Survival Unaffected From Addition of Ramucirumab or Merestinib to Standard First-Line Chemotherapy for Metastatic Biliary Tract Cancer

The addition of ramucirumab (Cyramza) or merestinib to standard of care cisplatin and gemcitabine in the first-line setting was well tolerated but did not significantly improve survival for patients with molecularly unselected, locally advanced or metastatic biliary tract cancer, according to results from a phase 2 trial (NCT02711553) published in Lancet Oncology.

Progression-free survival (PFS) events were reported to occur in 73% (n = 77) of patients in the ramucirumab group, 67% (n = 68) of patients in the merestinib group, and 75% of patients in the pooled placebo group (n = 76). The median PFS was 6.5 months (80% CI, 5.7-7.1), 7.0 months (80% CI, 6.2-7.1), and 6.6 months (80% CI, 5.6-6.8) in the ramucirumab (HR, 1.12; 80% CI, 0.90-1.40, two-sided P = .48), merestinib (HR, 0.92; 80% CI, 0.73-1.15; two-sided P = .64), and pooled placebo groups, respectively.

“Based on our results, the role of angiogenesis and MET inhibitors in biomarker-unselected and histologically unselected patients with biliary tract cancer remains investigational,” the investigators wrote.

Investigators enrolled patients who were 18 years or older with histologically or cytologically confirmed, non­resectable, recurrent, or metastatic biliary tract adenocarcinoma. In order to be eligible, patients were not able to receive prior therapies in addition to having an ECOG performance status of 0 or 1, a life expectancy of at least 3 months, and measurable disease via RECIST 1.1.

Patients who enrolled on the study received either 8 mg/kg of ramucirumab intravenously on days 1 and 8 in 21-day cycles or intravenous placebo, merestinib at 80 mg daily, or oral placebo once daily. Treatment continued until disease progression, unacceptable toxicity, death, or discontinuation request. All patients included in the research received a chemotherapy backbone, consisting of 25 mg/m² of cisplatin and 1000 mg/m² gemcitabine intravenously on days 1 and 8 in 21-day cycles with a maximum of 8 cycles.

The primary end point of the research was investigator-assessed PFS, and key secondary end points were overall survival (OS), objective response rate (ORR), disease control rate, safety, and patient-reported outcomes (PROs) of disease-specific symptoms.

A total of 309 patients were enrolled and randomly assigned to the ramucirumab (n = 106), merestinib (n = 102), or placebo groups (n = 101) between May 25, 2016, and August 8, 2017. Median age was 62 years (Interquartile range [IQR], 55-69).

At the OS data cutoff point of March 18, 2019, a total of 226 patients had died, of 84 whom were in the ramucirumab group, 71 were from the merestinib group, and 71 were from the pooled placebo group. Investigators reported a median OS of 10.5 months (80% CI, 8.5-11.8), 14.0 months (80% CI, 12.0-16.4), and 13.0 months (80% CI, 11.4-15.3) in the ramucirumab (HR, 1.33; 80% CI, 0.96-1.86; P = .087), merestinib (HR, 0.95; 80% CI, 0.67-1.34; P = .76), and pooled placebo groups, respectively.

Additional findings from the trial indicated that the ORR was 31.1% (95% CI, 22.3%-39.9%) for patients in the ramucirumab cohort, 19.6% (95% CI, 11.9%-27.3%) for patients in the merestinib cohort, and 32.7% (95% CI, 23.5%-41.8%) in the pooled placebo cohort. Complete responses were observed in 0, 3, and 2 patients in the ramucirumab, merestinib, and pooled placebo groups, respectively, and partial responses were seen in 33, 17, and 31 patients in each respective group.

Common grade 3 or higher treatment­emergent adverse effects (TEAEs) in the ramucirumab, merestinib, and placebo groups, respectively, included neutropenia (49% vs 47% vs 33%), thrombocytopenia (35% vs 19% vs 17%), and anemia (27% vs 16% vs 19%).

Any grade serious TEAEs were observed in 51% of patients in the ramucirumab group, 55% of patients in the merestinib group, and 48% of patients in the pooled placebo group. Serious TEAEs were observed more frequently in the experimental groups than the placebo group and included cholangitis (5% vs 1%) and sepsis (4% vs 2%) in the ramucirumab group vs the placebo group, as well as neutropenia (5% vs 1%) and pulmonary embolism (5% vs 1%) in the merestinib group vs the placebo group.

Common treatment-related AEs in the ramucirumab, merestinib, and placebo groups, respectively, included thrombocytopenia (6% vs 2% vs 6%), neutropenia (3% vs 5% vs 1%), and pulmonary embolism (3% vs 2% vs 1%).

“Further understanding of the molecular biology that drives biliary tract malignancies and mechanisms of resistance is needed to identify novel targets and therapies that work for the approximately 60% of patients with biliary tract cancer who do not have a mutation that is currently actionable,” the investigators concluded.

Reference

Valle JW, Vogel A, Denlinger CS, et al. Addition of ramucirumab or merestinib to standard first-line chemotherapy for locally advanced or metastatic biliary tract cancer: a randomised, double-blind, multicentre, phase 2 study. Lancet Oncol. 2021;22(10):1468-1482. doi:10.1016/S1470-2045(21)00409-5