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Medical Policy

Policy Num:      05.001.034
Policy Name:    Tropomyosin Receptor Kinase Inhibitors for Locally Advanced or Metastatic Solid Tumors Harboring an NTRK Gene Fusion
Policy ID:          [05.001.034]  [Ar / B / M + / P+]  [5.01.31]

Last Review:     April 19, 2024
Next Review:     Policy Archived

Related Policies: None

Tropomyosin Receptor Kinase Inhibitors for Locally Advanced or Metastatic Solid Tumors Harboring an NTRK Gene Fusion

Summary

Description

The tropomyosin receptor kinase (TRK)-receptor family is encoded by the 3 neurotrophic receptor tyrosine kinase (NTRK) genes (NTRK1, NTRK2, and NTRK3) that code for 3 proteins. In healthy tissue, the TRK pathway is involved in the development and functioning of the nervous system as well as cell survival. However, NTRK gene fusions, which are rare kinase fusion events, create oncogenic proteins which activate a signaling cascade implicated in cell proliferation, survival, and angiogenesis. Both larotrectinib and entrectinib disrupt the activity of tropomyosin receptor kinase TRK proteins. However, entrectinib additionally inhibits 2 other kinases; anaplastic lymphoma kinase and proto-oncogene tyrosine-protein kinase.

Summary of Evidence

For individuals with solid tumors that have an NTRK gene fusion who receive larotrectinib, the evidence includes pooled results of 3, single-arm prospective studies. Relevant outcomes are overall survival, disease-specific survival, change in disease status, quality of life, treatment-related morbidity and treatment-related mortality. Three single-arm studies evaluating the efficacy of larotrectinib in 159 pediatric and adult patients with unresectable or metastatic solid tumors with an NTRK gene fusion are ongoing. Pooled results of the first 55 sequentially enrolled patients have been published. All patients were required to have progressed on systemic therapy for their disease, if available, or would have required surgery with significant morbidity for locally advanced disease. Objective response rate by independent review committee was 79% (95% confidence interval 72 to 85); complete response 16% and partial response 63%. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with solid tumors that have an NTRK gene fusion who receive entrectinib, the evidence includes pooled results of 3, single-arm prospective studies. Relevant outcomes are overall survival, disease-specific survival, change in disease status, quality of life, treatment-related morbidity and treatment-related mortality. Integrated analysis of the 3 pivotal trials with a total of 54 patients with NTRK fusion-positive, locally advanced or metastatic solid tumors was reviewed. All patients were required to have progressed on systemic therapy for their disease, if available, or would have required surgery with significant morbidity for locally advanced disease. Objective response rate by an independent review committee was 57.4% (95% confidence interval 43 to 71). The median duration of response was 10.4 months. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable.

Objective

The objective of this evidence review is to assess whether the use of larotrectinib or entrectinib improves the net health outcome in individuals with solid tumors that have a neurotrophic receptor tyrosine kinase gene fusion.

Policy Statements

Larotrectinib and entrectinib are considered medically necessary when ALL of the following are met:

1. Individual has a confirmatory diagnosis of a solid tumor which is metastatic OR when surgical resection is likely to result in severe morbidity.

2. The tumor has an NTRK gene fusion without a known acquired resistance variant.

3. Individual has progressed following standard of care OR failed standard of care for the given solid tumor.

4. Must be prescribed by an oncologist/hematologist.

5. Individual does NOT have any U.S. Food and Drug Administration (FDA) labeled contraindications to the requested agent and is intended to be used consistently with the FDA approved label (see policy guidelines).

Larotrectinib and entrectinib are considered investigational in all other situations.

Policy Guidelines

Larotrectinib

Larotrectinib is available in an oral capsule or liquid formulation given orally twice daily, with or without food. It is dosed based on body surface area:

• For body surface area ≥1 m²: 100 mg

• For body surface area <1m²: 100 mg/m²

Dose modifications

For Grade 3 or 4 adverse reactions

Withhold larotrectinib until adverse reaction resolves or improves to baseline or Grade 1. Resume at the next dosage modification if resolution occurs within 4 weeks. Permanently discontinue larotrectinib 1) if an adverse reaction does not resolve within 4 weeks or 2) in patients who are unable to tolerate larotrectinib after 3 dose modifications. The recommended dosage modifications for larotrectinib for adverse reactions are summarized in Table PG1.

