Bringing new cancer treatments to patients is a race against time, and drug developers feel pressure to move quickly. However, dose finding can present a significant rate limiting step, as developers may struggle to find the optimal dosage for maximum efficacy and minimal toxicity.
The story of sotorasib, a breakthrough treatment for KRAS-mutated non-small-cell lung cancer (NSCLC), offers valuable lessons for the future of dose optimization in oncology.
> Read more on sotorasib's development in the full commentary here.
The sotorasib story: Why dose optimization matters
In early sotorasib trials, a 960 mg dose was found effective for treating NSCLC, but later studies indicated that a 240 mg dose might offer similar benefits with fewer side effects. Yet, the 960 mg dose was maintained for clinical use in FDA labeling.
This decision underscores a central dilemma in oncology drug development: how and when to evaluate for the optimal dose dosing. Without early and comprehensive dose optimization, developers risk either underdosing patients, leading to reduced efficacy, or overdosing, increasing the risk of adverse effects. In either case, the patient’s outcomes may be compromised.
Sotorasib’s development is an example of how crucial early dose optimization is in bringing safe and effective drugs to market. The drug’s initial approval came from promising data on tumor response, but after accelerated approval was granted, follow-up studies suggested that lower doses might achieve similar results. This sparked discussions about the ideal dose and the role of post-marketing trials in refining dosing strategies.
Despite indications that a lower dose might suffice, the 960 mg dose was retained based on survival data and efficacy outcomes. This experience highlights the importance of designing trials that incorporate comprehensive dose-finding efforts early on, rather than trying to "retrofit" a solution after approval.
Project Optimus: An FDA Oncology Initiative
The FDA’s Project Optimus seeks to ensure that the kind of retrospective dose optimization we saw with sotorasib becomes less common. By encouraging developers to evaluate multiple doses early—ideally before pivotal trials—Project Optimus aims to make dose selection a more data-driven, strategic decision rather than a reactive one.
For drug developers, this means that dose-finding studies should no longer be an afterthought. Instead, they should be integrated into the earliest phases of clinical development to provide robust data that inform later trial stages. In the case of sotorasib, such early optimization might have streamlined the decision-making process and provided greater clarity on the best dose for patients.
Strategies for Effective Dose Optimization
Incorporate Dose-Finding in Early Trials
- By integrating randomized dose-finding cohorts in Phase 1b or Phase 2 trials, developers can gather comparative data on both efficacy and safety at different dose levels. This strategy not only helps identify the optimal dose but also enables early adjustments based on patient responses. Bayesian adaptive designs, for example, allow for real-time modifications of dosing strategies during a trial.
Leverage Pharmacokinetic/Pharmacodynamic (PK/PD) Modeling
- Advanced PK/PD modeling can predict the optimal dosage based on drug exposure and its effects on target engagement. This modeling helps identify dosing regimens that maximize clinical benefits while minimizing side effects, particularly important in oncology where treatment can have severe toxicities. Simulating various scenarios ensures that patients receive the right dose for their specific needs.
Consider Adaptive Trial Designs
- Adaptive trial designs offer flexibility to adjust dosing throughout a study, based on accumulating data. If early data suggest that a lower dose is equally effective, subsequent patients can be enrolled at that dose. This adaptability allows trials to respond to new insights and improves both patient outcomes and trial efficiency.
Explore Alternative Dosing Schedules
- Beyond selecting a single dose, developers should consider alternative dosing schedules—such as intermittent dosing or maintenance therapy after a loading dose—to balance efficacy with tolerability. These strategies can help reduce the cumulative toxicity patients face without sacrificing treatment effectiveness.
Precision medicines in oncology drug development
As oncology becomes increasingly personalized, dose optimization must also reflect the diversity of patients and their unique responses to treatment. Precision medicine allows for the tailoring of doses to individual needs, improving outcomes and reducing unnecessary exposure to high doses. By investing in biomarker development and companion diagnostics early, developers can ensure that the right patients receive the right dose, at the right time.
Collaborating with regulatory agencies
The success of oncology drug development also hinges on close collaboration with regulatory agencies. Early engagement with the FDA—through Pre-IND or End-of-Phase meetings—allows for alignment on dose optimization strategies and ensures that trials meet regulatory expectations. Even products that are granted Breakthrough Designation, will still need to robustly evaluate dose as part of their clinical development program.
Post-approval and the role of real-world data
Even after a drug is approved, the need for dose optimization continues. Post-marketing trials and real-world data collection are essential to understanding long-term efficacy, safety, and patient outcomes. Sotorasib’s post-approval studies showed that even after accelerated approval, the optimal dose needed further refinement—a testament to the importance of ongoing data collection.
Embracing innovation and collaboration in oncology drug development
The future of oncology drug development lies in embracing innovation—whether through novel trial designs, PK/PD modeling, or adaptive dosing strategies. By working closely with regulatory bodies and leveraging precision medicine, drug developers can optimize treatments faster and more effectively. For those navigating these complexities, partnering with the right CRO is a critical first step.
Precision for Medicine specializes in guiding our partners through the intricacies of oncology drug development, from pre-IND meetings to post-approval studies. Our experience ensures that every decision is informed by data and aligned with regulatory requirements, helping to bring the best therapies to patients faster and more effectively.
Optimize your development strategy by partnering with Precision’s clinical, translational, and regulatory experts for your next oncology program.
