Moonshot Initiative Promotes Next Generation of Molecular Cancer Diagnostics

Moonshot Initiative Promotes Next Generation of Molecular Cancer Diagnostics

Cancer is the common thread through several fronts of U.S. regulatory development, whether approval of targeted therapeutics; coverage and reimbursement decisions for advanced diagnostic laboratory tests (ADLTs); or expansion of FDA regulatory oversight over laboratory developed tests (LDTs). The disease is also a healthcare and research and development (R&D) focus of the Obama administration. Just as instrumental as cancer’s high societal burden and aging-driven rise in incidence, the proliferation of its genetic analytes and druggable targets has caught the attention of regulators. Next-generation sequencing (NGS) has facilitated the sudden leap of research-stage diagnostics into the clinical lab. In the United States, regulators have addressed the new frontiers of cancer diagnostics through payment reform (Protecting Access to Medicare Act [PAMA]), patient safety of proprietary lab testing services (FDA draft guidance on LDT regulation), and the presidential Cancer Moonshot Initiative. The approach behind the Moonshot initiative holds the most promise to accelerate the U.S. market development of advanced molecular cancer diagnostics.

The Cancer Moonshot was announced by President Obama during his State of the Union address in January 2016. The initiative aims to promote cancer research through regulatory reform, increased National Institutes of Health (NIH) funding in targeted research areas, and improved collaboration between private and public sector researchers. Provisions of the initiative have been stalled or weakened by funding shortfalls, but progress to date has been made in regulatory reform and private sector collaboration.

Implicit to several research areas chosen by the Moonshot initiative’s panel of experts is the recognition of the challenge posed by the granularity of individual cancer cases. Tumors are highly heterogeneous, both between patients and even stages of disease within one patient. Addressing cancer in its various forms requires personalized medicine or targeted therapies that are matched to patients using companion diagnostics (CDx) or tests for specific mutations. Increasingly utilized in tandem for cancer treatment, therapies and tests are expected to be reviewed and approved together under an Oncology Center of Excellence established under the Food and Drug Administration (FDA) as part of White House efforts in cancer.

In June 2016, Richard Pazdur was appointed as the acting director of the FDA’s virtual Oncology Center of Excellence. The center brings together regulatory scientists and other reviewers with expertise cancer diagnostics and cancer therapeutics. The FDA’s history of reorganization has been responsive to the development and specialization of cancer products – the Office of Hematology and Oncology Products (OHOP) was created in 2005 to consolidate the review of cancer therapeutics; OHOP then organized disease-specific teams in 2011; and most recently in 2016 integrated the review of biologics and devices alongside therapies. With its Center of Excellence, the FDA plans to keep pace with innovation in cancer products and improve upon its review rate that included 61 approvals for cancer therapeutics under OHOP between January 2010 and July 2016.

Introduction to Companion Diagnostics (CDx)

Captured under other terms such as personalized medicine, precision medicine and pharmacogenomics, companion diagnostics are used to identify eligible patients for targeted cancer therapies, patients at a heightened risk for serious side effects or to monitor patient response to implemented therapies. Companion diagnostics are also commonly used in research to enroll patients in clinical trials for targeted therapies appropriate only for a subset of tumors. Some of the first major companion diagnostics for cancer were BCR-ABL and HER2 assays. The former can be assayed from blood and used to diagnose forms of leukemia or monitor leukemia for resistance to first-line tyrosine kinase inhibitor (TKI) therapeutics like imatinib. In a way a precursor to industry-aspired liquid biopsy techniques, BCR-ABL assays can inform disease state through the quantification of blood-based BCR-ABL mutation markers present in circulating abnormal white blood cells. HER2 tests use either gene or protein biomarkers from tissue samples to detect forms of breast cancer susceptible to Herceptin and other targeted oncology drugs.

Other common FDA-approved, molecular companion diagnostics test for KRAS, ALK and EGFR mutations found in two of the most common forms of cancer – lung and colorectal cancers. Remaining FDA-approved companion diagnostics are for breast cancer (BRCA1/BRCA2 and other BRCA gene-related analysis by sequencing), blood cancers detected from bone marrow samples, and lung cancer using other molecular markers.

Molecular Cancer Companion Diagnostics (CDx) Pipeline Expected to Benefit from New FDA Review Process

There is a dense web of partnerships between pharmaceutical, biotechnology and diagnostic companies for the advancement of cancer therapies. The following selection of molecular cancer companion diagnostics – submitted to the FDA, preparing for submission, or integral parts of ongoing clinical trials – would stand to benefit from an expedited joint review process alongside therapeutics that could become standardized as part of the FDA initiative.

