Gemcitabine with or without ramucirumab as second-line treatment for malignant pleural mesothelioma (RAMES): a randomised, double-blind, placebo-controlled, phase 2 trial

Our plain-English summary of Gemcitabine with or without ramucirumab as second-line treatment for malignant pleural mesothelioma (RAMES): a randomised, double-blind, placebo-controlled, phase 2 trial, by C. Pinto, P.A. Zucali, M. Pagano, et al (The Lancet. Oncology, 2021).

The study

• Authors: C. Pinto, P.A. Zucali, M. Pagano, F. Grosso, G. Pasello, M.C. Garassino, M. Tiseo, H. Soto Parra, F. Grossi, F. Cappuzzo, F. de Marinis, P. Pedrazzoli, M. Bonomi, L. Gianoncelli, M. Perrino, A. Santoro, F. Zanelli, C. Bonelli, A. Maconi, S. Frega, E. Gervasi, L. Boni, G.L. Ceresoli
• Journal: The Lancet. Oncology
• Published: 2021;22(10):1438-1447
• Type of article: Randomized trial
• Cited by: 85 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: 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.

Methods: RAMES was a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial done at 26 hospitals in Italy. Eligible patients were aged 18 years or older, had Eastern Cooperative Oncology Group performance status 0-2, and histologically proven malignant pleural mesothelioma progressing during or after first-line treatment with pemetrexed plus platinum. Patients were randomly assigned (1:1) to receive intravenous gemcitabine 1000 mg/m2 on days 1 and 8 every 3 weeks plus either intravenous placebo (gemcitabine plus placebo group) or ramucirumab 10 mg/kg (gemcitabine plus ramucirumab group) on day 1 every 3 weeks, until tumour progression or unacceptable toxicity. Central randomisation was done according to a minimisation algorithm method, associated with a random element using the following stratification factors: ECOG performance status, age, histology, and first-line time-to-progression. The primary endpoint was overall survival, measured from the date of randomisation to the date of death from any cause. Efficacy analyses were assessed in all patients who had been correctly randomised and received their allocated treatment, and safety analyses were assessed in all patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT03560973, and with EudraCT, 2016-001132-36.

Findings: Between Dec 22, 2016, and July 30, 2018, of 165 patients enrolled 161 were correctly assigned and received either gemcitabine plus placebo (n=81) or gemcitabine plus ramucirumab (n=80). At database lock (March 8, 2020), with a median follow-up of 21·9 months (IQR 17·7-28·5), overall survival was longer in the ramucirumab group (HR 0·71, 70% CI 0·59-0·85; p=0·028). Median overall survival was 13·8 months (70% CI 12·7-14·4) in the gemcitabine plus ramucirumab group and 7·5 months (6·9-8·9) in the gemcitabine plus placebo group. Grade 3-4 treatment-related adverse events were reported in 35 (44%) of 80 patients in the gemcitabine plus ramucirumab group and 24 (30%) of 81 in the gemcitabine plus placebo group. The most common treatment-related grade 3-4 adverse events were neutropenia (16 [20%] for gemcitabine plus ramucirumab vs ten [12%] for gemcitabine plus placebo) and hypertension (five [6%] vs none). Treatment-related serious adverse events were reported in five (6%) in the gemcitabine plus ramucirumab group and in four (5%) patients in the gemcitabine plus placebo group; the most common was thromboembolism (three [4%] for gemcitabine plus ramucirumab vs two [2%] for gemcitabine plus placebo). There were no treatment-related deaths.

Interpretation: Ramucirumab plus gemcitabine significantly improved overall survival after first-line standard chemotherapy, with a favourable safety profile. This combination could be a new option in this setting.

Funding: Eli Lilly Italy.

Translation: For the Italian translation of the abstract see Supplementary Materials section.

Copyright © 2021 Elsevier Ltd. All rights reserved.

