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Welcome to this third in a series of 4 CME/CE/CPE-certified educational ClinicalThought™ commentaries on the optimal management of patients with head and neck cancers. In this commentary, Aarti Bhatia, MD, MPH, discusses the diagnosis and treatment of NTRK fusions in patients with head and neck cancer.
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As precision medicine becomes the new standard of care for many patients with cancer, clinicians must be familiar with actionable targets, available testing platforms, and new therapies. For patients with NTRK fusions, proper identification and treatment can lead to vast improvements in outcomes. In this commentary, I use a case example to introduce the clinical considerations for a patient with an NTRK fusion.
Ms. AB is a 42-year-old woman with metastatic, radioiodine-refractory PTC who is being followed for multiple lung nodules. On recent imaging, she is found to have more rapid disease progression. A CT-guided biopsy was obtained from one of the peripheral lung lesions and sent for pathology confirmation and molecular profiling. The pathology report confirmed metastatic PTC and sequencing identified an NTRK3 gene fusion.
What are her treatment options? A TRK inhibitor? An antiangiogenic multikinase inhibitor like lenvatinib? Or a clinical trial?
Before we discuss my treatment recommendation, let’s review some key aspects of NTRK fusion–positive cancers as well as clinical considerations for patients harboring these alterations.
Overview of NTRK Fusions
The TRK family of receptors includes 3 transmembrane proteins: TRK A, B, and C. These are encoded by the NTRK1, 2, and 3 genes expressed in human neuronal tissue and activated by ligands called neurotrophins. They mediate downstream signaling via the MAPK and PI3K/AKT pathways, thus affecting neuronal cell development and survival. Fusions involving NTRK genes constitute the main molecular alterations that drive TRK activation in a constitutive, ligand-independent fashion.
NTRK fusions were initially reported in colorectal and PTC but have since been found in multiple tumor types in both adult and pediatric patients. These cancer types can be categorized based on the frequency with which these fusions are detected. First are common tumor types like melanoma; lung, colorectal, pancreatic, and breast cancers; and other solid or hematologic cancers where NTRK gene fusions are found in fewer than 1% of patients. Second, are tumors like PTC and gastrointestinal stromal tumors (GIST), which harbor NTRK gene fusions in 5% to 25% of cases. Third, are rare tumors like secretory breast carcinoma, mammary analogue secretory carcinoma (MASC) of the salivary gland, and infantile fibrosarcoma, where NTRK gene fusions are seen with > 90% incidence. In PTC, the presence of an NTRK fusion gene correlates with a younger age of disease onset and a more aggressive clinical course, manifested by higher T-stage, and nodal and distant metastases.
NTRK fusions can be diagnosed using a variety of methods. DNA/RNA-based next-generation sequencing (NGS) is the most reliable. The identification of the fusion partner with NTRK can only be made on an NGS platform. In addition, other potential oncogenic drivers can also be detected. However, NGS is expensive and has the longest wait time for results.
FISH and reverse transcriptase polymerase chain reaction (RT-PCR) have been used to detect NTRK fusions that involve recurrent partners such as in MASC, infantile fibrosarcomas, and secretory breast carcinoma. They have a faster turnaround time for results and a lower cost but are largely limited to the detection of a single driver alteration. NGS takes approximately 3 weeks, compared with 1-2 weeks for RT-PCR and 7-10 days for FISH.
IHC can detect TRK overexpression as a surrogate for the presence of an NTRK fusion. IHC, using a pan-TRK antibody, is a sensitive predictor for the presence of a fusion protein. In resource-strapped clinical settings and in tumor types where NTRK fusions are rare, consider IHC, which takes approximately 1 day for results, as a screening tool and perform NGS as a confirmation for those who test positive.
When to Test
When to test for the presence of an NTRK fusion gene depends on the disease type and stage of presentation. Patients with curative-stage disease where standard-of-care therapies will be used need not be tested for NTRK fusions. Patients with advanced malignancies that already have another known driver mutation, such as EGFR/RAS/BRAF mutations or ALK/ROS1 fusions in lung cancer, or a BRAF mutation in PTC, or KIT/PDGFRA/BRAF or SDH mutations in GIST tumors, also need not be tested for an NTRK fusion because driver genetic alterations are almost always mutually exclusive. The remainder of these patients with advanced malignancies should be tested for NTRK fusions.
The most appropriate time to test would be when palliative systemic therapy is being considered, either before first-line therapy for tumors with a high prevalence of NTRK fusions, or after progression on standard therapy for other tumor types. It is also appropriate to retest patients who have progressed on a TRK inhibitor, to identify the responsible resistance mechanisms, which can then guide subsequent therapy, either with a second-generation TRK inhibitor or another targeted therapy.
Approved TRK Inhibitors
During the past few years, several TRK inhibitors have been tested in clinical trials. Larotrectinib and entrectinib both have a tumor-agnostic approval by the FDA for treatment of solid tumors harboring NTRK fusions in adult and pediatric patients, based on response rates of 75% and 57%, respectively. Several of these patients had very durable responses and many could then be consolidated with curative intent therapy. Both agents have favorable overall toxicity profiles. Dose-reduction rates were low and treatment discontinuation occurred in < 5% of patients. Occasional, low-grade on-target adverse events can occur, including dizziness, paresthesias, weight gain, and cognitive changes.
Let’s return to our case. Ms. AB was started on larotrectinib and had an excellent response to treatment. However, after 10 months of treatment, her lung nodules started to grow again.
When Patients Progress on NTRK Inhibitors
Durable responses have been achieved with TRK inhibitors in TRK fusion–positive cancers. When solitary-site progression develops, local therapy such as radiation or surgery may be considered. The combination of local therapy and continued TRK inhibitor beyond progression can prolong disease control. More widespread disease progression occurs due to development of either on-target or off-target resistance. On-target resistance is acquired due to the emergence of TRK kinase domain mutations and possibly may be overcome with a second-generation TRK inhibitor on clinical trial. Selitrectinib is a second-generation, selective TRK inhibitor that has been tested in a phase I trial in pediatric and adult patients with NTRK fusion–positive cancers, who had progressed on at least 1 previous TRK inhibitor. Preliminary efficacy data suggest an ORR of 45%, and responses were seen across all the on-target resistance mutations. Repotrectinib is another second-generation TRK inhibitor that is being studied in patients with NTRK fusion–positive solid tumors that have progressed on at least 1 prior line of chemotherapy and 1-2 prior TRK inhibitors. The FDA recently granted repotrectinib a fast track designation. If off-target resistance has emerged, disease-specific standard-of-care therapies or clinical trials to address those resistance mechanisms could be considered.
In summary, although a rare entity, appropriate identification and treatment of patients with NTRK fusion–positive cancers, including head and neck cancers, can have a profound impact on their quality of life and overall survival.