 29 short review 30 Innovative strategies in advanced gastric cancer K Table 1 Innovative therapeutic strategies for advanced gastric cancer, which are already approved by authorities Study name Therapeutic agent Phase Histology Therapy Control group Findings Population Approval Reference line number ATTRACTION-2 Nivolumab III Advanced gastric or GEJ ≥ 3 Placebo Median OS: 5.26 vs 4.14 months (HR 0.63, Asia 2017–2019 (PD-L1 indepen- [4, 6] cancer 95% CI 0.51–0.78); p < 0.0001 dent): Japan, South Korea, Taiwan, Singapore and Switzer- land KEYNOTE-059 Pembrolizumab II Advanced gastric and GEJ ≥ 2 No control group ORR: 15.5%; 95% CI 10.1–22.4% North and South 2017 (CPS ≥ 1): [5, 7] cancer America, Asia, FDA → 07/2021 withdrawal Europe by company CheckMate 649 Nivolumab + III Advanced 1 Chemotherapy Median OS: nivo + CHT 14.4 (95% CI North and South 2021 (PD-L1 independent): [8, 9] chemotherapy; non-HER2-positive gas- 13.1–16.2) vs CHT 11.1 months (95% CI America, Australia, FDA (ipilimumab + tric, GEJ or esophageal 10.0–12.1) in PD-L1 CPS ≥ 5pts Asia, Europe nivolumab) adenocarcinoma 5 trials Pembrolizumab Ib, II 149 patients with MSI-H ≥ 2 No control group ORR (retrospective analysis): 39.6% (95% CI: North and South 2017 (MSI-H; without satis- [11] (KEYNOTE: cancers 31.7, 47.9) America, Australia, factory alternative treatment 016, 164, 012, Asia, Europe options): FDA 028, and 158) KEYNOTE-158 Pembrolizumab II MSI-H advanced non-col- ≥ 2 No control group TMB-H (retrospective analysis): ORR: 29% North and South 2020 (TMB-H; without satis- [12] orectal cancer (95% CI 21–39); DoR: not reached America, Australia, factory alternative treatment Asia, Europe options): FDA KEYNOTE-811 Pembrolizumab + III HER2-positive metastatic 1 Placebo + ORR: pembro 74% (95% CI 66–82) vs placebo North and South 2021 (HER2-positive, PD-L1 [24, 25] trastuzumab and gastric/GEJ cancer trastuzumab and 52% (95% CI 43–61) arm; one-sided p-value America, Australia, independent): FDA chemotherapy chemotherapy < 0.0001 Asia, Europe DESTINY- Trastuzumab derux- II HER2-positive advanced ≥ 3 Chemotherapy Median OS: 12.5 (95% CI 9.6–14.3) vs 8.4 Asia 2021 (HER2-positive; prior [26, 27] Gastric01 tecan gastric/GEJ cancer months (95% CI 6.9–10.7); HR 0.59 (95% CI trastuzumab-based regimen): 0.39–0.88); p = 0.0097 FDA, Japan FIGHT Bemarituzumab + II FGFR2b-positive, 1 Chemotherapy + Median OS: 25.4 months (95% CI: 13.8, n.r.) North America, 2021 (FGFR2b-positive, [29, 30] chemotherapy HER2-negative advanced placebo vs 11.1 months (95% CI: 8.4, 13.8) for pts with Australia, Asia, HER2-negative): FDA gastric/GEJ cancer ≥ 10% FGFR2b+; HR 0.41 (95% CI 0.23–0.74) Europe CI confidence interval, CPS Combined Positive Score, DoR Duration of response, EMA European Medicines Agency, FDA Food and Drug Administration, FGFR2b fibroblast growth factor receptor 2b, GEJ gastroesophageal junction, HER2 human epidermal growth factor receptor 2, HR hazard ratio, MSI-H high microsatellite instability, n.r. not reached, ORR overall response rate, OS overall survival, PD-(L)1 programmed cell death receptor (ligand) 1, PFS progression-free survival, TMB-H high tumor mutational burden short review studies showed a significant benefit for all patients However, it is surmised that these “cold” tumors enrolled [4], most trials indicate that specific patient can be transformed into “hot” and inflamed tumors by subgroups (such as high PD-L1 expression or high mi- several strategies including neutralizing immunosup- crosatellite instability [MSI-H]) profit most from im- pression at the tumor site by combining immunother- mune checkpoint inhibition [5]. Thus, the evaluation apeutic approaches, modifying the tumor vasculature of PD-L1 expression using Combined Positive Score by targeting endothelial growth, targeting the tumor (CPS) became part of the routine diagnostic work-up cells themselves with chemotherapy, inducing local of tumor tissue. Yet, the cut-off levels for therapeu- inflammation with radiation therapy, or increasing the tic approvals are still widely discussed. The results frequency of tumor-specific T cells with personalized of the ATTACTION-II trial were published indepen- approaches such as CAR T cell therapy [13]. dent of PD-L1 expression and led to an approval of Combination with targeted therapies nivolumab independent of CPS expression [6]. However, in the phase II KEYNOTE-059 trial the Especially, the combinationwithtargeted therapy for cut-off level for PD-L1-positivity was defined as angiogenesis and growth pathways has gained impor- CPS ≥ 1 (median response duration was 16.3 [1.6+ tance in recent years. to 17.3+] months in patients