(NTRK) fusions, although rare, have been identified as an important driver of oncogenic activity in a variety of cancer types.

First identified in 1986 from a tumor sample in a patient with colorectal cancer,

rearrangements were among the first oncogenic fusion products described in literature.

targetedonc.com/precision-medicine/trk-inhibitors

gene fusions have been identified &ldquo;across the board in both adults and kidssome unusual tumors, [including] secretory tumors of the salivary gland and the breast, pediatric tumors, congenital nephromas, infantile fibrosarcomas, GBM [glioblastoma], thyroid carcinoma, and sarcoma in both adults and children. And then in adults, lung cancer, pancreatic cancer, cholangiocarcinoma, colorectal cancer, and melanoma.&rdquo;

Tropomyosin receptor kinase (TRK) A, B, and C proteins are encoded by neurotrophic receptor tyrosine kinase genes 1, 2, and 3 (

gene family are enriched in neural tissues

and play an important role in mediating neurotrophic signaling.

Specifically, TRK A, B, and C function to regulate cell proliferation, apoptosis, differentiation, and survival of neurons in the peripheral and central nervous systems (CNS).

Although TRK A, B, and C are most frequently activated by nerve growth factor, brain-derived neurotrophic factor, and neurotrophin-3,

respectively, it is likely that these receptorligand relationships are not specific, with the receptors harboring potential to be activated by a variety of ligands.

An inter- or intrachromosomal rearrangement involving the 3&rsquo; end of the NTRK proto-oncogene to the 5&rsquo; end of an unrelated gene results in the production of aberrant protein products that cause inappropriate activation of the TRK kinase domain; this activity in turn triggers a cascade of signaling pathways, including MAPK, PI3K, and PLC&upsih;.

Activation of these signaling cascades and other pathways by proliferating tumor cells, in this manner, confers a survival benefit and is ultimately functional in cell proliferation, differentiation, survival, and angiogenesis.

Notably, most of the 5&rsquo; gene fusion partners within the NTRK family that have been identified to date contain a dimerization domain, which would explain subsequent constitutive activation resulting in uninterrupted downstream signaling. However, at least 2

partners do not exhibit this pattern. A similar pattern has been recognized in

rearrangements, which possess transforming properties, despite the absence of 5&rsquo; fusion partners with known dimerization domains. It may be the case in such

rearrangements that the loss of key 5&rsquo; sequences acts as an autoinhibitory signal, and a similar pattern may be present in TRK family fusions.

gene fusions cause resultant TRK kinases to stay constantly active, without requiring a ligand to modulate activity.

These constitutively active kinases cause &ldquo;oncogene addiction,&rdquo; irrespective of tissue origin, driving cancer cell growth and metastases.

Indeed, evidence is emerging that at least some of the known

gene fusions may be capable of simultaneous, dual activation of multiple downstream pathways, which may enable proproliferative as well as antiapoptotic signaling.

&ldquo;Researchers in oncology identified that there were unique translocations, or fusions, of these

genes with other partners that led to constitutive or continued signaling in cancer cells, truly driving their growth and their metastases,&rdquo; said David Hong, MD, in a video interview with

). &ldquo;What&rsquo;s interesting is that in more common tumors like lung and colorectal, although the prevalence is very low1% or lower&mdash;the patients who have no mutations, other than

gene fusions, seem to be the ones who probably harbor these fusions. There are, however, a subset of tumors, MSI [microsatellite instability]high tumors, particularly MSI-high colorectal cancers, that seem to also have a higher prevalence of

TRK proteins A, B, and C may have a high degree of homology within their intracellular kinase domains.

They are each composed of a transmembrane region, an intracellular domain with a kinase domain, and an extracellular domain for the purpose of ligand binding. Ligation triggers oligomerization of the receptors and phosphorylation in the intracytoplasmic kinase domain, resulting in activation of signaling cascades that influence cell proliferation, differentiation, and survival.

Proper regulation of TRK activity is critical for cell functioning; upregulation of TRK receptor levels has been shown in many CNS-related disorders, including epilepsy, neuropathic pain, and depression.

Similarly, autocrine and paracrine signaling by TRK receptors is associated with protumor activity in a number of cancer types.

Research designed to understand the oncogenic activation of

TRK A may serve as model for understanding the causative elements in constitutive activation of all 3 TRK proteins.

gene rearrangements, deletions, and splice variants share a common loss of some of the extracellular domain of TRK A, suggesting a critical regulatory sequence within that domain (and potentially within B and C).

