Abstract: Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are implicated in various cancers, including those of the lung and thyroid. The prevalence of NTRK fusions is 0.1 to 0.3% in non–small cell lung cancer (NSCLC) and as high as 26% in pediatric papillary thyroid carcinoma. Detection methods include immunohistochemistry, fluorescence in situ hybridization, reverse transcription polymerase chain reaction, and next-generation sequencing. Management of NTRK fusion–positive lung cancer primarily involves targeted therapies, notably the tyrosine receptor kinase (TRK) inhibitors larotrectinib and entrectinib. Both agents demonstrate high response rates and durable disease control, particularly in metastatic adenocarcinoma of the lung. They are preferred as first-line treatments because of their efficacy over immunotherapy. Possible adverse events include dizziness, weight gain, neuropathy-like pain, and liver enzyme elevation. Larotrectinib and entrectinib also produce robust and durable responses in NTRK fusion–positive thyroid cancer that is refractory to radioactive iodine. Second-generation TRK inhibitors that have been designed to overcome acquired resistance are under investigation.
Diagnosing NTRK Fusions in Lung and Thyroid Cancer
David S. Hong, MD
Douglas E. Johnson Endowed Professor
Deputy Chair of the Department of Investigational Cancer Therapeutics [A Phase I Program]
Division of Cancer Medicine
Clinical Medical Director of the Clinical and Translational Research Center (CTRC)
University of Texas MD Anderson Cancer Center
Houston, Texas
Note: This Roundtable was conducted before the accelerated approval of repotrectinib on June 13, 2024, for NTRK
fusion–positive solid tumors.
Overview of NTRK Gene Fusions
The neurotrophic tropomyosin receptor tyrosine kinase (NTRK) genes 1, 2, and 3 include 3 closely related tropomyosin receptor kinase (TRK) proteins—TRKA, TRKB, and TRKC, respectively.1,2 Normally, these proteins signal downstream of neurotrophins via phospholipase-C gamma (PLCγ), Ras/mitogen-activated protein (Ras/MAP) kinase, and the phosphoinositide 3-kinase (PI3K)-protein kinase B (PKB) and AKT pathways to stimulate cell proliferation and survival. These proteins are first of all important for neuronal development in utero, and they also retain some normal postnatal function within the nervous system, including the regulation of appetite, proprioception, and pain.
NTRK rearrangements, and more specifically gene fusions, are the most common mechanism of TRK oncogene activation.3 NTRK fusions are reminiscent of BCR–ABL fusions in leukemia, in which an unrelated 5′ upstream gene partner is fused to 1 of the 3 kinase domains within the NTRK gene. The results of this fusion are constitutive expression, with the chimeric protein driven by the promoter from the 5′ partner and ligand-independent activation of the resulting kinase domain. NTRK fusions can be oncogenic. Like other driver mutations, NTRK fusions tend to be mutually exclusive, with one notable exception. NTRK fusion–positive colorectal cancer (CRC) appears to be a unique subset of CRC that has a high tumor mutational burden (TMB) and is microsatellite instability-high (MSI-H).4
Numerous NTRK gene fusions have been reported across a broad range of tumors in both adults and children. The frequency of NTRK gene fusions is variable and appears highly dependent on the tumor type, with some tumors appearing to be nearly pathognomonic for NTRK fusions. The frequencies of NTRK fusions are often classified in 3 broad categories (Table 1).5,6 The high-frequency category includes tumors in which NTRK fusions are defining molecular features, with frequencies of 85% or higher. The low-frequency category includes tumors in which the frequency of NTRK fusions tends to be less than 5% (and most often <1%). An intermediate category includes somewhat common tumors in which NTRK fusions occur at frequencies between approximately 5% and 25%.
Prevalence of NTRK Fusions in Lung Cancer
The prevalence of NTRK fusions in non–small cell lung cancer (NSCLC) is estimated to be between 0.1% and 0.3%, on the basis of data from multiple studies.7 For example, in a study published in 2023, Overbeck and colleagues used real-world screening of 1068 unselected patients in Germany over an 18-month period to report on the frequency of NTRK gene fusions.8 Overall, 982 of 1068 samples were successfully evaluated. The overall prevalence of NTRK fusions in this population was 0.2% (2 cases among 982). Frequencies of 0.1% and 0.16% in NSCLC were reported in 2 large studies,9,10 whereas a frequency of 0.23% was identified in another study of 4872 patients with NSCLC.11
The frequency of NTRK fusions in NSCLC is markedly less than the frequencies of other canonical gene fusions in this tumor type—namely, those involving ALK, ROS1, or RET. Although the frequency is highest in adenocarcinoma NSCLC, NTRK fusions have also been identified in patients with squamous cell NSCLC as well as neuroendocrine carcinoma of the lung and sarcomatoid carcinoma of the lung.
The clinicopathologic features of NTRK fusion–positive NSCLC were reported from a study of 11 patients.11 The median age at diagnosis in this group was 48 years, with a range from 25 to 86 years. The percentages of male and female patients were 55% and 45%, respectively. Patients reported either a no or low smoking history (0-5 pack-years; 73%) or a high smoking history (>20 pack-years; 27%); however, overall there was no smoking history (median of 0 pack-years; range, 0-58). Of the 11 patients, the majority had adenocarcinoma histology (82%), followed by squamous cell carcinoma (9%) and neuroendocrine carcinoma (9%). Although NTRK fusions, like other gene fusions, were shown to occur most typically in patients of middle age with no smoking history, this study demonstrated that NTRK fusions can occur across age groups and smoking status, prompting the recommendation to screen all patients with NSCLC for NTRK fusion.
