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Combine and conquer: challenges for targeted therapy combinations in early phase trials
Juanita S Lopez1, Udai Banerji1
1Drug Development Unit, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sycamore House, Downs Road, London SM2 5PT, UK.
Abstract:
Our increasing understanding of cancer biology has led to the development of molecularly targeted anticancer drugs. The full potential of these agents has not, however, been realised, owing to the presence of de novo (intrinsic) resistance, often resulting from compensatory signalling pathways, or the development of acquired resistance in cancer cells via clonal evolution under the selective pressures of treatment. Combinations of targeted treatments can circumvent some mechanisms of resistance to yield a clinical benefit. We explore the challenges in identifying the best drug combinations and the best combination strategies, as well as the complexities of delivering these treatments to patients. Recognizing treatment-induced toxicity and the inability to use continuous pharmacodynamically effective doses of many targeted treatments necessitates creative intermittent scheduling. Serial tumour profiling and the use of parallel co-clinical trials can contribute to understanding mechanisms of resistance, and will guide the development of adaptive clinical trial designs that can accommodate hypothesis testing, in order to realize the full potential of combination therapies.
Insights
Molecularly targeted anticancer drugs show promise, but resistance limits their effectiveness. Combining therapies and adaptive trial designs are key to overcoming resistance and maximizing clinical benefits for cancer patients.
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.
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