FDA approves osimertinib for first line use in lung cancer with EGFR mutation

By Anthony Magliocco MD

TAGRISSO delivered unprecedented median progression-free survival of 18.9 months versus 10.2 months for EGFR-TKIs (erlotinib or gefitinib) in 1st-line EGFRm NSCLC

 

the US Food and Drug Administration (FDA) has approved TAGRISSO® (osimertinib) for the 1st-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) mutations (exon 19 deletions or exon 21 L858R mutations), as detected by an FDA-approved test. The approval is based on results from the Phase III FLAURA trial, which were presented at the European Society of Medical Oncology 2017 Congress and published in the New England Journal of Medicine.

 

The results of the phase III FLAURA trial were impressive with dramatic improvements to progression free survival.

The FLAURA trial compared TAGRISSO to current 1st-line EGFR tyrosine kinase inhibitors (TKIs), erlotinib or gefitinib, in previously untreated patients with locally advanced or metastatic EGFR-mutated (EGFRm) NSCLC. TAGRISSO met the primary endpoint of progression-free survival. PFS results with TAGRISSO were consistent across all pre-specified patient subgroups, including in patients with or without central nervous system (CNS) metastases. Overall survival data were not mature at the time of the final PFS analysis.

 

Osimertinib was previously approved for use as second line therapy in patients who had progressed on a TKI treatment or for those whose tumors developed a T790M mutation confering resistance to the first generation TKI therapies.

Osimerinibs mechanism of action is thought to be irreversible binding to the EGFR receptor.  Perhaps this explains the improvement in PFS compared to other TKIs. These findings are potentially practice changing.

Despite these impressive improvements in PFS almost all patients eventually fail targeted therapies with TKI agents. Consequently more work is needed to understand the biological mechanisms of resistance and progression in lung cancer patients to enable more effective therapies to be developed.

https://www.onclive.com/web-exclusives/fda-approves-frontline-osimertinib-for-nsclc

Loxo Oncology work with Illumina to develop Cdx NGS assay for Larotrectinib (NTRK) and LOXO-292 (RET)

Anthony Magliocco MD

In an important announcement Industry sequencing leader Illumina and LOXO Oncology, released that they are working on developing a companion diagnostic for larotrectinib, a NTRK inhibitor and LOXO-292 which targets ret.

 

It appears that they intend to use the TST170 as a basis and perhaps a DX version of the Nexseq 500

This is an important development for 2 reasons. The first is the molecular alterations in question are relatively rare, but they can occur in any tumor type regardless of the tissue of origin. The second is the identification of a standard instrument platform and multi-gene assay panel that is already in clinical use (Moffitt has recently deployed a version of TST170 for patient care as Moffitt STAR) will undoubtedly expedite the capability to scale this test for widespread deployment accross laboratories

The fact that TST170 is so comprehensive potentially offers the opportunity for other oncology drug developers to consider using this versatile assay as a companion diagnostic as well.

https://ir.loxooncology.com/press-releases/loxo-oncology-and-illumina-to-partner-on-developing-next-generation-sequencing-based-pan-cancer-companion-diagnostics

STAMFORD, Conn. and SAN DIEGO, April 10, 2018 (GLOBE NEWSWIRE) —  Loxo Oncology (Nasdaq:LOXO) and Illumina, Inc. (Nasdaq:ILMN) today announced a global strategic partnership to develop and commercialize a multi-gene panel for broad tumor profiling, resulting in a distributable, next-generation sequencing (NGS) based companion diagnostic (CDx) with a pan-cancer indication. The co-development partnership will seek approval for a version of the Illumina TruSight Tumor 170 as a companion diagnostic (CDx) for Loxo Oncology’s larotrectinib, which targets NTRK gene fusions, and LOXO-292, which targets RET gene alterations, across tumor types.