Prevalence of NTRK Fusions in Thyroid Cancer
The prevalence of NTRK fusions in thyroid cancer differs across studies and in different tumor types, with the highest prevalence observed in pediatric papillary thyroid cancers and in radiation-induced thyroid cancer. Across various studies of sporadic thyroid cancer in adults, the frequencies of NTRK fusions reported were 2.22% (of 451 tumors), 2.28% (of 571 tumors), 2.34% (of 513 tumors), 5.7% (of 70 tumors), 2.9% (of 243 tumors), and 3.1% (of 351 tumors).9,12-16 In comparison, the frequency of NTRK fusions in post-Chernobyl cases of thyroid cancer was 14.5% of 62 cases.13 NTRK fusions occur at a much higher rate in pediatric papillary thyroid carcinoma, reported at a frequency of 26% in a study of 27 cases.17 In a study of 93 cases of pediatric papillary thyroid carcinoma, NTRK fusions were identified in 17 patients (18.3%).18
Clinicopathologic features of NTRK fusion–positive thyroid cancers in 11 patients with primary thyroid cancer (10 adults and 1 adolescent) were reported.12 Of the 11 patients, 8 were female. All patients were radiation-naive except 1 patient who had received low-dose radiotherapy for acne during adolescence 30 years prior. At initial presentation, each patient had a large, infiltrative mass that was pathologically staged as T2 (9%) or T3 (91%), and all patients had cervical lymph node involvement. At presentation, 3 patients (27%) had pulmonary metastases; in 3 additional patients, pulmonary metastases developed over the course of their disease.
In a study of pediatric patients with papillary thyroid carcinoma, of 14 patients identified with NTRK fusion–positive tumors, nearly all (11 patients) were female.18 The mean age at diagnosis was 15.9 (±2.4) years, and the mean tumor size was 20.1 (±10.4) mm. The tumor histology was identified as classic (14.3%), follicular (57.1%), a mixture of classic and follicular (21.4%), or other (7.1%). Multifocality was identified in 50.0% and extrathyroidal extension in 42.9%.
Detection of NTRK Fusions
Several methods are available to identify NTRK fusions in solid tumors.15,19,20 Each of these methods has benefits and drawbacks that drive their utility in the clinic (Table 2).
Immunohistochemistry (IHC) offers a widely available, inexpensive method with a rapid turnaround to identify NTRK fusions. IHC results in antibody-based visualization of TRK protein expression and staining patterns that correlate with the TRK fusion partner. Although powerful in its relative simplicity, IHC can be associated with false-positive results and therefore is often used as an initial screening test.
Fluorescence in situ hybridization (FISH) uses probes to track anomalous NTRK gene fusion partners. Benefits of FISH include high sensitivity, relatively rapid turnaround time, and ability to work with limited tumor content, particularly in formalin-fixed, paraffin-embedded specimens. Drawbacks revolve around the low throughput of this technique, particularly because it must be repeated for all 3 NTRK genes.
Reverse transcription polymerase chain reaction (RT-PCR) begins with primer-specific reverse transcription of RNA to complementary DNA. This DNA is then amplified and detected via a fluorogenic probe. The use of sequence-specific primers requires knowledge of both fusion partners, limiting the use of RT-PCR for the detection of NTRK fusions.
Next-generation sequencing (NGS) implements either a targeted approach (focusing on a panel of genes) or whole-genome sequencing to examine multiple genomic alterations simultaneously. Either DNA sequencing or RNA sequencing can be used. The RNA sequencing approach is considered the more useful because it allows detection of larger fusion partners that may not be detected by DNA NGS.
Who Should Be Tested for NTRK Fusions?
Clinical decisions for testing can vary across institutions. Some NTRK fusion testing is histology-driven, with routine testing used for tumor types in which it facilitates the diagnosis (eg, infantile fibrosarcoma, secretory breast carcinoma, and MASC, among others). For other tumor types, the decision to test may be driven by the history. For example, NTRK fusion testing should be considered when a patient’s tumor is negative for other oncogenic drivers or a patient has relapsed/refractory disease.
In cases of advanced or metastatic NSCLC specifically, the National Comprehensive Cancer Network (NCCN) guidelines include NTRK fusion testing in the list of broad molecular profiling tests recommended for cases with adenocarcinoma histology.21 Additionally, it is recommended that broad molecular profile testing include NTRK fusions in cases of squamous cell carcinoma.
The NCCN guidelines for thyroid cancer recommend molecular diagnostics in all cases of advanced thyroid cancer.22 NTRK fusions are seen in papillary thyroid cancer as well as in the cancers that differentiate from papillary thyroid cancer and become more aggressive, such as high-grade papillary thyroid cancer and anaplastic thyroid cancer. The fusions are typically not seen in purely follicular thyroid cancers or in medullary thyroid cancers.
References
1. Okamura R, Boichard A, Kato S, Sicklick JK, Bazhenova L, Kurzrock R. Analysis of NTRK alterations in pan-cancer adult and pediatric malignancies: implications for NTRK-targeted therapeutics [published online November 15, 2018]. JCO Precis Oncol. doi:10.1200/PO.18.00183.
2. Laetsch TW, Hong DS. Tropomyosin receptor kinase inhibitors for the treatment of TRK fusion cancer. Clin Cancer Res. 2021;27(18):4974-4982.
3. Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol. 2018;15(12):731-747.