Companion Diagnostic Company



Market/Trial Status

Foundation Medicine

‘BRCAness’ signature seq test for non-BRCA1/BCRA2 mutations related to DNA repair deficiencies

Rucaparib (Clovis Oncology) – a PARP inhibitor

Preparing for PMA submission


Gene expression (RNA) test for exon 14-skipping mutations of MET gene by RT-PCR or seq

Glesatinib (Mirati Therapeutics) for NSCLC with oncogenic MET gene alterations

Phase II

Myriad Genetics

BRACAnalysis CDx seq test service (LDT)

Already approved as CDx with olaparib (AstraZeneca); in trials for other PARP inhibitors

Phase III

Myriad Genetics

myChoice HRD seq test for detection of HRD or DNA repair deficiencies

Niparib (Tesaro) for ovarian cancer

Phase III

NanoString Technologies

nCounter microarray platform with 20-gene expression panel from tissue samples

REVLIMID (Celgene Coporation) for DLBCL subtypes

Phase III

Advanced Cell Diagnostics

RNAscope RNA ISH assay for HRG expression (Leica BOND platform)

Seribantumab (Merrimack) for NSCLC

Phase II

Foundation Medicine

Assays for the identification of alterations to a number of genes for homologous recombination repair (HRR), including BRCA

Olaparib (AstraZaneca)

N/A; research to identify applicable cancers

NanoString Technologies

Modified Prosigna Breast Cancer microarray on nCounter platform

Enzalutamide (Astellas Pharma) for triple-negative breast cancer

Phase II


NRAS PCR on Rotor-Gene Q Mdx platform

Binimetinib (Array Biopharma) for melanoma

Phase III

Guardant Health

Guardant360 plasma-based NGS for detection of MET gene mutations and amplifications

Glesatinib (Mirati Therapeutics) for NSCLC

Phase II


RNA seq test for NOTCH3 gene expression

Tarextumab (Oncomed Pharmaceuticals) for small cell lung cancer

Phase II


NGS assay for the detection of NTRK1/2/3, ROS1 and ALK gene alterations

Entrectinib (Ignyta) for various tumors

Phase II


RT-PCR test for detection of AR-VY gene expression (RNA) in CTCs on Rotor Gene Q Mdx platform

Galeterone (Tokai Pharmaceuticals) for castration-resistant prostate cancer

Phase III

Abbott Molecular

PCR test for the detection of MYD88 L265P mutation in tumor biopsy samples

IMO-8400 (Idera Pharmaceuticals) for Waldenström’s macroglobulinemia and DLBCL lymphomas

Phase I/II

Cancer Moonshot Initiative Could Launch Universal CDx

Efforts to improve collaboration and information sharing between U.S. public and private sector researchers could also aid the development of universal companion diagnostic tests. These sequencing-based assays could be used for the detection of a group or panel of disease-related gene mutations and replace mutation-specific molecular assays. Current private sector efforts to develop universal companion diagnostics predominate in the area of oncology. While private companies have formed consortia for the development of universal companion diagnostics, the broad scope of such tests could also be supported by information from public sector primary research centers. The initiative has already provided for the launch of the Blood Profiling Atlas pilot or an open database of liquid biopsies. Including the Blood Profiling Atlas project, the following are four leading projects for the development of a universal companion diagnostic test:

  • Next-generation sequencing leader Illumina agreed to deals in August 2014 with pharmaceutical companies AstraZeneca, Janssen Biotech and Sanofi for the development of a sequencing-based universal companion diagnostic test for use with cancer therapies.
  • Thermo Fisher Scientific entered into an agreement in September 2014 with GlaxoSmithKline (GSK) and Pfizer for the development of an NGS test with sequencing targets informed by the content of the Oncomine Cancer Research Panel. The universal CDx test could initially serve as an enrollment tool across drug programs before submission for FDA premarket approval as a test on Thermo’s Ion Personal Genome Machine (PGM) Dx platform.
  • Foundation Medicine (majority-owned by Roche since 2015) has developed FoundationOne for solid tumors and FoundationOne Heme for blood cancers. Both tests identify multiple gene mutations relevant to clinical trial enrollment and the efficacy of targeted cancer therapies. Foundation Medicine’s long-term goal is the development of a universal companion diagnostic or highly multiplexed NGS assay for the identification of a spectrum of CDx or pharmacogenetics-related gene mutations.
  • The Blood Profiling Atlas project has 20 participants that will provide liquid biopsy study data for aggregation and sharing. Participants include AstraZeneca, Eli Lilly, Epic Sciences, Memorial Sloan Kettering Cancer Center, Foundation Medicine, Genentech (Roche), Guardant Health, Novartis, Personal Genome Diagnostics, Pfizer, Thermo Fisher Scientific, University of Michigan, and University of South California. Study data will be curated by a partnership between Open Commons Consortium, University of Chicago, and Seven Bridges.

Validation of universal companion diagnostic tests will also require unprecedented engagement with regulators. The U.S. FDA has yet to approve a multiplex or panel companion diagnostic test and would be thorough in its review of any such product due to companion diagnostics’ high impact on patient outcomes. Over 100 oncogenes have been discovered and hundreds of cancer drugs are in development.  Private sector-matched genes, drugs and cellular pathways will require coordinated regulator review already envisioned under the Center of Excellence. The future review and validation of universal or panel companion diagnostic tests will also draw from the consolidated expertise.