PMO Live 2015 – Highlights from Thursday July 23

PMO Live Day 2 Highlights

The second day of the 2015 Fourth Annual PMO Live Conference of the Global Biomarkers Consortium (GBC) opened with a review of yesterday’s presentations and a preview of today’s talks by the meeting’s co-chair, Dr. Hope Rugo. She stressed the multidisciplinary nature of the day’s proceedings that makes GBC unique among molecular biomarker/personalized medicine conferences. Not only is it focused on the basic biology and genetics of molecular biomarker development, but also includes in-depth discussions of the practical application of novel molecular pathways and biomarkers to clinical management issues across a wide variety of solid tumors and hematologic malignancies. This is truly a forum where basic scientists, healthcare providers, pharmacists, regulators, and industry representatives can interact. Dr. Rugo remarked, “We had interesting discussions yesterday on the heterogeneity of human cancers and the role of biomarkers in helping to direct therapy. Today we will continue this discussion and move into prevention and early detection, and how biomarkers have impacted oncology clinical trials.”

Keynote Presentation on Targeting Genetic Drivers in Premalignancy

The first session of the day was a keynote presentation by Dr. Scott Lippman, who is Director of the University of California (UC) San Diego Moores Cancer Center, Senior Associate Dean and Associate Vice Chancellor for Cancer Research and Care and Professor of Medicine and Chugai Pharmaceutical Chair at UC San Diego, and Adjunct Professor at the Salk Institute for Biological Studies, Sanford-Burnham Medical Research Institute. Dr. Lippman’s presentation was on targeting genetic drivers in early cancer or premalignancy. Using lung adenocarcinoma as a model, he discussed oncogenic genetic drivers in these tumors. Dr. Lippman also touched upon genetic driver events in oral premalignancy and how certain targeted agents can prevent progression to oral cancer. He stressed the need for identification of genetic drivers in premalignant and benign conditions, identification of high-risk populations carrying these genetic aberrations, the need to identify populations most likely to respond to targeted agents, and ongoing research in the identification of new targets for intervention, both in cancer and premalignant conditions.

Case Studies of Innovative Molecular Pathways and Biomarkers in Treating Hematologic Malignancies

This strictly clinical session focused on presentations of typical cases in acute and chronic myelogenous leukemia by Dr. Jorge Cortes, multiple myeloma by Dr. A. Keith Stewart, chronic lymphocytic leukemia (CLL) by Dr. Michael Keating, and lymphoma by Dr. Joseph Connors, with a discussion by the experts regarding how they would manage patients with these hematologic malignancies to achieve personalized care. These dynamic “Expert’s Perspective” presentations engaged the attendees in making management decisions on the use of molecular biomarkers in real-life cases in these tumor types, using the latest data from the literature and recent meetings to support and explain why certain management decisions are made. The “this is how I would do it” approach has been a huge audience favorite at GBC, and the medical hematologists and oncologists in the audience engaged in a dynamic discussion during this session. Dr. Cortes focused on discussions of the molecular biomarkers and genetic mutations related to resistance to TKI therapy in chronic myeloid leukemia (CML), and the development of combination therapy to prevent emergence of resistance to existing agents. He also discussed the genetic and immunologic characteristics of CML patients who relapse early after TKI therapy. This was followed by his discussion of biomarker use in stratifying risk in acute myelogenous leukemia (AML) and the development of new targeted agents (eg, FLT3 inhibitors) for this malignancy. Dr. Stewart’s presentation on biomarkers that are used in treating multiple myeloma (MM) focused on a clinical vignette of a patient with stage III IgGk MM. “There are ~1000 exomes that define the genomic landscape of MM, but only a limited set of genes that are recurrently mutated in MM and are actionable (eg, BRAF and IDH1),” Dr. Stewart said. Using his case as an anchor, he described the use of gene-expression levels of cereblon in determining the efficacy and safety of pomalidomide as an example of immunomodulating agents. Dr. Keating’s presentation on biomarkers in CLL concerned the relationship between certain genetic mutations (IgVH, 13q, 11q, 17p) and time to treatment failure with FCR triple therapy. He discussed the clinical data with targeted agents that are more effective in patients with these mutations—eg, alemtuzumab and lenalidomide. There are also novel mutations in CLL that impact survival (eg, TP53 andNOTCH1) as well as response to therapy, but new agents in development may be safe and effective in treating patients with these mutations (inhibitors of BTK, PI3K-delta, and Syk). Dr. Connors then addressed the role of biomarkers in treating lymphoma. He started his presentation by showing that over the past 50 years, there has been a >60% reduction in death from cardiovascular disease, but only a ~5% reduction in cancer-related deaths. He then discussed what advances have been made in treating cancer. With respect to molecular biomarkers, Dr. Connors suggested that “biomarkers are most useful when they alter treatment decisions.” In that vein, she reviewed the molecular diagnosis of lymphoma gene-expression subtypes, using diffuse large B-cell lymphoma (DLBCL) as a model, and the impact that this assessment has had in directing therapy with targeted agents such as BTK inhibitors. A discussion followed this session regarding the cost of developing and value in using molecular biomarkers in cancer. “Any time you can identify a biomarker that tells you what not to treat with is of great value and saves costs of cancer care,” suggested Dr. Connors. However, Dr. Cortes was of the opinion that “many biomarkers will make very little difference in how you treat patients, and are therefore not worth the cost of development, but others are more significantly impactful.”