4. Wang H, Li ZW, Ou Q, Wu X, Nagasaka M, Shao Y, Ou SI, Yang Y. NTRK fusion positive colorectal cancer is a unique subset of CRC with high TMB and microsatellite instability. Cancer Med. 2022;11(13):2541-2549.
5. Nguyen MA, Colebatch AJ, Van Beek D, Tierney G, Gupta R, Cooper WA. NTRK fusions in solid tumours: what every pathologist needs to know. Pathology. 2023;55(5):596-609.
6. Shulman DS, DuBois SG. The evolving diagnostic and treatment landscape of NTRK-fusion-driven pediatric cancers. Paediatr Drugs. 2020;22(2):189-197.
7. Liu F, Wei Y, Zhang H, Jiang J, Zhang P, Chu Q. NTRK fusion in non-small cell lung cancer: diagnosis, therapy, and TRK inhibitor resistance. Front Oncol. 2022;12:864666.
8. Overbeck TR, Reiffert A, Schmitz K, et al. NTRK gene fusions in non-small-cell lung cancer: real-world screening data of 1068 unselected patients. Cancers (Basel). 2023;15(11):2966.
9. Gatalica Z, Xiu J, Swensen J, Vranic S. Molecular characterization of cancers with NTRK gene fusions. Mod Pathol. 2019;32(1):147-153.
10. Rosen EY, Goldman DA, Hechtman JF, et al. TRK fusions are enriched in cancers with uncommon histologies and the absence of canonical driver mutations. Clin Cancer Res. 2020;26(7):1624-1632.
11. Farago AF, Taylor MS, Doebele RC, et al. Clinicopathologic features of non-small-cell lung cancer harboring an NTRK gene fusion [published online July 23, 2018]. JCO Precis Oncol. doi:10.1200/PO.18.00037.
12. Chu YH, Dias-Santagata D, Farahani AA, et al. Clinicopathologic and molecular characterization of NTRK-rearranged thyroid carcinoma (NRTC). Mod Pathol. 2020;33(11):2186-2197.
13. Leeman-Neill RJ, Kelly LM, Liu P, et al. ETV6-NTRK3 is a common chromosomal rearrangement in radiation-associated thyroid cancer. Cancer. 2014;120(6):799-807.
14. Rosen EY, Goldman DA, Hechtman JF, et al. TRK fusions are enriched in cancers with uncommon histologies and the absence of canonical driver mutations. Clin Cancer Res. 2020;26(7):1624-1632.
15. Solomon JP, Linkov I, Rosado A, et al. NTRK fusion detection across multiple assays and 33,997 cases: diagnostic implications and pitfalls. Mod Pathol. 2020;33(1):38-46.
16. Okamura R, Boichard A, Kato S, Sicklick JK, Bazhenova L, Kurzrock R. Analysis of NTRK alterations in pan-cancer adult and pediatric malignancies: implications for NTRK-targeted therapeutics [published online November 15, 2018]. JCO Precis Oncol. doi:10.1200/PO.18.00183.
17. Prasad ML, Vyas M, Horne MJ, et al. NTRK fusion oncogenes in pediatric papillary thyroid carcinoma in northeast United States. Cancer. 2016;122(7):1097-1107.
18. Pekova B, Sykorova V, Dvorakova S, et al. RET, NTRK, ALK, BRAF, and MET fusions in a large cohort of pediatric papillary thyroid carcinomas. Thyroid. 2020;30(12):1771-1780.
19. Solomon JP, Hechtman JF. Detection of NTRK fusions: merits and limitations of current diagnostic platforms. Cancer Res. 2019;79(13):3163-3168.
20. Repetto M, Chiara Garassino M, Loong HH, et al. NTRK gene fusion testing and management in lung cancer. Cancer Treat Rev. 2024;127:102733.
21. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Non-small cell lung cancer. Version 5.2024. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Updated April 23, 2024.
22. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Thyroid carcinoma. Version 2.2024. https://www.nccn.org/professionals/physician_gls/pdf/thyroid.pdf. Updated March 12, 2024.
Management of Patients with NTRK Fusion–Positive Lung Cancer
Alexander Drilon, MD
Chief of the Early Drug Development (EDD) Service
Division of Solid Tumor Oncology, Department of Medicine
Memorial Sloan Kettering Cancer Center
New York, New York
The Current Standard of Care
To best understand the current standard of care for the treatment of NTRK fusion–positive lung cancer, it is first important to point out that these fusions are most frequently found in adenocarcinoma NSCLC. However, they can also be detected in squamous cell lung carcinomas and neuroendocrine lung cancers. Thus, the standard of care can change from one histology to another. For the purposes of this discussion, we will focus on the treatment of metastatic adenocarcinoma of the lung, the most frequent type of lung cancer with NTRK fusions.
If an NTRK fusion is not immediately identified in the tumor tissue, patients with metastatic NSCLC are generally treated in the first-line setting with either immunotherapy alone or chemoimmunotherapy.1 However, there is a growing recognition from the IMMUNOTARGET Registry that NSCLC tumors harboring oncogenic drivers (such as NTRK fusions) do not have a high likelihood of response to immunotherapy.2 This may be because such cancers are less genomically complex and thus less immunogenic. Most providers avoid the use of immunotherapy in driver-positive NSCLC, even in the background of high programmed death ligand 1 (PD-L1) levels.
Therefore, for an NTRK fusion–positive NSCLC, recognizing that the level of activity of targeted therapies like larotrectinib and entrectinib is high, the preference is to start with the best drug up front (ie, the targeted agent), then later move to chemotherapy in the second line.1 In cases in which some form of lung cancer is initially diagnosed, then an NTRK fusion is found later after a first-line treatment has already been started, it is perfectly reasonable to continue that therapy if it is working. However, if the patient shows a suboptimal response or continues to experience cancer-associated symptoms, it makes sense to switch to a TRK inhibitor even in the absence of formal progression.
