Gemcitabine Plus Ramucirumab Improves Overall Survival in Malignant Mesothelioma

Article

Patients who were treated with ramucirumab plus gemcitabine experienced improved overall survival compared with patients treated with gemcitabine plus placebo.

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

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