with PD-L1-positive and The combination of nivolumab and regorafenib is 6.9 [2.4 to 7.0+] months and PD-L1-negative tumors) currently under investigation. The recently published and, thus, pembrolizumab was approved by the Food phase Ib REGONIVO trial found encouraging antitu- and Drug Administration (FDA) as a third and fur- mor activity in patients with gastric cancer in a third ther line therapy in CPS ≥ 1 patients with metastatic and further line setting (median PFS 5.6 months), gastroesophageal adenocarcinoma [5, 7]. However, thus, warranting additional investigations in larger by July 2021, the company voluntarily withdrew this cohorts [14]. Furthermore, ramucirumab was investi- accelerated approval indication. gated in combination with paclitaxel plus nivolumab However, the CheckMate 649 trial found that pa- and showed promising anti-tumor activity (me- tients with CPS≥ 5 showed the most significant ben- dian OS 13.8 months [95% CI 8.0–19.5 months] in efit (overall survival hazard ratio [OS HR] 0.71, 98.4% CPS ≥ 1 patients) [15]. Another approach evaluated CI 0.59–0.86; p < 0.0001) when adding nivolumab to the combination treatment of lenvatinib, a multiki- standard chemotherapy. Interestingly, this combina- nase inhibitor of VEGF receptors and other receptor tion was approved by the FDA in 2021 regardless of tyrosine kinases, with pembrolizumab and a response PD-L1 expression status and is currently under inves- rate of 69% (95% CI 49–85) was demonstrated [16]. tigation by the European Medicines Agency (EMA) [8, There are several ongoing trials evaluating the 9]. combination of the checkpoint inhibitor durvalumab Other important and already established biomark- with targeted therapies, e.g., with cabozantinib in ers that indicate response to checkpoint inhibition are CAMILLA trial and with raumucirumab in a phase Ib MSI, which is surmised to be high (MSI-H) in around trial [17, 18]. 4–5% of all advanced Western gastric tumor cases, and tumor mutational burden (TMB) [10]. Thus, the Combination of anti-PD-1/PD-L1 drugs with other checkpoint inhibitors FDA approved immunotherapy with pembrolizumab for the treatment of unresectable or metastatic MSI-H Although the concept of neutralizing immunosup- and TMB-H solid tumors that have progressed fol- pression at the tumor site by combining immunother- lowing prior treatment independent of tumor location apeutic approaches, the combination of anti-PD- and which have no satisfactory alternative treatment 1/PD-L1 drugs with other checkpoint inhibitors, so far options (“tissue agnostic approvals”) [11, 12]. no practice changing trials can be reported in gastric These findings underline the importance of patient cancer. However, several studies suggest promising selection and changed the face of gastric cancer treat- new combination strategies including combination ment. with cytotoxic T lymphocyte antigen-4 (CTLA-4; drug: ipilimumab; trials: CheckMate-032 [19], Moonlight trial [20]), lymphocyte activation gene-3 (LAG3; drug: Strategies to overcome the immune cold tumors relatlimab; trials: FRACTION [21], REACTION), T cell As mentioned above, a major issue concerning im- immunoglobulin and mucin-domain containing-3 munotherapy is that only a subset of patients achieve (TIM-3), T cell immunoglobulin and ITIM domain responses. Thus, the identification of underlying (TIGIT), V-domain Ig suppressor of T cell activation mechanisms for primary resistance to immunother- (VISTA), OX40 (CD134) and B and T cell lymphocyte apy are of major concern [13]. Recent studies charac- attenuator (BTLA) [22, 23]. terized these immunologically “cold” tumors by a lack of infiltrating T cells in the tumor microenvironment. Consequentially, tumor cells stay unrecognized by the immune system and, thus, do not respond to checkpoint inhibition. K Innovative strategies in advanced gastric cancer 31 short review tient outcome with these new treatment options, it Targeted therapy for gastroesophageal tumors is of highest importance to define these subgroups more accurately. The evaluation and implementation Targeting HER2 beyond trastuzumab: of new biomarkers seems to be the key for adequate In the field of HER2-positive (human epidermal patient selection leading to high treatment efficacy. In growth factor receptor 2) gastroesophageal cancer, case of immunotherapy, this selection is mainly based a recently published phase II trial evaluating first- on PD-L1 expression, MSI status and, more recently, line pembrolizumab and trastuzumab in combina- on TMB. However, looking at response rates it is ev- tion with chemotherapy showed promising response ident that despite these