Rethinking cancer drug dosing: How Project Optimus is redefining oncology drug dose optimisation

Oncology Drug Development Is Undergoing a Fundamental Shift

For decades, oncology dose selection has been driven by a simple principle: identify the maximum tolerated dose (MTD) and advance it into later-stage development. While this approach was appropriate for traditional cytotoxic chemotherapies, the emergence of targeted therapies, biologics and immunotherapies has exposed limitations.

Today’s cancer treatments often achieve meaningful clinical activity without requiring the highest tolerable dose. Yet many development programmes continue to rely on historical dose-escalation paradigms that may overlook opportunities to improve long-term tolerability, patient adherence and overall treatment outcomes.

Recognising this challenge, the FDA launched Project Optimus, an initiative that is changing expectations for oncology dose optimisation. The programme signals a decisive move away from selecting the highest dose patients can tolerate and toward identifying the dose that delivers the best balance of efficacy, safety and quality of life.

Why Dose Optimisation Matters

Insufficient dose evaluation can have significant consequences for patients, sponsors and regulators alike. Chronic low-grade toxicities may compromise treatment adherence, while severe adverse events can lead to dose reductions, treatment discontinuations and diminished therapeutic benefit. In some cases, inadequate dose optimisation may delay approvals, trigger post-marketing requirements or jeopardise a product's commercial and regulatory success.

At the same time, patients with advanced and metastatic cancers continue to need rapid access to therapies that are not only effective, but also safe and sustainable for long-term use.

The New Regulatory Expectation

Project Optimus establishes a roadmap for oncology dose optimisation, which should be integrated early and systematically throughout oncology development programmes. The FDA is encouraging sponsors to generate robust pharmacokinetic (PK), pharmacodynamic (PD), exposure-response and patient-reported outcome data, while comparing multiple dose levels before pivotal studies whenever feasible.

Importantly, expedited development pathways do not remove the need for dose optimisation. Instead, sponsors are expected to demonstrate that dose selection decisions are supported by comprehensive clinical evidence and a clear understanding of benefit-risk trade-offs.

What This Whitepaper Covers

This whitepaper examines the scientific and regulatory drivers behind Project Optimus and explores the practical implications for oncology developers. It highlights:

• Why traditional MTD-based development is increasingly inadequate for modern cancer therapies
• Practical examples of the oncology dose-selection conundrum
• Practical examples of toxicities in novel anti-cancer therapies using traditional dose-finding paradigms
• Sotorasib: the poster child for Project Optimus
• What does Project Optimus propose?
• Global regulatory guidance for dose selection in oncology medicines
• Potential limitations of Project Optimus
• Is the FDA waiving dose optimisation for orphan drugs?
• Examples of dose-finding done right with Project Optimus

As Project Optimus continues to influence global oncology development, organisations that proactively adopt dose-optimisation strategies will be better positioned to accelerate development timelines, strengthen regulatory submissions and deliver more sustainable treatment outcomes for patients.

Download the full whitepaper to explore how oncology developers can adapt their clinical development strategies to meet evolving regulatory expectations and maximise the probability of long-term success.