CADTH Reimbursement Review

Entrectinib (Rozlytrek)

Sponsor: Hoffmann-La Roche Limited

Indication: For the treatment of extracranial solid tumours with NTRK gene fusion.

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Ethics Review

Stakeholder Input

Clinical Review

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Introduction

The neurotrophic tyrosine receptor kinase (NTRK) genes encode the neurotrophin family of receptors.¹ The fusion of NTRK genes results from chromosomal rearrangements that — based on preclinical data — lead to constantly activated downstream signalling pathways without the need for ligands.² Although reported to be prevalent in 0.28% of all solid cancers, NTRK oncogenic fusions are observed with variable frequency across a spectrum of pediatric and adult cancers. The frequency depends, in part, on the number of patients screened and on the NTRK fusion detection technique used.¹ In adults in Canada, the 3 most common cancers are lung, colorectal, and breast cancer.³ NTRK fusions are generally less prevalent in common cancers (presenting in 0.1% to 1% of non–small cell lung cancers [NSCLCs]^4-6 and in 2% to 3% of sporadic colorectal cancers [CRCs]⁴); however, NTRK fusion is more common in certain colorectal tumours with high levels of microsatellite instability (MSI-H)^7,8 and in primary thyroid cancers (6%).⁹ In contrast, NTRK fusions are nearly ubiquitous among rare cancer types, such as mammary analogue secretory carcinoma (MASC) and infantile fibrosarcoma (IFS).^4,10

Entrectinib is an inhibitor of tropomyosin receptor kinases (TRK) TRKA, TRKB, and TRKC (encoded by the NTRK1, NTRK2, and NTRK3 genes, respectively), ROS proto-oncogene 1 (ROS1) (encoded by the gene ROS1), and anaplastic lymphoma kinase (ALK) (encoded by the gene ALK). Entrectinib is indicated for the treatment of adult patients who have unresectable, locally advanced or metastatic extracranial solid tumours (including brain metastases) with NTRK gene fusion without a known acquired resistance mutation and no satisfactory treatment options. Entrectinib received a Notice of Compliance with conditions (NOC/c) for this indication on February 10, 2020, from Health Canada pending the results of new information to verify its clinical benefit. The sponsor’s reimbursement request is per the Health Canada–approved indication.

The product monograph states that a validated assay is required for the selection of patients with NTRK fusion–positive unresectable, locally advanced or metastatic extracranial solid tumours, including brain metastases. NTRK fusion–positive status should be established before initiating entrectinib therapy.

Entrectinib is available as 100 mg and 200 mg capsules. The recommended dose is 600 mg orally once daily. From the starting dose of 600 mg once daily, the dose can be reduced twice (i.e., to 400 mg once daily and then to 200 mg once daily) if there is a need to manage adverse events (AEs). It is recommended in the product monograph that patients are treated until disease progression or unacceptable toxicity. Health Canada has not authorized an indication for entrectinib for pediatric use; there are no recommendations in the product monograph regarding dosing in pediatric patients.

The objective of this systematic review is to assess the beneficial and harmful effects of entrectinib (600 mg orally once daily) for the treatment of adult patients who have unresectable, locally advanced or metastatic extracranial solid tumours (including brain metastases) with NTRK gene fusion without a known acquired resistance mutation and no satisfactory treatment options.

Stakeholder Perspectives

The information in this section is a summary of input provided by the patient groups who responded to CADTH’s call for patient input and from clinical experts consulted by CADTH for the purpose of this review.

Patient Input

Four patient groups provided input into CADTH’s review: Lung Health Foundation (LHF); Lung Cancer Canada (LCC); Colorectal Cancer Canada (CCC); and the Canadian Breast Cancer Network (CBCN). All of the groups obtained information through surveys to support their input. Patient groups expressed the need for treatments that could extend progression-free survival (PFS), delay disease progression, relieve cancer-related symptoms, improve quality of life, and minimize side effects from treatment. Also, patents wish to reduce the impact of cancer on their ability to care for children and dependents, continue working, spend time with loved ones, participate in social activities, travel, maintain friendships, and pursue personal interests. Similar to the clinicians who provided input to CADTH, the patient groups highlighted inconsistency across Canadian jurisdictions with access to NTRK fusion testing. Patients emphasized a desire for NTRK fusion testing to be available earlier with the hope of avoiding exposure to alternative treatments that may be less effective and associated with more AEs than a therapy targeting tropomyosin receptor kinase (TRK).