biomarkers there is still sig- rates and, thus, was the impulse for a randomized nificant percentage of patients who do not respond phase 3 clinical trial (KEYNOTE-811) [24]. First re- to treatment. Thus, underlining the fact that further sults of the KEYNOTE-811 trial found that the overall strategies should be implemented to develop predic- response rate (ORR) was 74% (95% CI 66–82) in the tive markers. pembrolizumab arm and 52% (95% CI 43–61) in the Another critical issue is to overcome so called “cold” placebo arm (one-sided p-value < 0.0001) and, thus, tumors, thereby improving treatment response. New the combination of pembrolizumab, trastuzumab combination strategies including combinations of the and chemotherapy (ToGA regimen) has been recently inhibition of the PD-(L)1 axis with chemotherapy, ra- approved by the FDA for the first-line treatment of diation therapy, other immune checkpoint inhibitors HER2-positive advanced gastric cancer [25]. and targeted therapies are underway into clinical Another new approach that was recently approved practice to overcome this treatment resistance. by the FDA for HER2-positive patients who have re- Finally, critical issues to consider for new drug ap- ceived a prior trastuzumab-based regimen is the drug provals are tolerability, impact on quality of life, and trastuzumab deruxtecan, a novel antibody-drug con- financial considerations. Future studies need to in- jugate [26]. The drug was evaluated by the phase II clude these major considerations in clinical trial de- DESTINY-Gastric01 trial in a third and further line sign in order to achieve more adequate implementa- setting in comparison to chemotherapy and showed tion of new therapeutic agents into real-life cohorts a significantly longer median OS (12.5 vs. 8.4 months; and guidelines. HR 0.59; 95% CI 0.39–0.88; p = 0.01) [27]. In conclusion, recently published studies led to a paradigm change of advanced gastric cancer treat- ment and several new innovative approaches are Attempts for novel targets underway to further improve the management of Claudin 18.2 (CLDN18.2) protein is physiologically patient subgroups. confined to gastric mucosa tight junctions and is exposed on the cancer cell surface upon malignant Take home message transformation. In the phase II FAST trial, patients with advanced New innovative targets and drugs are underway to im- gastric cancer and a CLDN18.2 expression in ≥ 70% of prove the care of patients with advanced gastric cancer. tumor cells were treated with the anti-Claudin 18.2 an- This mini-review highlights promising new treatment tibody zolbetuximab in combination with chemother- approaches and their clinical relevance. apy. Zolbetuximab generated prolonged OS rates in this patient subgroup (HR 0.55; 95% CI 0.39–0.77; Funding The authors gratefully acknowledge Medical Univer- p < 0.0005) [28]. Based on this data, two phase III tri- sity of Vienna’s core funding to the Department of Medicine I. als have been initiated, which will reveal first results Funding Open access funding provided by Medical University within the next few years. of Vienna. Fibroblast growth factor receptor 2b (FGFR2b) is another very interesting target, which was tested in Conflict of interest H.C. Puhr has received travel support the FIGHT study. The anti-FGFR2b antibody bemar- from Eli Lilly, MSD, Novartis, Pfizer and Roche. A. Ilhan- ituzumab in combination with chemotherapy as first- Mutlu participated in advisory boards from MSD, BMS and Servier, received lecture honoraria from Eli Lilly, MSD, BMS line revealed very promising results in FGFR2b-posi- and Servier, is the local PI for clinical trials sponsored by BMS tive patients, which led to the designation of bemar- andRoche andreceivedtravel support from BMS, Roche, Eli ituzumab as a breakthrough therapy by the FDA (OS Lilly and Daiichi Sankyo. HR 0.66; 95% CI 0.39–1.12) [29, 30]. Open Access This article is licensed under a Creative Com- mons Attribution 4.0 International License, which permits Discussion use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit Despite the improvement of modern cancer medicine to the original author(s) and the source, provide a link to including immunotherapies and targeted therapies, the Creative Commons licence, and indicate if changes were new therapeutic approaches seem to be efficiently in made. The images or other third party material in this article only specific subgroups of patients. To improve pa- are included in the article’s Creative Commons licence, unless 32 Innovative strategies in advanced gastric cancer K short review indicated otherwise in a credit line to the material. 