Biomarker-guided Larotrectinib for all cancer types?

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June 09, 2017 –  It’s only a couple of days that the American Food & Drug Administration (FDA) approved for the first time a cancer treatment for any solid tumor, irrespective of the tumor’s original location, as long as the targeted tumor is carrying a specific genetic feature (i.e., a specific biomarker). Thus, biomarkers referred to as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) qualify solid tumors under certain conditions (see the newest FDA drug label for details) for treatment with Pembrolizumab (Keytruda), equivalent to a major extension of the clinical indications for Pembrolizumab (Keytruda).

Larotrectinib, a small organic molecule with 2 stereochemical centres targeting TRK Fusion biomarker.

At the American Society of Clinical Oncology (ASCO) 2017 Annual Meeting (Abstract LBA2501),  there was another molecule presented that eventually might follow this path of biomarker-guided (targeted) treatment of tumors irrespective of the tumor’s original location. Participants at ASCO and the reporting media alike hailed Larotrectinib, a novel targeted drug that shows remarkable responses in seemingly every cancer type in which it has been tested, as the “first oral tumor-agnostic therapy”. In fact, while Pembrolizumab (Keytruda) is an immunotherapy and administered intravenously, the new Larotrectinib is a targeted agent taken orally.

Larotrectinib, a small organic molecule, is selective for tropomyosin receptor kinase (TRK) fusions, which are found across a range of different cancer types, including both rare and common cancers. According to the lead study author, Dr. David Hyman, Larotrectinib has shown high response rates in all 17 tumor types in which it has been tested so far. Thus, the overall response rate was 76%, and complete responses were seen in 12% of patients, all of whom had advanced cancers. At the meeting, Dr. Hyman presented results from 55 patients with TRK fusions enrolled in three ongoing Phase 1 and Phase 2 clinical trials. All patients (12 children and 43 adults) had locally advanced or metastatic cancer, including colon, lung, pancreatic, thyroid, salivary, and gastrointestinal cancers, as well as melanoma and sarcoma. You will find the clinical trail information here at NCT02576431, NCT02122913, and NCT02637687.

According to Dr. Hyman, TRK fusions are rare but occur in many different cancer types. The employment of high-throughput next-generation sequencing techniques in multiple tumor types during the last few years has identified NTRK1, NTRK2, and NTRK3 gene rearrangements encoding novel oncogenic fusions in 19 different tumor types to date. These recent developments have led to revisit the old oncogene Trk, (originally identified as oncD), which encodes the TPM3-NTRK1 gene fusion and was one of the first transforming chromosomal rearrangements identified about 30 years ago. Today, in the age of precision medicine, it serves as a biomarker target for the anti-cancer agent Larotrectinib.

It will be interesting to learn, both from ongoing clinical trials and from the use, once Larotrectinib is approved, in the generalised targeted patient population, how many patients out of all patients who are carriers of the biomarker actually respond to the Larotrectinib treatment with full or partial remissions. It will also be interesting to learn what other, possibly genetic, markers the fully responsive patients is going to carry. Larotrectinib being a small molecule taken by the oral route, bioavailability may be an important confounding factor of efficacy. Metabolism and disposition of Larotrectinib may vary considerably from one patient to the next based based on variations in genes coding for metabolising enzymes and drug transporters.

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About the Author
Joseph Gut - thasso Ph.D.; Professor in Pharmacology and Toxicology. Senior expert in theragenomic and personalized medicine and individualized drug safety. Senior expert in pharmaco- and toxicogenetics. Senior expert in human safety of drugs, chemicals, environmental pollutants, and dietary ingredients.

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