Clinician Input

Input From Clinical Experts Consulted by CADTH

A panel of 3 clinical oncologists from across Canada provided input for this review. Given that entrectinib is approved for use in a manner that is independent of tumour histology (with the exception of primary central nervous system [CNS] tumours), each of the clinicians on the review team has expertise in the diagnosis and management of different types of primary tumours. The clinicians consulted by CADTH felt that it was difficult to fully characterize the unmet need for patients who could be eligible for treatment with entrectinib. This is due to the breadth of potentially advanced solid tumours that may harbour NTRK fusion mutations and to variability in the availability and effectiveness of potential alternative therapies. However, the clinical oncologists agreed that, in the case of metastatic solid malignancies, virtually all patients eventually progress on currently available therapies, with the possible exception of select patients with select cancer types who are receiving immunotherapies.

The clinicians noted that the appropriateness of recommending that patients try other treatments before initiating treatment with entrectinib would depend on the cancer subtype and the efficacy of front-line therapy. As with the patient group input, the clinical experts consulted by CADTH agreed that TRK-targeting therapies, such as entrectinib, should be considered early in the course of treating cancers involving NTRK fusion. This agreement was based on the following rationale:

• Entrectinib may be associated with higher response rates, have a better safety profile, and be more tolerable than existing alternatives.

• Given its mechanism of action and the available evidence, the clinical experts believed that entrectinib would be efficacious in patients with NTRK gene fusions and advanced disease, regardless of the number of prior therapies.

• Patients may no longer be fit for any systemic therapy after receiving alternative treatments (e.g., poor performance status).

• The presence of NTRK fusion mutations is clinically actionable and the Canadian consensus guidelines recommend the use of TRK inhibitors as the preferred option for patients with NTRK fusion tumours.

Treatments targeting the tumour site (as opposed to the TRK) were perceived as likely to be less effective and potentially more toxic than a TRK-targeting therapy (i.e., entrectinib or larotrectinib), particularly for tumours where the alternative is chemotherapy. All clinicians noted that there is considerable variability in access to NTRK fusion testing across tumour sites and across Canadian jurisdictions. The determination of when to identify targeted therapies (such as entrectinib) as potential treatment options is influenced by whether or not tumours are routinely tested for NTRK fusion and the timing of such testing.

The clinicians noted that in adults, clinically meaningful outcomes could include objective response; non-progression; patient-reported improvements in ability to perform activities; improved survival; stabilization, improvement, or reduced severity of symptoms; or no deterioration in quality of life. Clinicians noted that treatment response is typically assessed every 3 months, and once response is established or remission achieved, the interval may be prolonged. The clinicians noted that treatment failure would be determined by disease progression, treatment intolerability, poor quality of life (e.g., poor PS), or patient request to discontinue treatment.

Clinician Group Input

Five clinician groups provided input into this review, including LCC and the Lung Cancer, Breast Cancer, Gastrointestinal (GI) Cancer, and Head, Neck, and Thyroid (HNT) Cancer Drug Advisory Committees (DACs) from Ontario Health Cancer Care Ontario (OH-CCO). The input from the clinician groups was similar to the input from the clinical experts consulted by CADTH with respect to the unmet medical needs of adult patients who have unresectable, locally advanced or metastatic extracranial solid tumours (including brain metastases) with NTRK gene fusion without a known acquired resistance mutation and no satisfactory treatment options. The clinician groups also noted that the place in therapy for entrectinib would vary depending on the tumour site, the availability of safe and effective alternative therapies, and the timing of access to NTRK fusion testing. Input regarding important end points, timing and criteria for evaluation, and likely discontinuation criteria was the same as that provided by the experts consulted by CADTH.

Clinical Evidence

Pivotal Studies and Protocol Selected Studies

Description of Studies

The submission for entrectinib was based on a pooled analysis of 3 multi-centre, open-label, single-arm trials of entrectinib in adults with advanced or metastatic solid tumours: ALKA (phase I), STARTRK-1 (phase I), and STARTRK-2 (an ongoing phase II basket trial). The primary evaluation for the pooled analysis was based on a May 31, 2018, clinical cut-off date (CCOD), and the evaluation has subsequently been updated with larger sample sizes and longer follow-ups (October 31, 2018, and August 31, 2020). Whenever available, the CADTH report reflects the most recent analysis (CCOD of August 31, 2020).