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Janjigian YY, Bendell J, Calvo E, Kim JW, Ascierto PA, ated approval to pembrolizumab for advanced gastric Sharma P, et al. CheckMate-032 study: efficacy and cancer. 2017. https://www.fda.gov/drugs/resources- safety of nivolumab and nivolumab plus ipilimumab in pa- information-approved-drugs/fda-grants-accelerated- tientswithmetastaticesophagogastriccancer. JClinOncol. approval-pembrolizumab-advanced-gastric-cancer.Ac- 2018;36(28):2836–44. cessed01July2021. 20. Al-Batran S-E, Pauligk C, Goetze TO, Riera-Knorrenschild J, 8. Janjigian YY, Shitara K, Moehler M, Garrido M, Salman P, Goekkurt E, Angermeier S, et al. Modified FOLFOX versus Shen L, et al. First-line nivolumab plus chemotherapy modified FOLFOX plus nivolumab and ipilimumab in versus chemotherapy alone for advanced gastric, gastro- patients with previously untreated advanced or metastatic oesophageal junction, and oesophageal adenocarcinoma adenocarcinoma of the stomach or gastroesophageal (CheckMate 649): a randomised, open-label, phase 3 trial. junction: Moonlight, a randomized phase 2 trial of Lancet. 2021;398(10294):27–40. the German Gastric Group of the AIO. J Clin Oncol. 9. FoodandDrugAdministration. FDAapprovesnivolumabin 2019;37(15_suppl):TPS4144. combinationwithchemotherapyformetastaticgastriccan- 21. Aanur P, Gutierrez M, Kelly RJ, AjaniJA,KuGY, Denlinger CS, cer and esophageal adenocarcinoma. 2021. https://www. et al. FRACTION (Fast Real-time Assessment of Com- fda.gov/drugs/resources-information-approved-drugs/ bination Therapies in Immuno-Oncology)-gastric cancer fda-approves-nivolumab-combination-chemotherapy- (GC): a randomized, open-label, adaptive, phase 2 study of metastatic-gastric-cancer-and-esophageal. Accessed 01 nivolumab in combination with other immuno-oncology July2021. (IO) agents in patients with advanced GC. J Clin Oncol. 10. Polom K, Marano L, Marrelli D, De Luca R, Roviello G, 2017;35(15_suppl):TPS4137. Savelli V, et al. Meta-analysis of microsatellite instability 22. Qin S,XuL,Yi M, YuS,Wu K, Luo S. Novel immune inrelationtoclinicopathologicalcharacteristicsandoverall checkpoint targets: moving beyond PD-1 and CTLA-4. Mol survivalingastriccancer. BrJSurg. 2018;105(3):159–67. Cancer. 2019;18(1):155. 11. Food and Drug Administration. FDA approves pem- 23. Alves Costa SC, Facchinetti F, Routy B, Derosa L. New brolizumab for adults and children with TMB-H solid tu- pathways in immune stimulation: targeting OX40. ESMO mors. 2020. https://www.fda.gov/drugs/drug-approvals- Open. 2020;5(1):e573. and-databases/fda-approves-pembrolizumab-adults- 24. Janjigian YY, Maron SB, Chatila WK, Millang B, Cha- and-children-tmb-h-solid-tumors. Accessed 01 July van SS, Alterman C, et al. First-line pembrolizumab and trastuzumab in HER2-positive oesophageal, gastric, or gas- 12. Food and Drug Administration. FDA grants ac- celerated approval to pembrolizumab for first tis- K Innovative strategies in advanced gastric cancer 33 short review tro-oesophageal junction cancer: an open-label, single- placebo-controlled, phase II study of bemarituzumab arm,phase2trial. LancetOncol. 2020;21(6):821–31. (bema) combined with modified FOLFOX6 in 1L FGFR2b+ 25. Food and Drug Administration. FDA grants accelerated advanced gastric/gastroesophageal junction adenocarci- approval to pembrolizumab for HER2-positive gastric noma(GC).JClinOncol. 2021;39(15_suppl):4010. cancer. 2021. https://www.fda.gov/drugs/resources- 30. ASCO Post Staff. FDA pipeline: bemarituzumab granted information-approved-drugs/fda-grants-accelerated- breakthrough therapy designation for FGFR2b-overex- approval-pembrolizumab-her2-positive-gastric-cancer. pressing, HER2-negative gastric cancer. 2021. https:// Accessed01July2021. ascopost.com/news/april-2021/fda-pipeline-bemarituzu 26. Food and Drug Administration. FDA approves fam- mab-granted-breakthrough-therapy-designation-for-fgfr trastuzumab deruxtecan-nxki for HER2-positive gastric 2b-overexpressing-her2-negative-gastric-cancer/.Ac- adenocarcinomas. 2021. https://www.fda.gov/drugs/ cessed01July2021. resources-information-approved-drugs/fda-approves- Publisher’s Note Springer Nature remains neutral with regard fam-trastuzumab-deruxtecan-nxki-her2-positive-gastric- to jurisdictional claims in published maps and institutional adenocarcinomas. Accessed01July2021. affiliations. 27. ShitaraK,BangY-J,IwasaS, SugimotoN, RyuM-H,Sakai D, et al. Trastuzumab deruxtecan in previously treated HER2- positivegastriccancer. NEnglJMed. 2020;382(25):2419–30. 28. SahinU,TüreciÖ,ManikhasG,Lordick F, Rusyn A,Vyn- nychenko I, et al. FAST: a randomised phase II study of 7 For latest news from interna- zolbetuximab (IMAB362) plus EOX versus EOX alone for tional oncology congresses see: first-line treatment of advanced CLDN18.2-positive gas- http://www.springermedizin.at/ tric and gastro-oesophageal adenocarcinoma. Ann Oncol. memo-inoncology 2021;32(5):609–19. 29. Catenacci DVT, Kang Y-K, Saeed A, Yamaguchi K, Qin S, Lee K-W, et al. FIGHT: a randomized, double-blind, 34 Innovative strategies in advanced gastric cancer K http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png memo - Magazine of European Medical Oncology Springer Journals

