October 2015, Vol. 4, No. 5

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Comprehensive Genomic Profiling Advances Clinical Trials

PMO Live

Comprehensive genomic profiling of tumors can identify more targeted treatment options than “hots pot” tests and enable innovative trial designs, said Roman Yelensky, PhD, at PMO Live 2015.

Unvalidated diagnostic tests with poor accuracy represent a challenge to informed targeted treatment decisions for patients with cancer.

Therapies targeting the genomic alterations that drive an individual patient’s disease can be remarkably effective. This approach is part of a broader trend in clinical oncology as the understanding of disease is being transformed, said Yelensky, Vice President, Biomarker and Companion Diagnostic Development, Foundation Medicine, Inc, Cambridge, MA.

“Lung adenocarcinoma is probably the best example; over the past 10 to 12 years, it has morphed from a relatively undifferentiated histological diagnosis to what today is a very rich molecular understanding of the drivers of this disease,” he said. “It creates opportunities to improve outcomes for patients, but also great challenges not just for drug development, but in particular for diagnostic tests. How does one reliably detect these alterations for cancer patients broadly from routinely available tissue?”

Matching the correct targeted therapy to the correct patient is diagnostically challenging as the number of clinically relevant genomic alterations increases. There are dozens of known clinically relevant cancer genes in non–small cell lung cancer, for instance. These genes are altered by multiple mechanisms: base substitutions, short insertion/deletion, focal amplification, homozygous deletion, and gene rearrangements leading to gene fusion.

“If you think about the traditional model for assays for these biomarkers, that model breaks down,” said Yelensky. “Patients have very limited tissue to test all these markers, so new approaches are needed.”

Further, low tumor purity in many clinical specimens requires diagnostic tests with high accuracy. Many clinical cancer specimens are small-needle biopsies, fine-needle aspirations, and cell blocks. Therefore, sample preparation needs to be optimized to maximize accuracy and isolate sufficient material for diagnostic testing from tiny specimens.

Addressing Challenges with NGS

Foundation Medicine developed a next-generation sequencing (NGS) cancer genomic profile that addresses many of these challenges, he said. Translating research-grade NGS into a comprehensive clinical cancer diagnostic assay requires extensive optimization.

Its comprehensive genomic profile for all solid tumors simultaneously detects all clinically relevant classes of genomic alterations in a single assay. It focuses on 314 known clinically and biologically relevant cancer genes. The comprehensive NGS assay also permits testing small amounts of tissue from routine formalin-fixed and paraffin-embedded specimens, including needle biopsies (≥50 ng of DNA).

“Validation is critically important, so we had to come up with new strategies for validating this kind of comprehensive testing approach,” he said. Reference samples of cell line pools with known alterations, including mutant allele frequency, indel length, and amplitude of copy change validated high accuracy and reproducibility required for clinical use.

A report is generated from the testing that shows the genomic alterations identified and the targeted therapies and clinical trials that may be relevant based on those genomic alterations.

An overview of the first 2221 cases profiled in a Clinical Laboratory Improvement Amendments–certified laboratory demonstrated 1614 (76.4%) of samples with at least 1 actionable alteration. The definition of actionable is an FDA-approved targeted therapy for that tumor type or in another tumor type or a clinical trial of the therapy that targets the identified alteration in the gene.

NGS has enabled a rapid cycle of discovery to clinic in some instances. RET fusions were discovered in lung cancer in 2012. The time lapse from this discovery to the first reports of clinical response to RET inhibitors was about 1 year.

Advancing Revolutionary Clinical Trial Design

The development of innovative clinical trials is an attempt to bring breakthroughs in NGS and targeted therapy to more patients. Foundation Medicine is participating in a groundbreaking collaborative clinical trial called Lung-MAP.

“Squamous cell lung cancer has not had the same progress as lung adenocarcinoma; there are fewer targets, fewer approved therapies, and survival is quite poor,” said Yelensky. “In many ways, it’s an orphan disease.”

Lung-MAP is a clinical trial conducted in patients with squamous cell lung cancer organized by the National Cancer Institute and Southwestern Oncology Group Cancer Research. It is designed as a multidrug, multiarm biomarker-driven trial to which 5 pharmaceutical partners are contributing drugs.

Patients in Lung-MAP are tested through comprehensive genomics. Based on alterations found on testing, they are directed to one of the various arms targeting those markers. Drugs can graduate to phase 2 and 3 depending on efficacy; drugs can be rolled in or rolled out as the trial progresses. “The trial can function essentially in perpetuity,” said Yelensky.

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