This hypothesis is further supported by study results demonstrating that the alteration of the immunoglobulin-like structure of TRK A responsible for ligand-specific binding results in spontaneous and ligand-independent dimerization.

Although the incidence of TRK fusionpositive cancers vary, they may occur in approximately 1% of all solid tumors.

It is estimated that approximately 1500 to 5000 new cases of

-positive cancers occur each year in the United States.

Among those cancers types most likely to be seen in clinical practice,

gene fusion incidence is generally <5%, although the true incidence is somewhat unknown in the nascent era of next-generation sequencing (NGS) adoption.

gene fusions are more common in certain pediatric and adult cancers (

Advances in the understanding of TRK family biology, coupled with the growing recognition of TRK alterations as drivers of oncogenesis across tumor types, has fueled interest in the development of small molecule inhibitors of TRK. Despite the recognition since the 1980s of

rearrangements being consequential in tumor growth, development, and survival, the most significant progress in the development of TRK inhibitors have arguably occurred in the past decade.

These developments have been propelled, in some measure, by the emergence of NGS techniques and technologies that are capable of identifying

These capabilities led directly to the discovery that most

gene alterations are associated with uncontrolled kinase activation, thereby suggesting a role for inhibitors of said activity as part of a personalized drug approach.

Because the majority of residues of the kinase domain, those that potentially interact with ligands in the ATP binding site, are conserved across members of the TRK family, drug research has largely focused on pan-inhibitors, rather than selective inhibitors, of the 3 distinct TRK receptor isoforms.

To date, most research on TRK inhibition has focused on drugs that competitively bind the ATP binding site to obviate autophosphorylation that would otherwise drive downstream signaling, although other strategies for TRK inhibition, including nonATP-competitive inhibitors at allosteric binding sites that target the downstream activity of TRK activation, have also been explored.

Currently, 2 NTRK inhibitors are approved for the treatment of patients with solid tumors that have

Larotrectinib inhibits TRK A, B, and C proteins. Approved in November 2018, larotrectinib is indicated for the treatment of pediatric and adult patients with solid tumors that have

gene fusions without any known acquired mutations that are metastatic or where surgical resection is likely to result in severe morbidity, have no satisfactory alternative treatments, or have progressed following treatment.

Larotrectinib&rsquo;s mechanism of action is to bind with and competitively inhibit the ATP-binding site on the TRK molecule, thus interfering with autophosphorylation of the TRK kinase domain, slowing or stopping downstream signaling.

Preclinical study results have shown that larotrectinib demonstrated dose-dependent inhibition of cell proliferation in numerous cell lines.

In July 2016, the FDA granted larotrectinib a breakthrough therapy designation for adult and pediatric patients with advanced solid tumors positive for

gene fusions, becoming the first therapy to receive a tissue-agnostic designation.

&ldquo;The approval of larotrectinib was really a mini first,&rdquo; noted Hong. &ldquo;It was a first approval of a drug in both pediatrics and adults at the same time. It was not only the very first histology-agnostic approval, but also the first genetic mutation or driver approval for any histology-agnostic indication.&rdquo; Currently, larotrectinib has the largest initial and follow-up data set in patients with

Larotrectinib is being studied as part of an ongoing clinical trial program involving a phase I study in adults, phase I/II study in children, and phase II basket study among adolescents and adults.

In a report on the first 55 consecutively enrolled patients, the overall response rate (ORR) determined by an independent review committee was 75% among patients ranging in age from 4 months to 76 years with 17 unique TRK fusionpositive tumor types, all identified with NGS or fluorescence in situ hybridization.

The trial investigators determined that the ORR was slightly higher at 80%.

Seven of 55 patients (13%) achieved a complete response. Median duration of response and median progression-free survival (PFS) had not yet been reached at the time of reporting.

The majority of adverse events (AEs) were grade 1 or 2, and clinically significant AEs were uncommon. The most common grade 3 and 4 AEs were anemia (11%), an increase in alanine aminotransferase or aspartate aminotransferase levels (7%), weight increase (7%), and a decrease in the neutrophil count (7%).

In a supplementary data set that included 35 additional patients, the ORR was determined to be 74%, with 14% of patients in the supplemental group (n = 5) achieving a complete response. With a median follow-up of 5.5 months, median duration of response had not been reached.

