Combination therapies are reshaping the future of cancer care. Finding the right dose for each regimen is one of the field’s most complex and consequential challenges. Recent regulatory shifts and advances in trial design are empowering sponsors to move beyond the traditional “maximum tolerated dose” (MTD) paradigm. The focus is now on data-driven strategies that maximize both efficacy and safety.

Why Dose Optimization Matters More Than Ever

Combination regimens, which pair immunotherapies, targeted agents, and cytotoxic chemotherapies, and biologics, are now central to modern oncology practice. These combinations can deepen patient responses and delay resistance. However, they also introduce new complexities in determining the optimal dose for each component.

Historically, dose selection relied on the MTD, especially for cytotoxic agents. With the rise of new, innovative therapies, higher doses do not always translate to better outcomes. In fact, the optimal biological dose may be lower than the MTD, balancing efficacy with tolerability and long-term safety.

The Regulatory Revolution: Project Optimus and Beyond

The U.S. Food and Drug Administration (FDA) has catalyzed a paradigm shift with initiatives like Project Optimus. This program encourages sponsors to move away from MTD. It emphasizes the need for robust, randomized data on safety and efficacy across a range of doses before registration trials begin.

FDA guidance from August 2024 and July 2025 underscores the expectation that sponsors use all available evidence, including pharmacokinetics (PK), pharmacodynamics (PD), exposure-response (E-R) analyses, and more, to justify dose selection. The message is clear: finding the right dose is as important as finding the right drug.

However, global trials must also meet requirements from other regulatory bodies such as the European Medicines Agency (EMA) and its evolving guidance, as well as the National Medical Products Administration (NMPA) in China, which has its own unique requirements. These differences can create operational complexity and regulatory uncertainty, especially for combination therapies where multiple agents and interactions are involved.

Best Practices for Dose Optimization in Combination Trials

1. Rigorous Preclinical and Clinical Profiling

Sponsors must begin with robust data on each agent’s pharmacology, toxicology, and clinical safety. Biomarkers, such as circulating tumor DNA (ctDNA), can provide dynamic insights into response and resistance, supporting model-informed drug development (MIDD).

2. Innovative Trial Designs

Modern dose-escalation designs go beyond the classic 3+3 algorithm. Model-based approaches (such as Continual Reassessment Method and Bayesian Logistic Regression Model) and model-assisted designs (such as Bayesian Optimal Interval Design and Keyboard) offer greater efficiency and safety, especially for complex combinations.

3. Adaptive and Patient-Centered Approaches

Randomized dose selection, adaptive designs, and interim analyses help sponsors focus on the most promising dose levels. These strategies ensure that both known and unknown patient variables are balanced, supporting confident dose selection.

4. Data-Driven Decision Making

Exposure-response modeling, Cox proportional hazards analysis, and tumor growth inhibition models are powerful tools for identifying optimal doses. These methods account for confounding factors and population variability, ensuring that dose recommendations are robust and generalizable.

Operational and Global Considerations

Sponsors must plan for operational feasibility, regulatory requirements across regions, and the complexities of enrolling diverse patient populations. Partnering with experienced clinical research organizations (CROs) can streamline trial execution, data management, and regulatory engagement. This accelerates the path to optimized, patient-centered therapies.

Toward a New Standard in Oncology

As combination therapies redefine the oncology landscape, dose optimization is emerging as a pivotal determinant of clinical and commercial success. By integrating translational science, adaptive trial designs, and model-informed development, sponsors can meet evolving regulatory standards and, most importantly, improve outcomes for patients with cancer.

Partnering with IQVIA empowers organizations to confidently navigate the complexities of combination dose optimization. IQVIA’s deep expertise in clinical trial design, advanced analytics, and regulatory strategy accelerates the development of optimized, effective, and well-tolerated combination regimens. Through innovative approaches and global collaboration, IQVIA is helping sponsors deliver better therapies and brighter futures for patients worldwide.

To learn more about design, modeling, and operational considerations of combination therapy dose optimizations for biotech and pharma, download our white paper.

To learn more about integrating best practices and regulatory expectations when optimizing doses for cancer combination therapies, download our insight brief.