Table PG1. Recommended Dosage Modifications for Larotrectinib for Adverse Reactions

For Coadministration with Strong CYP3A4 Inhibitors

Coadministration of strong CYP3A4 inhibitors with larotrectinib should be avoided. If it cannot be avoided, reduce the larotrectinib dose by 50%. After the inhibitor has been discontinued for 3 to 5 elimination half-lives, resume the larotrectinib dose taken prior to initiating the CYP3A4 inhibitor.

For Coadministration with Strong CYP3A4 Inducers

Coadministration of strong CYP3A4 inducers with larotrectinib should be avoided. If it cannot be avoided, double the larotrectinib dose. After the inducer has been discontinued for 3 to 5 elimination half-lives, resume the larotrectinib dose taken prior to initiating the CYP3A4 inducer.

For Patients with Hepatic Impairment

Reduce the starting dose of larotrectinib by 50% in patients with moderate (Child-Pugh B) to severe (Child-Pugh C) hepatic impairment.

Monitoring

• Liver tests including ALT and AST should be monitored every 2 weeks during the first month of treatment, then monthly thereafter and as clinically indicated.

• Advise patients and caretakers of the risk of neurologic adverse reactions. Advise patients not to drive or operate hazardous machinery if experiencing neurotoxicity. Withhold and modify dosage, or permanently discontinue larotrectinib based on severity.

• Can cause fetal harm. Advise females with reproductive potential of potential risk to the fetus and to use effective contraception.

Entrectinib

Entrectinib is available in an oral capsule given orally once daily, with or without food. It is dosed as follows:

• For adults: 600 mg orally once daily

• For pediatric patients 12 years and older: Recommended dose is based on body surface area as follows:

  • For body surface area ≥1.5m²: 600 mg once daily

  • For body surface area 1.11 to 1.50m²: 500 mg once daily

  • For body surface area 0.91 to 1.10m²: 400 mg once daily

Dose modifications

The recommended dosage reductions for adverse reactions are provided in Table PG2.

Table PG2. Recommended Dosage Modifications for Entrectinib for Adverse Reactions

a For a subsequent modification, permanently discontinue entrectinib in patients who are unable to tolerate entrectinib after 2 dose reductions.

For dosage modifications for specific adverse reactions, refer to the prescribing label.

For Coadministration with Moderate and Strong CYP3A4 Inhibitors

Avoid coadministration of entrectinib with moderate or strong CYP3A inhibitors. If coadministration cannot be avoided, reduce the entrectinib dose as follows:

• Moderate CYP3A Inhibitors: 200 mg orally once daily

• Strong CYP3A Inhibitors: 100 mg orally once daily

After discontinuation of a strong or moderate CYP3A inhibitor for 3 to 5 elimination half-lives, resume the entrectinib dose that was taken prior to initiating the CYP3A inhibitor.

Monitoring

• Assess left ventricular ejection fraction prior to treatment initiation with entrectinib in patients with symptoms or known risk factors for congestive heart failure.

• Monitor patients for clinical signs and symptoms of congestive heart failure.

• Liver tests including ALT and AST should be monitored every 2 weeks during the first month of treatment, then monthly thereafter and as clinically indicated.

• Assess serum uric acid levels prior to initiation and periodically during treatment with entrectinib. Monitor patients for signs and symptoms of hyperuricemia.

• Monitor patients who have or who are at risk for QTc interval prolongation. Assess QT interval and electrolytes at baseline and periodically during treatment.

• Advise patients and caretakers of the risk of neurologic adverse reactions. Advise patients not to drive or operate hazardous machinery if experiencing neurotoxicity. Withhold and modify dosage, or permanently discontinue larotrectinib based on severity.

• Can cause fetal harm. Advise females with reproductive potential of potential risk to the fetus and to use effective contraception.

Coding

See the Codes table for details.

Benefit Application

BlueCard/National Account Issues

State or federal mandates (eg, Federal Employee Program) may dictate that certain U.S. Food and Drug Administration approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only by their medical necessity.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

Background

The neurotrophic receptor tyrosine kinase (NTRK) gene fusions are uncommon kinase fusion events that drive tumorigenesis in a small fraction of solid tumors, regardless of tissue type.^1, The tropomyosin receptor kinases (TRK) proteins A, B, and C are encoded by the genes NTRK1, NTRK2, and NTRK3 respectively. In healthy tissue, the TRK pathway is involved in the development and functioning of the nervous system as well as cell survival. Chromosomal rearrangements involving in-frame fusions of these genes with various partners can result in constitutively-activated chimeric TRK fusion proteins that are oncogenic, promoting tumor cell proliferation and their survival. Larotrectinib and entrectinib is a kinase inhibitor of TRK A, B, and C protein. However, entrectinib additionally inhibits 2 other kinases : anaplastic lymphoma kinase and proto-oncogene tyrosine-protein kinase.

