TRK fusion-positive cancers and TRK inhibitor therapy

INTRODUCTION — 

Tropomyosin receptor kinase (TRK) proteins are encoded by neurotrophic tyrosine receptor kinase (NTRK) genes. Fusions involving one of these three genes can produce a chimeric TRK fusion protein that drives downstream signaling and cancer growth. As a result, NTRK fusions have emerged as important targets for cancer therapy. TRK tyrosine kinase inhibitors (TKIs) have demonstrated robust and durable activity in TRK fusion-positive solid tumors. Three TRK TKIs are now approved for treatment of NTRK fusion-positive cancers regardless of the site of disease origin; these represent "tissue-agnostic" drug approvals. This topic will review the prevalence, diagnosis, and management of TRK fusion-positive cancers.

Other topics address other primary site agnostic approaches. (See "Overview of advanced unresectable and metastatic solid tumors with DNA mismatch repair deficiency or high tumor mutational burden".)

BIOLOGY AND PREVALENCE

Normal and tumor biology — The TRK receptor family comprises three transmembrane proteins: TRKA, TRKB, and TRKC. These proteins are encoded, respectively, by NTRK1 (which maps to chromosome 1q21-q22), NTRK2 (which maps to chromosome 9q22.1), and NTRK3 (which maps to chromosome 15q25) [1]. TRK receptors are expressed in neuronal tissue and play a central role in nervous system development during embryogenesis [2]. Following birth, TRK receptors remain primarily expressed by neuronal tissues, and are involved in pain sensing, memory, weight homeostasis, and proprioception [3].

NTRK fusions were among the first gene rearrangements described in cancer [4]. These fusions produce a chimeric TRK oncoprotein that leads to constitutive activity and potential overexpression of the kinase, both of which can drive uninterrupted downstream signaling, oncogenic transformation, and tumor growth [5-7]. NTRK fusions (as opposed to mutations or amplifications) are the primary molecular alterations involving NTRK that result in therapeutically-relevant oncogenic and transforming potential [5].

Although dozens of unique NTRK fusions have been identified, several features are often shared, including the following:

●A non-NTRK gene fusion partner in the 5' (upstream) position that may be expressed in the tissue type in which it is found

●Inclusion of the NTRK segment that encodes the full-length TRK kinase domain in the 3' (downstream) position

Although fusions may involve any of the three NTRK genes, most of those identified to date involve either NTRK3 or NTRK1, although particular tumor types such as primary brain tumors may have a higher frequency of NTRK2 fusions [5,8,9].

Prevalence — TRK fusions are broadly distributed across a variety of adult and pediatric cancers (table 1). This distribution follows two general patterns:

Rare cancers with a high frequency of TRK fusions — TRK fusions are enriched in several rare cancer types (occurring at estimated frequencies as high as >90 percent in select series). These histologies include the following:

●Infantile fibrosarcoma [10-14]

●Congenital mesoblastic nephroma (cellular subtype) [11,15]

●Secretory breast carcinoma [16,17]

●Secretory carcinoma of the salivary gland, also known as mammary analogue secretory carcinoma [18-20]

In general, these cancers present in children (including infants), although secretory breast and salivary gland carcinomas predominately occur in adolescence or later in life, respectively [17,21,22]. (See "Malignant salivary gland tumors: Treatment of recurrent and metastatic disease", section on 'Secretory (NTRK gene fusion positive)' and "Pathology of breast cancer", section on 'Secretory carcinoma'.)

As NTRK fusions are pathognomonic of these cancers, identifying an NTRK fusion can help with diagnosis if routine morphologic analyses are ambiguous. As an example, salivary cancers initially classified as "acinic cell carcinomas" have been reclassified as secretory carcinomas after identification of ETV6-NTRK3 which can be produced by the recurrent translocation t(12;15)(p13;q25) [18,23,24].

Common cancers with a low to intermediate frequency of TRK fusions — TRK fusions are also found in many common cancers (table 1), albeit at a much lower frequency (often <1 percent ), which include [25-31]:

●Non-small cell lung cancer

●Breast cancer other than secretory cancer

●Colorectal and appendiceal cancer

●Pancreatic cancer

●Cholangiocarcinoma

●Renal cell cancer

●Head and neck cancer (other than secretory carcinoma)

●Sarcoma, not otherwise specified

●Gastrointestinal stromal tumors

●Melanoma

●Glioblastoma multiforme

In addition to these solid tumors, TRK fusions rarely can be found in hematologic malignancies (eg, acute lymphoblastic/myeloid leukemia and multiple myeloma) and other cancers such as histiocytic and dendritic cell neoplasms [32].