Innovative strategies in metastatic gastric cancer: a short review

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short review memo (2022) 15:29–34 https://doi.org/10.1007/s12254-021-00762-w Innovative strategies in metastatic gastric cancer: a short review Hannah Christina Puhr · Aysegul Ilhan-Mutlu Received: 6 July 2021 / Accepted: 22 September 2021 / Published online: 19 October 2021 © The Author(s) 2021 Summary Recent innovative advances, especially MSI-H High microsatellite instability concerning immunotherapeutic agents and targeted n.r. Not reached therapies, have changed the face of modern oncol- ORR Overall response rate ogy. The year 2020 represents a milestone in the OS Overall survival treatment of gastroesophageal cancer because sev- PD-(L)1 Programmed cell death receptor (ligand) 1 eral trials showed promising survival benefits, at least PFS Progression-free survival for a specific subgroup of patients. Not only im- TMB-H High tumor mutational burden munotherapeutic agents, but also targeted therapies seem to be beneficial, particularly when the target Introduction is well defined and the threshold value is selected appropriately. Thus, many new innovative treatment Gastric cancer is a major contributor to global dis- strategies are underway and might lead to a further ease burden and, thus, new treatment options are des- paradigm change in the therapy of patients with ad- perately needed to improve the outcome of patients vanced gastric tumors. This review gives a concise suffering from this devastating disease [1]. Although overview of these new therapeutic options and re- advances in immunotherapy as well as targeted ther- cently approved strategies as well as ongoing studies. apy at the beginning of the 21st century have led to major breakthroughs in various types of cancer, these Keywords Gastroesophageal cancer · Gastric cancer · high expectations could only recently be met in trials Immunotherapy · Targeted therapy · Upper concerning gastric cancer [2]. Thus, new innovative gastrointestinal cancer · Advanced cancer targets and drugs are underway to improve the care of patients with gastric cancer. The aim of this mini- Abbreviations review is to concisely highlight some promising new CI Confidence interval treatment approaches of metastatic gastric cancer and CPS Combined Positive Score their clinical relevance. Trials, which showed clini- DoR Duration of response cal and statistical relevant data leading to approval of EMA European Medicines Agency new therapeutic strategies by appropriate authorities FDA Food and Drug Administration for advanced gastric cancer patients in recent years, FGFR2b Fibroblast growth factor receptor 2b are listed in Table 1. GEJ Gastroesophageal junction HER2 Human epidermal growth factor receptor 2 Immunotherapy for gastric cancer HR Hazard ratio Current treatment landscape with H. C. Puhr, MD · A. Ilhan-Mutlu, MD PhD () immunotherapeutic agents Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria So far, the most promising immunotherapeutic tar- aysegul.ilhan@meduniwien.ac.at get in gastric cancer patients was the programmed cell death receptor 1 (PD-1)/programmed cell death H. C. Puhr, MD hannah.puhr@meduniwien.ac.at ligand 1 (PD-L1) checkpoint axis [3]. Although some K Innovative strategies in advanced gastric cancer 29 short review 30 Innovative strategies in advanced gastric cancer K Table 1 Innovative therapeutic strategies for advanced gastric cancer, which are already approved by authorities Study name Therapeutic agent Phase Histology Therapy Control group Findings Population Approval Reference line number ATTRACTION-2 Nivolumab III Advanced gastric or GEJ ≥ 3 Placebo Median OS: 5.26 vs 4.14 months (HR 0.63, Asia 2017–2019 (PD-L1 indepen- [4, 6] cancer 95% CI 0.51–0.78); p < 0.0001 dent): Japan, South Korea, Taiwan, Singapore and Switzer- land KEYNOTE-059 Pembrolizumab II Advanced gastric and GEJ ≥ 2 No control group ORR: 15.5%; 95% CI 10.1–22.4% North and South 2017 (CPS ≥ 1): [5, 7] cancer America, Asia, FDA → 07/2021 withdrawal Europe by company CheckMate 649 Nivolumab + III