Plethora of Clinical Trials Explore Gastric Cancer Treatments

The National Institutes of Health estimates that gastric cancer will account for 1.8% of all cancer deaths in the United States in 2020.¹

The most recent global statistics from 2018 show that the disease ranked fifth in cancer incidence rates (Figure 1), representing more than 1 million new cases diagnosed in 2018.²

Pathogenesis and Epidemiology

Gastric cancer occurs when cells in the lining of the stomach proliferate and grow abnormally, causing tumor formation. Over time, the tumor can invade surrounding tissues, leading to metastases in other organs of the body. The most common form of gastric cancer is adenocarcinoma.³ Risk factors and statistics are shown in Figure 2.^1,4 Trends in mortality rates associated with gastric cancer are declining by 32%, leading to an overall 5-year relative survival and a 69% 5-year relative survival for localized gastric cancer.¹

Diagnosis and Staging

Upper endoscopy is typically used for the primary diagnosis of gastric cancer along with other modalities to determine staging, such as computed tomography, hematologic testing, laparoscopic surgery, positron emission tomography, tumor biopsy, and ultrasound.³ Staging is based on the tumor, nodes, and metastasis systems. Additional testing for human epithelial growth factor receptor- 2 (HER2) expression and programmed death-ligand 1 (PD-L1) expression, as well as microsatellite instability or mismatch repair genomic testing, can help determine eligibility for targeted therapy or immunotherapy. The National Comprehensive Cancer Network (NCCN) does not offer screening recommendations for patients not diagnosed with gastric cancer.⁵

Treatment

Surgery remains the only known curative treatment for gastric cancer.⁴ In patients who are considered medically fit with a resectable tumor, surgery is the first-line treatment with optional subsequent chemoradiation. For patients with resectable gastric cancer, the NCCN recommends a fluoropyrimidine-based doublet with either cisplatin or oxaliplatin, with the latter generally expressing less toxicity. For patients with metastatic, recurrent, or unresectable gastric cancer, chemotherapy is the primary treatment option, with the same recommended chemotherapy regimens as resectable gastric cancer.⁵

Significant attention has been focused on the newer targeted immunotherapies for gastric cancer: ramucirumab, pembrolizumab, and trastuzumab. Pharmacologic options for patients whose cancer expresses certain traits, such as overexpression of HER2, include trastuzumab, whereas microsatellite instability-high or deficient mismatch repair solid tumors can be targeted by pembrolizumab. Ramucirumab is a vascular endothelial growth factor receptor-2 antibody that targets angiogenesis and is a potential adjunct to the preferred chemotherapy regimens, but efficacy data are lacking.⁵ The RAINFALL study (NCT02314117) was conducted to determine the benefit of adding ramucirumab to firstline chemotherapy regimens in patients with metastatic gastric or gastroesophageal junction adenocarcinoma. The results of this trial were not as promising as investigators had hoped, showing no change in overall survival compared with first-line chemotherapy regimens alone.⁶ The results of a retrospective observational study conducted in Japan suggest that ramucirumab is more of a third-line option or “salvage therapy.”⁷ Ongoing clinical trials are trying to further assess the place in therapy of ramucirumab, such as the RAMSES study in Germany that is comparing the effects of 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) alone and in combination with ramucirumab in patients who are HER2 negative with locally advanced esophagogastric adenocarcinoma.⁸

New Treatment

The results of a recent study offered promise with the use of dasatinib, a tyrosine kinase inhibitor, as a possible treatment option for gastric cancer. This study identified several kinases that are prominent in patients with gastric cancer, specifically ones that dasatinib is known to inhibit, warranting further studies assessing the drug’s efficacy in vivo.⁹

The EPOC 1706 phase 2 study (NCT03609359) looked at lenvatinib plus pembrolizumab in patients with recurrent or metastatic adenocarcinoma. In this study, 20 of 29 patients showed an objective response with no serious or grade 4 adverse events.¹⁰ These results show potential for future research.

