By Monique Biryiana

A phase III trial (RAINFALL) published in The Lancet Oncology reported that overall survival did not improve in patients with metastatic gastric or gastro-oesophageal junction adenocarcinoma; when they were administered ramucirumab with cisplatin and fluoropyrimidine chemotherapy.

Previous research suggests that VEGF and VEGFR-2-mediated signalling can contribute to increased angiogenesis, tumour aggressiveness and poorer survival in these patients.

Additionally, inhibiting the interaction between VEGF and VEGFR-2, through the use of a VEGFR-2-targeted antibody could sequester the receptor-mediated pathway to prevent angiogenesis. (Fuchs et al., 2016; Kim et al., 2009; Lieto et al., 2007; Maeda et al., 1996; Song, Gong and Wu, 2002)

As a VEGFR-2 antagonist, ramucirumab is able to inhibit the activation of this pathway in endothelial cells (Spratlin et al., 2010) and has demonstrated its efficacy when used as a second-line monotherapy, or in conjunction with paclitaxel. (Fuchs et al., 2014; Fuchs et al., 2019; Wilke et al., 2014)

However, outcomes remain poor among this patient population, which could be attributed to the lack of effective first-line therapies.

Therefore, this trial was designed to assess the safety and efficacy of this treatment regimen as a first-line therapy for patients with advanced gastric or gastro-oesophageal junction adenocarcinoma.

The RAINFALL study followed a randomised, placebo-controlled and double-blind design and took place in 126 centres in 20 countries. 

Between January 2015 and September 2016, a total of 645 eligible patients were randomly assigned (1:1) to receive both fluoropyrimidine and cisplastin in addition with either ramucirumab or a placebo.

Patients who received ramucirumab experienced a median progression-free survival (PFS) of 5.7 months, compared to placebo-treated patients, whose PFS was 5.4 months (HR = 0.753, 95% CI 0.0607-0.935, p=0.0106).

Unfortunately, these results could not be validated – as patient radiological data obtained from CT scans did not correspond with the investigator’s primary PFS assessment.

Furthermore, there was no detectable difference in the overall survival (OS) between patients treated with ramucirumab (OS = 11.2 months) and the placebo (OS = 10.7 months) (HR = 0.962, 95% CI 0.801-1.156, p=0.6757).

Patients administered with ramucirumab (50%) presented a higher frequency of serious adverse effects compared to patients in the placebo group (47%). This also included the occurrence of seven treatment-related deaths within each group.

Low-grade effects were also observed in both groups and included neutropenia, anaemia and hypertension.

Researchers concluded that a higher dose of ramucirumab (80 mg/m²) did not present a survival benefit to patients and should not be recommended as a first-line treatment.

Researchers also suggested that this negative outcome may be due to an imbalance between pro- and anti-angiogenic factors that deviate from the second-line setting; in which tumours may become more vulnerable.

Nonetheless, these results prompt further research into the use of ramucirumab as a first-line therapy.

In fact, the ARMANI study (NCT02934464) is currently underway and will attempt to determine the efficacy of ramucirumab and paclitaxel as a maintenance therapy in patients with advanced HER2-negative gastric or gastro-oesophageal junction cancer.

References:

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Kim, S., Shim, K., Jung, S., Yoo, K. and Lee, J. (2009). The Clinicopathological Significance of Tissue Levels of Hypoxia-Inducible Factor-1α and Vascular Endothelial Growth Factor in Gastric Cancer. Gut and Liver, 3(2), pp.88-94.
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Maeda, K., Chung, Y., Ogawa, Y., Kang, S., Ogawa, M., Sawada, T. and Sowa, M. (1996). Prognostic value of vascular endothelial growth factor expression in gastric carcinoma. Cancer, 77(5), pp.858-863.
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Spratlin, J., Cohen, R., Eadens, M., Gore, L., Camidge, D., Diab, S., Leong, S., O'Bryant, C., Chow, L., Serkova, N., Meropol, N., Lewis, N., Chiorean, E., Fox, F., Youssoufian, H., Rowinsky, E. and Eckhardt, S. (2010). Phase I Pharmacologic and Biologic Study of Ramucirumab (IMC-1121B), a Fully Human Immunoglobulin G1Monoclonal Antibody Targeting the Vascular Endothelial Growth Factor Receptor-2. Journal of Clinical Oncology, 28(5), pp.780-787.
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Wilke, H., Muro, K., Van Cutsem, E., Oh, S., Bodoky, G., Shimada, Y., Hironaka, S., Sugimoto, N., Lipatov, O., Kim, T., Cunningham, D., Rougier, P., Komatsu, Y., Ajani, J., Emig, M., Carlesi, R., Ferry, D., Chandrawansa, K., Schwartz, J. and Ohtsu, A. (2014). Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. The Lancet Oncology, 15(11), pp.1224-1235.
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