Epidemiology

The annual incidence of NTRK fusion-driven tumors is estimated to be 1,500-5,000 cases in the United States.^2,NTRK fusions may be more characteristic of rare cancers such as mammary analogue secretory carcinoma, secretory breast carcinoma, or infantile fibrosarcoma. The incidence of NTRK fusions is below 1% for most common cancers such as lung, prostate, and colon cancer. See Table 1.

Table 1. Neurotrophic Receptor Tyrosine Kinase Gene (NTRK) Fusions in Different Tumor Types

Reproduced from the U.S. Food and Drug Administration (FDA) Multi-Discipline Review of Larotrectinib3,DIPG: diffuse intrinsic pontine glioma; GBM: glioblastoma multiforme; GIST: gastrointestinal stromal tumor; HNSCC: head, neck, squamous cell carcinoma; NET: neuroendocrine tumor; NSCLC: non-small-cell lung cancer; NTRK: neurotrophic receptor tyrosine kinase.

Metastatic (failed prior therapy) and/or unresectable solid tumors are rarely curable and generally have a poor prognosis. According to the American Cancer Society, the estimated 5-year survival rates for metastatic breast, colon, lung, and melanoma are 29%, 14%, 6%, and 30%, respectively.^4, The likelihood of achieving a response to second-line or greater therapy is less than 50%; in the case of colon and non-small-cell lung cancer, much less than 50%. Evidence on the effect of NTRK gene fusions on prognosis is currently under investigation.^5,  

Current Treatment Options

Although there are multiple U.S. Food and Drug Administration (FDA) approved treatments for many common adult cancers that rarely have an NTRK fusion, such as lung, prostate, and colon cancer, there were no drugs approved specifically for patients with metastatic or unresectable solid tumors harboring an NTRK fusion prior to the approval of larotrectinib and entrectinib. Additionally, there are no approved treatments specific for mammary analogue secretory carcinoma, secretory breast carcinoma, and infantile fibrosarcoma, which frequently harbor NTRK fusions. Moreover, in some cases where resection is a potentially curative approach, surgery can result in unacceptable morbidity such as limb amputation (eg, in some patients with infantile fibrosarcoma). Currently available treatments are summarized in Table 2.

Neurotrophic Receptor Tyrosine Kinase (NTRK) Gene Fusion Testing

The presence of NTRK gene fusion can be detected by multiple methods including next-generation sequencing, reverse transcription-polymerase chain reaction, fluorescence in situ hybridization and immunohistochemistry.^6, Next-generation sequencing provides the most comprehensive view of a large number of genes and may identify NTRK gene fusions as well as other actionable alterations, with minimal tissue needed. The fluorescence in situ hybridization using break-apart probes can detect gene rearrangements in DNA that may generate a fusions transcript. The immunohistochemistry techniques have generally been used in the research setting. Reverse transcription-polymerase chain reaction is designed to identify only known translocation partners and breakpoints and cannot identify novel breakpoints or novel fusion partners. In the pivotal clinical trial, TRK fusions were identified by next-generation sequencing or by fluorescence in situ hybridization by each participating site.^7, The most common local assays used included those performed by Foundation Medicine (Cambridge, MA, USA)^8,9,, Memorial Sloan Kettering Cancer Center (New York, NY, USA),^10,11, and University of Washington (Seattle, WA, USA)^12, using previously published methods. Currently, the only FDA approved companion diagnostic test for larotrectinib and entrectinib is the FoundationOne^® CDx (Foundation Medicine).^13, Multiple commercial laboratories currently offer testing for NTRK1, NTRK2, and NTRK3 gene fusions.^6,

Regulatory Status

On November 26, 2018, larotrectinib (VITRAKVI, Loxo Oncology, Inc.) was approved by the FDA for the treatment of adult and pediatric patients with solid tumors that 1) have an NTRK gene fusion without a known acquired resistance mutation, 2) are metastatic or where surgical resection is likely to result in severe morbidity, and 3) have no satisfactory alternative treatments or have progressed following treatment. This indication was approved under accelerated approval based on overall response rate and duration of response as determined by independent radiologic review. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.^14,

On August 15, 2019, entrectinib (ROZLYTREK, Genentech Inc.) was approved by the FDA for the treatment of adults and pediatric patients 12 years of age and older with solid tumors that have a NTRK 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. This indication was approved under accelerated approval regulations based on overall response rate and duration of response as determined by independent radiologic review. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.^15,

Rationale

This evidence review was created in December 2018 and with a search of the PubMed database. The most recent literature update was performed through December 13, 2023.