In plain English

This randomised, double-blind, placebo-controlled phase 2 trial at 26 Italian hospitals enrolled people with malignant pleural mesothelioma that progressed during or after first-line pemetrexed plus platinum chemotherapy. Of 165 patients randomised between December 2016 and July 2018, the 161 who received treatment were analysed. All received gemcitabine plus either ramucirumab, an antibody against the blood-vessel receptor VEGFR-2, or placebo. Median overall survival was 13.8 months (70% confidence interval 12.7 to 14.4) with ramucirumab and 7.5 months (6.9 to 8.9) with placebo. The hazard ratio was 0.71 (70% confidence interval 0.59 to 0.85), one-sided p 0.028; the trial counted one-sided p values of 0.15 or lower as significant. Grade 3 to 4 treatment-related side effects occurred in 35 of 80 ramucirumab patients and 24 of 81 placebo patients; there were no treatment-related deaths. No significant benefit was seen in older patients or those with ECOG performance status 1 to 2, but the authors said these subgroups were small, lacked statistical power and needed cautious interpretation. The authors concluded the combination improved overall survival with a favourable safety profile.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Multicentre, randomised, double-blind, placebo-controlled phase 2 treatment trial (RAMES)
• Who was studied: Adults with malignant pleural mesothelioma that progressed during or after first-line pemetrexed plus platinum, treated at 26 hospitals in Italy. 165 patients were randomised between Dec 22, 2016 and July 30, 2018 (83 to gemcitabine plus placebo, 82 to gemcitabine plus ramucirumab). 161 were analysed (81 placebo, 80 ramucirumab).
• Exposure: Not an asbestos exposure study. The intervention was gemcitabine 1000 mg/m² intravenously on days 1 and 8 every 3 weeks, plus either ramucirumab 10 mg/kg or matching placebo intravenously on day 1 of each 3-week cycle.
• Main results:
  • Median overall survival was 7.5 months (70% CI 6.9 to 8.9) in the gemcitabine plus placebo group and 13.8 months (12.7 to 14.4) in the gemcitabine plus ramucirumab group. The hazard ratio was 0.71 (70% CI 0.59 to 0.85), with an unstratified log-rank test p of 0.028.
  • How significance was judged in this trial: all statistical tests were one-sided, and p values of 0.15 or lower counted as statistically significant.
  • Survival at 12 months was 33.9% (70% CI 28.3 to 39.5) in the placebo group and 56.5% (50.4 to 62.1) in the ramucirumab group. At 6 months it was 63.9% versus 76.0%.
  • Median progression-free survival was 3.3 months (70% CI 3.0 to 3.9) in the placebo group and 6.4 months (5.5 to 7.6) in the ramucirumab group. The hazard ratio was 0.79 (0.66 to 0.94), with p of 0.082.
  • Disease control was achieved in 42 (52%) of 81 placebo patients and 58 (73%) of 80 ramucirumab patients. Partial responses were seen in 8 (10%) of 81 placebo patients and 5 (6%) of 80 ramucirumab patients. There were no complete responses.
  • Grade 3 to 4 treatment-related adverse events occurred in 35 (44%) of 80 patients in the ramucirumab group and 24 (30%) of 81 in the placebo group.
  • There were no treatment-related deaths in either group.
  • A significant benefit was not seen in patients aged 70 years or older, nor in patients with ECOG performance status 1 to 2.
• The authors' conclusion: The authors concluded that ramucirumab plus gemcitabine improved overall survival after first-line standard chemotherapy, with a favourable safety profile. They said the combination warrants a further phase 3 trial.
• Limitations the authors state:
  • Phase 2 design with a relatively small sample size and low power in subgroup analyses.
  • The subgroups without a significant benefit were small and had insufficient statistical power, so the authors said those results should be interpreted with caution.
  • The proportional hazards assumption for progression-free survival was not met.
  • The choice to combine gemcitabine with ramucirumab was pragmatic rather than based on previous clinical data.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Gemcitabine, Ramucirumab, Pleural Mesothelioma, Angiogenesis, Mesothelioma, Performance Status, Pemetrexed (Alimta), ECOG Performance Status.

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