Based on data integrated from the primary and supplementary groups of patients, the investigators noted that larotrectinib was found to be efficacious regardless of tumor type or patient age.

&ldquo;Responses with larotrectinib appear to be independent of tumor type,&rdquo; Langer observed. &ldquo;In fact, they seem to be pretty consistent across the board regardless of tumor type. Responses were observed regardless of the number of prior regimens that were administered to the patients, and that is a common theme in the world of personalized therapy or precision medicine, where we are using very specific agents against very specific targets. Prior history to some extent may influence outcome, but not to the extent that we&rsquo;ve traditionally seen with systemic cytotoxics.&rdquo;

Phase I results from the phase I/II study in pediatric patients have been reported separately. Among enrolled infants, children, and adolescents aged 1 month to 21 years with locally advanced or metastatic solid tumors or CNS tumors that had relapsed, progressed, or were nonresponsive to available therapies, 14 of 15 patients (93%) with TRK fusionpositive cancers achieved an objective response as per RECIST 1.1, whereas none of the 7 patients with TRK fusion&ndash;negative cancers had an objective response.

Hong et al recently reported results from a multicenter, phase I dose-escalation study among adults with metastatic solid tumors. In the study,

gene fusion status was not used as an eligibility criterion.

Among 67 assessable patients, the objective response rate was 12% (n = 8); however, responses were seen in 7 of 8 patients with tumors harboring

gene fusions and in 1 patient with a tumor harboring an

gene amplification. No patients with an NTRK point mutation had an objective response. Corresponding reductions in tumor burden among all patients with tumors harboring an

All 70 patients were evaluated for safety; most treatment-related AEs were grade 1 or 2, and 60% of patients experienced grade 3 or worse treatment-emergent AEs, with the most common being anemia, fatigue, and increase in aspartate aminotransferase. Four percent of patients (none with an

gene fusion) discontinued treatment because of larotrectinib-related AEs. Moreover, the investigators reported no meaningful difference in treatment-related AEs among patients with or without

Because ORR appears to be particularly robust among pediatric patients, outcomes were analyzed among 83 adults (median age, 57 years; range, 20-80), in new data presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting. Among 74 evaluable patients, the ORR was 76% as assessed by investigators, with 9% achieving a complete response and 57% achieving a partial response; among 65 patients assessed by an independent review committee, the ORR was 68%, with 17% achieving complete response and 51% achieving a partial response. At the time of reporting, median duration of response had not been met after a median of 17.2 months. Following data cutoff, patients experienced mostly grade 1 and 2 AEs.

Additional findings from the 2019 ASCO Annual Meeting showed meaningful improvements in quality of life in patients treated with larotrectinib. The study evaluated 37 patients (13 pediatric and 24 adolescent or adult) with TRK-positive fusion cancers who were treated with larotrectinib. Patients who completed a baseline questionnaire and at least 1 follow-up quality-of-life questionnaire were eligible for evaluations. Improvement was defined as &ge;10-point improvement on the EQ-5D-5L (which measures health-related quality of life) or on the EORTC QLQ-C30 (which measures the physical, psychological, and social functions of patients with cancer), or &ge;4.5-point improvement on the PedsQL (which measures health-related quality of life specifically in pediatric patients). Results showed that 58%, 62%, and 77% of the patients demonstrated improvement in EQ-5D-5L, EORTC QLQ-C30, and PedsQL, respectively. Investigators noted that improvements were rapid and were sustained for a minimum of 2 cycles. Although the study size was relatively small, the results showed improvements in overall quality of life in both pediatric and adult  patients.

&ldquo;Almost 70% of these patients had significant quality-of-life improvement[s],&rdquo; said Hong, a rate that is unique to larotrectinib. Based on its robust clinical profile, Hong observed that &ldquo;larotrectinib particularly has been the most  effective small molecule kinase inhibitor I&rsquo;ve ever seen.&rdquo;

Entrectinib was approved in August 2019 for the treatment of adults and pediatric patients 12 years and older with solid tumors that have a

gene 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. Entrectinib was initially discovered as a result of a screening program designed to identify ALK kinase inhibitors. During early testing, it was found to be a highly potent inhibitor of ALK as well as of 2 closely related receptor tyrosine kinases, ROS1 and TRK. It was subsequently selected for clinical trials based on its safety and tolerability profile as well as its demonstrated ability to induce tumor regression in human xenograft models.