Notably, in addition to the treatment of metastatic solid tumors, the indications for both larotrectinib and entrectinib approved by the US Food and Drug Administration (FDA) allow their use in earlier stages of disease. Specifically, the label for both agents states that they can be used in patients either with metastatic disease or in whom surgical resection is likely to result in severe morbidity (eg, stage IIIb NSCLC).3,4
Clinical Data Supporting NTRK Inhibitors in Lung Cancer
Larotrectinib
Data from patients with lung cancer were gathered from 2 global, multicenter, registrational clinical trials: a phase 1 adult trial (NCT02122913) and a phase 2 basket trial (NAVIGATE) of adolescents older than 12 years and adults.5 A total of 20 patients with NTRK fusion–positive lung cancer were included in this combined analysis.6
Adult patients were treated with larotrectinib (100 mg twice daily), and treatment beyond progression was allowed if they continued to benefit. The median patient age was 48.5 years (range, 25.0-76.0), and the percentages of male and female patients were the same (50%/50%). Patient races included White (45%), Asian (40%), American Indian or Alaska Native (5%), and other (10%). Most patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (40%) or 1 (50%), although 1 patient (5%) had an ECOG performance status of 2 and 1 patient an ECOG performance status of 3. Half of the patients (50%) had central nervous system (CNS) metastasis at baseline. The vast majority of NTRK gene fusions identified involved NTRK1 (80%), 20% involved NTRK3, and no NTRK2 gene fusions were found. Patients were heavily pretreated, and all but 1 patient (95%) had received prior systemic therapy for their disease, with 50% of patients having received 3 or more prior systemic treatments.
The primary endpoint, investigator-assessed objective response rate (ORR) in 15 evaluable patients, was 73% (95% CI, 45-92). Of these responses, 1 (7%) was a complete response and 10 (67%) were partial responses. In addition, 3 patients (20%) had stable disease as the best response. All patients with measurable disease showed a reduction in target tumor size (Figure 1). Larotrectinib appeared to show CNS activity, and although intracranial response was not a study endpoint, CNS metastases were included as target lesions for 2 patients. By cycle 4, reductions in their CNS metastases of 59% and 100% were noted in these 2 patients.
For patients with an objective response, the median time to response was 1.8 months (range, 1.6-1.9), which was approximately the time to the first follow-up imaging examination in the trial. At a median follow-up of 17.4 months, the median duration of response (DOR) was 33.9 months (95% CI, 5.6-33.9) (Figure 2). At 12 months and 24 months, the DOR rates were 81% and 65%, respectively.
The secondary endpoint of median progression-free survival (PFS) was 35.4 months (95% CI, 5.3-35.4) at a median follow-up of 16.6 months (Figure 3). The 12- and 24-month PFS rates were 65% and 55%, respectively. In 11 of the 19 patients who had received at least one prior systemic therapy (58%), PFS was 2-fold longer with larotrectinib than their time to progression or treatment failure on their most recent prior therapy.
At a median follow-up of 16.2 months, the median overall survival (OS) was 40.7 months (95% CI, 17.2 to not estimable). The 12-month OS rate was 86%, and the 24-month OS rate was 75% (Figure 4).
Entrectinib
Similarly, a patient dataset from 3 clinical studies (the phase 1 ALKA-372-001 trial, the phase 1 STARTRK-1 trial, and the phase 2 STARTRK-2 basket trial) was used to evaluate entrectinib. All these studies enrolled patients aged 18 years or older with metastatic or locally advanced NTRK fusion–positive solid tumors.7 Patients were included in a prespecified integrated analysis if they had an NTRK fusion–positive solid tumor, had measurable disease, and had received at least one dose of entrectinib at or above the recommended phase 2 dose (600 mg once daily). In the first report of this integrated analysis, which had a data cutoff of May 31, 2018, and included 54 patients, NSCLC was the primary tumor type in 10 patients (19%). An objective response was achieved with entrectinib in 7 of these patients (70%; 95% CI, 35%-93%).
A subsequent update, with a data cutoff of August 31, 2020, included 22 patients with NSCLC, of whom 13 had CNS metastases at baseline.8 In this update, an objective response was reported in 14 patients (63.6%; 95% CI, 40.7%-82.8%). The median DOR in the responding patients was 19.9 months (95% CI, 10.4-29.4). Additional endpoints reported among the subset of patients with NSCLC were median PFS (14.9 months; 95% CI, 6.5-30.4) and median OS (not estimable; 95% CI, 20.8 to not estimable).
Selecting NTRK Inhibitors for Patients With Lung Cancer
Both larotrectinib and entrectinib are FDA-approved TRK inhibitors,3,4 but subtle differences underscore the different contexts in which they may be used. Larotrectinib is a selective TRK inhibitor of 3 different TRK proteins: TRKA, TRKB, and TRKC. In an evaluation of a broad panel of enzymes, only one other non-TRK kinase (TNK2) was inhibited, at an approximately 100-fold higher concentration. In contrast, entrectinib is a multikinase inhibitor that inhibits the 3 TRK proteins as well as ROS1 and ALK at similar potencies. Because of this more extensive kinase inhibition, entrectinib is also indicated in the treatment of ROS1 fusion–positive NSCLC.