Cancers that harbor TRK fusions at intermediate frequencies (1 percent or greater but less than 25 to 35 percent of cases) [33] include:

●Thyroid cancer, particularly in children (frequency 2 to 28 percent [28,34-37])

●Glioma (particularly select pediatric high-grade gliomas [38])

●Specific sarcomas, such as inflammatory myofibroblastic tumor [39]

●Spitzoid neoplasms

DIAGNOSIS

Available assays — While the US Food and Drug Administration has approved a specific test that uses next-generation sequencing (NGS) for NTRK fusion detection [40], a variety of NGS assays and other diagnostic modalities are available. Here, we will review the available diagnostic assays and recommended testing algorithms.

Next-generation sequencing (preferred approach) — Given the rarity of NTRK fusions in most cancers, "single-gene assays" that only test for an NTRK fusion are often impractical. Instead, NGS assays capable of simultaneously evaluating all classes of potentially actionable genomic alterations (single-nucleotide variants, indels, copy number alterations, structural rearrangements) across up to hundreds of genes are favored. NGS tests for an NTRK fusion in conjunction with other tumor-agnostic biomarkers (ie, high levels of microsatellite instability/deficient mismatch repair, high tumor mutational burden, and the presence of a RET fusion or BRAF V600E mutation) as well as relevant tumor-specific biomarkers. (See "Overview of advanced unresectable and metastatic solid tumors with DNA mismatch repair deficiency or high tumor mutational burden".)

NGS of tumor tissue is the preferred method for NTRK fusion identification and can be performed using deoxyribonucleic acid (DNA), ribonucleic acid (RNA), or both nucleic acids. RNA-based or RNA-inclusive methods are superior to DNA-only sequencing:

●The sensitivity of DNA-based NGS for NTRK fusion detection is lower than that of RNA-based NGS. This is because of factors including the large and repetitive introns of NTRK2 and NTRK3, as well as the diversity of potential NTRK fusion partners. These limitations are circumvented by many RNA-based sequencing methodologies, including anchored multiplex polymerase chain reaction and transcriptome sequencing.

●DNA-based sequencing may detect complex or ambiguous NTRK rearrangements of uncertain significance. These typically manifest as fusions that do not appear to include the NTRK kinase domain encoding region, or in which the upstream partner cannot be resolved. By comparison, RNA-based sequencing preferentially detects rearrangements that result in expressed transcripts, thus improving specificity.

NGS can also be performed using blood samples. Plasma-based, cell-free DNA, or circulating tumor DNA assays are sometimes referred to as "liquid tumor biopsies." While these assays can have more limited panels compared with tumor NGS assay, NTRK fusions can and have been detected, although the limitations of DNA-based tumor testing apply. Although the identifying an NTRK fusion using plasma NGS can select patients for TRK TKI therapy, the absence of an NTRK fusion should not be interpreted as definitive evidence and tumor-based testing is recommended. (See 'Testing approach' below.)

Immunohistochemistry — Similar to its use in other cancers (eg, anaplastic lymphoma kinase [ALK] immunohistochemistry [IHC] in ALK fusion-positive lung cancers), IHC can be performed as a potential screening tool for NTRK fusions. NTRK fusions can result in moderate to high levels of TRK oncoprotein expression in neoplastic tissue, and many non-neoplastic, non-neural tissues do not express TRK receptors to a meaningful degree. A pan-TRK antibody (EPR17341, Ventana, Roche) is available as an in vitro diagnostic device for NTRK fusion detection [41]. The epitope for this antibody is in a conserved region of the C-terminus of TRKA, TRKB, and TRKC. Studies have demonstrated excellent sensitivity and specificity for the detection of NTRK fusions [29,42]. Overall expression intensity and staining localization can be dictated by the upstream fusion partner.

Several caveats should be kept in mind. TRK expression is normal in certain tissues, specifically in neural tissues. As such, IHC positivity can occasionally be seen in cancers without TRK fusions [43], including in tumors with neuroendocrine differentiation. For this reason, we recommend that NGS be used to confirm the presence of an NTRK fusion in a TRK IHC-positive cancer, particularly in tumors for which TRK fusions are uncommonly found [43]. (See 'Testing approach' below.)

Some NTRK fusions, including ETV6-NTRK3, may be associated with relatively faint staining, and a false negative result on IHC [44]. In addition, IHC interpretation may be challenging in particular cancers such as gastrointestinal stromal tumors. Both experienced pathologists and proper controls are required for TRK IHC interpretation.

Fluorescence in situ hybridization — Fluorescence in situ hybridization (FISH) break-apart assays can detect NTRK fusions. Three separate FISH tests are needed to interrogate NTRK1, NTRK2, and NTRK3. This increases the amount of tissue required. For this reason, FISH testing has been more commonly used to evaluate tumor types that harbor a pathognomonic or highly common fusion type (eg, ETV6-NTRK3 that is frequently found in infantile fibrosarcoma or secretory carcinoma). FISH testing is limited by several factors: interpretation of a positive result is subject to interobserver variability, the upstream fusion partner is often not identified, and false negative results can occur from small intrachromosomal deletions/rearrangements (as with NTRK1 fusions).