Similar to larotrectinib, entrectinib competitively binds the ATP-binding site.

Additional preclinical study results confirmed that entrectinib was a highly potent inhibitor of TRK A, B, and C; ALK; and ROS1 kinases. Testing showed that it abolished autophosphorylation in a colorectal carcinoma cell line. Of note, it also displayed favorable bloodbrain barrier penetration in a murine xenograft model, suggesting its potential utility in treating brain metastases after relapse following initial lines of therapy.

Positive clinical results after treatment with entrectinib have also been reported in a patient with stage IV lung adenocarcinoma with a tumor harboring an

and in a patient with glioblastoma with a tumor harboring a

Entrectinib was studied in 2 phase I trials, ALKA-371-001 and STARTRK-1, with 54 and 65 patients participating, respectively. Patients in the ALKA-372-001 trial were treated on 1 of 3 dosing schedules to establish appropriate dosing: with or without fasting, taken continuously daily, or using drug holidays. Patients in STARTRK-1 were treated with a continuous dosing schedule for 28 days. The majority of treatment-related AEs were grade 1 or 2 in severity and were reversible with dose modiﬁcations, with no dose-limiting toxicities reported. Commonly reported treatment-related AEs of any grade included fatigue/asthenia (46%), dysgeusia (42%), paresthesias (29%), nausea (28%), and myalgias (23%). No significant differences in toxicity were noted between the 2 studied dosing schemas.

&ldquo;There are some minor differences in toxicity, I believe, between larotrectinib and entrectinib,&rdquo; noted Langer. &ldquo;Entrectinib does seem to cause some anemia. Both can cause fluid retention and weight gain, but [with] entrectinib they seem to be a bit more pronounced. And there is some neuropathyperipheral paresthesias, peripheral sensory neuropathy associated with entrectinib. The total incidence is about 13% to 14%, with maybe about 4% or so that&rsquo;s grade 3&mdash;so, it&rsquo;s clearly manageable, but a bit more pronounced. How these stack up against other agents or other upcoming agents remains to be seen, but I think for the most part, these patients can be readily managed with the tools that we have currently for [adverse] effects.&rdquo;

Overall, responses were observed in patients with nonsmall cell lung cancer (NSCLC), colorectal cancer, mammary analogue secretory carcinoma, melanoma, and renal cell carcinoma as early as 4 weeks after starting treatment and lasting as long as >2 years.

Among 24 patients with extracranial solid tumors who might meet eligibility for enrollment in a phase II study (defined as having a tumor harboring

; no prior tyrosine kinase inhibitor [TKI] exposure; and minimal exposure of 600 mg entrectinib daily), the ORR was 100% in 3

Additionally, treatment responses were noted in 5 of 8 patients with known primary or metastatic brain involvement prior to treatment: patients with

- (n = 1), ROS1- (n = 2), and ALK- (n = 1) rearranged NSCLC and 1 patient with

&ldquo;The nice thing about entrectinib is [that] it hits all, targeting

,&rdquo; noted Langer. &ldquo;The drug that we typically use in ALK, alectinib, has no activity in ROS1 and essentially no activity in NTRK. So as time goes on, we&rsquo;re going to need to be more cognizant of the various differences among the TKIs and where the bulk of activity exists.&rdquo;

An integrated analysis of ALKA-372-001 and STARTRK-2 was recently reported.

A blinded independent central review determined an ORR of 57.4%, a median duration of response of 10.4 months, a median PFS of 11.2 months, and a median overall survival of 20.9 months. Of the 54 evaluable patients, 10 patients had

gene fusionpositive NSCLC, with 6 of them also having CNS involvement. In this subgroup, the ORR was 70% (7 of 10 patients). Among the 6 patients with CNS involvement, 2 patients had a complete intracranial response, 2 had a partial response, 1 had stable disease, and 1 was not evaluable. Sixty-eight patients with

gene fusionpositive tumors who received at least 1 dose of entrectinib were evaluated for safety. Regarding treatment-related AEs, 32.4% of patients experienced grade 3 AEs; 2.9% experienced grade 4 AEs; 4.4% discontinued treatment; and 39.7% had a dose reduction because of an AE.