The pooled analysis for the August 31, 2020 CCOD consisted of the following datasets:

• NTRK safety-evaluable population (N = 193): all patients with an NTRK fusion–positive tumour who received at least 1 dose of entrectinib

• NTRK efficacy-evaluable population (N = 121; 98% from STARTRK-2): all patients with NTRK fusion–positive extracranial primary tumours who received at least 1 dose of entrectinib, had measurable disease at baseline, and had at least 12 months of follow-up

• NTRK efficacy-evaluable population with CNS metastases at baseline (N = 19, based on blinded independent central review [BICR] assessment): the subpopulation used for the evaluation of the “intracranial efficacy” end points.

Nearly all patients in the pooled analysis were from the STARTRK-2 trial, in which patients received entrectinib at the dosage recommended in the Canadian product monograph (i.e., a starting dosage of 600 mg once daily with up to 2 dose reductions permitted to manage AEs).

The primary outcomes in the pooled analysis were objective response rate (ORR), defined as the proportion of patients with a best overall response (BOR) of either complete response (CR) or partial response (PR), according to Response Evaluation Criteria in Solid Tumours Version 1.1 (RECIST 1.1) and as determined by BICR; duration of response (DOR); and best objective response (BOR). Secondary efficacy end points in the pooled analysis included time to tumour response (TTR); clinical benefit rate (CBR), defined as the proportion of patients with CR, PR, or stable disease for at least 6 months; PFS; and overall survival (OS). In addition, the sponsor pre-specified the following intracranial efficacy end points that were evaluated in the pooled subset of patients who had CNS metastases at baseline: intracranial ORR (IC-ORR), intracranial duration of response (IC-DOR), and intracranial progression-free survival (IC-PFS). Health-related quality of life (HRQoL) data were evaluated only in the STARTRK-2 trial and included change from baseline in the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30); the EORTC Quality of Life Questionnaire Lung Cancer 13 (QLQ-LC13) for the subset of patients with NSCLC; and the EORTC Quality of Life Questionnaire Colorectal Cancer 29 (QLQ-29) for the subset of patients with metastatic colorectal cancer (mCRC).

The NTRK efficacy-evaluable analysis set (N = 121) was 51.2% female, with a mean age of 55.9 years (64.5% were less than 65 years of age). Baseline Eastern Cooperative Oncology Group Performance Status (ECOG PS) results were 0 (43.8%), 1 (47.1%), or 2 (9.1%). The majority of patients had previously received some form of anti-cancer therapy (n = 97; 80.2%); 74 patients (61.2%) had received prior radiotherapy and 103 patients (85.1%) had received previous cancer surgery. Approximately 30.6% of patients did not have prior systemic anti-cancer therapy. For those with a history of prior systemic therapy, 28.9% had 1 line, 21.5% had 2 lines, 9.9% had 3 lines, and 5.8% had 4 lines. The most frequent systemic prior anti-cancer therapy was chemotherapy (n = 88; 72.7%), followed by targeted therapy (n = 24; 19.8%), immunotherapy (n = 13; 10.7%), and hormonal therapy (n = 10; 8.3%).

The solid tumour types that were reported for at least 5% of the patients included sarcoma (n = 26; 21.5%); MASC (n = 24; 19.8%), NSCLC (n = 22; 18.2%); thyroid cancer (n = 13; 10.7%); colon cancer (n = 10; 8.3%); and breast cancer (n = 7; 5.8%). Nearly all patients had metastatic disease at baseline (96.7%). The most common metastatic sites were lung (61.2%) and lymph nodes (55.4%). There were 19 patients (17.2%) with CNS metastases at baseline, as assessed by BICR, with 17 patients (14.0%) reporting prior radiotherapy of the brain.

Efficacy Results

A summary of the results for key efficacy end points is provided in Table 2. Unless otherwise noted, the efficacy results reported are from the August 2020 CCOD.

ORR: In the NTRK efficacy-evaluable dataset, the ORR by BICR was 61.2% (95% confidence interval [CI], 51.87 to 69.88). A BOR of CR or PR was demonstrated by 15.7% and 45.5% of patients, respectively. The point estimates for ORR ranged widely across tumour types, and the CIs reflected a high degree of uncertainty for many tumour types. At least 1 patient demonstrated a response to treatment in each of the tumour types, with the exception of neuroblastoma (n = 1). The ORR for the larger subgroup populations were generally consistent with the results for the overall population; however, a higher proportion of tumour response was reported among the patients with salivary MASC tumours (20 out of 24; 83.3% [95% CI, 62.6 to 95.3]) and a lower proportion was reported for those with colorectal carcinoma (2 out of 10; 20% [95% CI, 2.5 to 55.6]).

