Randomized phase 2 study of the addition of ramucirumab or merestinib to standard first line therapy for advanced or metastatic biliary tract cancer

Juan Valle, et al.

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Biliary tract cancers (BTC) are aggressive, rare GI malignancies with poor outcomes; approximately half of patients succumb to disease within 1 year. We evaluated the efficacy and safety of ramucirumab or merestinib with first-line cisplatin-gemcitabine in patients with advanced BTC.
Methods: This global, double-blind, phase 2 study was carried out in 81 sites across 18 countries. Eligible patients who were treatment naïve, ≥18 years, with non-resectable, recurrent or metastatic biliary tract adenocarcinoma, an ECOG performance status of 0 or 1, received cisplatin-gemcitabine (25mg/m2-1000mg/m2) (day-1 and day-8, every 21-days, 8-cycles) and were randomized 2:1:2:1 to receive either intravenous (IV) ramucirumab 8mg/kg/placebo (same cycle) or oral merestinib 80mg/oral placebo (daily) until disease progression. Randomization was done by an interactive web response system; stratified by primary tumor site, geographic region and metastatic disease. Primary objective was investigator-assessed PFS (intention-to-treat population). This study, registered at ClinicalTrials.gov, NCT02711553, is ongoing for long-term follow-up.
Findings: 309 patients were randomized (25-May-2016 through 08-August-2017); 106 to the RAM arm, 102 to the MER arm and 101 to the placebo arm; 306 received ≥1 treatment dose. Median PFS (80% CI) was 6.47 (5.7-7.1) months in ramucirumab arm (n=106), 6.97 (6.2-7.1) months in merestinib arm (n=102), and 6.64 (5.6-6.8) months in pooled placebo arm (n=101) (ramucirumab vs placebo: HR 1.12, 80% CI 0.90-1.40; merestinib vs placebo: HR 0.92, 80% CI 0.73-1.15). Median follow-up time (IQR) (data cutoff 16-February-2018.) was 10.9 (8.1-14.1) months. Grade ≥3 adverse events (AEs) occurred in 90 (86.5%) of 104 patients in ramucirumab, 87 (85.3%) of 102 in merestinib, compared to 81 (81.0%) of 100 patients in placebo; most commonly neutropenia (ramucirumab: 51 [49.0%]; merestinib: 48 [47.1%]; placebo: 33 [33.0%]), thrombocytopenia (ramucirumab: 36 [34.6%]; merestinib: 19 [18.6%]; placebo: 17 [17.0%]) and anemia (ramucirumab: 28 [26.9%]; merestinib: 16 [15.7%]; placebo: 19 [19.0%]). Approximately half the patients reported serious AEs (ramucirumab: 53 [51.0%]; merestinib: n=56 [54.9%]; placebo: n=48 [48.0%]). Treatment-related deaths, deemed related by the investigator, occurred in 1 patient in RAM arm (cardiac arrest) and 2 patients in MER arm (1 pulmonary embolism and 1 sepsis).
Interpretation: Adding ramucirumab or merestinib to first-line cisplatin-gemcitabine was well-tolerated, with no new safety signals but did not improve PFS in patients with molecularly-unselected advanced BTC. The role of these targeted inhibitors remains investigational, highlighting the need for further understanding of biliary tract malignancies and the contribution of molecular selection.
Original languageEnglish
JournalLancet Oncology
Publication statusAccepted/In press - 6 Jul 2021

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