Advanced 1 Chemotherapy Median OS: nivo + CHT 14.4 (95% CI North and South 2021 (PD-L1 independent): [8, 9] chemotherapy; non-HER2-positive gas- 13.1–16.2) vs CHT 11.1 months (95% CI America, Australia, FDA (ipilimumab + tric, GEJ or esophageal 10.0–12.1) in PD-L1 CPS ≥ 5pts Asia, Europe nivolumab) adenocarcinoma 5 trials Pembrolizumab Ib, II 149 patients with MSI-H ≥ 2 No control group ORR (retrospective analysis): 39.6% (95% CI: North and South 2017 (MSI-H; without satis- [11] (KEYNOTE: cancers 31.7, 47.9) America, Australia, factory alternative treatment 016, 164, 012, Asia, Europe options): FDA 028, and 158) KEYNOTE-158 Pembrolizumab II MSI-H advanced non-col- ≥ 2 No control group TMB-H (retrospective analysis): ORR: 29% North and South 2020 (TMB-H; without satis- [12] orectal cancer (95% CI 21–39); DoR: not reached America, Australia, factory alternative treatment Asia, Europe options): FDA KEYNOTE-811 Pembrolizumab + III HER2-positive metastatic 1 Placebo + ORR: pembro 74% (95% CI 66–82) vs placebo North and South 2021 (HER2-positive, PD-L1 [24, 25] trastuzumab and gastric/GEJ cancer trastuzumab and 52% (95% CI 43–61) arm; one-sided p-value America, Australia, independent): FDA chemotherapy chemotherapy < 0.0001 Asia, Europe DESTINY- Trastuzumab derux- II HER2-positive advanced ≥ 3 Chemotherapy Median OS: 12.5 (95% CI 9.6–14.3) vs 8.4 Asia 2021 (HER2-positive; prior [26, 27] Gastric01 tecan gastric/GEJ cancer months (95% CI 6.9–10.7); HR 0.59 (95% CI trastuzumab-based regimen): 0.39–0.88); p = 0.0097 FDA, Japan FIGHT Bemarituzumab + II FGFR2b-positive, 1 Chemotherapy + Median OS: 25.4 months (95% CI: 13.8, n.r.) North America, 2021 (FGFR2b-positive, [29, 30] chemotherapy HER2-negative advanced placebo vs 11.1 months (95% CI: 8.4, 13.8) for pts with Australia, Asia, HER2-negative): FDA gastric/GEJ cancer ≥ 10% FGFR2b+; HR 0.41 (95% CI 0.23–0.74) Europe CI confidence interval, CPS Combined Positive Score, DoR Duration of response, EMA European Medicines Agency, FDA Food and Drug Administration, FGFR2b fibroblast growth factor receptor 2b, GEJ gastroesophageal junction, HER2 human epidermal growth factor receptor 2, HR hazard ratio, MSI-H high microsatellite instability, n.r. not reached, ORR overall response rate, OS overall survival, PD-(L)1 programmed cell death receptor (ligand) 1, PFS progression-free survival, TMB-H high tumor mutational burden short review studies showed a significant benefit for all patients However, it is surmised that these “cold” tumors enrolled [4], most trials indicate that specific patient can be transformed into “hot” and inflamed tumors by subgroups (such as high PD-L1 expression or high mi- several strategies including neutralizing immunosup- crosatellite instability [MSI-H]) profit most from im- pression at the tumor site by combining immunother- mune checkpoint inhibition [5]. Thus, the evaluation apeutic approaches, modifying the tumor vasculature of PD-L1 expression using Combined Positive Score by targeting endothelial growth, targeting the tumor (CPS) became part of the routine diagnostic work-up cells themselves with chemotherapy, inducing local of tumor tissue. Yet, the cut-off levels for therapeu- inflammation with radiation therapy, or increasing the tic approvals are still widely discussed. The results frequency of tumor-specific T cells with personalized of the ATTACTION-II trial were published indepen- approaches such as CAR T cell therapy [13]. dent of PD-L1 expression and led to an approval of Combination with targeted therapies nivolumab independent of CPS expression [6]. However, in the phase II KEYNOTE-059 trial the Especially, the combinationwithtargeted therapy for cut-off level for PD-L1-positivity was defined as angiogenesis and growth pathways has gained impor- CPS ≥ 1 (median response duration was 16.3 [1.6+ tance in recent years. to 17.3+] months in patients with PD-L1-positive and The combination of nivolumab and regorafenib is 6.9 [2.4 to 7.0+] months and PD-L1-negative tumors) currently under investigation. The recently published and, thus, pembrolizumab was approved by the Food phase Ib REGONIVO trial found encouraging antitu- and Drug Administration (FDA) as a third and fur- mor activity in patients with gastric cancer in a third ther line therapy in CPS ≥ 1 patients with metastatic and further line setting (median PFS 5.6 months), gastroesophageal adenocarcinoma [5, 7]. However, thus, warranting additional investigations in larger by July 2021, the company voluntarily withdrew this cohorts [14]. Furthermore, ramucirumab was investi- accelerated approval indication. gated in combination with paclitaxel plus nivolumab