Discussion
taxane-treated, neutropenia, fatigue, diarrhea, neurotoxicity
CPS, NEUTROPENIA
A high number of first-line taxane-treated patients with GEA relapse and require a second-line treatment. However, data is scarce, whether they benefit more from a re-exposure to a taxane-containing therapy, such as the standard regimen paclitaxel and ramucirumab, than from a taxane-free regimen. Therefore, the Phase III RAMIRIS trial will prospectively provide evidence on the safety and efficacy of second-line FOLFIRI‐Ram after progression on first-line platinum/5-FU in patients pretreated with a taxane.Clinical data shows, that second-line treatment with FOLFIRI-Ram is safe and shows no additional neurotoxicity. In the evaluation of the RAMIRIS phase II portion the feasibility of FOLFIRI-Ram could be confirmed: Grade 3 or higher AEs reported were mainly neutropenia (20% in die experimental group vs. 22% in the standard group), diarrhea (8% in die experimental group vs. 3% in the standard group fatigue) and.fatigue (6% in die experimental group, no fatigue was reported in the standard group). Serious treatment-related AEs were observed in 14% of patients in the experimental group and 23% of patients in the standard group [Studies show that the combination of FOLFIRI-Ram or Irinotecan and ramucirumab compares favorably to the standard regimen paclitaxel and ramucirumab [The study was designed and initiated in 2015. During this time, no patients with GEA were treated with immunotherapy as standard of care. Therefore, pre-treatment with immunotherapy was not explicitly mentioned in the eligibility criteria. Since immunotherapy is now standard of care for selected patients according to the CPS (combined positive score), patients pretreated with immunotherapy can be included. There are even signals from retrospective analysis that immunotherapy pretreated patients have an improved survival when subsequently treated with the combination of Ramucirumab plus chemotherapy versus chemotherapy alone due to a synergistic effect of immunotherapy and anti VEGF-receptor therapy [The outcomes of the retrospective study evaluating FOLFIRI-Ram as a second-line treatment for patients with GEA by Klempner et al. and the phase III trial investigating ramucirumab and irinotecan in third-line treatment or beyond for GEA patients by Sakai et al. resulted already in the inclusion of FOLFIRI-Ram or irinotecan-Ram in the NCCN Clinical Practice Guidelines as a second-line treatment for GEA [In summary published data strongly supports the rationale for expansion to phase III of the RAMIRIS trial. If the results can be confirmed they will affect the current treatment guidelines, recommending the combination therapy of FOLFIRI-Ram for taxane-pretreated patients with advanced GEA.