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Chief, Early Drug Development
Memorial Sloan Kettering Cancer Center
New York, New York
Alexander Drilon, MD, has disclosed that he has received consulting fees from AbbVie, AstraZeneca, BeiGene, BergenBio, Blueprint Medicines, Exelixis, Helsinn, Hengrui Therapeutics, Ignyta/Genentech/Roche, Loxo/Bayer/Lilly, MORE Health, Pfizer, Takeda/Ariad/Millennium, TP Therapeutics, Tyra Biosciences, and Verastem; funds for research support from Foundation Medicine; funds for research support paid to his institution from Exelixis, GlaxoSmithKline, Pfizer, PharmaMar, Taiho, and Teva; and royalties from Wolters Kluwer.
The FDA approvals of the TRK inhibitors larotrectinib and entrectinib in 2018 and 2019 represented only the second and third tumor agnostic drug approvals, with these agents both indicated for patients who have advanced solid tumors with NTRK fusions and no satisfactory alternative therapy. Although NTRK fusions occur rarely in most solid tumor types (< 5% frequency), it is important to test for this alteration, as larotrectinib and entrectinib can be effective against NTRK fusion–positive malignancies and provide a viable treatment modality for patients who may have otherwise been lacking therapeutic options. In this commentary, I discuss a case from my own practice to illustrate how I approach testing for NTRK fusions and treating patients with TRK inhibitors.
Case Study: Treatment of a Patient With an NTRK Fusion–Positive Carcinoma
A 40-year-old man was diagnosed at another institution with a mammary analogue secretory carcinoma with lung metastases. Tumor tissue was sent for next-generation sequencing (NGS), which identified an ETV6-NTRK3 fusion, a fusion that is typically enriched in mammary analogue secretory carcinoma. The patient was referred to our institution for treatment with a TRK inhibitor, as the referring care team recognized that NTRK fusions are actionable. The patient received daily oral entrectinib and had a robust and rapid response to therapy. When he arrived at our institution, he had substantial visible external disease involving the ear and cheek, with bulky tumors in those regions. Within the first 4 weeks of entrectinib therapy, he had visible regression of the lesions on his head, with subsequent confirmed radiologic and metabolic responses to therapy. His response was durable and lasted for more than 3 years.
In terms of tolerability, the patient had no major issues with the drug. He did have some mild positional dizziness and a slight increase in appetite, but these events were not dose limiting and did not interfere with chronic dosing of entrectinib. As with many patients who have metastatic disease, the case patient eventually developed disease progression and another biopsy was performed. This revealed the continued presence of the initial ETV6-NTRK3 fusion; however, an acquisition of a mutation in NTRK3 was also identified. For patients with progression on the first-generation TRK inhibitors larotrectinib or entrectinib, the next-generation TRK inhibitors selitrectinib and repotrectinib are currently in development and have shown promise in early-phase trials. Selitrectinib and repotrectinib were designed not just to hit the original NTRK fusion but also to address resistance mediated by the emergence of mutations involving the TRK kinase domain. In the case of this patient, he was eligible for a clinical trial with repotrectinib and, after receiving this agent, re-established disease control, with clear external disease regression and confirmed radiologic response. His response was again durable, lasting more than 2.5 years.
This case illustrates that NTRK fusions are actionable alterations. Despite the fact that these alterations are rare in most solid tumor types, I would recommend testing all patients with solid tumors for NTRK fusions using NGS. This type of sequencing can also yield valuable information regarding other actionable alterations, including microsatellite instability and tumor mutation burden. When testing for NTRK fusions, the NGS assay should preferably include RNA, as DNA-based testing can occasionally miss select NTRK fusions.
Both larotrectinib and entrectinib are approved for patients who have advanced solid tumors with NTRK fusions and no satisfactory alternative therapy. Both agents have been associated with robust, durable responses across tumor types in clinical trials, but there are currently no head-to-head trials comparing these agents. As noted with the case patient, there are certain class-specific adverse events to be aware of with TRK inhibitors. The TRK pathway plays a role in nervous system development and maintenance, and as such, on-target neurologic adverse events, including dizziness, ataxia, paresthesia, and cognitive changes have been observed with the first-generation agents larotrectinib and entrectinib, as well as increased appetite and thirst.
Have you treated a patient with a solid tumor with a TRK inhibitor? If so, what were your most informative experiences? Please share your thoughts in the comments box and answer the polling question on your screen.
Want to know more? Sign up here to attend CCO’s online Webinar, “Advances in Tumor Agnostic TRK Inhibitor Therapy and NTRK Fusion Testing,” at 12:00 PM Eastern time on Wednesday, July 15, during which I will discuss patient case studies and recent advances in NTRK testing and TRK inhibitor use with our esteemed panel, including George D. Demetri, MD, and Pashtoon Kasi, MD.
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