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An Analysis of Toxicity and Response Outcomes from Dose Brock et al. BMC Cancer (2021) 21:777 https://doi.org/10.1186/s12885-021-08440-0 RESEARCH ARTICLE Open Access Is more better? An analysis of toxicity and response outcomes from dose-finding clinical trials in cancer Kristian Brock1* ,VictoriaHomer1, Gurjinder Soul2, Claire Potter1,CodyChiuzan3 and Shing Lee3 Abstract Background: The overwhelming majority of dose-escalation clinical trials use methods that seek a maximum tolerable dose, including rule-based methods like the 3+3, and model-based methods like CRM and EWOC. These methods assume that the incidences of efficacy and toxicity always increase as dose is increased. This assumption is widely accepted with cytotoxic therapies. In recent decades, however, the search for novel cancer treatments has broadened, increasingly focusing on inhibitors and antibodies. The rationale that higher doses are always associated with superior efficacy is less clear for these types of therapies. Methods: We extracted dose-level efficacy and toxicity outcomes from 115 manuscripts reporting dose-finding clinical trials in cancer between 2008 and 2014. We analysed the outcomes from each manuscript using flexible non-linear regression models to investigate the evidence supporting the monotonic efficacy and toxicity assumptions. Results: We found that the monotonic toxicity assumption was well-supported across most treatment classes and disease areas. In contrast, we found very little evidence supporting the monotonic efficacy assumption. Conclusions: Our conclusion is that dose-escalation trials routinely use methods whose assumptions are violated by the outcomes observed. As a consequence, dose-finding trials risk recommending unjustifiably high doses that may be harmful to patients. We recommend that trialists consider experimental designs that allow toxicity and efficacy outcomes to jointly determine the doses given to patients and recommended for further study. Keywords: Dose finding, Phase I, Toxicity, Efficacy, Response, Monotone, Cancer Background altogether. This sequential and adaptive approach con- A goal of dose-finding clinical trials is to evaluate out- tinues until the experimental design identifies a suitable comes under a set of investigational doses. A common dose. This pattern of starting low and seeking to escalate general approach starts by giving a relatively low dose to dose justifies the descriptor dose-escalation trials. a small cohort of patients. The outcomes of this cohort The most common approach [1, 2] in dose-escalation affect the dose given to the next. For instance, if no unac- trials is the family of rule-based A+B designs, the most ceptable toxic reactions are seen in this initial cohort, the famous example of which is the perennial 3+3 design [3]. next cohort is likely to be given a higher dose. However, It evaluates doses in cohorts of three patients, using a set if outcomes are adverse, the next cohort might be given of rules to escalate dose so long as an unacceptably high the same dose or a lower dose, or the trial might be halted incidence of dose-limiting toxicity (DLT) is not seen. The main alternative class of dose-escalation methodol- *Correspondence: [email protected] 1Cancer Research UK Clinical Trials Unit, University of Birmingham, ogy comprises the so-called model-based designs. These Birmingham, UK use statistical models to estimate the dose-event curve. Full list of author information is available at the end of the article Whilst model-based methods are used far less frequently © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/)appliestothedatamade available in this article, unless otherwise stated in a credit line to the data. Brock et al. BMC Cancer (2021) 21:777 Page 2 of 18 than rule-based methods, two designs that have seen rel- Chiuzan et al. [2] found that over half of the trials investi- atively wide use in recent years [2] are the continual gated a targeted therapy or immunotherapy and the over- reassessment method (CRM) [4] and the escalation with whelming majority used an MTD-seeking method. With overdose control (EWOC) method [5]. these novel treatment classes, the rationale for assuming Biostatisticians have encouraged trialists to shift from that efficacy always increases in dose is less clear. rule-based to model-based methods, largely because they There are notable instances in the literature where offer better performance [6–8]. The two approaches, how- a monotonic dose-efficacy relationship has not been ever, share some fundamental assumptions. Firstly, they observed. For