&ldquo;[Both entrectinib and larotrectinib have] high CNS penetrance, so patients with brain involvement will frequently respond,&rdquo; Langer explained. &ldquo;In the original phase I and phase II studies, the overall response rate again was on the order of 70%, 75%. It was a 55% intracranial response. We would never see that with standard systemic chemotherapy, but we are seeing that increasingly with our newer generation of tyrosine kinase inhibitors,&rdquo; said Langer.

A number of candidate TRK inhibitors have been identified and have entered various stages of development.

To date, a select few have accumulated data from use in human patients.

BAY2731954 (formerly known as LOXO-195) was specifically designed in parallel with larotrectinib in anticipation of the potential for acquired resistance to TRK inhibitors.

In preclinical studies, BAY2731954 demonstrated inhibitory activity in various TRK kinasemutated tumor models, in which larotrectinib showed reduced or no inhibitory activity.

In addition to confirmatory studies in mice, the latter authors also reported rapid clinical response to therapy in an adult patient with

rearranged colorectal cancer soon after starting BAY2731954, as well as visible tumor regression in a previously palpable mass in the head and neck region within  15 days of initiating BAY2731954 treatment in a pediatric patient with a

BAY2731954 was evaluated in 31 patients (n = 20 in a phase I study [NCT03215511] and n = 11 in an FDAexpanded access single-patient protocol) aged &ge;4 weeks with a locally identified

gene fusion who had progressed or were intolerant to &ge;1 prior NTRK inhibitor.

In the phase I study, treatment-emergent AEs that occurred in >3 patients included dizziness/ataxia (65%), nausea/vomiting (50%), anemia (30%), myalgia (20%), abdominal pain (20%), fatigue (20%), and lymphopenia (20%). Five patients, all adults, experienced dose-limiting toxicities, including ataxia/dizziness

&ldquo;Response rates [for BAY2731954] in those with an established TRK kinase abnormality is close to 50%, 9 patients of 20,&rdquo; said Langer. &ldquo;My initial read on the toxicity is that [this] may be somewhat harder to deal withnausea and vomiting, myalgias, [and] abdominal pain in addition to fatigue and edema and constipation.&rdquo;

Repotrectinib is a rationally designed, next-generation TKI designed to potently inhibit clinically recalcitrant solvent-front substitutions involving ROS1, TRKA-C, and ALK, in addition to wild-type

, and other clinically relevant, nonsolvent-front mutations.

Repotrectinib is smaller in size compared with clinically available ROS1, TRK, and ALK inhibitors, suggesting it will have favorable penetration of the human brain. By targeting the center of the ATP binding site, it circumvents steric hindrance from solvent-front substitutions. In preclinical testing, it demonstrated potent antiproliferative activity against both wild-type and mutated

in cellular inhibitory assays and xenograft models.

The drug is currently being studied in a phase I/II clinical trial (NCT03093116); outcomes in 2 patients have been reported. The first, a Caucasian man aged 44 years who experienced progression on several prior lines of therapy (crizotinib, entrectinib, doxorubicin, and entrectinib plus trametinib), had a &ldquo;rapid and dramatic&rdquo; response to repotrectinib within the first few days of treatment and later had a partial response, which was confirmed with radiologic imaging. The second patient was an Asian never-smoker woman, aged

41 years, with stage IV NSCLC. The patient received 1 cycle of carboplatin, pemetrexed, and bevacizumab while awaiting insurance authorization for crizotinib. She had a durable response on the latter for 12 months, but then showed increasing mediastinal lymphadenopathy on imaging. After confirmation of a

solvent-front mutation, the patient was enrolled in a phase I trial involving repotrectinib. Partial response per RECIST v1.1 was subsequently achieved with a duration of response of 7.4 months, and there was also response in the CNS for 9 months with progression controlled by whole-brain radiation.

&ldquo;Response rates to date are 80% [in patients with

] and 66% in those with prior exposure to other TKIs, including crizotinib,&rdquo; said Langer.

TREATMENT IMPLICATIONS AND FUTURE DIRECTIONS

The availability of small molecule TRK inhibitors presents both opportunities and challenges in clinical practice. Although

gene fusions are considered rare events, they have nonetheless been identified in a variety of cancer types.

Targeted inhibition of TRK has proven to be a highly effective strategy in clinical trials. The ORR associated with larotrectinib is approximately 75%, with data still emerging regarding the clinical effectiveness of entrectinib.

