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S. Mandrekar
Moderator of
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MS 28 - Future Clinical Trials (ID 46)
- Event: WCLC 2015
- Type: Mini Symposium
- Track: Other
- Presentations: 4
- Moderators:S. Mandrekar, M. Redman
- Coordinates: 9/09/2015, 14:15 - 15:45, 205+207
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MS28.01 - Trial Designs (ID 1973)
14:20 - 14:40 | Author(s): M. Redman
- Abstract
- Presentation
Abstract not provided
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MS28.02 - Master Protocols (ID 1974)
14:40 - 15:00 | Author(s): S. Malik
- Abstract
- Presentation
Abstract:
Major advances in the understanding of molecular pathways that regulate tumor growth have led to development and FDA approval of new anticancer agents leading to improved survival in patients with certain cancer types. A common cancer like Non Small Cell Lung Cancer (NSCLC) is now subdivided in a number of molecularly defined subsets. Large randomized trials are not feasible anymore. This challenge to accrue to small subsets with availability of multiple drugs for each has led to novel trial design strategies like “Master Protocols” with multiple arms that are biomarker driven. Master Protocols are ideal if multiple molecular targets are known to drive tumor growth, if there is pre-clinical/clinical evidence that these targets can be pharmacologically inhibited and if the drugs to be tested are available. These protocols provide consistency of drug development approach regardless of intended target, utilize resources (including patient resources) in an efficient manner and have potential of bringing safe and effective drugs to patients faster. On the other hand these trials are time and resource intense, and some trials with public/private partnership have added need of a high level coordination. Part of NCI precision medicine initiative has led to “Master Protocols” like Lung-MAP, ALCHEMIST and NCI-MATCH. The Lung-MAP trial is evaluating patients with squamous cell lung cancer who have progressed beyond at least one line of therapy. The study divides patients into multiple treatment arms based on the molecular profiles of their cancers testing efficacy of targeted drugs. Promising results in any arm can lead to testing the drugs in that treatment arm in more patients, with the goal of more rapid drug approvals in these small subsets of squamous cell lung cancer patients. ALCHEMIST is testing the benefits of molecularly targeted adjuvant (post-surgical) treatment of patients with early-stage lung adenocarcinomas whose tumors have either an EGFR gene mutation or an anaplastic lymphoma kinase (ALK) gene rearrangement. Depending on the genetic abnormality in a tumor, the patient will be randomized to receive the EGFR protein kinase inhibitor erlotinib or the ALK protein kinase inhibitor, crizotinib against a placebo. The Food and Drug Administration (FDA) has approved these molecularly targeted therapies for advanced lung adenocarcinoma in patients with the relevant genetic changes. It is expected that most patients with early lung adenocarcinoma who are screened will not be eligible for the therapeutic portion of this trial because their tumors will not have the necessary mutations. However, the tumor samples from these patients will be saved, and, if they relapse while on standard treatment, their tumors will be biopsied again and analyzed for insight into the progression of their disease and for potential therapeutic approaches suggested by this analysis. The NCI-MATCH trial will test a large number of agents in virtually any tumor type in which appropriate abnormalities are identified. This umbrella protocol will examine between 20 and 25 drugs, including those that have been FDA-approved for the treatment of cancer at another tumor site or experimental agents that have shown activity against a known target at one or more tumor sites. If the response rate to a particular agent is high, the number of patients evaluated with that treatment would be expanded to further explore whether the targeted treatment represents a substantial advance over standard chemotherapy. If a tumor becomes resistant to the first test drug, it will be re-biopsied to see if another targeted therapy might be effective and to understand the basis for resistance to the initial treatment. By studying multiple agents at the same time, a higher proportion of patients will be eligible for the trial, and efficient progress can be made in the assessment of clinical benefit.
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MS28.03 - Biomarkers (ID 1975)
15:00 - 15:20 | Author(s): F.R. Hirsch
- Abstract
- Presentation
Abstract not provided
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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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Author of
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ORAL 23 - Prevention and Cancer Risk (ID 121)
- Event: WCLC 2015
- Type: Oral Session
- Track: Prevention and Tobacco Control
- Presentations: 1
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ORAL23.01 - A Randomized Phase IIb Trial of Myo-Inositol in Smokers with Bronchial Dysplasia (ID 856)
10:45 - 10:56 | Author(s): S. Mandrekar
- Abstract
- Presentation
Background:
Previous preclinical studies and a phase I clinical trial suggested myo-inositol may be a safe and effective lung cancer chemopreventive agent. We conducted a randomized, double blind, placebo-controlled, phase IIb study to determine the chemopreventive effects of myo-inositol in smokers with bronchial dysplasia.
Methods:
Smokers with ≥1 site of dysplasia identified by autofluorescence bronchoscopy-directed biopsy were randomly assigned to receive oral placebo or myo-inositol, 9 g once/day for two weeks, and then twice/day for 6 months. The primary endpoint was change in dysplasia rate after six months of intervention on a per participant basis. Other trial endpoints reported herein include Ki-67 labeling index and pro-inflammatory, oxidant/anti-oxidant biomarker levels in blood and bronchoalveolar lavage fluid (BAL).
Results:
Seventy four (n=38 myo-inositol, n=36 placebo) participants with a baseline and 6-month bronchoscopy were included in all efficacy analyses. The complete response and the progressive disease rates were 26.3% versus 13.9% and 47.4% versus 33.3%, respectively, in the myo-inositol and placebo arms (p=0.76). The mean percent change in Ki67 labeling index in bronchial biopsies with dysplasia was -22.8% and -6.2%, respectively, in the myo-inositol and placebo arms (p=0.34). Compared with placebo, myo-inositol intervention significantly reduced IL-6 levels in BAL over 6 months (p=0.03) and had borderline significant effects on BAL myeloperoxidase (p= 0.06) level.
Conclusion:
The heterogeneous response to myo-inositol suggests a targeted therapy approach based on molecular alterations is needed in future clinical trials to determine the efficacy of myo-inositol as a chemopreventive agent.
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