Addition of Ramucirumab or Merestinib to First-Line Chemotherapy in Advanced Biliary Tract Cancer

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In a phase II trial reported in The Lancet Oncology, Juan W. Valle, MD, and colleagues found that no progression-free survival benefit was achieved with the addition of either the VEGFR2 inhibitor ramucirumab or the MEK inhibitor merestinib to first-line cisplatin/gemcitabine chemotherapy in patients with locally advanced or metastatic biliary tract adenocarcinoma. 

Juan W. Valle, MD

Juan W. Valle, MD

Study Details

In the double-blind trial, 309 patients from sites in 18 countries were randomly assigned 2:1:2:1 between May 2016 and August 2017 to receive intravenous ramucirumab at 8 mg/kg (n = 106) or placebo on days 1 and 8 in 21-day cycles or oral merestinib at 80 mg (n = 102) or placebo once daily until disease progression or unacceptable toxicity (n = 101 for pooled placebo group). All patients received cisplatin at 25 mg/m² and gemcitabine at 1,000 mg/m² on days 1 and 8 in 21-day cycles for a maximum of eight cycles.

The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population.

Progression-Free Survival

Median follow-up for progression-free survival at data cutoff (February 2018) was 10.9 months (interquartile range = 8.1–14.1 months). Median progression-free survival was 6.5 months (80% confidence interval [CI] = 5.7–7.1 months) in the ramucirumab group (hazard ratio [HR] = 1.12, 80% CI = 0.90–1.40, P = .48, vs pooled placebo group), 7.0 months (80% CI = 6.2–7.1 months) in the merestinib group (HR = 0.92, 80% CI = 0.73–1.15, P = .64, vs pooled placebo group), and 6.6 months (80% CI = 5.6–6.8 months) in the pooled placebo group.

At data cutoff for overall survival (March 2019), median overall survival was 10.5 months (80% CI = 8.5–11.8 months) in the ramucirumab group (HR = 1.33, 80% CI = 0.96­1.86, P = .087, vs placebo group), 14.0 months (80% CI = 12.0­–16.4 months) in the merestinib group (HR = 0.95, 80% CI = 0.67–1.34, P = .76, vs placebo group), and 13.0 months (80% CI = 11.4–15.3 months) in the pooled placebo group.


  • Neither ramucirumab nor merestinib improved progression-free survival when added to chemotherapy.
  • Median progression-free survival was 6.5 months with ramucirumab/chemotherapy, 7.0 months with merestinib/chemotherapy, and 6.6 months with chemotherapy alone.

Objective response rates were 31.1% in the ramucirumab group (P = .88 vs placebo), 19.6% in the merestinib group (P = .024 vs placebo), and 32.7% in the pooled placebo group.

Adverse Events

The most common grade ≥ 3 adverse events across all groups were neutropenia (49% of ramucirumab group, 47% of merestinib group, 33% of pooled placebo group), thrombocytopenia (35%, 19%, and 17%), and anemia (27%, 16%, and 19%). Serious adverse events occurred in 51%, 55%, and 48% of patients, respectively; the most common considered related to treatment were thrombocytopenia (6%, 2%, and 6%), neutropenia (3%, 5%, and 1%), and pulmonary embolism (3%, 2%, and 1%).

Treatment-related adverse events led to discontinuation of therapy in 9%, 4%, and 4% of patients, respectively. Treatment-related death occurred in one patient in the ramucirumab group, due to cardiac arrest, and in two patients in the merestinib group, due to pulmonary embolism and sepsis.  

The investigators concluded, “Adding ramucirumab or merestinib to first-line cisplatin/gemcitabine was well tolerated, with no new safety signals, but neither improved progression-free survival in patients with molecularly unselected, locally advanced, or metastatic biliary tract cancer. The role of these targeted inhibitors remains investigational, highlighting the need for further understanding of biliary tract malignancies and the contribution of molecular selection.”

Dr. Valle, of the Division of Cancer Sciences and Department of Medical Oncology, University of Manchester and The Christie NHS Foundation Trust, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Eli Lilly and Company. For full disclosures of the study authors, visit