IC-ORR: The BICR-assessed IC-ORRs were 52.6% (95% CI, 28.86 to 75.55) and 63.6% (95% CI, 30.8 to 89.1) for all patients with baseline CNS disease (10 out of 19 responded) and those with measurable disease at baseline (7 out of 11 responded), respectively. A subgroup analysis demonstrated similar results for those who had no prior brain radiotherapy or brain radiotherapy greater than or equal to 6 months before the initiation of treatment (55.6%; 95% CI, 21.2 to 86.3 [n = 9]) and those with prior brain radiotherapy within 6 months of initiating treatment with entrectinib (50.0%; 95% CI, 18.7 to 81.3 [n = 10]).

TTR: The median times to objective response were 1.0 month (95% CI, 0.9 to 1.0) for the overall population and 1.3 months (95% CI, 0.9 to 2.8) for patients with CNS metastases at baseline.

DOR: The DOR among responders was 20.0 months (95% CI, 13.0 to 38.2). For the patients who demonstrated a CR or PR with entrectinib, responses of at least 6 months, 12 months, 18 months, 24 months, 30 months, and 36 months were reported for 58 patients (78%), 46 patients (62%), 32 patients (43%), 20 patients (27%), 10 patients (14%), and 4 patients (5%), respectively. The event-free probabilities were 0.82 (95% CI, 0.73 to 0.91) at 6 months, 0.66 (95% CI, 0.55 to 0.77) at 12 months, 0.49 (95% CI, 0.37 to 0.61) at 24 months, and 0.39 (95% CI, 0.24 to 0.53) at 36 months.

IC-DOR: The IC-DORs among responders were 17.2 months (95% CI, 7.4 to not estimable [NE]) and 22.1 months (95% CI, 7.4 to NE) for all patients with baseline CNS disease and those with measurable disease at baseline, respectively.

CBR: The CBR was 63.6% (95% CI, 54.8 to 71.7).

PFS: The median PFS was 13.8 months (95% CI, 10.1 to 19.9), with a total of 72 patients (59.5%) experiencing progressive disease (PD) or death at the August 31, 2020 CCOD. Updated subgroup analyses for PFS were not reported for the August 2020 CCOD.

IC-PFS: The median PFS was 10.1 months (95% CI, 6.3 to 26.7), with a total of 13 patients (68.4%) experiencing CNS PD or death at the August 2020 CCOD (5 PD events and 8 deaths).

OS: The median OS was 33.8 months (95% CI, 23.4 to 46.4); a total of 49 patients (40.5%) had died at the time of the August 2020 CCOD. Among those with CNS metastases at baseline, the median OS was 19.9 months (95% CI, 7.9 to NE), with 52.6% having died at the time of the August 2020 CCOD.

Table 2: Summary of Key Results From Integrated Efficacy Analysis

CI = confidence interval; CR = complete response; DOR = duration of response; NE = not estimable; NR = not reported; ORR = overall response rate; OS = overall survival; PD = progressive disease; PFS = progression-free survival; PR = partial response; SD = stable disease; TTR = time to response.

Source: Supplemental Efficacy Results (clinical cut-off date: August 31, 2020).¹¹

Harms Results

Table 3 provides a summary of AEs reported in the safety-evaluable population (N = 193). Nearly all patients who were NTRK fusion–positive experienced at least 1 AE (99.5%); 46.1% of patients experienced at least 1 serious adverse event; 69.4% experienced at least 1 AE greater than or equal to grade 3. The proportions of patients with AEs leading to dose interruption or dose reduction were 54.4% and 26.9%, respectively. The proportion of patients with an AE leading to discontinuation was 14.5%.

The product monograph for entrectinib provides detailed recommendations for the management of AEs that require temporary interruption, dose reduction, or discontinuation of treatment with entrectinib. The clinical experts consulted by CADTH indicated that those recommendations are a reasonable reflection of how patients would be managed in clinical practice. The product monograph also includes black box warnings that the drug may cause congestive heart failure and fetal harm when administered to a pregnant woman. The clinical experts consulted by CADTH noted that the patients would likely be screened and monitored for risk factors and symptoms related to heart failure before treatment and during follow-up visits while on treatment. Overall, the clinical experts consulted by CADTH agreed that the safety and tolerability of entrectinib was reasonable.