Reverse transcriptase polymerase chain reaction — Reverse transcriptase polymerase chain reaction probes are designed to detect specific fusion events. For example, probes designed to detect ETV6-NTRK3 do not allow detection of other fusions. This makes use relatively limited, considering the wide variety of NTRK fusions.

Testing approach — The complexity of diagnostic assays and the variable frequency of these events across cancer types have led to the development of NTRK fusion testing algorithms [22,28,45,46]. We recommend the following approach:

Tumors with a high frequency of NTRK fusions — For cancers with a high frequency of NTRK fusions (>20 percent), we recommend NGS of both DNA and RNA when available (see 'Rare cancers with a high frequency of TRK fusions' above). If either returns with a positive result, the cancer is considered to be TRK-positive.

In more resource-constrained environments where NGS cannot be run, pan-TRK IHC could be used as a screening tool (FISH is as a reasonable alternative), particularly for cancers in which NTRK fusions are pathognomonic of the histology (eg, secretory carcinomas, infantile fibrosarcomas):

●Positive IHC or FISH result – IHC or FISH positivity alone may be considered sufficient evidence of the presence of a TRK fusion oncoprotein. Confirmatory orthogonal testing can be deferred.

●Negative IHC or FISH result – Given the possibility of false negatives with IHC or FISH, we recommend secondary screening, ideally using NGS that includes RNA testing.

Tumors with a low to intermediate frequency of NTRK fusions — For cancers with a low to intermediate frequency of NTRK fusions (<20 percent), we recommend NGS of both DNA and RNA. (See 'Common cancers with a low to intermediate frequency of TRK fusions' above.)

●Positive result – DNA- and/or RNA-based identification of an NTRK fusion that is predicted to be in-frame and contain the domain encoding the full-length TRK kinase (along with identification of the non-NTRK gene partner) is considered a positive result. This is sufficient to prescribe TRK TKI therapy without the need for additional testing.

●Ambiguous result – Structural variants detected using DNA-based testing that do not meet the criteria specified above (eg, out-of-frame fusions or variants of undetermined significance) should undergo confirmatory testing with either RNA-based sequencing (preferred, if not already done) or pan-TRK IHC.

●Negative result – If the assay included both DNA and RNA sequencing, we recommend no additional testing. If the assay included only DNA sequencing, we recommend the following:

•For tumors in which DNA sequencing identified a tumor-tissue-relevant oncogenic alteration (eg, KRAS, BRAF, or EGFR mutation, or RET, ROS1, or ALK fusion), additional testing for an NTRK fusion could be deferred as these alterations are often mutually exclusive. Note that rare cases of NTRK fusions co-occurring with other drivers have been identified de novo. Furthermore, colorectal cancers can have high levels of microsatellite instability or be mismatch repair deficient while harboring an NTRK fusion concurrently.

•If DNA sequencing did not identify a tumor-tissue-relevant oncogenic alteration, we recommend reflex RNA-based NGS when available. In one proof-of-concept study, RNA sequencing in "driver-negative" non-small cell lung cancers identified occult kinase fusions in 11 percent of cases, including NTRK fusions [47].

In summary, NGS of both DNA and RNA is the preferred method for NTRK fusion identification, although testing approaches should account for various resource environments, the pretest probability TRK fusion positivity, and the assays available to the pathologist or ordering clinician. Plasma-based testing should be considered reliable when positive; a negative result should prompt tumor-based testing if not already performed.

Our approach is consistent with an American Society of Clinical Oncology provisional clinical opinion on somatic genomic testing in patients with advanced cancer, stating that NTRK fusion testing should be performed in patients with metastatic or advanced solid tumors who may be candidates for TRK inhibitor therapy considering the prevalence of NTRK fusions in individual tumor types [48].

TRK INHIBITOR ACTIVITY — 

The following agents have been approved for the treatment of TRK fusion-positive cancers:

●Larotrectinib, a selective inhibitor of TRKA/B/C

●Entrectinib, a multikinase inhibitor of TRKA/B/C and other kinases like ROS1

●Repotrectinib, a multikinase inhibitor of TRKA/B/C and other kinases like ROS1

Efficacy of TRK inhibitors in TRK TKI-naïve patients — The approvals of larotrectinib, entrectinib, and repotrectinib in the United States, Europe, and elsewhere were based on integrated analyses of patients with NTRK fusion-positive cancers treated on different clinical trials within the same drug development program. The proportion of NTRK fusion-positive cancers, brain metastases, and pediatric or adolescent and young adult (AYA) patients varied per program. These data are summarized as follows:

●Larotrectinib – Larotrectinib was the first TRK TKI to be approved in a tumor-agnostic and age-agnostic fashion for NTRK fusion-positive cancers [49]. It is available as an oral solution and as a capsule.

