We would like to thank Roy et al. and Kothari for their thoughtful letters to the editor concerning our recent paper “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” in Cancer Research, Statistics and Treatment. We have read these letters carefully and provide below our responses to the questions raised by them. We hope the authors of these letters, and the readership of the Journal, find them helpful.
Prior treatment with bevacizumab was allowed in the REVEL study. The absence of patients pre-treated with bevacizumab within the Indian subgroup of 55 patients represents either pure chance or, perhaps, elements of revealed practice in India. In addition, while the REVEL protocol excluded patients who had been previously treated with docetaxel, prior taxane use was allowed. Of the patients enrolled in REVEL, 15% had received prior bevacizumab with platinum chemotherapy and 24% a prior taxane.
Roy et al. appear to suggest that bevacizumab represents the first-line standard of care in India. However, patients were eligible for entry into the REVEL trial only upon progression on first-line treatment; therefore our study was not designed to look at first-line care.
In response to the questions posed by Roy et al. and Kothari, the REVEL trial supplement, Figure 3 SA showed the efficacy outcomes for patients by prior bevacizumab treatment, prior taxane treatment, histology, and EGFR mutation status. These are, however, subgroup analyses for the entire intent-to-treat population. Similar data have not been generated for the Indian subgroup due to small patient numbers.
Kothari mentions the elevated risk of pulmonary hemorrhage in squamous cell carcinoma (SCC) associated with bevacizumab and asks us to comment on whether this increased risk of bleeding was also evident in those receiving ramucirumab. While we didn't examine this question for the Indian subgroup, Table 7S in the supplement to the main REVEL trial showed the rates of pulmonary hemorrhage found among patients with SCC randomized to receive ramucirumab. Histological analyses in routine care settings appear to show that there was no major difference in pulmonary hemorrhage between patients with squamous and non-squamous non-small cell lung cancer (NSCLC) when treated with ramucirumab.
Both Roy et al. and Kothari correctly point to the transformative effect of immunotherapy approval on lung cancer treatment, and their question as to where ramucirumab can best sit within this new treatment landscape is pertinent. The REVEL trial was designed before immunotherapy became the standard of care in the first-line treatment of non-biomarker-driven NSCLC; however the ongoing prospective Phase II investigator-initiated trial, SCORPION, will generate evidence of sequential immunotherapy alongside platinum-based chemotherapy followed by ramucirumab combined with docetaxel.
Roy et al. also cite a meta-analysis which concludes that the use of ramucirumab in patients with advanced cancer was associated with an increased risk of treatment-related serious and possibly fatal adverse events. This meta-analysis included studies across different tumor types, with each indication having its own unique benefit–risk profile. Furthermore, only 6 of the 10 studies in the meta-analysis had led to ramucirumab's regulatory approval. The results of the meta-analysis should be interpreted in this context.
Based on the data of the REVEL trial and the Indian subset analysis, the Central Drugs Standard Control Organization (CDSCO) considers ramucirumab combined with docetaxel to be a safe and effective treatment option for Indian patients with advanced NSCLC that has progressed on platinum-based chemotherapy.
Financial support and sponsorship
Scientific writing support was provided by Eli Lilly.
Conflicts of interest
There are no conflicts of interest.
The authors would like to acknowledge Mr Alan Ó Céilleachair, an employee of Eli Lilly and Company, for his writing and editorial contributions.
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2. Kothari RK. Ramucirumab in stage IV nonsmallcell lung cancer: Indian data Cancer Res Stat Treat. 2022 In this issue.
3. Prabhash K, Doval DC, Rangarajan B, Somani N, Pruthi A, Dyachkova 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
4. Garon EB, Ciuleanu T-E, Arrieta O, Prabhash K, Syrigos KN, Goksel T, et al Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): A multicentre, double-blind, randomised phase 3 trial Lancet. 2014;384:665–73
5. Kawachi H, Tamiya M, Matsumoto K, Tamiya A, Yanase T, Tanizaki S, et al Efficacy and safety of ramucirumab and docetaxel in previously treated patients with squamous cell lung cancer: a multicenter retrospective cohort study Invest New Drugs. 2022;40:634–42
6. Matsuzawa R, Morise M, Ito K, Hataji O, Takahashi K, Hara T, et al P47.14 study design of SCORPION: Multi-center, phase II study following platinum-based chemotherapy plus ICIs in patients with NSCLC J Thoracic Oncol. 2021;16:S1102–3
7. Effing SMA, Gyawali B. Assessing the risk-benefit profile of ramucirumab in patients with advanced solid tumors: A meta-analysis of randomized controlled trials EClinicalMedicine. 2020;25:100458
8. Minutes of 32nd
Meeting of The Technical Committee Held On 26.04.2016 Under The Chairmanship Of DGHS For Supervising Clinical Trials On New Chemical Entities In The Light of Directions of The Hon'ble Supreme Court of India on 03.01.2013. 2016 Hearing before the Technical Committee of the Central Drugs Standard Control Organisation Available from: https://cdsco.gov.in/opencms/resources/UploadCDSCOWeb/2018/UploadCommitteeFiles/32ndechnicaCommittee.pdf
. [Last accessed on 2022 Jun 10]