Combine and conquer: challenges for targeted therapy combinations in early phase trials

Area of Science:

• Oncology
• Cancer Biology
• Pharmacology

Background:

• Advances in cancer biology have spurred the development of molecularly targeted anticancer drugs.
• Intrinsic (de novo) and acquired resistance mechanisms, often involving compensatory signaling pathways or clonal evolution, limit the clinical efficacy of these targeted agents.
• Combination therapies offer a strategy to circumvent resistance and improve patient outcomes.

Purpose of the Study:

• To explore challenges in identifying optimal drug combinations and combination strategies for cancer treatment.
• To address complexities in delivering combination targeted therapies to patients.
• To investigate methods for overcoming resistance to molecularly targeted anticancer drugs.

Main Methods:

• Reviewing current understanding of resistance mechanisms to targeted cancer therapies.
• Analyzing strategies for combining targeted treatments.
• Discussing challenges in drug delivery and patient treatment schedules.
• Highlighting the role of serial tumor profiling and co-clinical trials.
• Proposing adaptive clinical trial designs for hypothesis testing.

Main Results:

• Combination targeted treatments can overcome certain resistance mechanisms, offering clinical benefits.
• Identifying optimal drug combinations and strategies remains a significant challenge.
• Treatment-induced toxicity and pharmacodynamic limitations necessitate creative intermittent dosing schedules.
• Serial tumor profiling and co-clinical trials aid in understanding resistance.
• Adaptive clinical trial designs are crucial for testing hypotheses in combination therapy.

Conclusions:

• Realizing the full potential of molecularly targeted anticancer drugs requires overcoming resistance through combination therapies.
• Creative intermittent dosing schedules are necessary due to toxicity and pharmacodynamic constraints.
• Advanced approaches like serial tumor profiling, co-clinical trials, and adaptive trial designs are essential for guiding the development and application of effective combination therapies.