Approval was based on an initial dataset of 55 patients treated on one of three trials: a phase I adult trial, a phase I/II pediatric SCOUT trial, and a phase II adolescent and adult NAVIGATE basket trial [8]. An updated report in an expanded cohort of 159 adults and children with NTRK fusion-positive cancers (including the 55 patients) and 15 tumor types has since been published [50]. With nearly three times the original number of patients, the objective response rate was 79 percent (95% CI 72-85), with a 16 percent complete response rate and a 63 percent partial response rate. As with other TRK TKIs, responses were observed across fusion types (NTRK1, NTRK2, and NTRK3 fusions with different upstream partners). The median duration of response was 35 months, the median progression-free survival was 28 months, and the median overall survival was 44.4 months.

●Entrectinib – In the United States, entrectinib is approved for adults and pediatric patients older than one month with solid tumors that have an NTRK fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have progressed following treatment or have no satisfactory standard therapy. Oral pellets within a packet are available for patients able to swallow soft food (eg, applesauce, yogurt, pudding). Capsules may be opened and prepared as an oral suspension (with water or milk) and administered orally or via enteral tube in infants/children or adults unable to swallow capsules.

The activity of entrectinib was published separately for adult and pediatric/AYA patient cohorts. The initial adult dataset had 54 adult patients treated on the phase I ALKA-372-001, phase I STARTRK-1, and phase II STARTRK-2 basket trials [51]. In an updated analysis with 121 adults and 14 tumor types, the objective response rate was 61 percent (95% CI 51.9-69.9), with a 16 percent complete response rate and a 46 percent partial response rate [52]. The median duration of response was 20 months, the median progression-free survival was 14 months, and the median overall survival was 34 months. Pediatric and AYA patients were treated on the phase I/II STARTRK-NG trial [53]. In 26 patients with NTRK fusion-positive cancers, the objective response rate was 58 percent (95% CI 36.9-76.7), with a 27 percent complete response rate and a 31 percent partial response rate. The median duration of response and median progression-free survival were not reached.

●Repotrectinib – Repotrectinib received accelerated approval for adult and pediatric patients 12 years and older with solid tumors that have an NTRK fusion, are locally advanced or metastatic or where surgical resection is likely to result in severe morbidity, and that have progressed following treatment or have no satisfactory alternative therapy [54]. Repotrectinib is currently only available as oral capsules.

Adult and pediatric data have been reported separately. In the phase I/II TRIDENT-1 trial 40 adult patients with NTRK fusion-positive, TKI-naïve cancers were treated. The response rate was 58 percent (95% CI 41-73) [54], with a 12 percent complete response rate and a 45 percent partial response rate. Durability data have not matured; the median duration of response and median progression-free survival have not been reached. The 12-month duration of response was 86 percent and the 12-month progression-free survival was 56 percent. Updated pediatric data from the phase I/II CARE study were reported in a poster presentation at the International Society of Pediatric Oncology conference in 2024. The response rate for TKI-naïve patients with NTRK fusions was 60 percent. For those who previously received a TKI, the response rate was 25 percent. The duration of response ranged from 7.6 to >14.8 months [55].

Intracranial efficacy of TRK inhibitors — A subset of NTRK fusion-positive cancers have significant rates of brain metastasis, most commonly non-small cell lung cancer and melanoma. In addition, select pediatric and adult primary brain tumors harbor NTRK fusions. TRK TKIs can have antitumor activity in these patients as summarized below:

●Larotrectinib – In the expanded 159-patient approval dataset, 13 nonprimary brain tumor patients (8 percent) harbored baseline central nervous system (CNS) metastasis [50,56,57]. Nine of 12 (75 percent) evaluable patients had overall responses (extracranial and intracranial). Of these patients, three had Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 measurable intracranial disease: one had a complete intracranial response, one had a partial intracranial response, and one had stable intracranial disease, with the remaining patients achieving stable disease according to investigator assessment. Additional information is available from a report of 20 patients with NTRK fusion-positive lung cancers; of the eight with evaluable CNS metastases, five (63 percent) had a partial response, with response duration ranging from 0.03 to 20 months [58].

In a combined analysis of 33 patients with NTRK fusion-positive primary CNS tumors previously treated with standard chemotherapy and enrolled in the two clinical trials (including 19 high-grade gliomas, 8 low-grade gliomas), larotrectinib was associated with a 30 percent objective response rate. The median time to response was 1.9 months, and the duration of treatment ranged from 1.2 to 31.3+ months [59].

●Entrectinib – In the 54-patient adult approval dataset [51], 26 nonprimary brain tumor patients harbored CNS metastases at baseline. There were 21 objective responses by blinded central review (58 percent), which included two complete responses [52]. The median duration of response was 17 months (95% CI 6-29.4). The phase II portion of the STARTRK-NG trial in children and young adults with solid extracranial or primary CNS tumors included 15 individuals whose cancers harbored an NTRK fusion [53]. There were nine objective responses (60 percent), five of which were complete.

