Randomized controlled trials (RCTs) are conducted when clinical equipoise between treatment options exists. However, some RCTs in patients with non-small-cell lung cancer continue to use chemotherapy as the control arm several years after chemotherapy was proven inferior to anti-PD-1 antibodies. Here, we highlight why the justifications for using an inferior treatment in the control arm are invalid and offer solutions that are applicable across tumour types.
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Garon, E. B. et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl. J. Med. 372, 2018–2028 (2015).
Mok, T. S. K. et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet 393, 1819–1830 (2019).
Reck, M. et al. Five-year outcomes with pembrolizumab versus chemotherapy for metastatic non-small-cell lung cancer with PD-L1 tumor proportion score ≥ 50. J. Clin. Oncol. 39, 2339–2349 (2021).
Gandhi, L. et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N. Engl. J. Med. 378, 2078–2092 (2018).
Kolata, G. F. D. A. Panel rejects Lilly’s cancer drug tested only in China. The New York Times, https://www.nytimes.com/2022/02/10/health/fda-cancer-drug-china.html (10 February 2022).
WMA–The World Medical Association. WMA Declaration of Helsinki–Ethical Principles for Medical Research Involving Human Subjects. wma.net, https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/ (accessed 16 March 2022).
Gyawali, B., Carson, L. M., Berry, S. & Moraes, F. Y. Challenges of globalization of cancer drug trials- recruitment in LMICs, approval in HICs. Lancet Reg. Health Am. 7, https://doi.org/10.1016/j.lana.2021.100157 (2022).
US FDA. FDA approves cemiplimab-rwlc for non-small cell lung cancer with high PD-L1 expression. fda.gov, https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-cemiplimab-rwlc-non-small-cell-lung-cancer-high-pd-l1-expression (22 February 2021).
Gyawali, B. et al. Biases in study design, implementation, and data analysis that distort the appraisal of clinical benefit and ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS) scoring. ESMO Open 6, 100117 (2021).
Sydes, M. R. et al. Issues in applying multi-arm multi-stage methodology to a clinical trial in prostate cancer: the MRC STAMPEDE trial. Trials 10, 39 (2009).
We are grateful to A. Robinson of the Department of Oncology, Queen’s University, Ontario for his thoughtful comments on this manuscript, for which he received no compensation.
B.G. has acted as a consultant of Vivio Health. A.K. declares no competing interests.
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Kartolo, A., Gyawali, B. Should the control arms of randomized trials have an expiry date?. Nat Rev Clin Oncol 19, 425–426 (2022). https://doi.org/10.1038/s41571-022-00624-2