Project Optimus: Why does the oncology dosing paradigm need to change?

Introduction

The emergence of targeted therapies, biologics and immunotherapies has transformed the oncology treatment landscape, raising important questions about whether traditional dose-finding approaches remain fit for purpose. Historically, oncology drug development has relied on identifying the maximum tolerated dose (MTD) using the conventional 3+3 trial design. However, this paradigm was developed for cytotoxic chemotherapies and may not adequately account for the unique pharmacokinetic (PK), pharmacodynamic (PD), dose-response and exposure-response characteristics of modern anti-cancer therapies.

This blog explores why the FDA's Project Optimus initiative is driving a shift in oncology dose optimisation, highlighting the limitations of traditional dose-escalation strategies and the potential consequences of insufficient dose evaluation. It examines real-world evidence from reviews of approved oncology medicines, discusses the challenges of dose selection in targeted therapies, and presents examples of anti-cancer drugs that required dose modifications to improve safety and tolerability.

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Historically, dose-finding trials for oncology medicines have followed a paradigm of determining the MTD to be used in later-phase clinical trials.

The MTD paradigm often takes the form of a 3+3 trial design in which three patients are given a selected dose of a therapeutic agent, and if there are no dose-limiting toxicities (DLTs), an escalated dose is given to a further three patients. This continues until two out of three patients get DLTs and the MTD is identified. This dose selection paradigm typically involves a limited number of patients over a short observation period.^1-3

However, this dose-finding programme was originally designed for cytotoxic chemotherapies, which followed a steep dose-response relationship,  with an inherent lack of target specificity. Furthermore, patients may have been more willing to accept toxicity due to a lack of treatment options.^1-3 All of these considerations have been significant in driving an MTD paradigm. However, the treatment landscape has changed significantly. Modern oncology therapies include molecularly targeted agents (MTAs), biologics and immunotherapies (as single agents or in combination),¹ all of which act on specific molecular pathways that are critical to cancer cell proliferation. The reason this is important in the context of dose selection and dose escalation is that these targeted therapies have an inherently different dose-response relationship compared with cytotoxic chemotherapies. In addition, the MTD dosing paradigm has a short observation period, which is better suited to limited/defined-treatment-duration cytotoxic chemotherapy; consequently, this paradigm does not adequately evaluate dosing during the longer-term treat-to-progression posology of contemporary targeted therapies.¹ Utilising the historical MTD dosing paradigm doesn’t sufficiently consider pharmacokinetics (PK), pharmacodynamics (PD), and dose- and exposure-response relationships, to select a dosage(s) for later-stage trials.^1,3 As a result, novel therapies may show a similar efficacy to the MTD, but at lower doses.

Project Optimus recognises that insufficient dose evaluation may lead to increased chronic low-grade toxicity, which may jeopardise long-term maintenance on an effective therapy.² Additionally, severe toxicities can lead to dose reductions, premature discontinuation in clinical trials and irreversible toxicities that reduce a patient’s options to benefit from future therapies with overlapping toxicity. Both low-grade chronic and acute severe toxicity may narrow the treatment landscape, potentially impacting the overall survival (OS) of cancer patients.² From a medicine developer’s regulatory perspective, the consequences of not optimising dosage can include the medicine not being approved, being withdrawn from the market, or requiring additional time-consuming and costly dosing exploration in phase 3 or post-marketing studies.

Even with the evolution of targeted therapies to treat cancers, many advanced and metastatic cancers remain incurable, and patients are still waiting for safe, tolerable and efficacious therapeutic options, making the rapid access to such medicines critical.

Practical examples of the oncology dose-selection conundrum

To put the need for better dosing paradigms in a practical perspective, a review of sixty European Public Assessment Reports from oncology medicines approved between 2015 and 2020 was conducted to determine if the optimal dose was selected in the novel anti-cancer agents that were approved. The review highlighted that:⁴

• A dose-response relationship was identified in five dossiers (8%)
• The MTD was the selected dose for 15 anti-cancer agents (25%)
• The MTD was not determined in 27 out of 60 cases (59%)

Additionally, when the MTD was determined but not selected as the final dose, the dose selection criteria included toxicity, exposure response, PK data and PD data in 7 out of 18 cases.⁴ For protein kinase inhibitors and monoclonal antibodies (mAbs), tolerability was analysed separately as it was determined that the dosing interval and mitigation of adverse events (AEs) differ for these types of therapies.⁴

Regarding the median discontinuation, dose reduction and dose interruption rates due to AEs of protein kinase inhibitors were 10%, 26% and 45% for monotherapy and 13%, 47% and 55% for combination therapy, respectively.⁴ The median discontinuation rates due to AEs for mAbs were 8% for monotherapy and 26% for combination therapy.⁴