Nevertheless, data from phase I studies of entrectinib provide suggestive evidence of treatment responses in patients who harbor extracranial solid tumors and/or CNS tumors or  metastases with

Other TRK-specific and multikinase inhibitors in development with activity against TRK offer additional promise for fulfilling the promise of targeted therapy in the era of precision medicine.

gene fusion incidence across cancer types, coupled with the relative rarity of

raises questions about who to test, and when, and how such testing should be conducted. NGS is the gold standard when it comes to identifying patients with

gene fusions. It does, however, have its limitations.

feature long introns that make them difficult to detect in standard NGS panels.

&ldquo;You really need what&rsquo;s called RNAseq, or RNA-based NGS, in order to capture some of that,&rdquo; said Hong. &ldquo;It&rsquo;s important for individual clinicians to talk to their pathologists [and] to talk to molecular pathologists if they&rsquo;re on staff. And if the tissue is sent out to a commercial outfit, to talk to the vendor who is actually providing the assay and doing the screening, [to find out] whether NTRK is properly covered [and] whether they have DNA- or RNA-based assays,&rdquo; said Langer.

One inherent challenge with small molecule TRK inhibitors in general, and likely with all small molecule inhibitors approaching or in clinical practice, will be to develop clinical practice guidelines that allow for efficient identification of patients with fusion-positive cancers. Indeed, although mass screening of all solid tumors with a broad NGS panel may seem ideal, such an approach may not be economically viable or practical.

One possible solution may be to approach the idea of targeted testing based on reported incidence of

gene fusions in the given cancer while also considering the incidence of TRK expression in that cancer type. Thus, cancers associated with a high incidence of

gene fusions could be targeted for testing, whereas those with a low expected incidence of

gene fusions but high expression of TRK would be included in a second category and those associated with low incidence of both

gene fusions and TRK expression would be tested only in specialized circumstances.

What those categories might look like in practical terms, however, remains unclear.

&ldquo;Most patients with metastatic cancer should be tested for not only

gene fusion but other alterations. With that said, I understand logistically in the community and in so many other countries, why that&rsquo;s not possible,&rdquo; said Hong. &ldquo;I can&rsquo;t test everybody. So, one of the things that I think is clear from the data, is that patients [with

], it&rsquo;s worth [testing to determine] if this patient really has an

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5. Kaplan DR, Martin-Zanca D, Parada LF. Tyrosine phosphorylation and tyrosine kinase activity of the TRK proto-oncogene product induced by NGF.

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7. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children.

2018;378(8):731-739. doi: 10.1056/NEJMoa1714448.

8. Stransky N, Cerami E, Schalm S, et al. The landscape of kinase fusions in cancer.

9. Amatu A, Sartore-Bianchi A, Siena S. NTRK gene fusions as novel targets of cancer therapy across multiple tumour types.

. 2016;1(2):e000023. doi: 10.1136/esmoopen-2015-000023.

10. Arevalo JC, Conde B, Hempstead BL, et al. TrkA immunoglobulin-like ligand binding domains inhibit spontaneous activation of the receptor.

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11. Hsiao SJ, Zehir A, Sireci AN, Aisner DL. Detection of tumor NTRK gene fusions to identify patients who may benefit from tyrosine kinase (TRK) inhibitor therapy.

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Pharmaceuticals Inc; 2019. labeling.bayerhealthcare.com/html/products/pi/vitrakvi_PI.pdf. Accessed August 19, 2019.

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Articles

Clinical Articles

NTRK fusions, although rare, have been identified as an important driver of oncogenic activity in a variety of cancer types.&nbsp;Advances in the understanding of TRK family biology, coupled with the growing recognition of TRK alterations as drivers of oncogenesis across tumor types, has fueled interest in the development of small molecule inhibitors of TRK.

Tropomyosin Receptor Kinase as a Target for the Treatment of Solid Tumors

Given the rapidly evolving tyrosine kinase inhibitor (TKI) landscape, can you reflect on the significance of tropomyosin receptor kinase (

) gene fusions? Specifically, how will they continue to shape the treatment spectrum?

fusions are found across many different cancers, both select rare tumors where these are found at high frequencies and more common tumors where these are found at lower frequencies. While we&rsquo;ve known about the TRK pathway for a few decades now, only in the last few years [have we] demonstrated that

fusions are highly actionable in the clinic. The 2 first-generation agents that explored this activity are larotrectinib and entrectinib. Both achieve high response rates and durable disease control across various cancers. As such, these drugs are approved in a tumor-agnostic fashion for the treatment of these fusions in both the United States and Japan.