Table 3: Summary of AEs (Safety-Evaluable Population)

AE = adverse event; NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; SAE = serious adverse event.

Source: Supplemental Efficacy Results (clinical cut-off date: August 31, 2020).¹¹

Critical Appraisal

Internal Validity

Due to the rarity of NTRK fusion cancers, the sponsor conducted pooled analyses of efficacy and safety as the basis for the regulatory and reimbursement review submissions. Although the pooled analyses included patients from 3 trials, nearly all of the patients were from the STARTRK-2 trial (98% and 97% of patients in the efficacy and safety analyses sets, respectively). This reduces the potential uncertainty that can arise from between-study heterogeneity (e.g., differences in study design, objectives, phases, outcome measures, and eligibility criteria across trials) that has been previously noted by CADTH for larotrectinib. Despite the use of pooled analyses, the sample sizes for each individual cancer type were too small, as would be expected due to the low prevalence of NTRK gene fusions (9 out of 14 tumour types contained fewer than 10 patients); the resulting 95% CI was too wide to evaluate the consistency of the effect of entrectinib on different tumour types.

The efficacy end points were evaluated using BICR-assessed outcomes for the primary analyses (with investigator-assessed outcomes provided as a sensitivity analysis). This is an important design feature because the trials were all open-label, single-arm studies. DCR, PFS, and OS are important end points for evaluating the efficacy of cancer treatments; however, these cannot be interpreted in the absence of a control group. In addition, a number of survival outcomes (PFS, OS, and DOR) were analyzed using the Kaplan–Meier method to pool data across the 3 trials, which could be problematic given that traditional survival analysis methods (such as Kaplan–Meier curves) rely on the assumption that a single survival distribution can be used to estimate the survival outcome for all patients included in the analysis. However, as noted previously, nearly all of the patients were derived from a single trial (STARTRK-2), limiting concerns about the pooled approach for survival analyses. HRQoL analyses were conducted for only 1 of the trials (STARTRK-2), and these were limited by the open-label administration of entrectinib, the lack of a comparator group, the absence of statistical testing, and the small sample size for disease-specific instruments for those with NSCLC (N = 12) and mCRC (N = 7).

External Validity

The patient population in the pooled analysis was considered a reasonable reflection of the target population in Canada (i.e., adults with NTRK fusion–positive, unresectable, locally advanced or metastatic extracranial solid tumours). Not all solid tumour types were represented in the pooled analysis, and the majority of tumour types were seen in fewer than 10 patients. This resulted in wide CIs within subgroup analyses, reducing confidence in the generalizability of the results. Patients included in the pooled analysis had ECOG PS scores of 0, 1, or 2. The clinical experts noted the relatively fast median TTR along with the high rate of response and favourable toxicity profile. These are key considerations for potentially making entrectinib available to patients with an ECOG PS of 3 (a population that was not studied in the clinical trials) in situations where the oncologist believes that tumour-related symptoms are driving the PS.

Nearly all patients in the pooled analysis received entrectinib at the dosage recommended in the Canadian product monograph (i.e., a starting dosage of 600 mg once daily with up to 2 dose reductions permitted to manage AEs).

There were no direct or indirect comparisons filed by the sponsor to evaluate the comparative efficacy and safety of entrectinib versus larotrectinib or other alternative therapies.

Indirect Comparisons

No studies have directly compared entrectinib versus larotrectinib for patients with NTRK-positive tumours. The sponsor did not include an indirect comparison in its application to CADTH because it believes meaningful comparisons are not feasible due to the following challenges: NTRK fusions are expressed in only 1% or less of all solid tumours; patient enrolment in trials is low; ongoing trials are single arm and open label, and the study population is heterogeneous with regard to baseline characteristics (e.g., age, ECOG status, tumour site, and presence of CNS metastases). In the absence of direct or indirect evidence comparing entrectinib and larotrectinib in the submission, CADTH conducted a literature search to identify any relevant published indirect comparisons. CADTH identified 1 matching-adjusted indirect comparison (MAIC) of entrectinib versus larotrectinib in adult patients with NTRK gene fusion–positive tumours.