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, 2 domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Tropomyosin Receptor Kinase Inhibitors

Clinical Context and Therapy Purpose

The purpose of tropomyosin receptor kinase (TRK) inhibitors such as larotrectinib and entrectinib for individuals with locally advanced or metastatic solid tumors that 1) have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation, 2) are metastatic or where surgical resection is likely to result in severe morbidity, and 3) have no satisfactory alternative treatments or have progressed following treatment, is to provide a treatment option that is an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is patients with locally advanced or metastatic solid tumors that 1) have an NTRK gene fusion without a known acquired resistance mutation, 2) are metastatic or where surgical resection is likely to result in severe morbidity, and 3) have no satisfactory alternative treatments or have progressed following treatment.

Interventions

The therapy being considered is larotrectinib and entrectinib. As per the U.S. Food and Drug Administration (FDA), the tissue agnostic pathway draws from the strength of scientific evidence that a biomarker identifies a population with common characteristics (e.g., serves as primary oncogenic driver when present) regardless of tumor histology and location, the strength of evidence that drug has the same pharmacologic effects on the biomarker across tumor types in nonclinical and clinical studies, and the ability to reliably identify the biomarker across tumor types, where the biomarker-defined population is a subset of a specific tumor type.^3,

Larotrectinib and entrectinib are labeled for oral use and are self-administered in the home setting.

Comparators

Comparators vary according to indication. There are multiple FDA approved treatments for many common adult cancers that rarely have an NTRK fusion, such as lung, prostate, and colon cancer ; there are no drugs approved specifically for patients with metastatic or unresectable solid tumors harboring an NTRK fusion. Additionally, there are no approved treatments for mammary analogue secretory carcinoma, secretory breast carcinoma, and infantile fibrosarcoma, which frequently harbor NTRK fusions. Moreover, in some cases where resection is a potentially curative approach, surgery can result in unacceptable morbidity such as limb amputation (e.g., in some patients with infantile fibrosarcoma). Currently available treatments are summarized in Table 2.

Table 2. Current Treatment Options for Selected Solid Tumors That May Harbor Neurotrophic Receptor Tyrosine Kinase (NTRK) Gene Fusions

Adapted from FDA Multi-Discipline Review of Larotrectinib3CNS: central nervous system; EGFR: epidermal growth factor receptor; FDA: U.S. Food and Drug Administration; NSCLC: non-small-cell lung cancer; NTRK: neurotrophic receptor tyrosine kinase; PDL1: Programmed death-ligand; ROS: Proto-oncogene tyrosine-protein kinase.

Outcomes

The general outcomes of interest in oncology are overall survival, disease-specific survival, quality of life, treatment-related mortality and morbidity. The FDA generally considers overall response rate (ORR) of sufficient magnitude and duration to be a surrogate endpoint reasonably likely to predict clinical benefit in patients with refractory solid tumors.

ORR can be measured by the proportion of patients with best overall confirmed response of complete response) or partial response by the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1),^16, or Response Assessment in Neuro-Oncology criteria,^17, as appropriate by a blinded and independent adjudication committee.

