In the last year, the US Food and Drug Administration (FDA) has approved several immunotherapies for the treatment of patients with gastric and gastroesophageal junction (GEJ) adenocarcinoma, which are rapidly changing the treatment paradigm for this disease. In the frontline setting for patients with metastatic disease, this includes Merck’s Keytruda (pembrolizumab) in combination with trastuzumab and chemotherapy for patients with human epidermal growth factor receptor 2 (HER2) positive tumours, and Bristol-Myers Squibb’s (BMS) Opdivo (nivolumab) in combination with chemotherapy for patients with HER2-negative disease. Keytruda in combination with chemotherapy has also been approved specifically for GEJ patients. In the second line, HER2-positive patients in the US and Japan now also have the option of receiving Daiichi Sankyo’s/AstraZeneca’s antibody-drug conjugate Enhertu (trastuzumab deruxtecan). Enhertu’s approval has begun to alter the standard of care in the second-line setting in these markets.

Key opinion leaders interviewed by GlobalData have identified the previous lack of options for patients with advanced disease as the most pressing unmet need, which will be partially met by these approvals. Other checkpoint inhibitor combinations are also expected to launch in the next ten years, providing additional options for patients. These include Zymework’s bispecific antibody targeting HER2, zanidatimab, in combination with BeiGene’s programmed cell death protein 1 (PD-1) inhibitor tislelizumab, and Macrogenics/Zai Labs’s HER2 antibody Margenza (margetuximab) in combination with either the bispecific dual-affinity re-targeting (DART) tebotelimab, which targets PD-1 and (lymphocyte activating 3) LAG-3, or Incyte’s PD-1 inhibitor retifanlimab. The zanidatimab combination with tislelizumab and chemotherapy appears to be particularly exciting, with data from a Phase II study of zanidatimab in combination with chemotherapy in the first-line setting showing this agent elicited a 75% objective response rate in HER2-positive patients. The combination with tislelizumab is expected to compete strongly with Keytruda in combination with trastuzumab and chemotherapy in the first-line setting.

Only around 20% of gastric and GEJ patients, however, are classified as HER2-positive, and this status can change as patients progress through lines of therapy, with some patients subsequently presenting as HER2-negative. In addition, a subset of patients either are ineligible or simply fail to respond to immunotherapies. As such, novel drugs are also needed beyond checkpoint inhibitors. Several pipeline agents are in the later stages of development and could be highly impactful for patients with specific mutations. These include Amgen’s anti-fibroblast growth factor receptor 2 (FGFR2) antibody bemarituzumab for patients with more than 70% FGFR2 amplification, and Astellas Pharma’s anti-claudin 18.2 antibody zolbetuximab. Studies have estimated that up to 30% of patients may be eligible for each of these therapies, and Phase II trials for both have shown encouraging results.

The raft of recent approvals has been much needed in this disease setting, where typical survival for patients with advanced disease is dismal. But while immunotherapies have transformed outcomes in other indications, their efficacy in patients with gastric and GEJ cancers has been less dramatic, as illustrated by the high-profile failure of several trials featuring immune checkpoint inhibitors. As a result, while there are now undoubtedly major changes occurring in the treatment of patients with advanced gastric and GEJ cancers, more needs to be done to develop novel therapies that can target specific biomarkers, as well as reduce the number of patients progressing to advanced disease.