Pronounced clinical benefit of FOLFIRI plus ramucirumab as second-line therapy for docetaxel pre-treated patients with advanced gastro-oesophageal adenocarcinoma
The phase II RAMIRIS trial evaluated whether a combination of FOLFIRI and ramucirumab would delay the disease progression of patients with advanced gastric cancer who failed one prior line of palliative chemotherapy. To this end, FOLFIRI plus ramucirumab was compared to paclitaxel plus ramucirumab, a frequently used second-line treatment in this setting. With a response rate of 25% and a median progression-free survival (PFS) of 4.6 months, the study demonstrated that mainly docetaxel pre-treated patients seem to derive a pronounced benefit from the FOLFIRI-ramucirumab combination. If these results can be confirmed in the ongoing phase III study, they will most likely lead to a change in treatment guidelines, recommending FOLFIRI-ramucirumab for taxane-pre-treated patients with advanced gastro-oesophageal adenocarcinoma.
Ramucirumab as monotherapy or in combination with paclitaxel is a proven second-line option for advanced gastro-oesophageal adenocarcinoma (GEA). However, more and more patients are pre-treated with docetaxel in the perioperative or first-line setting and for those patients, the benefit of a combination of ramucirumab and paclitaxel is unclear. These patients are likely to benefit more from another, non-cross resistant chemotherapy backbone, such as FOLFIRI. In this respect, the phase II RAMIRIS trial evaluated the addition of ramucirumab to FOLFIRI as a second-line treatment option for patients with advanced GEA.
This randomized, multicentre phase II trial enrolled 111 patients with GEA who progressed during or within six months after their last dose of first-line treatment with a fluoropyrimidine/platinum-containing regimen, with or without anthracycline or docetaxel. All patients had an ECOG performance status ≤ 1. Patients were randomised (2:1) to either FOLFIRI plus ramucirumab (8mg/kg) every two weeks (arm A) or paclitaxel (80 mg/m2 on days 1, 8 and 15 of each 28-day cycle) plus ramucirumab (8 mg/kg) every two weeks (arm B). Stratification was done based on previous docetaxel-containing therapy (yes versus no) and time of progression during or after end of first-line therapy (≤ 3 months versus > 3 months).
The RAMIRIS phase II trial enrolled 111 patients with a median age of 61 years. Of the enrolled patients, 65% had received prior therapy with docetaxel. Most patients were male (67%), 55% had an ECOG performance status of 1 and 93% presented with relevant comorbidities. In total, 110 patients were analysed within the intention to treat population (ITT, 72 patients in the FOLFIRI-ramucirumab arm and 38 patients in the paclitaxel-ramucirumab arm).
In the ITT population, there was no significant difference in median overall survival (OS) between both study arms, with a median OS of 6.8 months for patients in the FOLFIRI arm and 7.6 months for patients in the paclitaxel arm (p= 0.89). The median PFS in the ITT population was 3.9 months for patients treated with FOLFIRI plus ramucirumab and 3.6 months for patients in the paclitaxel-ramucirumab arm (p= 0.14). Interestingly, the clinical benefit of the FOLFIRI-based regimen seemed to be more pronounced in patients with prior docetaxel use (72/110). In this cohort, the median PFS was 4.6 months for patients treated with FOLFIRI-ramucirumab, which was more than twice as long as the 2.1 months median PFS observed in patients treated with paclitaxel-ramucirumab (p = 0.007). In docetaxel pre-treated patients, the median OS was 7.5 and. 6.6 months for FOLFIRI-ramucirumab and paclitaxel-ramucirumab, respectively (p = 0.47).
In the ITT population, 3% of the patients in both the FOLFIRI and paclitaxel-arm obtained a complete response. In the FOLFIRI-arm, 19% of patients had a partial response and 39% had stable disease, as compared to 8% and 42% for patients treated with paclitaxel-ramucirumab. As such, the objective response (ORR) and disease control rates (DCR) were 22% and 61% with FOLFIRI-ramucirumab and 11% and 58% with paclitaxel-ramucirumab, respectively. In total, 72 patients assessable for response were pre-treated with docetaxel. In these patients, the ORR was 25% for patients in the FOLFIRI-arm and 8% for patients in the paclitaxel arm. DCR was 65% and 37% for patients treated with FOLFIRI-ramucirumab and paclitaxel-ramucirumab, respectively. The tolerability of both therapies was similar.
The RAMIRIS trial demonstrates the feasibility of combining FOLFIRI with ramucirumab as a second-line treatment regimen for patients with advanced GEA. With a response rate of 25% and a median PFS of 4.6 months, especially docetaxel pre-treated patients derived a pronounced benefit from the FOLFIRI-ramucirumab combination. These results strongly confirm the scientific rationale for the RAMIRIS phase III trial, which is currently ongoing. If these results can be confirmed in the phase III setting, they will likely lead to a change in treatment guidelines, recommending FOLFIRI-ramucirumab for taxane-pre-treated patients with advanced or metastatic GEA.
Lorenzen S, Thuss-Patience PC, Pauligk C, et al. FOLFIRI plus ramucirumab versus paclitaxel plus ramucirumab as second-line therapy for patients with advanced or metastatic gastroesophageal adenocarcinoma with or without prior docetaxel: Results from the phase II RAMIRIS Study of the AIO. Presented at ASCO 2020; Abstract 4514.