Loxo Oncology Inc. and Illumina Inc. have struck up a strategic partnership to develop and commercially launch a multigene panel companion diagnostic (Cdx) for broad tumor profiling. The next-generation sequencing (NGS) diagnostic would carry a pan-cancer indication. The companies plan to pursue an approval for a variation of Illumina's Trusight Tumor 170 along with Loxo Oncology's therapies, larotrectinib and Loxo-292, which affect NTRK gene fusions and RET gene alterations, respectively.

Under the collaboration, Illumina will helm efforts toward FDA regulatory approval for the class III device and therapies, class II designation for profiling tumors, and efforts to obtain CE Mark. Stamford, Conn.-based Loxo Oncology will develop Trusight Tumor 170 with Illumina as a class III Dx to coincide with the designated treatments. The duo also will seek approval for the panel's additional assays as a tumor profile.

Comprehensive detection

"A Cdx version of Trusight Tumor 170 would be offered on the Nextseq 550Dx platform to drive the transformation from single-gene testing, to a comprehensive molecular profile of a patient's tumor, which can inform therapeutic selection," Garret Hampton, executive vice president of clinical genomics at Illumina, told BioWorld, addiing that the Cdx "will be a distributable kit that enables laboratories to conduct these tests internally. Distributable diagnostic solutions, such as a Cdx version of Trusight, in combination with the Nextseq 550Dx platform, are key to the democratization of precision oncology by enabling customers to perform comprehensive tumor profiling in their own laboratory.

"As this future Cdx was built to be tissue agnostic, the laboratory can identify these gene alterations in samples regardless of their tissue of origin. This would be the first distributable companion diagnostic of this kind," said Hampton. "Our goal is to be the leader in oncology sequencing applications to support therapy selection and monitoring. FDA approval of a Cdx version of Trusight Tumor 170 represents a large step toward achieving that goal."

Trusight method

San Diego-based Illumina's Trusight Tumor 170 NGS searches out amplifications, fusions, point mutations and splice variants across 170 genes known to be linked to solid tumors. As a Cdx, the NGS panel can offer greater genetic information to care teams and guide treatment.

Trusight Tumor 170 is a foundational Dx that operates with genes targeted by various academic institutions, pharmaceuticals and industry guidelines. The technology's assay process is the basis for its oncology Dx, and can be expanded into liquid biopsy and immune-oncology. DNA and RNA can be tested through a single integrated method and amounts as small as 40 ng from formalin-fixed, paraffin-embedded samples.

"Loxo Oncology is developing targeted therapies for cancers driven by underlying genetic alterations, so diagnostics are critical to identifying appropriate patients," Jacob Van Naarden, chief business officer at Loxo Oncology, told BioWorld. "We piloted numerous NGS assays and believe Trusight Tumor 170 delivers the highly sensitive detection of NTRK fusions and RET fusions/mutations, which are the genetic alterations targeted in our larotrectinib and LOXO-292 programs, respectively, as well as many other actionable tumor alterations. We believe that a test with broad applicability across cancers has the best chance of being utilized routinely by physicians.

"There isn't a currently available NGS solution that incorporates highly sensitive detection of TRK fusions; the ability to detect other actionable targets is run locally, and falls under the CMS national coverage determination," said Van Naarden.

Cancer therapeutics

Larotrectinib received FDA breakthrough therapy designation, orphan drug designation and rare pediatric disease designation. The therapy is an oral tropomyosin receptor kinase inhibitor aimed at treating cancers with neurotrophic tyrosine receptor kinase (NTRK) gene fusion, an unusual fusion which is thought to signal cancer growth in various portions of the body. The therapy has led to an investigator-assessed confirmed 80 percent overall response rate (ORR) and 75 percent centrally assessed confirmed ORR in varied tumors, and in adults and children.

Loxo-292 is an oral candidate being developed to treat cancers with irregularities in the rearranged during transfection (RET) kinase, linked to some colon cancers, 2 percent of non-small-cell lung cancer (NSCLC), 10 to 20 percent of papillary thyroid cancer, and 60 percent of medullary thyroid cancer. Because those cancers are dependent on RET kinase, the therapy inhibits its signaling and resistance.

Loxo Oncology also entered an exclusive global collaboration last fall with Bayer AG to develop the therapies, Loxo-292 and larotrectinib. While the two will jointly develop the medications, Loxo will manage clinical trials, and regulatory steps in the U.S., and Bayer will handle regulatory approval outside the U.S. and commercial efforts globally. (See BioWorld, Nov. 15, 2017.)

Pan-cancer Dx

Earlier this month, The Cancer Genome Atlas consortium published a treasure trove of data across 30 articles in numerous Cell Press journals based on its PanCancer Atlas collaboration. The Atlas brings together NGS information to illuminate relationships between gene mutations and locations among 33 types of tumors. Through the research, interaction between mutations was uncovered as well as identification of close to 60 driver genes. (See BioWorld, April 6, 2018.)

At the close of 2017, Foundation Medicine Inc., of Cambridge, Mass., received FDA approval and CMS preliminary national coverage designation for Foundationone Cdx, a pan-cancer Dx thought to be the most comprehensive detection test on the market. The Dx is able to detect four-class alterations in 324 genes associated with solid tumors, as well as molecular changes. The company's Onecdx test also was granted breakthrough device designation due to its potential for consolidation of several claims for Cdx testing. A few months earlier, Thermo Fisher Scientific Corp. won FDA approval for its simultaneous tumor sample and 23-gene analysis test for NSCLC, Oncomine Dx Target. Testing can help determine which therapy is best for the disease.