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Should the control arms of randomized trials have an expiry date?

Nature Reviews Clinical Oncology volume 19, pages 425–426 (2022)Cite this article

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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.

On 2 October 2015, pembrolizumab was granted FDA accelerated approval for patients with advanced-stage non-small-cell lung cancers (NSCLCs) with a PD-L1 tumour proportion score (TPS) ≥ 50% on the basis of data from the open-label, phase I KEYNOTE-001 trial, which showed an objective response rate of 45.2% and a median duration of response of 23.5 months1. Full approval was later granted on 24 October 2016 on the basis of data from two phase III randomized controlled trials (RCTs) (KEYNOTE-024 and KEYNOTE-042), which demonstrated improvements in median overall survival (OS) relative to platinum-doublet chemotherapy (26.3 versus 13.4 months and 20.0 versus 12.2 months, respectively)2,3. The long-term OS outcomes of patients with a PD-L1 TPS ≥ 50% are impressive; data from KEYNOTE-024 demonstrate a 5-year OS of 31.9% in the pembrolizumab group compared with 16.3% in the chemotherapy group, with the classic plateauing of the tail end of the survival curve indicating a subgroup of patients with long-term disease control3. Hence, any patient with advanced-stage NSCLC with no targetable driver alterations and a PD-L1 TPS ≥ 50% diagnosed after 2016 should receive pembrolizumab, provided access is not an issue. Even among patients with a PD-L1 TPS < 50%, chemotherapy plus immunotherapy has been established as the standard of care on the basis of results from KEYNOTE-189 (ref.4), resulting in FDA accelerated approval in May 2017 and regular approval in August 2018. However, clinical trials of newer ‘me-too’ immunotherapies (that is, other agents targeting PD-1 or PD-L1) continue to use chemotherapy alone as a control treatment, as was recently criticized by an FDA panel in the context of sintilimab5. In this Comment, we discuss the frequency, context and appropriateness of such control arms in modern NSCLC trials and offer some potential solutions that are applicable across tumour types.

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Acknowledgements

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.

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Authors and Affiliations

  1. Department of Oncology, Queen’s University, Kingston, Ontario, Canada

    Adi Kartolo & Bishal Gyawali

  2. Cancer Centre of Southeastern Ontario, Kingston, Ontario, Canada

    Adi Kartolo & Bishal Gyawali

  3. Department of Public Health Sciences, Queen’s University, Kingston, Ontario, Canada

    Bishal Gyawali

  4. Division of Cancer Care and Epidemiology, Queen’s University Cancer Research Institute, Kingston, Ontario, Canada

    Bishal Gyawali

Authors
  1. Adi Kartolo
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Correspondence to Bishal Gyawali.

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Competing interests

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

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