●Repotrectinib – In a multicohort study including patients with measurable CNS metastases at baseline, responses were seen in three of five (60 percent) of TKI-naïve patients and two of eight (25 percent) of TKI-pretreated cases [55].

Timing of therapy for advanced disease — All three TRK TKIs are approved for the treatment of advanced TRK fusion-positive cancers that "have no satisfactory alternative treatments or that have progressed following treatment" given the high response rates and durable disease control achieved with TRK inhibitors compared with standard-of-care therapies (eg, chemotherapy and/or immunotherapy) [60]; however, TRK inhibitors have been considered for first-line therapy in patients with advanced/metastatic cancers, for example advanced non-small cell lung cancer. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer", section on 'NTRK fusions'.)

Benefits of perioperative therapy in non-metastatic disease — In addition to advanced/metastatic disease, all three inhibitors have been approved for the treatment of locally advanced disease "where surgical resection is likely to result in severe morbidity."

The most significant experience with neoadjuvant use of a TRK inhibitor has been in the preoperative use of larotrectinib for pediatric sarcomas [61,62]. In the pediatric phase I SCOUT trial, five patients with locally advanced sarcomas were treated with neoadjuvant larotrectinib. All underwent successful curative-intent surgical resection, with three achieving complete or near-complete (>98 percent treatment effect) pathologic response; these three patients remained off larotrectinib between 7 and 15 months postoperatively. The remaining two patients who received neoadjuvant larotrectinib also received adjuvant larotrectinib postoperatively without radiographic evidence of disease at approximately 7 and 20 months, respectively, of ongoing treatment.

Anecdotally, we have administered larotrectinib preoperatively to patients with locally advanced pancreatic cancer and esophageal cancer (one each) and achieved marked downstaging in both cases, permitting subsequent definitive therapy for both. Others have reported the use of neoadjuvant larotrectinib in a patient with stage II NTRK fusion-positive pediatric thyroid cancer to allow more effective delivery of radioactive iodine [63]. Adjuvant larotrectinib was used after definitive surgical resection in two children with NTRK fusion-positive cancers (embryonal sarcoma of the kidney and anaplastic astrocytoma); adjuvant therapy was ongoing at 15 months [64].

Neoadjuvant and adjuvant TRK TKI should be considered in advanced, nonmetastatic, NTRK fusion-positive cancers. Use of perioperative targeted therapy parallels that of other oncogene-driven cancers for which neoadjuvant and/or adjuvant kinase inhibitor therapy is used, including KIT-mutant gastrointestinal stromal tumors [64], BRAF V600E/K-mutant melanomas, and EGFR-mutant and ALK fusion-positive lung cancers. (See "Systemic therapy for advanced non-small cell lung cancer with an activating mutation in the epidermal growth factor receptor" and "Anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer" and "Adjuvant and neoadjuvant therapy for gastrointestinal stromal tumors" and "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations".)

TRK INHIBITOR RESISTANCE — 

As with other targeted therapies, resistance may limit the efficacy of TRK inhibitors in TRK fusion-positive cancers. Resistance can be mediated by two major mechanisms [65-67].

NTRK resistance mutations — We pursue repeat NGS testing of tumor and/or plasma at the onset of resistance for patients who were on larotrectinib or entrectinib [68].

Acquired resistance mutations involving NTRK1, NTRK2, or NTRK3 (also referred to as "on-target" resistance) inhibit TRK inhibitor binding or affect the activity or conformation of the TRKA, TRKB, or TRKC kinases. Resistance mutations are often located in the kinase domain and involve specific parts of the kinase such as the solvent front, gatekeeper, and xDFG regions. Solvent front or gatekeeper mutations may be amenable to subsequent next-generation TRK TKI therapy, such as repotrectinib. By contrast, xDFG mutations may impart resistance to all currently approved TKIs, including repotrectinib. As such, we offer disease-specific treatment approaches rather than repotrectinib when xDFG mutations are found.

Examples of available data are as follows:

●Repotrectinib in TKI-pretreated patients – Repotrectinib is considered a next-generation TRK TKI as the drug was designed to inhibit resistance mutations that emerge with larotrectinib or entrectinib, such as those involving the solvent front or gatekeeper regions. Repotrectinib achieves a response rate of approximately 50 percent in TRK TKI pretreated patients with NTRK fusion-positive cancers. As reported in a conference abstract, of 48 TRK TKI-pretreated patients 24 patients had a partial response [69]. The median duration of response was 9.8 months, and the median progression-free survival was 7.4 months. Patients in this study had lung cancer, pancreatic cancer, cholangiocarcinoma, colorectal cancer, neuroendocrine tumor, thyroid cancer, soft tissue sarcoma, salivary gland cancer, breast cancer, peripheral nerve sheath tumor, and cancer of unknown primary.

In the subset of these patients whose cancer harbored an NTRK solvent front mutation, the objective response rate was 60 percent (95% CI 39-79); all responses were partial responses. The median time to response was 1.9 months. The median duration of response was 7.4 months, and the median progression-free survival was 8.6 months.