Many ongoing clinical trials for the treatment of gastric cancer are focusing on newer immunotherapy options, such as JAVELIN Gastric 100 (NCT02625610) in Germany and the DANTE study (NCT03421288) in Germany and Switzerland. JAVELIN Gastric 100 intended to determine the superiority of avelumab, a PD-L1 antibody, against the first-line treatment of a fluoropyrimidine-based doublet with oxaliplatin, in patients with unresectable, locally advanced, or metastatic adenocarcinoma.¹¹ DANTE is comparing FLOT in combination with atezolizumab to FLOT alone in the same setting.¹²

Conclusion

There is an abundance of ongoing clinical trials exploring a variety of pharmacologic agents for treating gastric cancer. Pharmacists play an integral role in collaborating with physicians to manage gastric cancer therapy. Through this multidisciplinary alliance, pharmacists enhance the prospects for favorable outcomes while reducing toxicities for patients.

Jerry A. Barbee Jr, PharmD, BCPS, CPh, and Glenn Schulman, PharmD, MS, BCPS, BCACP, BCGP, BCIDP, are clinical pharmacists in Pensacola, Florida.Taylor A. VandenBerg is a PharmD candidate at the University of Florida College of Pharmacy in Gainesville.

REFERENCES

• Cancer stat facts: stomach cancer. National Cancer Institute. Accessed June 28, 2020. https://seer.cancer.gov/statfacts/html/stomach.html
• Worldwide cancer data. World Cancer Research Fund. Accessed June 28, 2020. https://www.wcrf.org/dietandcancer/cancer-trends/worldwide-cancer-data
• Stomach cancer: risk factors. Cancer.Net. January 2019. Accessed July 2, 2020. https://www.cancer.net/cancer-types/stomach-cancer/risk-factors
• All about gastric cancer. OncoLink. Updated April 26, 2019. Accessed June 28, 2020. https://www.oncolink.org/cancers/gastrointestinal/gastric-cancer/all-about-gastric-cancer
• Ajani JA, D’Amico TA, Almhanna K, et al. Gastric cancer, version 3.2016, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2016;14(10):1286-1312. doi:10.6004/jnccn.2016.0137
• Fuchs CS, Shitara K, Di Bartolomeo M, et al; RAINFALL Study Group. Ramucirumab with cisplatin and fluoropyrimidine as first-line therapy in patients with metastatic gastric or junctional adenocarcinoma (RAINFALL): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(3):420-435. doi:10.1016/S1470-2045(18)30791-5
• Kawai S, Fukuda N, Yamamoto S, et al. Retrospective observational study of salvage line ramucirumab monotherapy for patients with advanced gastric cancer. BMC Cancer. 2020;20(1):338. doi:10.1186/s12885-020-06865-7
• FLOT vs FLOT/ramucirumab for perioperative therapy of gastric or GEJ cancer (RAMSES) (RAMSES/FLOT7). ClinicalTrials.gov. Updated April 22, 2020. Accessed July 2, 2020. https://clinicaltrials.gov/ct2/show/NCT02661971
• Montenegro RC, Howarth A, Ceroni A, et al. Identification of molecular targets for the targeted treatment of gastric cancer using dasatinib. Oncotarget. 2020;11(5):535-549. doi:10.18632/oncotarget.27462
• Kawazoe A, Fukuoka S, Nakamura Y, et al. Lenvatinib plus pembrolizumab in patients with advanced gastric cancer in the first-line or second-line setting (EPOC1706): an open-label, single-arm, phase 2 trial. Lancet Oncol. 2020;21(8):1507-1065. doi:10.1016/S1470-2045(20)30271-0
• Avelumab in first-line maintenance gastric cancer (JAVELIN Gastric 100). ClinicalTrials.gov. Updated May 7, 2020. Accessed July 2, 2020. https://clinicaltrials.gov/ct2/show/study/NCT02625610
• Phase II study of atezolizumab + FLOT vs FLOT alone in patients with gastric cancer and GEJ (DANTE). ClinicalTrials.gov. Updated March 24, 2020. Accessed July 2, 2020. https://clinicaltrials.gov/ct2/show/study/NCT03421288