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R. Gaynor
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MS 28 - Future Clinical Trials (ID 46)
- Event: WCLC 2015
- Type: Mini Symposium
- Track: Other
- Presentations: 1
- Moderators:S. Mandrekar, M. Redman
- Coordinates: 9/09/2015, 14:15 - 15:45, 205+207
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MS28.04 - Drug Development and Drug Approval (ID 1976)
15:20 - 15:40 | Author(s): R. Gaynor
- Abstract
- Presentation
Abstract:
Over the past decade, there have been rapid advances in cancer drug discovery and development. Much of this progress has resulted from a better understanding of the genetic changes in cancer and the development of agents that target the underlying biology of disease. In addition, an improved understanding of the immune system and cancer has resulted in the development of immune checkpoint inhibitors that have profound clinical activity in many tumors. Finally, the role of the tumor microenvironment in the regulation of tumor growth, metastatic spread, and modulation of the immune system is an area of intense investigation[1]. This enhanced understanding of the complex biology of cancer, and novel drugs against these new targets, have ushered in an exciting era in drug development leading to important new drug approvals[2]. An increasingly important aspect in both clinical development and drug approval is the incorporation of biomarkers and companion diagnostics to select patients more likely to benefit from specific therapies[3]. In lung cancer, the utilization of companion diagnostics has been key in the clinical development of TKIs directed at a variety of EGFR mutations and ALK alterations[4,5,6]. Other biomarker tests have been used to identify genes such as BRAF and ROS1 in order to develop clinical trials to test approved targeted agents with activity in patients with these molecular alterations[7]. Ongoing clinical studies exemplified by the Lung Master Protocol and NCI Match Protocol are utilizing biomarker panel strategies, including next generation sequencing (NGS), to identify patients with specific mutations in lung and other cancers respectively[4]. The use of NGS to characterize molecular alterations is also becoming more common to characterize patients’ tumors in both the academic and community settings. Immunohistochemistry assays continue to be a mainstay for understanding tumor biology and are also being utilized to quantitate markers such as PDL-1 expression in tumor immune cells in order to identify patients who are more likely to respond to immune checkpoint inhibitors[8]. In addition, analysis of biomarkers in liquid biopsies (e.g. plasma, spinal fluid) are being analyzed to provide supplemental information and/or to obviate the need for ongoing tumor biopsies during therapy[9]. Clinical development based on patient subset will increasingly be the norm, rather than the exception, in oncology. Rather than exclusively utilizing histology to screen patients for clinical trials, the use of basket trials to identify and treat patients of various histologies with agents targeted to similar molecular alterations is an approach which is increasingly being utilized[10]. In addition, retrospective analyses are being conducted to understand underlying molecular abnormalities of patients with exceptional responses to existing therapies and to use the information to design future clinical trials. One of the major challenges in clinical development is tumor heterogeneity and drug resistance. To prevent or overcome the development of drug resistance, combination therapies to target specific pathways are being explored. One such example is the use of BRAF and MEK inhibitors in the treatment of metastatic melanoma[11]. Many clinical studies in lung cancer are now incorporating mandatory tumor biopsies during the course of EGFR and ALK inhibitor therapy to identify evolving genetic changes in tumors during therapy in order to incorporate second and third generation TKIs. New mechanisms to facilitate the drug review and approval processes are underway[12]. One such mechanism is the Breakthrough Therapy (BT) Program. Breakthrough Therapy is intended to expedite the development and review of drugs for serious or life threatening conditions. Designation of a drug as a BT is based on preliminary clinical evidence that demonstrates that a new drug may have substantial improvement over available therapy and facilitates ongoing communication between the sponsor and the FDA to streamline the drug development process. Accelerated approval has been developed by the FDA for speeding the development and approval of promising therapies to treat serious disease that provides a meaningful therapeutic benefit over available therapy. Accelerated approval is based on an improvement in patient benefit utilizing surrogates of survival that are reasonably able to predict clinical benefit. The accelerated approval mechanism has been essential in facilitating new drug approvals of promising therapies. In addition, fast track designation is an FDA program intended to facilitate the development and expedite the review of drugs to treat serious medical conditions. This program allows sponsors to facilitate the review process for drug approval by having ongoing FDA interactions and utilizing a rolling review of submissions. Given the importance of biomarker-directed therapy, an additional critical component of the regulatory landscape is the review and approval of companion diagnostics at the same time as specific drug approvals. The drug-diagnostic co-development model is becoming increasingly common in oncology as biomarker-driven patient selection is required for many of the new targeted and immune therapies. Thus, an evolution in both the clinical development paradigm and the regulatory landscape is occurring based on the discovery and development of more effective, biomarker-directed targeted agents and novel immune checkpoint inhibitors.REFERENCES 1. Hanahan, D. and Weinberg, RA. Cell 2011; 144: 646-674. 2. Wolford, JE. and Tewari, KS. Future Onc. 2015; 11: 1931-1945. 3. Shen, T., Hans Pajaro-Van de Stradt, S., Yeat, NC., et al. Front in Genet. 2015; 6:215 in press. 4. Morgensztern, D., Campo, MJ., Dahlberg, S., et al. J. Thor. Onc. 2015; 10: S1-S63. 5. Somasundarsm, A., Socinski, MA., and Burns, TF. Informa 2014; 15: 2693-2707. 6. Kwak EL, Bang Y-J, Camidge DR, et al. N Engl J Med. 2010; 18: 1693-1703. 7. Camidge, DR., Pao, W., and Sequist, LV. Nature Rev. Clin. Onc. 2014; 11: 473-481. 8. Carbognin, L., Pilotto, S., Milella, M., et al. PLOS ONE 2015; 10:1371 in press. 9. Francis, G. and Stein, S. Int. J. Mol. Sci. 2015; 16: 14122-14142. 10. Catenacci, DVT. Mol. Onc. 2015; 9: 967-996. 11. Long, GV., Stroyakovskiy, D., Gogas, H., et al. NEJM 2014; 371: 1877-1888. 12. Kesselheim, AS. and Darrow, JJ. Clin. Pharm. & Ther. 2015; 97: 29-36.
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