Description of Studies

Garcia-Foncillas et al. (2022) conducted a MAIC to compare the efficacy and safety of entrectinib and larotrectinib in adults with NTRK fusion–positive tumours. The MAIC was funded by the manufacturer of larotrectinib; therefore, patient-level data were available for the larotrectinib-treated patients, but not for entrectinib-treated patients. The data used for entrectinib were derived from the earlier May 31, 2018 and October 31, 2018 CCODs (i.e., a smaller sample size than the August 31, 2020 CCOD data included in the current submission to CADTH). Adult patients were selected for inclusion in the MAIC if they were TRK inhibitor-naive and had NTRK fusion (as determined by an independent review committee) and an ECOG PS of 2 or less. Patients were matched according to the following baseline characteristics: sex, age, race, ECOG PS, tumour type, metastatic disease (versus locally advanced, unresectable disease), NTRK fusion type, prior lines of systemic therapy for metastatic disease, and CNS metastases.

Efficacy Results

Garcia-Foncillas et al. (2022) reported that, compared with entrectinib, larotrectinib was associated with a statistically significantly greater duration of OS (hazard ratio [HR] = 0.43; 95% CI, 0.23 to 0.83; P < 0.05) and DOR (HR = 0.49; 95% CI, 0.25 to 0.98; P < 0.05). The authors reported no statistically significant difference for PFS (HR = 0.66; 95% CI, 0.42 to 1.03; P = 0.07) or ORR (risk difference [RD] = 3.8; 95% CI, –11.7 to 19.3; P = 0.63). Results were similar in sensitivity analyses applying different specifications for the MAIC and using a simulated treatment comparison method.

Harms Results

There were no statistically significant differences reported between larotrectinib and entrectinib for serious treatment-related adverse events (TRAEs) or TRAEs leading to discontinuation.

Critical Appraisal

Several key details from the MAIC were not provided in the published study, limiting CADTH’s ability to appraise the reported study. However, the primary limitation of the results is due to the unanchored nature of the comparison, which would require the inclusion of all prognostic factors and effect modifiers to ensure unbiased results. Due to this limitation and others, drawing firm conclusions based on the results of this MAIC is not recommended.

Intra-Patient Growth Modulation Index Analysis

The sponsor provided the intra-patient comparison of efficacy in a single-arm trial of entrectinib in tumour-agnostic indications. The sponsor’s objective was to generate and analyze evidence for the comparative effectiveness of entrectinib by exploring the role of intra-patient comparison as an alternative to a traditional comparator arm.

Populations and Methods

Analyses were conducted on retrospectively collected data from the STARTRK-2 trial to generate intra-patient comparisons. There were 3 cohorts of patients based on their prior systemic therapy in the metastatic setting and the presence or absence of documented progression:

• In the “documented progression on prior therapy” cohort, patients received at least 1 systemic therapy for metastatic disease before commencing entrectinib, and there is clear documentation of PD on the most recent prior therapy, as captured in electronic case report forms.

• In the “no documented progression on prior therapy” cohort, patients received at least 1 systemic therapy for metastatic disease before commencing entrectinib and had no documentation of PD on the most recent prior therapy. This cohort includes patients who stopped prior therapy due to toxicity, completion of the course, or other reasons.

• In the “no prior therapy” cohort, patients received no prior systemic therapy for metastatic disease before starting entrectinib. However, they may have received prior (neo) adjuvant therapy.

A total of 71 patients with efficacy-evaluable NTRK fusion–positive disease who were enrolled in STARTRK-2 up to April 30, 2018 (data cut-off date: October 31, 2018) were included in the analysis. Of 71 patients, 51 patients had received systemic therapy before commencing entrectinib (38 had documented PD and 13 had no documented PD on the most recent prior systemic therapy); and 20 patients had not received prior systemic therapy. Among those who had received prior systemic therapy, 21 patients (41.2%) received 1 line, 20 patients (39.2%) received 2 lines, and 10 patients (19.6%) received 3 or more lines. The treatment regimens varied greatly within and between tumour types. The most common tumour types were sarcoma (22.5%), NSCLC (16.9%), MASC (16.9%), and thyroid cancer (9.9%).

The key analysis used was growth modulation index (GMI), as defined by the ratio of PFS on entrectinib to time to discontinuation (TTD) on the most recent prior therapy. TTD was chosen instead of time to progression (TTP) to measure the efficacy of the prior therapy due to the limited data available to define a TTP outcome reliably. A GMI ratio of greater than or equal to 1.3 was selected as the threshold to indicate a clinically meaningful benefit. Additional analyses explored TTD and ORR for entrectinib and prior systemic therapy.

