To further expand on the use of ramucirumab in GEA, the phase 2 HGCSG1603 study evaluated ramucimumab in combination with irinotecan in the second-line setting. This single-arm phase 2 study conducted in Japan enrolled 35 patients with GEA who progressed on a first-line regimen. The primary endpoint was PFS rate at 6 months. This study demonstrated a 26.5% PFS rate at 6 months. Median PFS was 4.2 months, and OS was 9.6 months. Although the study did not meet its pre-specified primary endpoint of a 39% PFS rate at 6 months, the secondary endpoints of OS and PFS were similar to historical references from the RAINBOW study. These results suggest that irinotecan and ramucirumab is an active combination in GEA and could be offered to patients who are not candidates for paclitaxel, for example those with significant neuropathy. The benefits of an irinotecan chemotherapy backbone in second-line therapy has been previously demonstrated in the phase 2 RAMIRIS study, which found clinically meaningful activity of a leucovorin calcium (calcium folinate), 5-fluorouracil, and irinotecan (FOLFIRI) and ramucirumab combination, as well as a decreased benefit from paclitaxel in patients with prior taxane exposure. 5 In summary, ramucirumab in combination with irinotecan-containing chemotherapy (either as a single agent or as part of FOLFIRI) is areasonable second-line treatment option for patients with advanced GEA, and this is already included in National Comprehensive Cancer Network guidelines.
Additional References
1. Janjigian YY, Shitara K, Moehler M, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): A randomised, open-label, phase 3 trial. Lancet. 2021;398:27-40. Doi: 10.1016/S0140-6736(21)00797-2
2. Sun JM, Shen L, Shah MA, et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): A randomised, placebo-controlled, phase 3 study. Lancet. 2021;398:759-771. Doi: 10.1016/S0140-6736(21)01234-4
3. Shitara K, Van Cutsem E, Bang YJ, et al. Efficacy and safety of pembrolizumab or pembrolizumab plus chemotherapy vs chemotherapy alone for patients with first-line, advanced gastric cancer: The KEYNOTE-062 phase 3 randomized clinical trial. JAMA Oncol. 2020;6:1571-1580. Doi: 10.1001/jamaoncol.2020.3370
4. Wilke H, Van Cutsem E, Cheul Oh S, et al. RAINBOW: A global, phase 3, randomized, double-blind study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in the treatment of metastatic gastric adenocarcinoma following disease progression on first-line platinum- and fluoropyrimidine-containing combination therapy: Results of a multiple Cox regression analysis adjusting for prognostic factors. J Clin Oncol. 2014;32(15 Suppl):4076. Doi: 10.1200/jco.2014.32.15_suppl.4076
5. Klempner SJ, Maron SB, Chase L, et al. Initial report of second-line FOLFIRi in combination with ramucirumab in advanced gastroesophageal adenocarcinomas: A multi-institutional retrospective analysis. Oncologist. 2019:24:475-482. Doi: 10.1634/theoncologist.2018-0602
Dr. Nataliya Uboha, MD