●Other TRK TKIs in TKI-pretreated patients – Multiple other next-generation TRK inhibitors have been explored to address on-target resistance. Selitrectinib (BAY 2731954, LOXO-195) is an example of a drug that has shown preliminary clinical activity in this setting [70,71], although the drug does not have approval in any regulatory environment. Clinical trials of next-generation TRK TKIs (including some with expanded access) have been initiated (NCT03215511, NCT03206931, NCT03093116, NCT04094610) and could be considered as options should repotrectinib not be available for use.

Activating non-NTRK resistance alterations — Identification of activating/oncogenic non-NTRK alterations, either alone or in combination with an NTRK resistance mutation, should prompt consideration of disease-specific standard-of-care therapies such as chemotherapy. As with many other oncogene-driven cancers, checkpoint inhibitor immunotherapy may not be highly effective, except for NTRK fusion-positive gastrointestinal cancers that are concurrently microsatellite instability-high.

Resistance to NTRK inhibitors involving the activation of a non-NTRK gene are also referred to as "off-target" or "bypass" resistance. Examples include KRAS mutations or MET amplification [65]. These alterations are typically acquired during TRK TKI therapy; however, these alterations may be also found de novo prior to TRK TKI exposure in rare cases, imparting primary TKI resistance. Furthermore, off-target resistance has co-occurred with NTRK resistance mutations. In either of these situations (a non-NTRK alteration or a non-NTRK alteration that co-occurs with an NTRK resistance mutation), subsequent TRK TKI monotherapy with a next-generation TRK TKI such as repotrectinib may not be beneficial. While combination therapies (eg, combination of TRK and MET TKIs for NTRK fusion-positive cancers with acquired MET amplification) have demonstrated activity preclinically and in case reports, no targeted therapy combination is approved for NTRK fusion-positive cancers.

TRK INHIBITOR SIDE-EFFECTS — 

TRK TKI therapy can be well tolerated, particularly with the selective TRK inhibitor larotrectinib. Of the first-generation TRK inhibitors, the rate, number, and severity of select adverse events appear to be more favorable with larotrectinib than entrectinib. Dose reduction occurred in 8, 29, and 38 percent of patients with larotrectinib, entrectinib, and repotrectinib, respectively. Dose discontinuation occurred in 9, 9, and 7 percent of patients with larotrectinib, entrectinib, and repotrectinib, respectively. Neurologic side-effects are more frequently observed (eg, dizziness) with repotrectinib, a next-generation agent that more potently inhibits TRK compared with larotrectinib and entrectinib.

TRK inhibition-related neurologic toxicities — The TRK pathway controls balance, appetite, pain sensitivity, and nerve maintenance in normal tissues. As a drug class, TRK inhibitors can have unique "on-target" neurologic consequences such as dizziness, weight gain, withdrawal pain, and paresthesias (with a perioral distribution for some patients) [72].

●Dizziness – Recommendations for management include carefully characterizing the type of dizziness that patients experience as supportive care measures can vary depending on the presentation. For example, meclizine seems beneficial for individuals with vertigo, and midodrine may be used for patients with orthostasis. Ultimately, the most effective intervention is dose reduction in refractory cases.

In a single institution series of 96 patients who received TRK TKI therapy, dizziness was observed in 41 percent of cases (39 of 96 patients); six had concurrent ataxia [72]. The median time to onset was two weeks, (range 3 days to 16 months). Symptoms were described as positional light-headedness most often (33 percent), but also as imbalance (18 percent), vertigo (8 percent), or mixed (5 percent). Dizziness was accompanied by orthostatic hypotension in 21 percent of cases (8 of 39 patients), although signs of volume depletion were absent. These underscore the different mechanisms by which TRK inhibition might lead to dizziness (eg, vertigo may represent a cerebellar issue while orthostasis may be related to autonomic insufficiency). Dose reduction resulted in symptom resolution in 7 of 9 patients.

Based on registrational data, the frequency of dizziness with the three TKIs is as follows: larotrectinib (27 percent), entrectinib (38 percent), and repotrectinib (63 percent). Notably, the adverse effect ataxia that qualifies as a form of dizziness was reported separately in some series (eg, the frequency of dizziness and ataxia was 63 and 28 percent, respectively, with repotrectinib).

●Weight gain – Management recommendations include serial monitoring of weight on TRK inhibitor therapy, paying careful attention to diet, increased exercise, pharmacologic management (potentially with the help of an endocrinologist or weight loss specialist), and ultimately TRK inhibitor dose reduction for moderate to severe and refractory weight gain.

