Addition of Ramucirumab to Gemcitabine in Second-Line Treatment of Malignant Pleural Mesothelioma

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In the Italian phase II RAMES trial reported in The Lancet Oncology, Pinto et al found that the addition of ramucirumab to gemcitabine improved overall survival in the second-line treatment of malignant pleural mesothelioma.

As noted by the investigators, “There is a preclinical rationale for inhibiting angiogenesis in mesothelioma. We aimed to assess the efficacy and safety of the anti–VEGFR-2 antibody ramucirumab combined with gemcitabine in patients with pretreated malignant pleural mesothelioma.”

Study Details

In the double-blind multicenter trial, 161 patients who had experienced disease progression during or after first-line pemetrexed/platinum were randomly assigned between December 2016 and July 2018 to receive gemcitabine at 1,000 mg/m² on days 1 and 8 every 3 weeks plus either ramucirumab at 10 mg/kg (n = 80) or placebo (n = 81) on day 1 every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was overall survival.

Overall Survival


  • The addition of ramucirumab to gemcitabine significantly prolonged overall survival.
  • Median overall survival was 13.8 vs 7.5 months, with 1-year rates of 56.5% vs 33.9%.

At database lock (March 2020), median follow-up was 21.9 months (interquartile range = 17.7–28.5 months). Median overall survival was 13.8 months (70% confidence interval = 12.7–14.4 months) in the gemcitabine/ramucirumab group vs 7.5 months (70% CI = 6.9–8.9 months) in the control group (hazard ratio [HR] = 0.71, 70% CI = 0.59–0.85, P = .028); 6- and 12-month rates were 76.0% vs 63.9% and 56.5% vs 33.9%, respectively.

Median progression-free survival was 6.4 months (70% CI = 5.5–7.6 months) in the gemcitabine/ramucirumab group vs 3.3 months (70% CI = 3.0–3.9 months) in the control group (HR = 0.79, 70% CI = 0.66–0.94, P = .082). Objective responses—all partial responses—were observed in 6% vs 10% of patients, with median response durations of 8.4 vs 5.4 months. Disease control rates were 73% vs 52%.

Adverse Events

Grade 3 or 4 treatment-related adverse events occurred in 44% of patients in the gemcitabine/ramucirumab group and 30% of the control group; the most common in the combination group were neutropenia (20% vs 12%), hypertension (6% vs 0%), and fatigue (5% vs 4%). Treatment-related serious adverse events occurred in 6% vs 5% of patients, the most commonly reported being thromboembolism (4% vs 2%). No treatment-related deaths were reported.

The investigators concluded, “Ramucirumab plus gemcitabine significantly improved overall survival after first-line standard chemotherapy, with a favorable safety profile. This combination could be a new option in this setting.”

Paolo Andrea Zucali, MD, of the Department of Biomedical Sciences, Humanitas University, Milan, is the corresponding author for The Lancet Oncology article.

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

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