Both agents are associated with high response rates and very durable disease control. Entrectinib was initially perceived to be a more CNS-penetrant drug. In practice, however, CNS responses have been observed with both entrectinib and larotrectinib. In the absence of a head-to-head trial comparing the 2 agents, it is difficult to know if one agent or the other is better for our NSCLC patients.
Managing Adverse Events
Several on-target adverse events (AEs) have been described with larotrectinib and entrectinib, and these indeed appear to be class effects resulting from TRK inhibition.9,10 One of the more well-recognized on-target (or TRK inhibition–related) AEs associated with either larotrectinib or entrectinib is dizziness. Often, the AE will decrease over time, as the patient’s body seemingly adjusts to the agent. However, in rare cases, the dizziness can be overwhelming, so that either a dose reduction or permanent discontinuation is required. Alternatively, supportive care agents like meclizine may be useful for vertigo, or midodrine for orthostatic hypotension.
Another common side effect is weight gain. Early in the clinical trials, the weight gain was initially attributed to the improved health of the patients. However, when it was determined that even patients with stable disease continued to gain weight, this AE was truly recognized as being attributable to the TRK inhibitor. The cause of the weight gain may be related to increased appetite modulation due to TRK inhibition. For weight gain, patients may benefit from seeing weight gain specialist partners in endocrinology, who may choose to intervene with weight loss drugs.
A third common and somewhat perplexing AE associated with TRK inhibitors is neuropathy-like or myalgia-mimicking withdrawal pain, likely due to inhibition of the TRK proteins regulating neurosympathetic processes in the body. This pain often occurs as withdrawal or rebound pain when a dose of the drug is missed—for example, one of the twice-daily doses of larotrectinib. This pain syndrome can occur in patients who have an underlying pain issue (eg, pre-existing knee arthritis), but this is not always the case. Support with pain medication may be needed for the pain flares, although amazingly, the pain can disappear in the first hour after the patient restarts the treatment.
Finally, the most common grade 3 AE that tends to occur is elevation of liver function enzymes. Although its occurrence as a grade 3 or higher event is relatively uncommon (approximately 2% to 3% of patients treated in clinical trials), either dose reduction or discontinuation is required.3,4
References
1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Non-small cell lung cancer. Version 5.2024. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Updated April 23, 2024.
2. Mazieres J, Drilon A, Lusque A, et al. Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry. Ann Oncol. 2019;30(8):1321-1328.
3. Larotrectinib [prescribing information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc; November 2023.
4. Entrectinib [prescribing information]. South San Francisco, CA: Genentech, Inc; January 2024.
5. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med. 2018;378(8):731-739.
6. Drilon A, Tan DSW, Lassen UN, et al. Efficacy and safety of larotrectinib in patients with tropomyosin receptor kinase fusion-positive lung cancers. JCO Precis Oncol. 2022;6(6):e2100418.
7. Doebele RC, Drilon A, Paz-Ares L, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020;21(2):271-282.
8. Demetri GD, De Braud F, Drilon A, et al. Updated integrated analysis of the efficacy and safety of entrectinib in patients with NTRK fusion-positive solid tumors. Clin Cancer Res. 2022;28(7):1302-1312.
9. Liu D, Flory J, Lin A, et al. Characterization of on-target adverse events caused by TRK inhibitor therapy. Ann Oncol. 2020;31(9):1207-1215.
10. Liguori V, Gaio M, Zinzi A, et al. The safety profiles of two first-generation NTRK inhibitors: analysis of individual case safety reports from the FDA Adverse Event Reporting System (FAERS) Database. Biomedicines. 2023;11(9):2538.
Management of Patients with NTRK Fusion–Positive Thyroid Cancer
Lori J. Wirth, MD
Associate Professor in Medicine
Harvard Medical School
Medical Director of the Center for Head and Neck Cancers
Massachusetts General Hospital
Boston, Massachusetts
The Current Standard of Care
Most well-differentiated thyroid cancers are cured by surgery alone, with thyrotropin suppression and radioactive iodine (RAI) added for patients with intermediate- or high-risk disease.1 However, RAI-refractory thyroid cancer eventually develops in a small subset of patients. In general, patients have indolent disease at their first presentation of recurrent and/or metastatic thyroid cancer and may not immediately require systemic therapy.
Because most cases of RAI-refractory thyroid cancer are relatively indolent, with a low, slow-growing tumor burden, there are typically no time constraints for gathering the molecular diagnostic information needed before the initiation of therapy.1 Often, a period of disease monitoring is planned to gain a better understanding of the rate of disease progression. Patients can have very slow disease progression and may not need systemic therapy immediately. Criteria to initiate systemic therapy include disease progression in the prior 6 to 14 months, symptomatic disease, anatomically threatening disease, and bulky disease. One exception is anaplastic thyroid cancer, a rare histologic subtype of thyroid cancer that is more aggressive and requires immediate treatment. However, turnaround times for testing have greatly improved, particularly when in-house testing is available. As a result, we generally can wait for the molecular diagnostics as well as BRAF status by IHC to make clinical decisions. Cases found to be positive for a BRAF V600E mutation will not harbor oncogenic kinase fusions, whereas those cases found to be BRAF wild-type may benefit from additional molecular diagnostic studies to identify NTRK fusions, RET fusions, tumor mutational burden‑high (TMB‑H) status, or MSI-H or defective mismatch repair (dMMR) status, all of which can be targeted with NCCN-recommended regimens.