The review concluded that the dose-response relationship had not been established for the majority of oncology medicines approved during this time period and that these medicines were not well tolerated, as reflected in the high discontinuation and dose reduction rates. The review also highlighted that, as there was inadequate dose-response data, it is unknown if the optimal dose was selected for the medicines that were approved. It is worth noting that these medicines were approved before the FDA introduced Project Optimus and before the European Medicines Agency’s (EMA’s) guideline on the clinical evaluation of anti-cancer medicinal products.⁴

So, to compare, a more recent review of anti-cancer drugs with initial EMA and FDA approval between 1 January, 2020 and 30 June, 2023 was conducted by Op ‘t Hoog et al., 2024 (Project Optimus was created in 2021).⁵ A total of 31 anti-cancer drugs were included, in which 20 out of the 31 anti-cancer drugs were considered to be potential candidates for dose optimisation.⁵ Specifically, the review deemed that the safety of 10 of the 31 drugs could be improved by reducing the dose without compromising efficacy, and a further 10 drugs could have the dosage regimen modified to improve patient convenience with less frequent dosing or reducing pill burden. Overall, the review considered 9 out of the 31 drugs had an optimum dose selection.⁵

Additionally, the review found that the traditional 3+3 trial design was the most frequently used dosing paradigm in phase 1 trials to select the recommended phase 2 dose (RP2D; 25 out of 31 drugs).⁵ Similar to the review by Maliepaard et al., 2021,⁴ the MTD was not determined in 19 of the 31 drugs in phase 1 trials, and this was determined to be due to no DLTs observed within the investigated dosing range.⁵

Among these 19 drugs where MTD was not determined, the highest administered dose within the investigated dosing range was used as the RP2D in five drugs; for the remaining 14 drugs, a lower dose was selected as the RP2D due to multiple reasons (e.g. target saturation or efficacy data).⁵ For 12 of 31 drugs, the MTD was determined, and in four of these 12 drugs, the MTD was selected as the RP2D. For the remaining eight drugs in which the MTD was determined, a lower dose than the MTD was selected as the RP2D. For only 3 out of 31 drugs, two or more dose levels were studied in phase 2.⁵

Both of the reviews highlight that the traditional 3+3 dose-finding design was widely used, with the MTD being either used as the RP2D or not being determined at all. Despite the development of targeted agents in oncology to enable precision medicine, the traditional 3+3 design does not necessarily lead to the selection of the most favourable dose, and the tolerability of these agents often remains poor. It is worth noting that although these reviews were conducted on anti-cancer drugs that were approved during Project Optimus’ inception, the phase 1 trials were most certainly conducted years before the FDA rolled out this initiative. Nevertheless, they confirm the shortcomings of the traditional dose-selection approach.

Practical examples of toxicities in novel anti-cancer therapies using traditional dose-finding paradigms

Regorafenib

Regorafenib (STIRVAGA®) is an oral multikinase inhibitor approved for colorectal cancer, gastrointestinal stromal tumour and hepatocellular carcinoma at a recommended dose of 160 mg. A meta-analysis investigated the scheduled treatment modifications of regorafenib associated with AEs across seven randomised controlled clinical trials involving 2,099 patients.⁶ The meta-analysis observed that regorafenib was associated with higher incidences of permanent discontinuation, dose interruptions and dose reductions in patients receiving regorafenib, which were 9.7%, 57.2% and 47%, respectively, compared with 3.3%, 16.7% and 7.7% in the placebo group at the recommended 160 mg dose.⁶ The meta-analysis also highlighted that in real-world practice and retrospective studies of regorafenib dosing, initial doses of 80-120 mg resulted in lower Grade 3-4 AEs but with similar efficacy to the recommended 160 mg dose.⁶ Similarly, using a dose-escalation strategy starting at 80 mg and increasing to 160 mg via 40 mg increases over 3 weeks also showed a safe and effective alternative dosing strategy to the initial 160 mg recommended dose.⁶

Shah et al. (2021)⁷ highlighted several other oncology therapies whose doses or dosing schedules were modified for safety and tolerability after approval(see Table 1 for details).⁷

Table 1: Oncology therapies with modified dosing

Summary

Traditional oncology dose-finding approaches were developed for cytotoxic chemotherapies and focused on identifying the maximum tolerated dose. However, the evolution of targeted therapies, biologics and immunotherapies has exposed limitations in this paradigm, particularly when treating patients over longer periods and when efficacy may be achieved at doses below the MTD.

Conclusions from reviews of approved oncology medicines demonstrate that dose-response relationships are often not fully established, while dose reductions, interruptions and discontinuations due to adverse events remain common. These findings suggest that traditional dose-selection methods do not always identify the most favourable dose for balancing efficacy and tolerability.

Project Optimus seeks to address these challenges by encouraging more comprehensive dose optimisation strategies that incorporate PK, PD and exposure-response data to support dose selection.

As oncology drug development continues to evolve, optimising dose selection will be critical to improving patient outcomes, reducing treatment-related toxicity and ensuring that novel therapies are both effective and sustainable for long-term use.

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