Results

For patients with PD on prior systemic therapy, median GMI was 2.53 (range = 0.09 to 61.5) with 25 patients (65.8%) having a GMI of greater than or equal to 1.3. For GMI thresholds of greater than or equal to 1.5, greater than or equal to 1.8, and greater than or equal to 2.0, 23 patients (60.5%), 23 patients (60.5%), and 22 patients (57.9%), respectively, met these thresholds. Of 7 patients with a GMI of less than 1.0, 4 patients (57.1%) were censored for PFS.

Kaplan–Meier survival analysis showed that curves for PFS and TTD on entrectinib were similar (HR of PFS to TTD = 1.08; 95% CI, 0.6 to 1.9), with a median PFS of 11.2 months (95% CI, 6.7 to NE) and a median TTD of 9.9 months (94% CI, 7.3 to 14.8) on entrectinib. Both PFS and TTD on entrectinib were longer than TTD on most recent prior therapy, which had a median of 2.9 months (95% CI, 2.0 to 4.9). The ORRs for entrectinib were 60.5% (all PR) in patients with documented progression on prior therapy, 46.2% (all PR) in patients with no documented progression on prior therapy, and 80% (5 CR and 11 PR) in patients with no prior therapy.

The ORRs for most recent prior systemic therapy were 15.8% (1 CR and 5 PR) in patients with documented progression on prior therapy and 7.7% (1 PR) in patients with no documented progression on prior therapy.

Critical Appraisal

The following important limitations were identified:

• GMI (or PFS ratio) is not a validated efficacy end point and does not take into consideration the impact of treatment on patient symptoms and quality of life (as acknowledged by the sponsor).

• The sponsor was unable to obtain the PFS data on prior systematic therapy and had to rely on TTD as a surrogate for PFS. This is particularly problematic if patients continue prior therapy beyond disease progression because PFS is overestimated.

• The GMI analysis assumes that tumour growth follows linear kinetics over time (i.e., the same growth rate at the time of diagnosis, for prior therapies, and at time of entrectinib treatment). Evidence suggests that this may not be a valid assumption and that some tumour growth may occur according to exponential or logarithmic rates. In addition, PFS is expected to decrease with successive lines of therapy.

• Two additional underlying assumptions of the GMI analysis are required to make this approach meaningful: participant characteristics regarding all sources of heterogeneity of interest are consistent over time; and measurements compared in the ratio are compatible — i.e., PFS on entrectinib is defined and assessed in the same manner as TTD (as a surrogate for PFS) on most recent prior therapy, and all other reasons for an event are the same. However, neither condition has been met. It is unclear how patients’ baseline characteristics, such as age and ECOG PS, which change over time, affect disease progression.

• The timing of tumour assessment while on entrectinib was controlled through standardized clinical trial protocols, but not when patients were receiving prior therapies outside of the clinical trial setting; RECIST 1.1 was used to assess entrectinib response, but not for prior therapies; and PFS on entrectinib was analyzed by BICR, whereas TTD on prior therapy was based on investigator assessment.

Summary

The results show longer PFS with entrectinib relative to the TTD with the last prior treatment; however, this observation relies on many assumptions, including the key assumption (i.e., TTD as a surrogate for PFS), which appears to be invalid, based on the information provided about the calculation of the GMI. There is no formal investigation of differences in the GMI by tumour type or other patient characteristics, and the descriptive individual GMI results suggest large variations in the GMI. It is unclear how some of the presented results were obtained or if inferences made with them are valid, given the intra-patient nature of the analysis. However, if the GMI can be considered a reliable comparison tool, it appears to support the case that entrectinib may be beneficial in many of the tumour types when other treatments have failed, and that this is the case across many patient characteristics, which would mitigate many of the concerns about patient heterogeneity (other than tumour type). Without inference (the presented CI), large variation in GMI is evident across the tumour types and remains a main limitation.

Exploratory Efficacy Analyses Comparing Entrectinib Against Standard of Care

The sponsor provided a report comparing OS in patients with NTRK fusion–positive solid tumours who were treated with entrectinib from the sponsor’s clinical trials (pooled dataset) against patients treated using standard of care from the Flatiron Health (FH) and Foundation Medicine Incorporated (FMI) clinico-genomic database.

Populations and Methods

The FH database is a US longitudinal database with de-identified data originating from approximately 280 cancer clinics and representing 2.8 million patients with cancer (the majority from community oncology settings). The FH data platform aggregates and processes patient-level data.