There are clearly defined quantitative thresholds for the follow-up of patients in oncology trials. A general rule is a continuation of treatment until disease progression or unacceptable toxicity. Long-term follow-up outside of a study setting is conducted to determine survival status.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Population Reference No. 1 

Larotrectinib

Non-Randomized Studies

Three multicenter, open-label, single-arm clinical trials: A Phase 1 Study of the Oral TRK Inhibitor Larotrectinib in Adult Patients With Solid Tumors Study(LOXO-TRK-14001; NCT02122913), A Phase 1/2 Study of the Oral TRK Inhibitor LOXO-101 in Pediatric Patients With Advanced Solid or Primary Central Nervous System Tumors (SCOUT; NCT02637687), and A Phase 2 Basket Study of the Oral TRK Inhibitor Larotrectinib in Subjects With NTRK Fusion-positive Tumors(NAVIGATE; NCT02576431) evaluated larotrectinib in pediatric and adult patients with unresectable or metastatic solid tumors (see Table 3). Drilon et al (2018) reported the pooled analysis of the first 55 consecutive patients at the primary data cutoff date of July 17, 2017,^6, Subsequent to the publication of these results, Hong et al (2020) reported longer followup data for the initial patient population (n=55) and for an additional 104 patients enrolled in 1 of the 3 studies through February 19, 2019 (N=159).^18, Study inclusion required patients (age ≥1 month) to have a locally advanced or metastatic solid tumor, to have received standard therapy previously (if available), and had adequate organ function. Patients with primary CNS tumors were excluded from the Hong et al analysis. The major efficacy outcome measures were ORR and duration of response (DOR), as determined by a blinded independent review committee according to RECIST v1.1.

In the Hong et al analysis, the included population was comprised of patients with NRTK gene fusions with 15 different types of cancers, most commonly soft tissue sarcoma (43%), thyroid (16%) and salivary gland (13%). The median age was 43 years (interquartile range 6.5 to 61 years), 48% male, and 86% had an Eastern Cooperative Oncology Group performance status from 0 to 1. Seventy-five percent of patients had metastatic disease and 25% had locally advanced unresectable disease. Over two thirds (78%) of patients had received prior systemic treatment for their cancer.

Table 3. Summary of Key Study Characteristics: Larotrectinib

BSA: body surface area; DOR: duration of response; LOXO-TRK-14001: A Phase 1 Study of the Oral TRK Inhibitor Larotrectinib in Adult Patients With Solid Tumors Study; NAVIGATE: A Phase 2 Basket Study of the Oral TRK Inhibitor Larotrectinib in Subjects With NTRK Fusion-positive Tumors; NTRK: neurotrophic receptor tyrosine kinase; PFS: progression-free survival; RCT: randomized controlled trial; SCOUT: A Phase 1 Study of the Oral TRK Inhibitor Larotrectinib in Adult Patients With Solid Tumors Study.

Results are summarized in Tables 4 and 5. The ORR was 79% (95% confidence interval 72% to 85%).^18, At the time of data cutoff (February 19, 2019), in 108 participants with confirmed response, the median DOR was 35.2 months (95% confidence interval 22.8 months to not estimable). Depending on the cancer site, ORR ranged widely from 0 to 100%. The safety population included 260 patients treated with larotrectinib. regardless of NTRK fusion status. Adverse event were primarily Grade 1 or 2, and were similar in pediatric and adult patients. Grade 3 adverse events occurred in 39% of patients, and Grade 4 events occurred in 17% of patients. Serious adverse events included pneumonia, pyrexia, abdominal pain and diarrhea, all occurring in 2% of included patients. Assessment of a causal relationship between larotrectinib and adverse events is limited due to the single-arm design of the study. There are specific dose modification and monitoring guidelines to manage the safety risks and detailed in the Policy Guidelines section.

Table 4. Summary of Key Study Results: Larotrectinib

 CR: complete response; DOR: duration of response;ORR: overall response rate; PR: partial response; RCT: randomized controlled trial.a at time of data cutoff. Safety population include all patients receiving larotrectinib regardless of NTRK fusion status

Table 5. Summary of Key Study Results: Larotrectinib (By Tumor Type)

CI: confidence interval; DOR: duration of response; NA: not applicable due to small numbers or lack of response; NE; not estimable; ORR: overall response rate; PD: progressive disease; RCT: randomized controlled trial; SD: stable disease.

The purpose of study limitations tables (see Tables 6 and 7) is to display notable limitations identified in each study. This information is synthesized as a summary of the body of evidence following each table and provides the conclusions on the sufficiency of the evidence supporting the position statement. A limitation in study design and conduct relates to the lack of RCTs. However, NTRK fusion cancers are rare and therefore conducting randomized trials would be challenging. A limitation in relevance is related to the generalizability of its results to populations that were not well represented in the pivotal study due to the small numbers of patients. Although the efficacy of larotrectinib is largely unknown in such cases, in settings where no treatment is available or where available treatment would result in significant morbidity or where the clinical effects of available treatments are modest, it is plausible to assume that larotrectinib may provide an advantage over available therapy for patients with NTRK fusion solid tumors. As per the FDA review, there was strong nonclinical support of the antitumor activity of larotrectinib across multiple cell lines and NTRK fusion partners, and clinically, durable tumor shrinkage occurred in a consistent fashion in patients with a variety of tumors harboring a diverse array of NTRK fusions. In light of these factors, the FDA review teams concluded that pooling of results from patients with NTRK fusion-solid tumors was warranted and supported a tissue agnostic indication.