TruSight Tumor 170 is a comprehensive, state-of-the-art, next-generation sequencing test that interrogates point mutations, fusions, amplifications and splice variants in 170 genes associated with common solid tumors. The CDx version of TruSight Tumor 170 will allow local laboratories to provide referring physicians with comprehensive genomic information, so that patients can be matched to the most appropriate therapeutic options. This version of TruSight Tumor 170 will run on the NextSeq 550Dx platform.

“We are leveraging our leadership in next-generation sequencing to deliver in-vitro diagnostic solutions to improve the management of cancer patients in the clinic,” said Garret Hampton, Ph.D., executive vice president of clinical genomics at Illumina. “To this end, we are partnering with leading biotechnology companies, such as Loxo Oncology, to develop companion diagnostics for best-in-class therapeutics. Distributable diagnostic solutions, such as a CDx version of TruSight Tumor 170, in combination with the NextSeq 550Dx platform, will enable labs to perform precision medicine testing in-house.”

Under the partnership, the companies will collaborate to validate a CDx version of TruSight Tumor 170 for NTRK fusions and RET fusions/mutations as a Class III FDA-approved diagnostic in conjunction with larotrectinib and LOXO-292, respectively. The companies are also planning to broaden the clinical utility of the full panel by obtaining regulatory approval for the other assay content, to be marketed as a tumor profiling test. Illumina will lead regulatory activities related to the Class III plans for NTRK and RET, the Class II plans for the tumor profiling content, and CE marking.

“We are very excited to announce this collaboration with Illumina, the world’s leader in NGS technology,” said Jacob Van Naarden, chief business officer of Loxo Oncology. “We have piloted numerous NGS assays, and the Illumina TruSight Tumor 170 assay has consistently demonstrated robust performance with its assessment of both DNA and RNA, including highly sensitive gene fusion detection. The broad 170-gene assay content has the potential to deliver meaningful insights from a single tumor specimen, identifying patients with NTRK fusions, RET fusions, RET mutations, and many other actionable tumor alterations. Furthermore, we believe that this collaboration will improve patient access to high-quality NGS testing because pathologists will be able to run TruSight Tumor 170 locally and receive reimbursement.”

Bringing Digital Droplet PCR into the Cancer Clinic for Treating Progressive Lung Cancer

By Anthony M Magliocco MD

Digital Droplet PCR, or ddPCR is a phenomenally sensitive, specific, and most importantly, precise method to measure target DNA.

One important application for this technology that is now reaching the clinical laboratory is the development of tests for monitoring circulating cell free DNA that is released from cancer cells.

The challenge of detecting cfDNA is monumental.  A tube of blood is loaded with a rich variety of complex biomolecules and cells including lymphocytes, neutrophils, platelets, and of course red corpuscles.  These cells, including RBCs, are loaded with nucleic acids and whats worse, they can easily rupture during blood draws or pre analytical handling.

Advanced lung adenocarcinoma, (NSCLC) is probably the single tumor type that has caused the largest advances in personalized oncology of solid tumors. Investigations into the molecular biology of this disease has uncovered the fact that NSCLC is a heterogeneous disease defined by distinct molecular subtypes and clear molecular driving pathways. Further the discovery of targetable driver mutations including presence of EGFR mutations among others has led to pivotal clinical trials proving the efficacy of the Tyrosine Kinase inhibitor Drugs (TKIs).  Further it seems that lung tumors with EGFR mutations are more likely to arise in women and non-smokers.

Despite the remarkable efficacy of TKI therapy in many patients with advanced NSCLC, the disease is relentless and frequently overcomes treatment by developing resistance mechanisms. The commonest mechanism of resistance is acquisition of EGFR T790M mutation which further enhances the activity of the EGFR pathway, driving growth of the lung cancer cells.

 

 

Fortunately, third generation non-competitive inhibitors of EGFR were developed that can overcome the development of T790M resistance -osimertinib or Tagresso from AZD.

