The REVEL trial, one of the largest second-line non-small-cell lung cancer (NSCLC) multicentric phase III randomized trials, reported that ramucirumab along with docetaxel was superior to docetaxel alone and led to prolongation of overall survival (OS) and progression-free survival (PFS) after first-line platinum failure in NSCLC across all the histologies.[1]
The recently published subset analysis from the Indian population by Prabhash et al. reported results similar to the overall results of the REVEL study with an acceptable safety profile. This provides us another treatment option in the second line or beyond in patients with advanced NSCLC.[2]
We would like to congratulate the authors for introducing this new treatment option for patients with advanced NSCLC.
However, the trial was designed prior to the era of immunotherapy and targeted therapies beyond the epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase alterations. Therefore, we do not really know the efficacy of this combination, if immune checkpoint inhibitors (ICIs) had been used in the first line. Secondly, the efficacy of the REVEL regimen is unclear in patients with actionable driver mutations/rearrangements as most of the patients included in this subset had an unknown EGFR status.
Bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody in combination with paclitaxel and carboplatin, is now the standard first-line option for advanced non-squamous NSCLC without a driver mutation.[34]
As the exploratory subset analysis by Prabhash et al.[2] did not permit the use of first-line bevacizumab, it did not answer the question regarding whether the use of another anti-VEGF monoclonal antibody, ramucirumab, would add value in patients who had received bevacizumab in the first-line setting.
Thirdly, the pooled analysis of the 5-year update of CheckMate 017 and 057 and KEYNOTE-010 showed superior OS with nivolumab and pembrolizumab as compared to docetaxel, respectively, in the second-line setting.[56] As there is no direct comparison between these ICIs and the ramucirumab with docetaxel combination, it will be difficult to decide which regimen is superior.
A systematic review and meta-analysis reported that the use of ramucirumab in different advanced solid tumors, including NSCLC, was associated with an increased risk of serious adverse events, while the treatment benefits were marginal to moderate.[7]
In the study by Prabhash et al.,[2] the median PFS in the ramucirumab arm was 5.6 months, while the median duration of therapy was 4.5 months (18 weeks), with nearly 60% of patients experiencing dose delays with substantial treatment-related adverse events. This indicates that the risk–benefit ratio of adding ramucirumab to docetaxel may be tilted more toward the side of adverse events than benefit and might raise the issue of whether the use of such an expensive drug in low- and middle-income countries like India is justified.[7]
In conclusion, we can offer ramucirumab with docetaxel to patients with advanced NSCLC without any actionable targets after progression on a platinum doublet and/or ICIs. This combination can be also used after the failure of first-line platinum, if there is any contraindication to immunotherapy.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
REFERENCES
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2. Prabhash K, Doval DC, Rangarajan B, Somani N, Pruthi A, D'yachkova Y, et al A multicenter, double-blind, randomized phase III trial of ramucirumab plus docetaxel versus placebo plus docetaxel for treatment of stage IV non-small cell lung cancer after disease progression on or after platinum-based therapy (REVEL): An Indian patient subgroup analysis Cancer Res Stat Treat. 2021;4:634–41
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