Disease Overview
Stomach or gastric cancer (GC) refers to any cancer arising in the lining of the stomach. The vast majority (95%) of these cancers are adenocarcinomas, and can be further grouped by anatomic origin. The clearest etiological distinction exists between adenocarcinomas of the gastric cardia (the anterior edge of the stomach surrounding the entry point of the esophagus), and those arising in the other anatomical subsites of the stomach - the fundus, body, pylorus, and the antrum. In most cases, gastric adenocarcinomas will begin in the muscularis mucosae and submucosa, then invading deeper lamina of the gastric wall.
Latest Key Takeaways
Stomach or gastric cancer (GC) refers to any cancer arising in the lining of the stomach. The vast majority (95%) of these cancers are adenocarcinomas, and can be further grouped by anatomic origin. The clearest etiological distinction exists between adenocarcinomas of the gastric cardia (the anterior edge of the stomach surrounding the entry point of the esophagus), and those arising in the other anatomical subsites of the stomach - the fundus, body, pylorus, and the antrum. In most cases, gastric adenocarcinomas will begin in the muscularis mucosae and submucosa, then invading deeper lamina of the gastric wall.
Latest Key Takeaways
- The publisher estimates that in 2018, there were 1.0 million incident cases of gastric cancer worldwide in adults aged 20 years and older, and forecasts that number to increase to 1.1 million incident cases by 2027.
- The majority of gastric cancer diagnoses (66.1%) worldwide are in males, ranging from 54.3% to 68.3% across regions.
- A major etiological factor of gastric cancer, especially in poorer countries, is Helicobacter pylori infection of the stomach wall. With H. pylori infections falling worldwide, the bacterium’s decreasing prevalence may have an effect on the future number of case diagnoses.
- Approximately 75% of all gastric cancer diagnoses are in Asia. Particularly high incidence rates in East Asia make Japan a very large market for gastric cancer medications.
- Early-stage gastric cancer is often asymptomatic, meaning that most diagnoses are only made in advanced disease. An exception to this trend is Japan, where proactive screening often discovers tumors in a locoregional setting.
- Due to the lack of curative treatments in advanced disease, the prognosis of gastric cancer is rather poor in most countries, with five-year survival rates standing at 20% worldwide. Even in Japan, where screening often catches early-stage tumors, relatively high rates of recurrence keep this rate at 71.5%.
- HER2, PD-1, and receptor tyrosine kinases (RTKs) are the most common molecular targets for both branded and pipeline drugs. However, the treatment landscape remains dominated by non-targeted chemotherapies, with most targeted agents confined to one or two treatment settings, where they are typically administered alongside chemotherapy.
- Despite a failed expansion to front-line therapy, the vascular endothelial growth factor receptor (VEGFR) antagonist Cyramza has until recently been the most successful targeted therapy in gastric cancer, having become the standard of care in second-line disease.
- Immune checkpoint inhibitors (ICIs) - specifically the PD-1 antagonists Opdivo and Keytruda - are in development in multiple treatment settings and have recently been made available for first-line disease following the success of KEYNOTE-811 and CheckMate 649.
- No targeted therapies exist for locoregional disease, although Opdivo and Keytruda are in ongoing Phase III trials for this setting.
- Trastuzumab biosimilars are now available, leading to a sharp decline in the market share of Herceptin.
- Set to succeed Herceptin, next-generation HER2 antibodies Margenza and Enhertu (an antibody-drug conjugate) are now expanding into gastric cancer, the latter of which has recently launched in Japan and the US.
- Though most pipeline drugs in late-stage development involve the classic molecular targets of PD-1/PD-L1 and RTKs, zolbetuximab is exploring the entirely novel target of claudin-18. Additionally, the pipeline ICI tebotelimab is a dual-affinity re-targeting antibody (DART) that is bispecific to LAG3 as well as PD-1.
- Until recently, no targeted agents were available for front-line HER2-negative gastric cancer (approximately 80% of cases), making it one of the largest areas of unmet need in the disease space. As a result, multiple drugs - including Opdivo, Yervoy, Keytruda, tislelizumab, bemarituzumab, and zolbetuximab - are now in late-stage development for this setting.
- The Opdivo-chemotherapy combination arm of CheckMate 649 became the first and thus far the only targeted therapy to show a benefit in HER2-negative first-line disease, where it is now approved in the US. CheckMate 649 also features a dual blockade arm of Yervoy and Opdivo. This combination has not produced any results yet but is known from some other solid tumor indications to be highly active and may become a standard of care if found to be similarly effective in gastric cancer.
- Underwhelming benefits seen in multiple Phase III trials of PD-1 inhibitor monotherapies (including in KEYNOTE-062 and KEYNOTE-061 for Keytruda and JAVELIN Gastric 100 for Bavencio) have stymied the launch of other single-agent checkpoint inhibitors in earlier lines of therapy, meaning that CheckMate 649 will be largely unchallenged for some time.
- Given the inconclusive results of KEYNOTE-062, Keytruda’s approval in first-line HER2-negative disease will likely hinge on KEYNOTE-859, which is evaluating Keytruda combined with chemotherapy and is slated for completion in 2023. KEYNOTE-062 also served as a confirmatory trial for Keytruda’s accelerated approval in third-line disease. This resulted in the FDA Oncologic Drugs Advisory Committee (ODAC) rescinding this approval (albeit in a staggered manner, so as to allow for sequencing of patients who were treated prior to the approval of Opdivo and thus were not able to receive a checkpoint inhibitor in the first line).
- By contrast, KEYNOTE-811 yielded some better news for Keytruda in front-line gastric cancer, where a combination of the PD-1 antibody with trastuzumab showed promising results in first-line HER2-positive disease and was subsequently approved by the FDA. Though this is a smaller market than the HER2-negative population treated with Opdivo, it nonetheless presents an opportunity to improve the first-line standard of care for gastric tumors overexpressing HER2, which has remained entirely unchanged for over a decade since the initial approval of trastuzumab.
- Two registration-enabling trials, DESTINY-Gastric04 and MOUNTAINEER-02 for Enhertu and Tukysa, respectively, are now underway following the success of Enhertu in heavily pretreated disease. Similar to the DESTINY-Gastric01 trial that produced Enhertu’s first approval in gastric cancer, these regimens are intended for HER2-positive tumors previously treated with trastuzumab, meaning patients may be able to receive two consecutive rounds of anti-HER2 interventions.
Table of Contents
OVERVIEW
DISEASE BACKGROUND
TREATMENT
EPIDEMIOLOGY
KEY REGULATORY EVENTS
LICENSING AND ASSET ACQUISITION DEALS
CLINICAL TRIAL LANDSCAPE
FUTURE TRENDS
RECENT EVENTS AND ANALYST OPINION
LIST OF FIGURES
LIST OF TABLES