instance, a major recent success in the each assume that the probability of DLT increases as development of novel anti-cancer drugs has been the PD-1 dose is increased. This reflects the toxicologists’ adage the blockade antibody, pembrolizumab. A phase I trial inves- dose makes the poison, a rule that is generally accepted tigated pembrolizumab doses of 1 mg/kg, 3 mg/kg and 10 without challenge. The 3+3, CRM and EWOC designs mg/kg every 2 weeks, and 2 mg/kg and 10 mg/kg every 3 all select doses based only on binary DLT outcomes in weeks in 30 patients with various malignancies [15]. Large pursuit of the maximum tolerable dose (MTD), the high- expansion cohorts in non-small-cell lung cancer (NSCLC) est dose with toxicity probability less than some critical further evaluated 495 patients at doses 2 mg/kg or 10 pre-specified value. So long as two doses are deemed tol- mg/kg every 3 weeks or 10 mg/kg every 2 weeks [16]. Sub- erable, the higher dose is favoured. Efficacy outcomes sequently, a phase III trial that contributed to a licensing like response or survival are not formally used in dose- application in NSCLC randomised 345 patients to pem- selection decisions. There are variants of the CRM design brolizumab 2 mg/kg, 346 to pembrolizumab 10 mg/kg, [9, 10] and other statistical approaches [11–13]fordose- and compared each of these experimental arms to a con- finding by co-primary toxicity and efficacy outcomes. trol arm comprising 343 patients randomised to docetaxel However, these have experienced comparatively little use [17]. Despite the wide range of doses investigated in large [2, 14]. sample sizes, the phase III trial observed very similar over- In dose-finding trials, investigators seek to identify tol- all survival and RECIST response outcomes in the two erable and efficacious doses. The reliance solely on a toxi- pembrolizumab doses, with each producing materially city outcome in the majority of dose-finding trials dictates better outcomes than the control arm. The drug was sub- that an assumption is made about the efficacy outcome. sequently licensed at 200 mg (i.e. not adjusted for patient The assumption is that higher doses are always more weight) every 3 weeks, reflecting the absence of extra effi- efficacious. cacy at higher doses. Assuming an average adult weight We refer to this as the monotonic efficacy assumption. of 70-80kg, the licensed dose is situated at the lower end In MTD-seeking trials, investigators will escalate dose of the doses investigated throughout these three clinical without formal reference to an efficacy outcome. When trials. the monotonic efficacy assumption holds, the MTD max- We naturally wonder about the suitability of the mono- imises the expectation of efficacy for a specified risk of tonic efficacy assumption in a wider sense. In this toxicity. However, a plausible way in which the monotonic manuscript, we investigate two related questions. What efficacy assumption can be violated is when the proba- evidence is there that the probabilities of a) toxicity, and bility of efficacy plateaus at some critical dose. Escalation b) efficacy increase in dose in modern cancer therapies? beyond this point exposes patients to a greater risk of toxicityfornoaccompanyingincreaseintheprobability Methods of efficacy. As such, the monotonic efficacy assumption We sought to identify a broad sample of manuscripts is rather more controversial than the monotonic toxicity reporting recent dose-finding clinical trials in oncology. assumption. Monotonic efficacy has a plausible rationale in the treat- Identifying manuscripts ments that have formed the backbone of anti-cancer ther- Chiuzan et al. [2] conducted a systematic review of the apies for decades. Cytotoxic treatments like chemother- methods used in cancer dose-finding trials. Their find- apy damage tumours and healthy tissue alike. The pres- ings mirrored those of Rogatko et al. [1]fromthepre- ence of toxicity is a sign that anti-tumour activity is vious decade that over 90% of dose-finding trials use probably happening as well. In this setting where toxi- a rule-based design like 3+3. The authors found 1,712 city and efficacy are broadly accepted to be coincident, manuscripts published between 2008 and the first half of the use of dose escalation designs became commonplace. 2014. The authors published in their paper a large table In recent years, however, numerous targeted therapies, summarising the trials that used model-based methods, immunotherapies and cell therapies have been approved like CRM or EWOC, of which there were 92 examples.
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