Can you discuss the broader trajectory and growing prominence of TKIs within the cancer treatment landscape?

The main contribution of TRK TKI therapy for

fusionpositive cancers is that it resulted in the first approval of a targeted therapy for any cancer type [for] patients of any age as long as their tumors harbor a

[gene] fusion. This represented a landmark approval in the targeted therapy space that echoed the approval of pembrolizumab for microsatellite instabilityhigh cancers of any type. The hope is that we continue to see more drugs approved in this fashion moving forward.

What are some of the most significant differences among first-, second-, and third-generation TKIs?

TRK TKIs fall into 2 major groups. As mentioned, larotrectinib and entrectinib are first-generation agents that were developed to target TRK. Larotrectinib is a selective TRK inhibitor, while entrectinib is a multikinase inhibitor that has activity against ROS1 and ALK in addition to TRK. Beyond these drugs, next-generation TKIs have been developed. These TKIs are not only more potent against TRK, but also address resistance mechanisms such as select

[neurotrophic receptor tyrosine kinase] mutations that can be acquired after progression on first-generation therapy. The 2 most prominent next-generation TKIs that are already being explored in the clinic on early-phase trials are LOXO-195 and repotrectinib.

Given the number of agents available, what are some factors that affect clinical treatment decisions?

This would depend on which TRK inhibitors are available to physicians either on or off trial. Both larotrectinib and entrectinib achieve substantial benefit in patients, and both have shown activity against various fusions, cancer types, and age groups. Central nervous system activity has also been reported for both agents. Thus, in TKI-na&iuml;ve patients, both drugs are reasonable treatment options. For patients [who] develop NTRK mutationmediated resistance, particularly those [who] develop solvent-front or gatekeeper mutations, LOXO-195 and repotrectinib should be considered. Both drugs have been shown to reestablish disease control in patients whose cancers develop these mutations after treatment with larotrectinib or entrectinib.

Can you share important takeaways regarding notable TKIs that are still in development and how they may advance the treatment armamentarium? How do you expect the TKI drug class to continue evolving over the next several years?

In EGFR-mutant and ALK fusionpositive lung cancers, we&rsquo;ve seen next-generation agents, such as osimertinib and alectinib, replace first-generation agents, such as erlotinib, with gefitinib and crizotinib. It remains unclear if next-generation TKI therapy will achieve better outcomes when used in the TKI-na&iuml;ve setting for

fusionpositive cancers. At least repotrectinib is currently being explored in TKI-na&iuml;ve patients, and data from that trial may give us a preliminary answer to this question. A next-generation agent, such as repotrectinib or LOXO-195 [BAY2731954], would need to achieve substantially longer disease control and comparable or improved safety relative to first-generation agents in order to be considered as the preferred approach in the treatment-na&iuml;ve setting.

Could you share your perspective on the research pipeline regarding

gene fusions? Specifically, what challenges and opportunities remain regarding the identification of actionable mutations and the agents in development that can effectively target them?

fusion space is the development of strategies to address off-target resistance. Some cancers will develop acquired resistance to a TRK inhibitor that is mediated by the activation of bypass pathways, such as MET, or [of] the RAS-RAF-MAPK pathway. Some of these alterations, such as MET amplification, could be addressed with combination therapy. There [are] early data to show that combination therapy (ie, a TRK inhibitor + MET inhibitor) can reestablish disease control in

-fused and MET-amplified preclinical models and in the clinic. Should the frequency of one of these resistance alterations be reasonably high, a dedicated trial could be considered to explore the utility of combination therapy. Addressing off-target resistance requires careful resequencing of a patient&rsquo;s cancer via a repeat biopsy or plasma cell-free DNA. The challenge with this is that, while useful, molecular profiling at resistance is not yet a standard of care, although ongoing trials have addressed this need by including coverage for repeat testing on a research basis.

Alexander Drilon, MD, speaks to the significance of <em>TRK </em>gene fusions and treatments for targeting these fusions in patients with cancer.

Tropomyosin Receptor Kinase as a Target for the Treatment of Solid Tumors

Tropomyosin Receptor Kinase as a Target for the Treatment of Solid Tumors

Q&A With Alexander Drilon, MD: Assessing the Evolving TRK Treatment Landscape