When Osimertinib first became available it was necessary to develop an ultra sensitive assay to detect the mutation in tissues and blood.

The Moffitt Cancer Center Morsani Laboratories, when faced with this challenge, decided to use a digital PCR approach because of its superior sensitivity, specificity and reasonable cost of operation.

Dr John Puskas worked diligently to develop and validate a cfDNA assay for EGFR T790M mutation using ddPCR for CLIA at the Moffitt Cancer Center.  Different PCR platforms were evaluated but the Bio-Rad QX200 was eventually selected for use.

The assay was superbly sensitive and precise as well as convenient to run.  The assay can detect mutant EGFR T790M down to 0.1% and can easily monitor blood concentration over time to give assessment of disease progression

 

 

The development of accurate and specific cfDNA assays to precisely monitor cancer progression in the metastatic setting is an important tool to potentially enable oncologists the opportunity to determine more rapidly f tumors are responding to treatment or not and make adjustments.

This novel opportunity to trace tumor evolution in real time, at a molecular level, could play a role in trials and treatments of the future where treatments are carefully adjusted to avoid the inadvertent development of treatment resistance due to over treatment.

 

MOFFITT NGS STAR* Enters Clinical Service

Moffitt’s latest NGS sequencing assay the Moffitt STAR (Solid Tumor Actionable Result) panel was validated by the Moffitt Morsani Molecular Laboratory and launched into service this month at the busy Florida Comprehensive Cancer Center in Tampa.

The assay is based on Illumina’s TruSight Tumor 170 assay which is a next-generation sequencing assay designed to cover 170 genes that are commonly designated as drivers in solid tumors. The assay evaluates both DNA and RNA and focuses on detecting actionable mutations which include SNV, dels, insertions, amplifications, and translocations. Such alterations are the target for many new targetable therapies including anti-EGFR agents, anti BRAF therapies and treatments targeting the Tropomyosin Receptor Kinase fusions (TRK) such as Larotrectinib.

Many key actionable mutations only occur rarely, making detection by single marker tests problematic and wasteful. However, the Moffitt STAR assay now allows the Moffitt molecular laboratory to screen patient tumors for multiple targetable mutations efficiently in a single test using a relatively small amount of nucleic acid extracted from routine formalin fixed, paraffin embedded tissues (FFPE). This important advance enables the Moffitt molecular diagnostic laboratory to effectively evaluate a patient for eligibility to receive treatment with a FDA approved targeted therapy, or be considered for clinical trial enrollment. Moffitt STAR is essentially an “All in one” test that can provide multiple functions.

Moffitt NGS STAR* is an exciting new “all in one” technology advance for Moffitt Cancer Center patients enabling rapid assessment of their tumors for presence of key mutations directing selection of effective approved targeted therapies or for qualification to enroll in the latest generation of clinical trials

Evidence is also emerging the assay, despite its mid size, Moffitt STAR could also reliably measure tumor mutational load and microsatellite instability. These molecular features are often associated with potential response to the latest immune check point inhibitors such as Pembrolizumab which has recently received FDA approval for use in tumors with high microsatellite instability.

Moffitt NGS STAR also provides information on tumor mutational burden and microsatellite instability- key features which may drive patient response to the latest immuno-oncology check point inhibitor therapies

Moffitt NGS STAR can also detect mutations in BRCA genes, a molecular feature that may predict response to parp inhibitors such as olaparib.

Moffitt NGS STAR can be performed on as little as 40ng of input nucleic acid.

Development and launch of Moffitt NGS STAR was made possible through collaboration with industry partners PierianDx and Illumina Inc.

The Moffitt Cancer center is one of the largest in the United States, is consistently ranked in the top cancer centers by U.S. News & World Report. Moffitt Cancer Center has a mission to “contribute to the prevention and cure of cancer” and the vision ” to transform cancer care through service, science, and partnership”

For further details contact anthony.magliocco@moffitt.org