Traditional chemotherapeutic agents (including paclitaxel and doxorubicin) generally have minimal efficacy in patients with metastatic differentiated thyroid cancer. Alternatively, targeted agents have been demonstrated to be effective and are recommended for patients with locally recurrent, advanced, and/or metastatic disease that is not amenable to RAI therapy.2 Although effective, none of these agents is curative, and their toxic effects may limit their use in some patients. Targeted agents used in this setting include anti-angiogenic multitargeted kinase inhibitors: sorafenib, lenvatinib, and cabozantinib, as well as selpercatinib or pralsetinib (for patients with RET gene fusion–positive tumors), dabrafenib/trametinib (for patients with BRAF V600E mutation–positive tumors), and pembrolizumab (for patients with TMB‑H tumors or with MSI-H or dMMR tumors that have progressed following prior treatment and for which no satisfactory alternative options are available. The TRK inhibitors larotrectinib and entrectinib are recommended for patients with NTRK gene fusion–positive tumors that are not amenable to RAI therapy. Responses to TRK inhibitors can be robust and durable, with long-term remission achievable (Figure 5).
It is difficult to compare these options in the absence of head-to-head trials. However, it is clear that the AE profiles of these agents differ significantly. In particular, larotrectinib and entrectinib tend to be better tolerated than the multitargeted kinase inhibitors, so that patients can remain on the full dose without dose modifications and without discontinuation for a much longer period of time.
Clinical Data Supporting TRK Inhibitors in Thyroid Cancer
Larotrectinib
A pooled data analysis from 3 clinical studies (a phase 1 adult trial [NCT02122913], a phase 1/2 pediatric trial [SCOUT] in patients younger than 21 years of age, and a phase 2 basket trial [NAVIGATE] of adolescents older than 12 years and adults) demonstrated the durable antitumor efficacy of larotrectinib across a population comprising 159 patients with multiple types of NTRK fusion–positive solid tumors.3 In 2022, Waguespack and colleagues reported a subset analysis of 29 adult and pediatric patients identified from this pooled dataset.4
All patients included had measurable locally advanced or metastatic thyroid carcinoma harboring an NTRK gene fusion and were treated with larotrectinib (100 mg twice daily in adults, 100 mg/m2 twice daily in pediatric patients). Larotrectinib was administered until disease progression, unacceptable toxicity, or study withdrawal, although patients could continue treatment beyond disease progression if the study investigator judged they were still benefitting from treatment. Among the 29 patients, the primary tumor histology was papillary thyroid carcinoma (69%), followed by anaplastic thyroid carcinoma (24%) and follicular thyroid carcinoma (7%). The median age was 60 years, although the ages ranged widely from 6 to 80 years (2 patients were children). At baseline, 4 patients showed evidence of CNS metastases. All NTRK fusions involved either NTRK1 (45%) or NTRK3 (55%), with no NTRK2 gene fusions identified. A total of 45% of the patient set had received no prior systemic therapies, whereas 24%, 24%, and 7% had received 1, 2, or 3 or more prior systemic therapies, respectively. The prior systemic therapy most often given was a tyrosine kinase inhibitor (38%).
The primary endpoint, ORR, was 71% (95% CI, 51%-87%) among the 28 evaluable patients in this subset; this included 2 complete responses (7%) and 18 partial responses (64%; Figure 6). An additional 4 patients (14%) had stable disease. Among the patients who achieved an objective response, the median time to that response was 1.87 months (range, 1.64-3.68), which in most cases corresponded to the first post-baseline assessment. A large difference was noted between the degrees of response in anaplastic and other thyroid carcinoma histologies (eg, papillary and follicular). Indeed, all 3 patients who showed evidence of disease progression had anaplastic thyroid carcinoma. The 4 patients with CNS metastases at baseline had a partial response as their best response; 2 patients showed intracranial tumor reductions of 14% and 46%.
Secondary efficacy endpoints included DOR, PFS, and OS. In the 20 responding patients, the estimated DOR rate at 12 months was 95% and at 24 months was 81% (Figure 7). In patients with either papillary or follicular histology, the DOR rates at 12 and 24 months were 100% and 84%, respectively. For patients with anaplastic thyroid carcinoma, the 12-month estimated DOR rate was 50%.
Overall, the PFS rate was 81% at 12 months and 69% at 24 months (Figure 8). PFS was markedly better in patients with differentiated thyroid carcinoma (either papillary or follicular histology: 100% and 84% at 12 and 24 months, respectively) than in patients with anaplastic histology (17%) at each time point. In patients with anaplastic thyroid carcinoma, after a median follow-up of 27.4 months, the median PFS was relatively short, at 2.2 months (95% CI, 0.9 to not estimable).
In the overall patient population, the estimated OS rates at 12, 24, and 36 months were 89%, 76%, and 65%, respectively (Figure 9). Again, these outcomes were markedly better in patients with either papillary or follicular thyroid carcinoma, with OS rates of 100% (12 months), 92% (24 months), and 79% (36 months). Comparatively, the OS rate in patients with anaplastic thyroid carcinoma was 50% at 12 months and 17% at 24 months, with patients reaching a median OS of 8.8 months (95% CI, 2.6 to not estimable) over a median follow-up of 27.4 months.
Entrectinib
As was described in the section on lung cancer, a patient dataset from 3 clinical studies (the phase 1 ALKA-372-001 trial, the phase 1 STARTRK-1 trial, and the phase 2 STARTRK-2 basket trial) was used to evaluate entrectinib. All these studies enrolled patients aged 18 years or older with metastatic or locally advanced NTRK fusion–positive solid tumors.5 This prespecified integrated analysis enrolled patients with an NTRK fusion–positive solid tumor if they had measurable disease and had received at least one dose of entrectinib at or above the recommended phase 2 dose (600 mg once daily).
