Ramucirumab, avelumab, and paclitaxel (RAP) as second-line treatment in gastro-esophageal adenocarcinoma, a phase II trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO).

Abstract

4051 Background: Combination of ramucirumab and paclitaxel is a standard second line therapy in gastro-esophageal adenocarcinoma (GEAC) (RAINBOW trial, Wilke et al., 2014). We integrated the PD-L1 inhibitor avelumab into this regimen aiming for synergistic efficacy. Methods: In a multicenter phase II trial (NCT03966118) pts with metastatic GEAC, after progression on platinum / fluoropyrimidine based palliative 1st-line, ECOG 0 or 1, were treated with ramucirumab 8 mg/kg (d1,15) + avelumab 10 mg/kg (d1,15) + paclitaxel 80 mg/m² (d1,8,15), q4w. Sample size calculation was based on a Simon 2-stage design with overall survival rate at 6 months as the primary endpoint (H0≤50%, H1≥65%). Results: 60 pts were enrolled, 59 were evaluable (ITT), median age 64.0 yrs (range 18-81), male 80%, female 20%, primary gastric 52%, GEJ 48%, histology intestinal 59.6%, diffuse 24.6%, mixed 15.8%. Previous treatment with platin/fluoropyrimidine 100%, previous taxanes 66%. At central pathology MSI-H 7%, PD-L1 CPS < 5: 54%; ≥5: 41%, NA 5%. Response by investigator (%) CR 3.4, PR 27.1, SD 49.2, PD 20.3; DCR 79.7%, independent radiology review will be presented. DOR: 8.2 mo (95%CI 6.7-9.7), PFS 5.4 mo (95%CI 4.2-6.6); 6-mo OS rate 71.2%; 12-mo OS rate 45.8%; med OS (ITT) 10.6 mo (95%CI 8.2-13.1), med OS CPS < 5: 9.4 mo (95%CI 7.2-11.2), CPS ≥5: 14.0 mo (95%CI 12.8-15.3), translational data (ct-DNA) will be analysed. Treatment was generally well tolerated and no unexpected toxicities occurred: Grade 3/4 AE above 5%: anemia 5%, leucopenia 12%, neutropenia 22%, diarrhea 5%, pain 10%, peripheral neuropathy 10%, hypertension 5%, non-neutropenic infection 5% including 1 CTC grade 5 due to an esophago-tracheal fistula. Conclusions: The med OS of 10.6 mo (in a population of 66% pretreated with taxanes) compares very favourably to 8.6 mo in the Western population RAINBOW trial (Shitara et al., 2016) and 7.6 mo in the RAMIRIS trial (Lorenzen et al., 2022). PD-L1 CPS≥ 5 seems to predict for an even better efficacy (med OS 14.0 mo). Second-line RAP is a very efficacious and well tolerated combination. Clinical trial information: NCT03966118.

Predictive Biomarkers for Immunotherapy in Gastric Cancer: Current Status and Emerging Prospects

“…Furthermore, a phase II trial conducted by the Arbeitsgemeinschaft Internistische Onkologie (AIO) evaluated the effectiveness of combining avelumab, ramucirumab, and paclitaxel as second-line therapy for GEJC patients. The trial findings indicated a median OS of 9.4 months for CPS < 5 patients compared to 14.0 months for CPS ≥ 5 patients, underscoring the prognostic value of CPS in predicting the response to immunotherapy in GC patients [24]. In the MAHOGANY study, an exploration was conducted involving the amalgamation of the anti-HER2 monoclonal antibody (margetuximab) and the anti-PD-1 monoclonal antibody (pembrolizumab) in individuals afflicted by trastuzumab-resistant HER2-positive gastro-esophageal adenocarcinoma.…”

Updated Immunotherapy for Gastric Cancer

“…Furthermore, data from the ATTRACTION-2 trial of a Japanese intention to treat population indicated better clinical effects of nivolumab with prior ramucirumab use [ 112 ]. Most recently, avelumab with paclitaxel plus ramucirumab in the phase II RAP trial showed better outcomes compared with a Western population in the RAINBOW trial (median OS, 10.6 vs. 8.6 months) [ 113 ]. Other combinations of immune checkpoint inhibitors with VEGF-targeted therapy have been reported.…”