A Keynote Presentation on the Industry Perspective on the Use of Biomarkers in Cancer—How Are They Really Used?

Following the exhaustive clinical discussions yesterday and today around the use of molecular biomarkers in driving management of solid tumors and hematologic malignancies, Dr. Roman Yelensky, who leads biomarker discovery and companion diagnostic assay development for Foundation Medicine’s pharmaceutical partnerships and oversees genomic data analysis for academic cancer research collaborations, spoke about his industry’s perspectives on personalized medicine in oncology and biomarker use. Dr. Yelensky was the perfect speaker on this topic, as he was a co-developer of the sequence analysis components of the FoundationOneTM next-generation sequencing (NGS)-based comprehensive cancer genomic profiling test and led assay validation studies supporting clinical laboratory accreditation. Dr. Yelensky’s presentation traced the progression of cancer diagnosis from a strictly histologic classification to histomolecular assessment, and the diagnostic challenges in using such a system. He noted that the number of known clinically relevant cancer genes across solid tumors is high, there is low tumor purity in many clinical specimens, and many clinical cancer specimens are small needle biopsies, fine needle aspirations, and cell blocks. Dr. Yelensky then reviewed FoundationOne’s testing matrix and clinical validation studies, and provided examples of molecular biomarkers that have been developed and successfully used in informing cancer therapy, especially in lung cancer and breast cancer. However, he cautioned that translating research-grade NGS to a comprehensive clinical cancer diagnostic assay requires extensive optimization and rigorous analytical validation to determine test accuracy and reproducibility prior to clinical use. On the positive side, comprehensive profiling can identify more targeted treatment options than “hot spot” tests and enable innovative trial designs; moreover, patients who have exhausted treatment options may show meaningful responses to targeted therapies identified as rational candidates. This presentation elicited an extremely lively discussion by attendees, with probing questions regarding next steps in Foundation Medicine’s data collection and biomarker assessment.

Molecular Biomarkers for the Early Detection of Cancer

Following the industry perspective on molecular biomarker testing, a session was held on the use of molecular biomarkers for the early detection of cancer. This has been a recurring theme in past GBC meetings and is always welcomed by the attendees. Discussions centered around the early detection of colorectal cancer (presented by Dr. Hemant Roy), lung cancer (presented by Dr. Avrum Spira), and breast cancer (presented by Dr. Susan Neuhausen). Dr. Roy provided his perspectives on the molecular genetic heterogeneity of colorectal cancer (CRC), and the current state-of-the-art on development of molecular biomarkers in blood, tissue, and stool for this malignancy, which affects 150,000 Americans every year. He also discussed the diagnostic value of colonoscopy and the prognostic value of certain biomarkers, including BRAF and Kras. Colonoscopy is negative for significant findings (adenoma or carcinoma) in >90% of screened subjects, so there is a need for pre-colonoscopy screening to identify high-risk patients. Dr. Roy concluded that biomarkers have a promising role in the early detection and risk stratification of colonic neoplasia, and that there are a number of blood, stool, and tissue biomarker assays for CRC (Cologuard, a multitarget stool DNA test, fecal microRNA tests, and FIT, a fecal immunochemical test), although the stage of development for clinical application of these assays is variable. Dr. Spira followed with a fascinating discussion on the use of bronchial airway gene expression as a biomarker of smoking and lung cancer, providing interesting data on a novel 23-gene genomic bronchial classifier (GBC; Percepta) to detect early lung cancer. Only 15% to 20% of smokers develop lung cancer; how do we identify those at-risk patients? In addition, Dr. Spira suggested that we need a diagnostic biomarker to distinguish benign from malignant lesions found on computed tomography (CT) of the chest, and a screening biomarker to identify smokers who are at highest risk for developing lung cancer. He showed that the combination of GBC plus bronchoscopy increased the sensitivity of detecting early lung cancer to 97%, compared with 75% for bronchoscopy alone. Even more interesting is that it appears that RNA obtained from brushings of the nasal mucosa provides a sample of this genomic classifier, and that the nose can act as a surrogate for the bronchial airway. This implies that nasal brushings can provide sufficient material to develop a gene-expression signature for the early detection of lung cancer, potentially making it possible to screen large populations with a relatively noninvasive technique. Finally, Dr. Neuhausen discussed the state of molecular biomarkers for the early detection of breast cancer. Although there are a number of genetic biomarkers beyond BRCA1 and BRCA2 that are being evaluated for their ability to predict risk for developing breast cancer, these are still in relatively early stages of development. “There is a pressing need to develop models to account for all breast cancer susceptibility genes,” Dr. Neuhausen stated, “but we’re not there yet.” This was another session that led to a lively discussion, especially the data around early lung cancer detection. “These are million dollar questions that you’re trying to answer,” an attendee stated as he formulated his questions.

