Emerging treatments

S-1 (tegafur, 5-chloro-2,4-dihydropyrimidine, and potassium oxonate)

S-1 (tegafur, 5-chloro-2,4-dihydropyrimidine, and potassium oxonate), a fourth-generation fluoropyrimidine, is prescribed as postoperative adjuvant chemotherapy for stage 2 or 3 gastric cancer in Asia and in some parts of Europe; it is not approved for use in the US.[26][79][80][81] One Cochrane review reported that, in patients with advanced gastric cancer, S-1 regimens improved overall survival modestly (<1 month) compared with fluorouracil-containing regimens.[57] Results from a subsequent phase 3 randomized controlled trial suggest that perioperative S-1 plus oxaliplatin (SOX) may have a role in the management of patients with locally advanced gastric cancer undergoing D2 gastrectomy.[82] S-1 is used in different doses and schedules in Asian and non-Asian populations.

Bemarituzumab

Bemarituzumab, a first-in-class monoclonal antibody against fibroblast growth factor receptor 2 (FGFR2b), is being investigated as a potential treatment for patients with FGFR2b overexpression and HER2-negative metastatic and locally advanced gastric and gastroesophageal adenocarcinoma. Bemarituzmab has been granted breakthrough therapy designation by the Food and Drug Administration (FDA) in combination with modified FOLFOX6 (fluoropyrimidine, leucovorin, and oxaliplatin) for this patient group, based on an FDA-approved companion diagnostic assay showing at least 10% of tumor cells overexpressing FGFR2b. The randomized phase 2 FIGHT trial showed that the combination of bemarituzumab plus modified FOLFOX6 resulted in numerically longer median progression-free survival and overall survival compared with modified FOLFOX6 alone.[83]​ Phase 3 trials are in progress.[84][85]

Cinrebafusp alfa

Cinrebafusp alfa, a fusion protein comprising a 4-1BB-targeting anticalin protein and a HER2-targeting antibody, has been granted orphan drug designation by the FDA for the treatment of HER2-high and HER2-low expressing gastric cancers.

Regorafenib

Regorafenib, an oral multikinase inhibitor, prolonged progression-free survival in one phase 2, randomized placebo-controlled trial of patients with refractory advanced gastric adenocarcinoma.[86] Post hoc analysis suggested that regorafenib improves deterioration-free survival without an excessively negative effect on quality of life.[87] INTEGRATE-IIa trial showed improved overall survival in participants treated with regorafenib compared with the placebo-treated group in patients with advanced gastroesophageal cancer.​[88][89]​​ One phase 3 trial (INTEGRATE-IIb) evaluating regorafenib plus nivolumab against standard chemotherapy in patients with refractory advanced gastroesophageal cancer is in progress.[89][90]

Margetuximab

Margetuximab is a monoclonal antibody that targets HER2-expressing tumors. It has been granted orphan drug designation by the FDA for the treatment of patients with gastric cancer. A phase 2/3 open-label trial assessing the effectiveness of margetuximab in combination with a checkpoint inhibitor (with or without chemotherapy), for patients with HER2-positive gastric cancer or gastroesophageal junction cancer, is ongoing.[91][92]

Evorpacept

Evorpacept is a CD47 checkpoint inhibitor. It has been granted orphan drug designation by the FDA for the treatment of patients with gastric cancer. In one phase 1 trial, 21.1% of patients with gastric cancer responded to treatment with evorpacept plus trastuzumab.[93] A phase 2/3 study is in progress.[94]

TJ-CD4B

TJ-CD4B is a bispecific antibody that binds to CLDN18.2-expressing cancer cells and the costimulatory molecule 4-1BB expressed on T cells. It has been granted orphan drug designation by the FDA for the treatment of patients with gastric cancer. A phase 1 trial is in progress.[95]

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