FOLFIRI-ramucirumab (FOLFIRI-Ram) versus ramucirumab-paclitaxel (Ram-Pac) in the second line (2L) for patients with advanced upper gastrointestinal (UGI) cancer: A real-world propensity-score matched analysis of survival.
Authors: Brown Timothy J. , Ruan Peifeng , Jones Amy Little , Verma Nilesh , Porembka Matthew R. , Badiyan Shahed , Wang Sam C. , Sanford Nina Niu , Kazmi Syed Mohammad Ali 
Published: January 2025

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Background:
The approach to 2L treatment of advanced UGI (gastric, esophageal, and gastroesophageal junction) cancers is guided primarily by the results of the RAINBOW trial, a global randomized phase III trial that demonstrated the benefit of Ram-Pac over paclitaxel. However, the onset of peripheral neuropathy limits its use in the palliative-intent setting. The RAMIRIS trial demonstrated the feasibility of 2L FOLFIRI-Ram compared to Ram-Pac, however it failed to meet the prespecified endpoint of ≥ 65% 6-month overall survival (OS). Despite this, FOLFIRI-Ram has emerged as an alternative 2L regimen and now endorsed in major society guidelines. Yet, comparative outcomes between FOLFIRI-Ram and Ram-Pac therapy in the real world are lacking.
Methods:
This study used the nationwide Flatiron Health electronic health record-derived deidentified database. During the study period (January 2011-June 2024), longitudinal patient-level data were derived from approximately 280 cancer clinics. Patients were eligible for inclusion if they had advanced unresectable or metastatic UGI cancer and received 2L treatment with either FOLFIRI-Ram or Ram-Pac. Demographics and lab values at the time of 2L initiation were extracted. Given anticipated imbalances in sample size, patients were matched 1:6 (FOLFIRI-Ram:Ram-Pac) for inclusion into the analytic dataset using a greedy match based on a logit model to predict propensity scores from key clinical and laboratory characteristics. The primary endpoint was OS from the start of 2L therapy, analyzed using the Kaplan-Meier method, log-rank test, and Cox proportional hazards model. A hybrid approach was used to construct a multivariate Cox model.
Results:
A total of 15,908 patients were included in the database, of whom 5189 received a 2L treatment. Of these, 631 patients received 2L Ram-Pac and 40 received 2L FOLFIRI-Ram. After matching, the final sample size was 240 patients who received Ram-Pac and 40 who received FOLFIRI-Ram. Baseline clinical and laboratory characteristics were well-balanced. The median OS from initiation of 2L FOLFIRI-Ram was 9.7 months (95% CI 6.9-12.3) and 7.6 months with 2L Ram-Pac (95% CI 6.3-9.2 months). The hazard ratio (HR) for death with FOLFIRI-Ram was 0.77 (95% CI 0.52-1.15, log-rank P=0.20) in reference to Ram-Pac. The adjusted HR death for FOLFIRI-Ram after adjustment for baseline albumin and white blood cell count was 0.87 (95% CI 0.58-1.30, p=0.49) in the final multivariate model.
Conclusions:
This real-world propensity-score matched analysis of patients with advanced UGI cancers receiving FOLFIRI-Ram or Ram-Pac supports the ongoing use of FOLFIRI-Ram in the 2L as an alternative to Ram-Pac. These data are consistent with results from the RAMIRIS study, however further prospective study is needed.