Table 6. Study Design and Conduct Limitations: Larotrectinib

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4.Comparative treatment effects not calculated.

Table 7. Study Relevance Limitations: Larotrectinib

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest.c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Section Summary: Larotrectinib

Three, single-arm studies evaluating the efficacy of larotrectinib in 159 pediatric and adult patients with unresectable or metastatic solid tumors with an NTRK gene fusion are ongoing. Pooled results of the first 55 sequentially enrolled patients have been published. All patients were required to have progressed on systemic therapy for their disease, if available, or would have required surgery with significant morbidity for locally advanced disease. The ORR by the Institutional Review Committee (primary study endpoint) was 79% (95% confidence interval72 to 85); complete response 16% and partial response 63%. Responses observed were independent of age, tumor type, NTRK gene or fusion partner.

Summary of Evidence

For individuals with solid tumors that have an NTRK gene fusion who receive larotrectinib, the evidence includes pooled results of 3, single-arm prospective studies. Relevant outcomes are overall survival, disease-specific survival, change in disease status, quality of life, treatment-related morbidity and treatment-related mortality. Three single-arm studies evaluating the efficacy of larotrectinib in 159 pediatric and adult patients with unresectable or metastatic solid tumors with an NTRK gene fusion are ongoing. Pooled results of the first 55 sequentially enrolled patients have been published. All patients were required to have progressed on systemic therapy for their disease, if available, or would have required surgery with significant morbidity for locally advanced disease. Objective response rate by independent review committee was 79% (95% confidence interval 72 to 85); complete response 16% and partial response 63%. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 2 

Entrectinib

Non-Randomized Studies

Four open-label, single-arm clinical trials (2 ongoing and 2 completed) have assessed the efficacy of entrectinib in patients with NTRK fusion-positive, locally advanced or metastatic solid tumors (Table 8). Data from the Phase I Multicenter, Open-Label Study of Oral Entrectinib (RXDX-101) in Adult Patients With Locally Advanced or Metastatic Cancer Confirmed to be Positive for NTRK1, NTRK2, NTRK, ROS1, or ALK Molecular Alterations (STARTRK-1), the Phase II Basket Study of Entrectinib for the Treatment of Patients With Locally Advanced or Metastatic Solid Tumors That Harbor NTRK1/2/3, ROS1, or ALK Gene Rearrangements (STARTRK-2), and the Phase I Study of Entrectinib-An Oral Pan-TRK, ROS1, and ALK Inhibitor in Patients With Advanced Solid Tumors With Relevant Molecular Alterations (ALKA-372-001) were reported in an integrated analysis of 54 adults.^21, Preliminary results from the Study Of Entrectinib (Rxdx-101) in Children and Adolescents With Locally Advanced Or Metastatic Solid Or Primary CNS Tumors And/Or Who Have No Satisfactory Treatment Options (STARTRK-NG) of 15 children/adolescents with NTRK fusion-positive solid tumors were published separately.^22,

Table 8. Summary of Clinical Trials: Entrectinib

ALK: anaplastic lymphoma kinase; ALK-372-001: Phase I Study of Entrectinib-An Oral Pan-TRK, ROS1, and ALK Inhibitor in Patients With Advanced Solid Tumors With Relevant Molecular Alteration; CNS: central nervous system; NTRK: neurotrophic receptor tyrosine kinase; NCT: national clinical trial; ROS1: Proto-oncogene tyrosine-protein kinase; STARTRK-1; A Phase 1, Multicenter, Open-Label Study of Oral Entrectinib (RXDX-101) in Adult Patients with Locally Advanced or Metastatic Cancer Confirmed to be Positive for NTRK1, NTRK2, NTRK3, ROS1, or ALK Molecular Alterations; STARTRK-2: An Open-Label, Multicenter, Global Phase 2 Basket Study of Entrectinib for the Treatment of Patients with Locally Advanced or Metastatic Solid Tumors That Harbor NTRK1/2/3, ROS1, or ALK Gene Rearrangements; STARTRK-NG: A Phase 1/2, Open-Label, Dose-Escalation and Expansion Study of Entrectinib (RXDX-101) in Children and Adolescents with No Curative First-Line Treatment Option, Recurrent or Refractory Solid Tumors and Primary CNS Tumors, with or without TRK, ROS1, or ALK Fusions; TRK: tropomyosin receptor kinase.a Trial conducted in Italy (EudraCT 2012-000148-88) 

