Gemcitabine with or without ramucirumab as second-line treatment for malignant pleural mesothelioma (RAMES): a randomised, double-blind, placebo-controlled, phase 2 trial
RCT (n=165, Italy) found ramucirumab, an anti-VEGFR-2 antibody, plus gemcitabine significantly improved overall survival after first-line standard chemotherapy vs. gemcitabine plus placebo (13.8 vs. 7.5 months; HR 0.71, 70% CI 0.59–0.85; p=0.028), with favourable safety profile
Source:
The Lancet Oncology
SPS commentary:
According to a commentary, since the FDA approved pemetrexed plus cisplatin for first-line treatment of mesothelioma in 2004, there has been a dearth of additional treatment options for this disease, and despite substantial effort, no other phase 3 study achieved a positive outcome for another 12 years, until the MAPS trial showed that the addition of bevacizumab to pemetrexed plus platinum improved progression-free and overall survival. Although it is not approved by regulatory agencies, bevacizumab is endorsed in treatment guidelines for patients with no contraindications to its use, with variable uptake depending on the geographical region. It notes no drugs have been approved for previously treated patients, but pemetrexed retreatment, gemcitabine, or vinorelbine are widely used, based on findings from single-group phase 2 trials and retrospective single-centre series; thus given this context, it is remarkable that in this past year five positive randomised trials were reported in this disease: the phase 3 CheckMate 743 and CONFIRM trials, and the phase 2 NVALT, VIM, and RAMES trials.
It considers RAMES to be a well-designed, well conducted, randomised, phase 2 trial with a positive and meaningful outcome, and might have been practice changing if published a few years earlier, but in October, 2020, the FDA-approved first-line treatment for mesothelioma was changed to ipilimumab plus nivolumab due to the compelling data from CheckMate 743. It notes that although RAMES offers another option, it is unclear where it fits into this new treatment paradigm. It cautions against the temptation to draw phase 3 conclusions from a randomised phase 2 trial and given the rapidly changing landscape for the treatment of mesothelioma, and the resultant uncertainty about where this regimen fits in the current treatment algorithm, the added value of a phase 3 trial of this regimen might not be worthwhile for an uncommon disease such as mesothelioma and the time needed to accrue eligible participants into a phase 3 study.