Gemcitabine Plus Ramucirumab Improves Overall Survival in Malignant Mesothelioma

Gemcitabine (Gemzar) plus ramucirumab (Cyramza) improved overall survival (OS) following treatment with first-line chemotherapy in patients with malignant mesothelioma, according to data from the phase 2 RAMES study (NCT03560973).

At a median follow-up of 21.9 months, investigators reported that OS was longer in the gemcitabine plus ramucirumab group (HR, 0.71; 70% CI, 0.59-0.85; P = .028). The median OS in the gemcitabine plus ramucirumab group was 13.8 months (70% CI, 12.7-14.4) and 7.5 months (70% CI, 6.9-8.9) in the gemcitabine plus placebo group.

A total of 161 patients were enrolled on the study and randomized 1:1 to either the gemcitabine plus placebo arm (n = 81) or the gemcitabine plus ramucirumab arm (n = 80). The baseline characteristics indicated that 86% (n = 138) of patients had epithelioid histology and 59% (n = 95) had a first-line time-to-progression of less than 6 months. At the database lock, 6% (n = 5) of patients in the gemcitabine plus placebo group and 8% (n = 6) in the gemcitabine plus ramucirumab were still on treatment.

Gemcitabine was administered intravenously at a dose of 1000 mg/m2 on days 1 and 8 every 3 weeks plus either 10 mg/kg of intravenous ramucirumab or a matched placebo on day 1 of every 3-week cycle. Treatment continued until the patient experienced progressive disease, unacceptable toxicity, or withdrawal of consent.

Additionally, 56% (n = 45) of patients in the gemcitabine plus placebo cohort and 49% (n = 39) in the gemcitabine plus ramucirumab cohort discontinued treatment because of radiological disease progression. A total of 17% (n = 14) of patients in the gemcitabine plus placebo group and 14% (n = 11) in the gemcitabine plus ramucirumab group discontinued treatment due to worsening clinical condition, defined as an ECOG performance status greater than 2.

In 10% (n = 8) of patients in the gemcitabine plus placebo group and 31% (n = 25) in the gemcitabine plus ramucirumab group had dose reductions. Additionally, 5% (n = 4) of patients in the gemcitabine plus placebo group and 11% (n = 9) in the gemcitabine plus ramucirumab group discontinued treatment due to toxicity.

At 6 and 12 months, the OS rate was 63.9% (70% CI, 57.9%-69.2%) and 33.9% (70% CI, 28.3%-39.5%) in the gemcitabine plus placebo group, compared with 76.0% (70% CI, 70.6%-80.5%) and 56.5% (70% CI, 50.4%-62.1%)in the gemcitabine plus ramucirumab group.

In the gemcitabine plus placebo group, the median progression-free survival (PFS) was 3.3 months (70% CI, 3.0-3.9) vs 6.4 months (70% CI, 5.5-7.6) in the gemcitabine plus ramucirumab group (HR, 0.79; 70% CI, 0.66-0.94; un-stratified log rank test P =.082). The 2-year restricted mean survival time indicated in the post hoc analysis was 6.6 months (70% CI, 5.8-7.4) in the gemcitabine plus placebo group and 8.3 months (70% CI, 7.5-9.1) in the gemcitabine plus ramucirumab group.

According to investigators, 10% (n = 8) of patients in the gemcitabine plus placebo group and 6% (n = 5) in the gemcitabine plus ramucirumab group had a partial response. Additionally, 42% (n = 34) of patients in the gemcitabine plus placebo cohort and 66% (n = 53) in the gemcitabine plus ramucirumab cohort achieved stable disease.

The disease control rate was 52% (n = 42) for patients in the gemcitabine plus placebo group (70% CI, 46%-58%) and 73% (n = 58) in the gemcitabine plus ramucirumab group (70% CI, 66%-78%). In total, 37% (n = 30) of those in the gemcitabine plus placebo group and 19% (n = 15) in the gemcitabine plus ramucirumab group experienced progressive disease.

In terms of safety, 44% (n = 35) of patients in the gemcitabine plus placebo group experienced grade 3/4 adverse effects (AEs), as well as 30% (n = 24) of those in the gemcitabine plus ramucirumab group. The most common grade 3/4 treatment-related AEs (TRAEs) in the ramucirumab and placebo cohorts, respectively, were neutropenia (20% vs 12%), hypertension (6% vs 0%), and fatigue (5% vs 4%).

Six percent (n = 5) of patients in the gemcitabine plus ramucirumab group and 5% (n = 4) in the gemcitabine plus placebo group experienced serious TRAEs. The most common serious TRAEs in either cohort were thromboembolism (4% vs 2%), and aspartate or alanine aminotransferase increase and fatigue each were observed in 1% of those in the ramucirumab group. Additionally, anemia and non-specific cardiac enzyme increase each occurred in 1% of patients in the placebo group. No treatment-related deaths occurred, with all deaths being attributed to disease progression.

Reference

Pinto C, Zucali PA, Pagano M, et al. Gemcitabine with or without ramucirumab as second-line treatment for malignant pleural mesothelioma (RAMES): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. Published Online September 6, 2021. doi:10.1016/S1470-2045(21)00404-6