Pivotal Trial(s)

Trial characteristics and results of the pivotal studies are summarized in Tables 9 to 11. The primary endpoint was objective response rate and duration of response assessed by blinded independent central review using RECIST v1.1.

In the integrated analysis of STARTRK-1, STARTRK-2, and ALKA-372-001 data,the median age was 58 years (range, 21 to 83 years), 89% had an ECOG performance score of 0 or 1, 63% had received prior anticancer therapy (20% received 1, 43% received ≥2) and 22% had CNS disease at baseline.^21, Median duration of follow-up was 12.9 months (interquartile range, 8.8 to 18.8 months). In 54 adult patients with NTRK fusion-positive solid tumors, the objective response rate was 57% and median DOR was 10.4 months. The safety population included 68 patients with NTRK fusion-positive solid tumors who had received any dose of entrectinib; median treatment duration for the safety evaluation was 7.9 months. Adverse events were graded using the National Cancer Institute Common Toxicity Criteria. Serious treatment-related adverse reactions were reported in 10% of patients. Permanent discontinuation due to treatment-related adverse events occurred in 4% of patients. Assessment of a causal relationship between entrectinib and adverse events is limited due to the single-arm design of the study.

Phase 2 results from the STARTRK-NG trial included 27 children and adolescents, 15 of whom had NTRK fusion-positive solid tumors.^22, The cut-off date for data analysis was September 2020. The objective response rate was 60% after a median duration of 11 months follow-up. Among the total Phase 2 population, 85% (23/27) had a Grade 3 or higher adverse event, most commonly weight gain (33% [9/27]) and a decrease in neutrophil count (22% [6/27]). The STARTRK-NG trial is ongoing, with expected completion in 2027.

Table 9. Summary of Key Study Characteristics: Entrectinib

ALK: anaplastic lymphoma kinase; ALK-372-001: Phase I Study of Entrectinib-An Oral Pan-TRK, ROS1, and ALK Inhibitor in Patients With Advanced Solid Tumors With Relevant Molecular Alteration; CNS: central nervous system; NTRK: neurotrophic receptor tyrosine kinase; NSCLC: non-small-cell lung cancer; ROS1: Proto-oncogene tyrosine-protein kinase; STARTRK-1; A Phase 1, Multicenter, Open-Label Study of Oral Entrectinib (RXDX-101) in Adult Patients with Locally Advanced or Metastatic Cancer Confirmed to be Positive for NTRK1, NTRK2, NTRK3, ROS1, or ALK Molecular Alterations; STARTRK-2: An Open-Label, Multicenter, Global Phase 2 Basket Study of Entrectinib for the Treatment of Patients with Locally Advanced or Metastatic Solid Tumors that Harbor NTRK1/2/3, ROS1, or ALK Gene Rearrangements; STARTRK-NG: A Phase 1/2, Open-Label, Dose-Escalation and Expansion Study of Entrectinib (Rxdx-101) in Children and Adolescents with No Curative First-Line Treatment Option, Recurrent or Refractory Solid Tumors and Primary CNS Tumors, with or without TRK, ROS1, or ALK Fusions.

Table 10. Summary of Key Study Results: Entrectinib

ALK-372-001: Phase I Study of Entrectinib-An Oral Pan-TRK, ROS1, and ALK Inhibitor in Patients with Advanced Solid Tumors with Relevant Molecular Alteration; CI: confidence interval; CNS: central nervous system; CR: complete response; DOR: duration of response; NE: not estimable; NTRK: neurotrophic receptor tyrosine kinase; ORR: overall response rate; OS; overall survival; PR: partial response; PFS: progression-free survival; STARTRK-2: An Open-Label, Multicenter, Global Phase 2 Basket Study of Entrectinib for the Treatment of Patients with Locally Advanced or Metastatic Solid Tumors That Harbor NTRK1/2/3, ROS1, or ALK Gene Rearrangements; TRK: tropomyosin receptor kinase.

