Abstract IA24: Tolerability and Efficacy of Antiangiogenic Agents and Novel Combinations – in Search of the Optimal Therapeutic Windows

Abstract Antiangiogenic agents are associated with toxicities due to “on-target” effects on neoangiogenesis, vascular dynamics and tissue repair as well as “off-target” side effects in the case of small molecular inhibitors. Nevertheless, the therapeutic window has proven to be adequate for conferring important clinical benefits in a number of advanced tumors. As antiangiogenic therapies became widely used in patient care, progresses have been made in the efforts to identify risk factors of serious adverse reactions and establish guidelines for risk mitigation. Still, therapeutic outcomes with individual agents are limited by the complexity of tumor survival and adaptive mechanisms. Combination of agents directed at multiple tumor growth/survival pathways holds the promise of overcoming the molecular complexity of cancer and brining deeper and more sustained tumor control in patients. Indeed synergistic antitumor effects have been demonstrated with a multitude of novel combinations in preclinical studies, and the last 15 years have seen hundreds of clinical trials for combinations among molecularly targeted agents, many involving antiangiogenic therapies. However, only a few have demonstrated meaningful improvement in clinical benefit. The therapeutic windows for most combinations have been difficult to identify in the backdrop of heterogeneous patient population with various tumor molecular contexts. The fundamental challenges include: 1) Intrinsic ability of cancer to adapt to any therapeutic stress unless there is cure, 2) Shared protective/adaptive mechanisms between tumor cells and normal cells which would limit the number and duration of target inhibitions that can be tolerated, 3) Lack of patient selection in most trials for tumors uniquely sensitive to the given regimen/agents. The “new generation” medicine is providing unprecedented opportunities for cancer therapy in general, and combination approaches in particular. For example, expanding knowledge of cancer has and will continue to reveal new targets unique to tumor cells. Advances in drug design have also made available therapeutics with exquisite specificity against altered gene products versus wide type counterparts in normal tissues. Most important is the emergence of immunotherapy as the new paradigm in oncology. Given the unique mechanism of action and durability of anticancer effects, immunotherapy should be considered a mainstay in combination strategies. Clinical trials for immunotherapy-based combinations are rapidly expanding, including those combining with antiangiogenic agents. Some have produced promising preliminary results, while others showed toxicity issues. Again, the key challenge remains to be the identification and optimization of therapeutic windows. Compared to “first-generation” combination studies, however, the rapidly evolving tools for research, biomarkers and drug/biologics design have now greatly facilitated our approach to the task and will significantly enhance the potential of achieving the therapeutic goals. The presentation will review the clinical experience with antiangiogenic therapeutics and novel combinations with focus on specific examples, and discuss tolerability issues, therapeutic windows, and considerations for optimizing therapeutic outcomes in the era of precision medicine, targeted therapies and immunotherapy. Citation Format: Helen X. Chen. Tolerability and efficacy of antiangiogenic agents and novel combinations – In search of the optimal therapeutic windows. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Angiogenesis and Vascular Normalization: Bench to Bedside to Biomarkers; Mar 5-8, 2015; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl):Abstract nr IA24.