The initial report of this integrated analysis, with a data cutoff of May 31, 2018, included 54 patients, of whom 5 were identified as having thyroid cancer. An objective response was achieved in 1 of these 5 patients. A subsequent update, with a data cutoff of August 31, 2020, included 13 patients with thyroid cancer.6 An objective response was achieved with entrectinib in 7 of these patients (53.8%; 95% CI, 25.1%-80.8%). The median DOR in the responding patients was 13.2 months (95% CI, 7.9 to not estimable). Additional endpoints reported among the subset of patients with thyroid cancer were median PFS (19.9 months; 95% CI, 6.5-33.8) and median OS (19.9 months; 95% CI, 14.5 to not estimable).
Selecting TRK Inhibitors for Patients With Thyroid Cancer
Both larotrectinib and entrectinib carry indications under accelerated approval for the treatment of patients with NTRK fusion–positive cancer if the cancer is metastatic or if surgical resection is likely to result in severe morbidity and the cancer has either progressed following treatment or no satisfactory alternative therapy is available.7,8 The clinical data reported thus far with the use of TRK inhibitors in thyroid cancer are limited to 29 patients treated with larotrectinib and 13 patients treated with entrectinib.4,6 Although both of these are relatively small numbers, given the rarity of the disease, it is fair to say that we have more experience with larotrectinib in patients with differentiated thyroid cancer. In general in these patients, larotrectinib was associated with a higher response rate and a longer PFS than was entrectinib, although the results cannot be directly compared. On the basis of these findings, although both agents are FDA-approved options, I tend to select larotrectinib when treating patients outside a clinical trial.
One important caveat is that initially the impression was that entrectinib was designed specifically to penetrate and remain in the CNS (later, larotrectinib was demonstrated to have excellent CNS activity as well).9-11 As a result, patients presenting with brain metastases tended to be enrolled in the entrectinib clinical trials; indeed, of the 13 patients with thyroid cancer included in the integrated analysis of entrectinib, 7 had CNS metastases. This is a high rate of CNS metastasis for thyroid cancer, suggesting that the patient population in the entrectinib studies probably was not the same thyroid cancer patient population that was enrolled in the larotrectinib studies.
Adverse Events Reported in Patients With Thyroid Cancer
AEs occurring with either larotrectinib or entrectinib are relatively similar, and both are very well tolerated; however, only larotrectinib has reported specific AE data in patients with thyroid cancer. Among the 29 patients with thyroid carcinoma included from the pooled analysis of 3 clinical trials, the most frequent treatment-related AEs were myalgia (28%), fatigue (28%), dizziness (28%), and elevated liver transaminases (28% with increased aspartate aminotransferase and 28% with increased alanine aminotransferase).4 These AEs were primarily grade 1 or 2 and were consistent with those reported in the full pooled analysis dataset.3 Just 2 patients experienced a grade 3 AE—one with anemia and the other with a decreased lymphocyte count. No patients permanently discontinued larotrectinib because of an AE.
Emerging Roles for TRK Inhibitors in Thyroid Cancer
TRK inhibition has also been explored in novel roles for thyroid cancer treatment. Accumulating evidence suggests that TRK inhibition with larotrectinib may cause a tumor to concentrate RAI more effectively. Case reports have begun to demonstrate a potential role of larotrectinib in RAI redifferentiation, which may further extend to its use as neoadjuvant therapy before initial RAI treatment.4,12,13 An open-label, phase 2 study is currently recruiting patients with NTRK fusion–positive differentiated thyroid cancer to evaluate larotrectinib followed by RAI therapy.14
One case study has been reported that showed a dramatic response of an anaplastic thyroid cancer to entrectinib.15 However, given the generally low response rate in patients with anaplastic histology in the larotrectinib pooled clinical trials, TRK inhibition should not yet replace chemoradiotherapy for patients with this more aggressive form of thyroid cancer.
Compared with papillary thyroid cancers in adult patients, those in pediatric patients tend to present as larger primary tumors with more extensive extrathyroidal involvement and an increased prevalence of both local and distant metastatic disease.16 Given the tolerability of these agents, it would be reasonable to consider using larotrectinib or entrectinib in patients who present with initially bulky disease that would be difficult to resolve with an R0 or R1 resection.
Resistance to TRK Inhibitors
Acquired resistance to the TRK inhibitors larotrectinib and entrectinib has been documented, primarily resulting from NTRK gene mutations that involve amino acid substitutions in the solvent-front region, gatekeeper residues, and xDFG motif substitutions.17,18 In addition, genomic alterations in complementary pathways, such as those involving MAPK, BRAF, KRAS, and MET, may also be implicated in acquired mechanisms of resistance to TRK inhibitors.19 The second-generation TRK inhibitors repotrectinib and selitrectinib were designed to overcome TRK inhibitor resistance and are currently under clinical investigation.20
References
1. Boucai L, Zafereo M, Cabanillas ME. Thyroid cancer: a review. JAMA. 2024;331(5):425-435.
2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Thyroid carcinoma. Version 2.2024. https://www.nccn.org/professionals/physician_gls/pdf/thyroid.pdf. Updated March 12, 2024.
3. Hong DS, DuBois SG, Kummar S, et al. Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials. Lancet Oncol. 2020;21(4):531-540.
4. Waguespack SG, Drilon A, Lin JJ, et al. Efficacy and safety of larotrectinib in patients with TRK fusion-positive thyroid carcinoma. Eur J Endocrinol. 2022;186(6):631-643.
