
==== Front
Oncologist
Oncologist
oncolo
The Oncologist
1083-7159
1549-490X
Oxford University Press US

10.1093/oncolo/oyae172
oyae172
Letter to the Editor
AcademicSubjects/MED00010
Oncolo/32
It is time to rethink randomized clinical trial approaches
https://orcid.org/0000-0002-0184-7946
Stewart David J Department of Medicine, University of Ottawa, Ottawa, ON K1H 8L6, Canada

dstewart@toh.ca
9 2024
10 7 2024
10 7 2024
29 9 e1235e1236
16 4 2024
15 6 2024
© The Author(s) 2024. Published by Oxford University Press.
2024
https://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

This letter to the editor comments on the recently published editorial by Fojo, LaRose, and Bates, and agrees that changes are needed in clinical research approaches.
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pmcIn their commentary,1 Fojo et al make excellent points. We agree there is ample evidence that sotorasib benefits patients with KRAS G12C mutations, effective lines of therapy are all important, sotorasib did not need to beat docetaxel, and many trials seriously challenge equipoise. Oncologists should do what they deem best for their patients.

It makes little sense for randomized controlled trials (RCTs) to compare drugs with differing mechanisms of action.2 Therapies may preferentially benefit different subpopulations. The rational approach is to offer one then the other, not one instead of the other. One might reasonably assess optimal drug sequence (A->B vs B->A), but it is unreasonable to discard one based on A-vs-B RCTs if each may benefit patients refractory to the other.2

In CodeBreak200,3 median progression-free survival (PFS) was 1.1 months longer with sotorasib vs docetaxel. However, as frequently happens,4 medians were distorted by Kaplan-Meier midpoint deviations. Half-life assessments mitigate this. Curve exponential decay nonlinear regression analysis using published methods4 indicated PFS half-lives of 6.1-vs-4.3 months with sotorasib-vs-docetaxel.

Hazard ratios correlate better with half-life ratios than with median ratios.4 This was the case here (PFS hazard ratio 0.66, half-life ratio 4.3/6.1 = 0.70, and median ratio 4.5/5.6 = 0.80).

For most therapies, if overall survival (OS) is undistorted by crossover, PFS half-life gains ≥ 1.5 months indicate a 90% probability of OS gains ≥ 2 months.5 Crossover ≥ 20% substantially reduces probability that OS differences will achieve significance.4 While OS is important, it can be an unreliable RCT endpoint due to crossover4 and long post-progression survival.6 We agree with Fojo et al,1 we must rethink OS as a primary RCT endpoint.5

We also agree that further trials should primarily assess who is most likely to benefit. This is most efficiently done using response as the outcome measure.2 This can subsequently be confirmed with non-randomized PFS/OS assessments. Subsequent assessment of real-world patients managed using different approaches can elucidate whether a factor is prognostic rather than predictive. We do not need RCTs for this.

Fojo et al are correct that targeted therapies can be toxic.1 However, the VP4-2023 trial demonstrated that dose reductions reduced sotorasib toxicity much more than efficacy.7 Many therapies have relatively flat dose-response curves.

With respect to setting the bar higher,1 it depends. Using RCTs to assess efficacy requires high accrual to show small gains.8 This slows progress by deviating resources from assessment of other options. Far fewer patients are needed to demonstrate high gains.2 A higher bar reduces trial costs.

However, only 20-30 patients are needed in phases I-II trials if single agent response rate is used to assess efficacy. In 25 trials of placebo/best supportive care, median objective response rate was 1%.2 The highest response rate was 4%. Hence, if even a minority of patients (≥10%?) experience durable responses, this may indicate a drug worth trying in patients with no good alternatives if toxicity and price are reasonable. RCTs are needed to confirm modest contributions of a drug to a combination,2 but are unnecessary with single agents.

Overall, we should rethink RCT approaches in assessing new therapies.2

Conflicts of interest

None directly related to this work. Unrelated: honoraria or advisory board or consulting fees from Merck, AstraZeneca, Abbvie, Pfizer and Amgen; owns a 3% interest in US Patent no. 9.675.663 (a test to predict response to TUSC2/FUS1 gene therapy). The Ottawa Hospital receives research support from a broad range of pharmaceutical companies. Royalties from book “A Short Primer on Why Cancer Still Sucks”.
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References

1. Fojo T , LaRoseM, BatesSE. The impact of exuberance on equipoise in oncology clinical trials: sotorasib as archetype. Oncologist. 2024;29 (4 ):275-277. 10.1093/oncolo/oyae042 38498045
2. Stewart DJ , KurzrockR. Fool’s gold, lost treasures, and the randomized clinical trial. BMC Cancer. 2013;13 :193. 10.1186/1471-2407-13-193 23587187
3. de Langen AJ , JohnsonML, MazieresJ, et al ; CodeBreaK 200 Investigators. Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRAS(G12C) mutation: a randomised, open-label, phase 3 trial. Lancet. 2023;401 (10378 ):733-746. 10.1016/S0140-6736(23)00221-0 36764316
4. Stewart DJ , BosseD, GossG, et al . A novel, more reliable approach to use of progression-free survival as a predictor of gain in overall survival: The Ottawa PFS Predictive Model. Crit Rev Oncol Hematol. 2020;148 :102896. 10.1016/j.critrevonc.2020.102896 32087510
5. Stewart DJ , RamsayT, NavaniV, et al . Progression-free survival gain: a reliable primary end point for drug registration that can accelerate patient access to urgently needed therapies. J Clin Oncol. 2024;42 (8 ):973-974. 10.1200/JCO.23.02259 38290085
6. Broglio KR , BerryDA. Detecting an overall survival benefit that is derived from progression-free survival. J Natl Cancer Inst. 2009;101 (23 ):1642-1649. 10.1093/jnci/djp369 19903805
7. Hochmair MJ , VermaelenK, MountziosG, et al . VP4-2023: Sotorasib 960 mg versus 240 mg in pretreated KRAS G12C advanced NSCLC. ESMO Virtual Plenary Abstracts. Ann Oncol. 2024;35 (1 ):142-144. https://www.annalsofoncology.org/article/S0923-7534(23)04996-7/pdf
8. Stewart DJ , KurzrockR. Cancer: the road to Amiens. J Clin Oncol. 2009;27 (3 ):328-333. 10.1200/JCO.2008.18.9621 19064964