Table 11. Summary of Key Study Results: Entrectinib (By Tumor Type)

CI: confidence interval; DOR: duration of response; ORR: overall response rate; MASC: mammary analogue secretory carcinoma

The purpose of limitation tables (see Tables 12 and 13) is to display notable limitations identified in each study. This information is synthesized as a summary of the body of evidence following each table and provides the conclusions on the sufficiency of the evidence supporting the position statement. A limitation in study design and conduct relates to the lack of RCTs. However, NTRK fusion solid tumors are rare and therefore conducting randomized trials would be challenging. Furthermore, pooling multiple primary tumor types with different natural histories into 1 trial may not be scientifically appropriate to demonstrate that entrectinib improves the OS in patients with NTRK fusion-positive solid tumors. A limitation in relevance is related to the generalizability of its results to populations that were not well represented in the pivotal study. Although the efficacy of entrectinib is largely unknown in such cases, in settings where no treatment is available or where available treatment would result in significant morbidity or where the clinical effects of available treatments are modest, it is plausible to assume that entrectinib may provide an advantage over available therapy for patients with NTRK fusion solid tumors. As per the FDA review for larotrectinib, another TRK receptor inhibitor approved for NTRK fusion-positive solid tumor, the FDA concluded that there was strong nonclinical support of the antitumor activity of larotrectinib across multiple cells lines and NTRK fusion partners, and clinically, durable tumor shrinkage occurred in a consistent fashion in patients with a variety of tumors harboring a diverse array of NTRK fusions. In light of these factors, the FDA review teams concluded that pooling of results from patients with NTRK fusion-solid tumors was warranted and supported a tissue agnostic indication.

Table 12. Study Design and Conduct Limitations: Entrectinib

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Table 13. Study Relevance Limitations: Entrectinib

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest.c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Section Summary: Entrectinib

Integrated data from 54 patients with NTRK fusion-positive, locally advanced or metastatic solid tumors from 3, single-arm ongoing studies who had completed a minimum of 6 months of follow-up were reviewed. The ORR by blinded independent central review was 57.4% in patients with NTRK fusion-positive solid tumors. The median DOR was 10.4 months.

Summary of Evidence

For individuals with solid tumors that have an NTRK gene fusion who receive entrectinib, the evidence includes pooled results of 3, single-arm prospective studies. Relevant outcomes are overall survival, disease-specific survival, change in disease status, quality of life, treatment-related morbidity and treatment-related mortality. Integrated analysis of the 3 pivotal trials with a total of 54 patients with NTRK fusion-positive, locally advanced or metastatic solid tumors was reviewed. All patients were required to have progressed on systemic therapy for their disease, if available, or would have required surgery with significant morbidity for locally advanced disease. Objective response rate by an independent review committee was 57.4% (95% confidence interval 43 to 71). The median duration of response was 10.4 months. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Supplemental Information

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American Society of Clinical Oncology

In 2022, the American Society of Clinical Oncology (ASCO) published a provisional clinical opinion on somatic genomic testing to inform treatment decisions in patients with metastatic or advanced cancer. The clinical opinion stated that neurotrophic receptor tyrosine kinase (NTRK) fusion testing should be performed in patients with metastatic or advanced solid tumors who may be candidates for TRK-inhibitor therapy (strength of recommendation: strong).^24,

National Comprehensive Cancer Network

Numerous National Comprehensive Cancer Network (NCCN) tumor-specific guidelines recommend larotrectinib and entrectinib in certain circumstances as a Category 2A intervention for NTRK gene-fusion positive solid tumors.(Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate). These include guidelines for management of:

• Breast cancer^25,

• Colon cancer^26,

• Esophageal cancer^27,

• Gastric cancer^28,

• Head and neck cancer^29,

• Hepatobiliary cancer^30,

• Melanoma^30,

• Non-small-cell lung cancer^30,

• Ovarian cancer^30,

• Pancreatic cancer^30,

• Rectal cancer^31,

• Soft tissue sarcoma^32,

• Thyroid carcinoma^33,

• Uterine and endometrial cancer^34,

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 14.

Table 14. Summary of Key Trials

NCT: national clinical trial.a Denotes industry-sponsored or cosponsored trial.

References

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Codes

Applicable Modifiers

N/A

Policy History