5. Doebele RC, Drilon A, Paz-Ares L, et al; trial investigators. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020;21(2):271-282.
6. Demetri GD, De Braud F, Drilon A, et al. Updated integrated analysis of the efficacy and safety of entrectinib in patients with NTRK fusion-positive solid tumors. Clin Cancer Res. 2022;28(7):1302-1312.
7. Larotrectinib [prescribing information]. Bayer HealthCare Pharmaceuticals Inc., Whippany, NJ. November 2023.
8. Entrectinib [prescribing information]. Genentech, Inc. South San Francisco, CA. January 2024.
9. Fischer H, Ullah M, de la Cruz CC, et al. Entrectinib, a TRK/ROS1 inhibitor with anti-CNS tumor activity: differentiation from other inhibitors in its class due to weak interaction with P-glycoprotein. Neuro-oncol. 2020;22(6):819-829. doi:10.1093/neuonc/noaa052
10. Menichincheri M, Ardini E, Magnaghi P, et al. Discovery of entrectinib: a new 3-aminoindazole as a potent anaplastic lymphoma kinase (ALK), c-ros oncogene 1 kinase (ROS1), and pan-tropomyosin receptor kinases (pan-TRKs) inhibitor. J Med Chem. 2016;59(7):3392-3408.
11. Rosen EY, Schram AM, Young RJ, et al. Larotrectinib demonstrates CNS efficacy in TRK fusion-positive solid tumors [published online May 16, 2019]. JCO Precis Oncol.
12. Lee YA, Lee H, Im SW, et al. NTRK and RET fusion-directed therapy in pediatric thyroid cancer yields a tumor response and radioiodine uptake. J Clin Invest. 2021;131(18):e144847.
13. Groussin L, Clerc J, Huillard O. Larotrectinib-enhanced radioactive iodine uptake in advanced thyroid cancer. N Engl J Med. 2020;383(17):1686-1687.
14. ClinicalTrials.gov. Larotrectinib to enhance RAI avidity in differentiated thyroid cancer. https://clinicaltrials.gov/study/NCT05783323. Updated May 16, 2024.
15. Damásio I, Simões-Pereira J, Donato S, et al. Entrectinib in the neoadjuvant setting of anaplastic thyroid cancer: a case report. Eur Thyroid J. 2022;12(1):e220179.
16. Hay ID, Johnson TR, Kaggal S, et al. Papillary thyroid carcinoma (PTC) in children and adults: comparison of initial presentation and long-term postoperative outcome in 4432 patients consecutively treated at the Mayo Clinic during eight decades (1936-2015). World J Surg. 2018;42(2):329-342.
17. Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol. 2018;15(12):731-747.
18. Russo M, Misale S, Wei G, et al. Acquired resistance to the TRK inhibitor entrectinib in colorectal cancer. Cancer Discov. 2016;6(1):36-44.
19. Cocco E, Schram AM, Kulick A, et al. Resistance to TRK inhibition mediated by convergent MAPK pathway activation. Nat Med. 2019;25(9):1422-1427.
20. Chen MF, Yang SR, Shia J, et al. Response to repotrectinib after development of NTRK resistance mutations on first- and second-generation TRK inhibitors. JCO Precis Oncol. 2023;7(7):e2200697.
Q&A: Barriers to Testing for NTRK Fusions in Metastatic Lung and Thyroid Cancer
David S. Hong, MD; Alexander Drilon, MD; and Lori J. Wirth, MD
Why is it important to test patients for any driver with an FDA-approved therapy?
Dr Drilon: Lung cancer is a type of cancer that is enriched for the following targets: EGFR, ALK, RET, ROS1, and NTRK, in addition to others. The approach should be to use a comprehensive test that captures all these different drivers. Even though some of them are much less common than others, given the high response rates and durable benefit associated with the use of targeted agents, testing is worthwhile because you hit the jackpot for a patient if you find the appropriate target.
What are some of the barriers to testing?
Dr Drilon: One of the barriers is education. Doctors’ insights will depend on when they were in medical school and their level of continuing education. Doctors need to be aware of targeted therapies, the associated molecular biology, how these newer treatments work, how the targets are detected, and how the tests work. For NTRK fusions, RNA-based NGS testing is preferred over DNA-based testing because of its superior sensitivity.
Can you discuss treatment of NTRK fusion–positive lung cancer according to stage?
Dr Drilon: In the stage IV setting, the targeted therapies larotrectinib and entrectinib really beat everything else in terms of response and durability. They are our best drugs for patients with NTRK fusions, and they should be used up front whenever possible. In the earlier-stage setting, perhaps a stage II NSCLC, obviously the intent is curative. If someone can get the surgery and then adjuvant chemotherapy, that is the recommended approach. There is no approval for adjuvant TRK inhibitor therapy, but one could consider a clinical trial.
Are there limits to how long treatment with a TRK inhibitor can last?
Dr Hong: I think treatment can last for as long as the patient continues to benefit. We know that patients on long-term larotrectinib have tolerated it fairly well. The primary mechanism of resistance occurs at the binding site of larotrectinib and entrectinib. Right now, the most relevant drugs currently under investigation for TRK inhibitor resistance are repotrectinib and selitrectinib. Repotrectinib is not particularly effective against the TRK xDFG resistance mutation, but it can overcome other mechanisms of resistance, including the solvent-front and gatekeeper mutations.
Are insurers reimbursing for TRK inhibitor agents?
Dr Wirth: Copays associated with these drugs vary. But fortunately, patient assistance programs that are generous are available to most patients with typical incomes so that most patients in the United States are able to access these therapies.