In the single-institution series discussed above, weight gain was reported in 53 percent of cases (51 of 96 patients). The median time to onset was one month. While based on registrational data, the frequency of weight gain with the three TKIs was 14 percent with larotrectinib, 25 to 39 percent with entrectinib, and 14 percent with repotrectinib, the single-institution series uncovered that the frequency and severity of weight gain increased with longer time on therapy [72], and long-term follow-up is essential. Weight gain was not due to worsening fluid retention, but to increased adipose tissue (assessed radiographically) due to increased caloric intake from increased appetite. This is consistent with preclinical data on the inhibition of TRKB causing hyperphagia in animal models.

Eight of the 10 patients who received pharmacologic management (glucagon-like peptide 1 analogs, metformin, bupropion, topiramate, sibutramine, or phentermine, either alone or in combination) lost weight or stopped gaining weight.

●Withdrawal pain – Given that TRK inhibitors can modulate pain receptors, chronic inhibition of TRK signaling may be associated with an increased setpoint for pain neurotransmitter signaling [73]. Drug discontinuation can thus result in withdrawal pain. Pharmacologic pain management including opioids or gabapentin is appropriate during the pain flare. Pain flares may be avoided by slowly tapering someone off the TRK TKI when appropriate.

In the single-institution series discussed above, withdrawal pain was observed in 28 of 81 patients (34 percent) who temporarily or permanently discontinued TRK TKI therapy [72]. Symptoms were described as diffuse achiness, muscle pain, and/or allodynia often accompanied by headache. The median time to onset was two days, and severity was grade 1, 2, or 3 in 12, 11, and 11 percent, respectively.

For those who temporarily discontinued therapy, the median duration was three days (range one to seven days), which was consistent with the median duration of drug hold (three days). For patients who permanently discontinued therapy, the median duration of flare was 14 days (range 10 to 26 days). Patients who had been taking the TRK inhibitor for longer than six months were more likely to experience withdrawal pain (63 versus 13 percent).

Pharmacologic interventions including opioids and gabapentin were of modest benefit in many patients. By contrast, for patients who temporarily discontinued therapy, restarting the TRK inhibitor resulted in rapid and often complete relief. For patients who discontinued therapy permanently, down-titration of TRK inhibitor therapy (25 percent decrease in dose every seven days) was beneficial in one patient.

Withdrawal pain has not been as well characterized in the registrational datasets of larotrectinib, entrectinib, and repotrectinib, likely because many cases occurred after patients came off TKI therapy.

Other neurologic toxicities — Other adverse events that were classified as neurologic were observed. Most were low grade; severe (grade 3 or 4) adverse events occurred in fewer than 10 percent of patients. The majority of neurologic adverse events developed within the first three months of treatment. These included dysgeusia, cognitive impairment (eg, confusional state, disturbance in attention, memory impairment, aphasia, mental status changes, hallucinations, and delirium), mood disorders (anxiety, depression, and agitation), sleep disorders, and vision disorders [54,74]. Dose reduction is recommended for substantial symptoms. Dose modification guidelines are available in the United States prescribing information for patients who develop neurotoxicity.

Non-neurologic toxicities — A variety of other side-effects have been observed, many of which are unlikely to be direct consequences of TRK inhibition.

Hepatotoxicity — All three TKIs can cause elevation in liver enzymes, which may be severe in a minority of cases. The United States prescribing information for each drug recommends that liver tests, including aspartate transaminase and alanine transaminase, be monitored every two weeks during the first month of treatment of entrectinib and two months of treatment of larotrectinib. Afterwards, larotrectinib and entrectinib require monthly monitoring and as clinically indicated; repotrectinib requires monitoring as clinically indicated. Dose modification recommendations are provided for severe hepatotoxicity during therapy.

Other toxicities — A number of toxicities have been reported with some TRK TKIs and not others:

●Cardiac toxicities – Across clinical trials, congestive heart failure occurred in 3.4 percent of patients treated with entrectinib, including grade 3 heart failure (2.4 percent). The median time to onset was two months. United States prescribing information for entrectinib recommends assessment of left ventricular ejection fraction prior to initiation of entrectinib in patients with heart failure or known risk factors for congestive heart failure, and that patients be closely monitored for clinical signs and symptoms of congestive heart failure, including shortness of breath and edema [75]. Heart failure is not listed in the prescribing information for larotrectinib or repotrectinib.

Across clinical trials, 3 percent of patients treated with entrectinib had prolongation of the corrected QT (QTc) interval (>500 milliseconds for some). Monitor patients who have or who are at significant risk for QTc interval prolongation, including those with known long QT syndrome, clinically significant bradyarrhythmia, and severe or uncontrolled heart failure and those taking other medicinal products associated with QT prolongation. The United States prescribing information for entrectinib recommends assessment of the QT interval and electrolytes at baseline and periodically during treatment, particularly for those with known long QT syndrome, clinically significant bradyarrhythmia, and severe or uncontrolled heart failure or who are taking other medicinal products associated with QT prolongation [75]. QT prolongation is not listed in the prescribing information for larotrectinib or repotrectinib.