A Keynote Presentation on the Impact of Molecular Biomarkers on Oncology Clinical Trials

Dr. Funda Meric-Bernstam, Chair of the Department of Investigational Cancer Therapeutics, Medical Director of the Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, Nellie B. Connally Chair in Breast Cancer Research, and Professor of Surgical Oncology at The University of Texas MD Anderson Cancer Center, delivered a keynote presentation on the impact of molecular biomarkers on oncology clinical trials. In her presentation, Dr. Meric-Bernstam discussed opportunities for genomically driven targeted therapy trials and her perspectives on how to leverage genomic profiling to increase the effectiveness of clinical studies in oncology. She cited a number of umbrella trials being conducted at MD Anderson as well as histology-independent basket trials being conducted under National Cancer Institute (NCI) auspices, and suggested strategies to improve clinical trial accrual by increasing the number of trials in which subjects are selected according to genomic or molecular profiling. She reviewed the design of the IMPACT2 and NCI-Match trials, demonstrating clinical trial protocols that are predicated on molecular profiling. Dr. Meric-Bernstam reviewed examples of mutations in actionable genes, and differentiated among genotype-selected, genotype-relevant, and genotype-matched trials. “Future challenges for oncology clinical trials include bringing evolving approaches to molecular characterization to the clinic, recognizing the additional value of integrated multianalyte analysis, accumulating data to make comprehensive testing billable/payable, and developing consortia to share best practices and initiate trials for rare alterations,” she stated. As expected, Dr. Meric-Bernstam’s presentation elicited a lively discussion.

Regulatory and Economic Aspects of Precision Medicine

The final session of the meeting focused on the regulatory and economic aspects of precision medicine in oncology. Dr. Andrew Stainthorpe, Director of the National Institute for Health and Care Excellence (NICE) program that receives and reviews Patient Access Schemes into NICE Technology Appraisal and the program that assesses new interventional procedures and devices for use in the UK National Health Service, reviewed the regulatory issues of companion biomarker tests in the United States and the European Union. In the United States, although the FDA has announced plans to expand its regulation to all genetic tests, this expansion has yet to take place. In the interim, the FDA continues to regulate test kits, and has begun to regulate genomics tools in clinical research. In the European Union, different countries have individual regulations about genomic testing, with the United Kingdom and Germany leading the way in evaluating not only clinical application but also cost-effectiveness. Dr. Stainthorpe then reviewed the current status of a number of biomarkers across a broad variety of tumors, when the biomarker tests should and should not be used, who should pay for the testing, and whether there is a reasonable way to decide who should pay. He ended his talk with a controversial question: “Is there a need for biomarker tests to be regulated or should access be unlimited and uncontrolled?” Dr. Stainthorpe’s presentation was followed by Dr. Michael Kolodziej, the National Medical Director, Oncology Solutions, Aetna. Dr. Kolodziej started his presentation by showing that based on the growth and aging of the US population, medical expenditures for cancer in 2020 are projected to reach at least $158 billion, a 27% increase over 2010, which is 2 to 3 times the rate of increase of other medical costs. This requires payers to assess genomic biomarker testing for their accuracy, clinical relevance, and economic value (which, in practical terms, constitutes an assessment of cost-savings and/or cost-effectiveness). The latter issue was highlighted in an example he provided of nivolumab therapy in lung cancer, where in the absence of a molecular biomarker to drive therapy for the most appropriate patients, nearly $20 billion could be spent on futile and potentially harmful therapy in patients who would not benefit from this drug and may be harmed by its adverse effects. The solutions he offered to this conundrum included collecting more data on clinical utility, optimizing patient outcomes and experience, and focusing providers on cost and value. “Personalized, precision medicine may offer a solution.” Following this session, Congress Co-chair Dr. Jorge Cortes provided closing remarks on another stimulating and informative meeting that had fostered debate and discussion, with interaction among basic scientists, clinicians, and other healthcare providers from various disciplines. Participants were then afforded a final networking opportunity to engage faculty in a “Meet the Experts” reception, to discuss issues on molecular biomarkers and personalized medicine in oncology and to visit the exhibit booths from Congress supporters.

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