However, the CheckMate 649 trial found that pa- and showed promising anti-tumor activity (me- tients with CPS≥ 5 showed the most significant ben- dian OS 13.8 months [95% CI 8.0–19.5 months] in efit (overall survival hazard ratio [OS HR] 0.71, 98.4% CPS ≥ 1 patients) [15]. Another approach evaluated CI 0.59–0.86; p < 0.0001) when adding nivolumab to the combination treatment of lenvatinib, a multiki- standard chemotherapy. Interestingly, this combina- nase inhibitor of VEGF receptors and other receptor tion was approved by the FDA in 2021 regardless of tyrosine kinases, with pembrolizumab and a response PD-L1 expression status and is currently under inves- rate of 69% (95% CI 49–85) was demonstrated [16]. tigation by the European Medicines Agency (EMA) [8, There are several ongoing trials evaluating the 9]. combination of the checkpoint inhibitor durvalumab Other important and already established biomark- with targeted therapies, e.g., with cabozantinib in ers that indicate response to checkpoint inhibition are CAMILLA trial and with raumucirumab in a phase Ib MSI, which is surmised to be high (MSI-H) in around trial [17, 18]. 4–5% of all advanced Western gastric tumor cases, and tumor mutational burden (TMB) [10]. Thus, the Combination of anti-PD-1/PD-L1 drugs with other checkpoint inhibitors FDA approved immunotherapy with pembrolizumab for the treatment of unresectable or metastatic MSI-H Although the concept of neutralizing immunosup- and TMB-H solid tumors that have progressed fol- pression at the tumor site by combining immunother- lowing prior treatment independent of tumor location apeutic approaches, the combination of anti-PD- and which have no satisfactory alternative treatment 1/PD-L1 drugs with other checkpoint inhibitors, so far options (“tissue agnostic approvals”) [11, 12]. no practice changing trials can be reported in gastric These findings underline the importance of patient cancer. However, several studies suggest promising selection and changed the face of gastric cancer treat- new combination strategies including combination ment. with cytotoxic T lymphocyte antigen-4 (CTLA-4; drug: ipilimumab; trials: CheckMate-032 [19], Moonlight trial [20]), lymphocyte activation gene-3 (LAG3; drug: Strategies to overcome the immune cold tumors relatlimab; trials: FRACTION [21], REACTION), T cell As mentioned above, a major issue concerning im- immunoglobulin and mucin-domain containing-3 munotherapy is that only a subset of patients achieve (TIM-3), T cell immunoglobulin and ITIM domain responses. Thus, the identification of underlying (TIGIT), V-domain Ig suppressor of T cell activation mechanisms for primary resistance to immunother- (VISTA), OX40 (CD134) and B and T cell lymphocyte apy are of major concern [13]. Recent studies charac- attenuator (BTLA) [22, 23]. terized these immunologically “cold” tumors by a lack of infiltrating T cells in the tumor microenvironment. Consequentially, tumor cells stay unrecognized by the immune system and, thus, do not respond to checkpoint inhibition. K Innovative strategies in advanced gastric cancer 31 short review tient outcome with these new treatment options, it Targeted therapy for gastroesophageal tumors is of highest importance to define these subgroups more accurately. The evaluation and implementation Targeting HER2 beyond trastuzumab: of new biomarkers seems to be the key for adequate In the field of HER2-positive (human epidermal patient selection leading to high treatment efficacy. In growth factor receptor 2) gastroesophageal cancer, case of immunotherapy, this selection is mainly based a recently published phase II trial evaluating first- on PD-L1 expression, MSI status and, more recently, line pembrolizumab and trastuzumab in combina- on TMB. However, looking at response rates it is ev- tion with chemotherapy showed promising response ident that despite these biomarkers there is still sig- rates and, thus, was the impulse for a randomized nificant percentage of patients who do not respond phase 3 clinical trial (KEYNOTE-811) [24]. First re- to treatment. Thus, underlining the fact that further sults of the KEYNOTE-811 trial found that the overall strategies should be implemented to develop predic- response rate (ORR) was 74% (95% CI 66–82) in the tive markers. pembrolizumab arm and 52% (95% CI 43–61) in the Another critical issue is to overcome so called “cold” placebo arm (one-sided p-value < 0.0001) and, thus, tumors, thereby improving treatment response. New the combination of pembrolizumab, trastuzumab combination strategies including combinations of the and chemotherapy (ToGA regimen) has been recently inhibition of the PD-(L)1 