●Skeletal toxicities – Bone fractures have occurred with TRK TKI therapy; the mechanism of action by which these occur remains unclear. For entrectinib, 5 percent of adult patients and 25 percent of pediatric patients had skeletal fractures [75]. In children, fractures occurred mainly in the setting of minimal or no trauma, although some patients have had radiologic abnormalities suggesting tumor involvement. For larotrectinib, bone fractures have been reported in 7 to 9 percent of patients. Repotrectinib increases the risk of skeletal fractures (eg, of the ribs, feet, spine, acetabulum, sternum, and ankles, some of which occurred at sites of disease and prior radiation therapy).

●Metabolic toxicities – Nearly 1 in 10 patients treated with entrectinib across clinical trials have experienced hyperuricemia, which was grade 4 in 1.7 percent and included one fatality due to tumor lysis syndrome. For repotrectinib, increased uric acid was reported in 21 percent of patients. The United States prescribing information for entrectinib and repotrectinib recommends assessment of serum uric acid levels prior to initiating therapy and periodically during treatment, and that patients be monitored for signs and symptoms of hyperuricemia [75].

SUMMARY AND RECOMMENDATIONS

●Molecular biology and prevalence of NTRK fusions

•Fusions involving one of the neurotrophic tyrosine receptor kinase (NTRK) genes can produce a tropomyosin receptor kinase (TRK) fusion oncoprotein that leads to overexpression of the kinase domain and/or constitutive activity of the kinase, both of which drive uninterrupted downstream signaling, oncogenic transformation, and tumor growth. (See 'Normal and tumor biology' above.)

•NTRK fusions are broadly distributed across a variety of adult and pediatric cancers (table 1). This distribution follows two general patterns: rare cancers that are enriched for NTRK fusions (eg, congenital infantile fibrosarcoma, and secretory breast or salivary gland cancers) and common cancers that have low to intermediate frequencies of NTRK fusions. (See 'Prevalence' above.)

●Diagnostic evaluation

•When available, next-generation sequencing of both DNA and RNA is the preferred detection method. (See 'Diagnosis' above.)

•However, if not available, assay choice to detect an NTRK fusion can be influenced by factors such as resources available in a practice environment and the frequency with which these fusions are found in a given tumor type (table 1). (See 'Testing approach' above.)

●Treatment with TRK inhibitors

•The presence of an NTRK fusion defines a diagnostic category for solid tumors, independent of site of origin, that is characterized by shared sensitivity to TRK inhibitors. Three TRK tyrosine kinase inhibitors (TKIs; larotrectinib, entrectinib, and repotrectinib) are now approved for treatment of TRK fusion-positive refractory solid tumors, regardless of the site of disease origin. (See 'TRK inhibitor activity' above.)

•All patients with TRK fusion-positive cancers should be offered treatment with a TRK inhibitor:

-For patients of all ages with metastatic disease, all three TRK TKIs have documented intracranial and extracranial activity. Larotrectinib appears to achieve the longest median progression-free and median overall survival reported thus far. Furthermore, it appears to be associated a lower frequency of select adverse events (eg, dizziness) compared with entrectinib and repotrectinib. TRK inhibitor therapy should be considered as soon as an NTRK fusion is identified, both in treatment-naïve patients and in those who have responded suboptimally to or progressed on other systemic therapies. (See 'Timing of therapy for advanced disease' above.)

-For patients of all ages with locally advanced disease in whom immediate surgical resection would result in significant morbidity, preoperative (neoadjuvant and/or adjuvant) use of TRK inhibition has been associated with downstaging and favorable outcomes in limited series. (See 'Benefits of perioperative therapy in non-metastatic disease' above.)

•Resistance limits the efficacy of TRK inhibitors. Repeat molecular profiling by tumor and/or cell-free DNA sequencing should be considered after TRK TKI progression. (See 'TRK inhibitor resistance' above.)

In patients with NTRK fusion-positive cancers who have progressed on larotrectinib or entrectinib, we offer the following, for each of the following subsets:

-Solvent front or gatekeeper mutations - The next-generation TRK TKI repotrectinib is an appropriate option.

-xDFG mutations – Disease-specific therapy is appropriate, given that such mutations may be less likely to respond to repotrectinib.

-non-NTRK alteration either alone or in combination with an NTRK resistance mutation – These mechanisms include KRAS mutation and MET amplification. Disease-specific therapy (eg, chemotherapy) is appropriate as such cancers may be less likely to respond to repotrectinib.

●TRK inhibitor side-effects

•Neurologic events such as dizziness, paresthesias, and weight gain should be monitored during TRK TKI therapy. Withdrawal pain with temporary or permanent TKI discontinuation can occur. (See 'TRK inhibitor side-effects' above.)

•Other adverse events such as liver function test abnormalities, heart failure, QT prolongation, skeletal fractures, and hyperuricemia can occur with one or more TRK TKIs. (See 'Non-neurologic toxicities' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges David Hyman, MD, who contributed to an earlier version of this topic review.