axis with chemotherapy, ra- approved by the FDA for the first-line treatment of diation therapy, other immune checkpoint inhibitors HER2-positive advanced gastric cancer [25]. and targeted therapies are underway into clinical Another new approach that was recently approved practice to overcome this treatment resistance. by the FDA for HER2-positive patients who have re- Finally, critical issues to consider for new drug ap- ceived a prior trastuzumab-based regimen is the drug provals are tolerability, impact on quality of life, and trastuzumab deruxtecan, a novel antibody-drug con- financial considerations. Future studies need to in- jugate [26]. The drug was evaluated by the phase II clude these major considerations in clinical trial de- DESTINY-Gastric01 trial in a third and further line sign in order to achieve more adequate implementa- setting in comparison to chemotherapy and showed tion of new therapeutic agents into real-life cohorts a significantly longer median OS (12.5 vs. 8.4 months; and guidelines. HR 0.59; 95% CI 0.39–0.88; p = 0.01) [27]. In conclusion, recently published studies led to a paradigm change of advanced gastric cancer treat- ment and several new innovative approaches are Attempts for novel targets underway to further improve the management of Claudin 18.2 (CLDN18.2) protein is physiologically patient subgroups. confined to gastric mucosa tight junctions and is exposed on the cancer cell surface upon malignant Take home message transformation. In the phase II FAST trial, patients with advanced New innovative targets and drugs are underway to im- gastric cancer and a CLDN18.2 expression in ≥ 70% of prove the care of patients with advanced gastric cancer. tumor cells were treated with the anti-Claudin 18.2 an- This mini-review highlights promising new treatment tibody zolbetuximab in combination with chemother- approaches and their clinical relevance. apy. Zolbetuximab generated prolonged OS rates in this patient subgroup (HR 0.55; 95% CI 0.39–0.77; Funding The authors gratefully acknowledge Medical Univer- p < 0.0005) [28]. Based on this data, two phase III tri- sity of Vienna’s core funding to the Department of Medicine I. als have been initiated, which will reveal first results Funding Open access funding provided by Medical University within the next few years. of Vienna. Fibroblast growth factor receptor 2b (FGFR2b) is another very interesting target, which was tested in Conflict of interest H.C. Puhr has received travel support the FIGHT study. The anti-FGFR2b antibody bemar- from Eli Lilly, MSD, Novartis, Pfizer and Roche. A. Ilhan- ituzumab in combination with chemotherapy as first- Mutlu participated in advisory boards from MSD, BMS and Servier, received lecture honoraria from Eli Lilly, MSD, BMS line revealed very promising results in FGFR2b-posi- and Servier, is the local PI for clinical trials sponsored by BMS tive patients, which led to the designation of bemar- andRoche andreceivedtravel support from BMS, Roche, Eli ituzumab as a breakthrough therapy by the FDA (OS Lilly and Daiichi Sankyo. HR 0.66; 95% CI 0.39–1.12) [29, 30]. Open Access This article is licensed under a Creative Com- mons Attribution 4.0 International License, which permits Discussion use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit Despite the improvement of modern cancer medicine to the original author(s) and the source, provide a link to including immunotherapies and targeted therapies, the Creative Commons licence, and indicate if changes were new therapeutic approaches seem to be efficiently in made. The images or other third party material in this article only specific subgroups of patients. To improve pa- are included in the article’s Creative Commons licence, unless 32 Innovative strategies in advanced gastric cancer K short review indicated otherwise in a credit line to the material. 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FAST: a randomised phase II study of 7 For latest news from interna- zolbetuximab (IMAB362) plus EOX versus EOX alone for tional oncology congresses see: first-line treatment of advanced CLDN18.2-positive gas- http://www.springermedizin.at/ tric and gastro-oesophageal adenocarcinoma. Ann Oncol. memo-inoncology 2021;32(5):609–19. 29. Catenacci DVT, Kang Y-K, Saeed A, Yamaguchi K, Qin S, Lee K-W, et al. FIGHT: a randomized, double-blind, 34 Innovative strategies in advanced gastric cancer K

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memo - Magazine of European Medical OncologySpringer Journals

Published: Feb 1, 2022

Keywords: oncology; medicine/public health, general

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