Median crude and matched, weighted OS durations were estimated through the Kaplan–Meier survival curve. HRs were estimated using weighted univariate Cox proportional hazards models for entrectinib-treated patients compared to non–entrectinib-treated patients. The index date for the end point analyzed is the start of entrectinib treatment for trial patients and the NTRK-positive test report date for those who received standard of care.

The nearest neighbour propensity score-matching model with replacement was used to perform the matching, with each match first done within each tumour type (i.e., direct match by tumour). Characteristics included in this analysis were tumour type and histology, age of patient, stage of cancer, number and type of previous treatment, and type of centre where patient is treated.

Patient Characteristics

Before matching, the study population with the same tumour types consisted of |||||| patients who received standard of care and |||||| entrectinib-treated patients. Compared with the standard-of-care group, patients in the entrectinib-treated group were younger (median age: ||||||||||||||||||||||||). The entrectinib-treated group included a higher proportion of women (||||||||||||||||||), treated patients only in academic centres, and had a lower proportion of patients with a history of smoking (||||||||||||||). Standard-of-care patients were more heavily treated at the index date (e.g., only |||||| had not received treatment before the index date versus |||||| in entrectinib patients), and were more likely to have stage IV disease at the time of initial diagnosis (||||||||||||). When the 2 cohorts were matched, the main analyses included only |||||| trial patients matched to |||||| standard-of-care patients, and only a moderate balance of cohorts could be achieved for the 4 a priori selected variables (i.e., ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

Results

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Critical Appraisal

The following important limitations prevent firm conclusions from being drawn based on the results of this analysis:

• The sample size for the comparison was very small, with only |||||| patients included in the standard-of-care group. CADTH acknowledges that NTRK fusion positive cancer is a rare condition; however, this remains an important limitation.

• There was heterogeneity across the entrectinib and standard-of-care groups even after propensity score matching.

• The groups were matched based solely on |||||| characteristics, which is not sufficient to control for potential confounding factors.

• There were missing values in relevant covariates, such as ECOG PS (||||||||||||||||||||||||||||||||||||||||||) and number of metastatic sites (under-reported in the real-world evidence data) that prevented their inclusion in the a priori matching.

• The sample size was too small to allow for exploration by subgroup of tumour types or lines of prior therapy (both of which were identified as subgroups of interest for CADTH’s review).

• Patients received entrectinib in a clinical trial setting. The timing of tumour assessment while on entrectinib was controlled through standardized clinical trial protocols, but not when patients were receiving prior therapies outside of the clinical trial setting; RECIST 1.1 was used to assess entrectinib response, but not for prior therapies; and PFS on entrectinib was analyzed by BICR, whereas TTD on prior therapy was based on investigator assessment.

Summary

The results show a longer median OS with entrectinib compared with standard of care (|||||||||||||||||||||||||||||||||||||||||||||||| versus ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||). Important limitations with this analysis, including the small sample size and heterogeneity across treatment groups, prevent firm conclusions from being drawn.

Conclusions

The clinical data supporting the efficacy of entrectinib in a histology-agnostic population of adult patients with NTRK fusion–positive cancer are derived from a pooled analysis of 3 open-label, single-arm trials, including 2 phase I trials (ALKA and STARTRK-1) and a phase II basket trial (STARTRK-2). In total, 121 and 193 adults with NTRK-positive cancer of different histologies were included in the most recent pooled analyses of efficacy and safety, respectively. Results showed that treatment with entrectinib treatment was associated with an ORR of 61.2% (95% CI, 51.87 to 69.88), with 15.7% and 45.5% of patients demonstrating CR or PR, respectively. The median time to response was 1 month (95% CI, 0.9 to 1.0), and the median DOR was 20 months (95% CI, 13.0 to 38.2). Across different tumour types, the ORR varied widely, with a similarly wide range of uncertainty. Combined with the differences in sample sizes across the different tumour types, the majority of which had been experienced by fewer than fewer than 10 patients, these factors limit the generalizability of the findings of the mixed cancer population. Among patients with CNS metastases at baseline (N = 19), the sponsor conducted analyses examining the intracranial efficacy of entrectinib with respect to CNS lesions. The IC-ORR was 52.6% (95% CI, 28.9 to 75.6) with a median IC-DOR of 17.2 months (95% CI, 7.4 to NE) and a median IC-PFS of 10.1 months (95% CI, 6.3 to 26.7).

While the rarity of NTRK fusion creates practical challenges in terms of conducting a randomized controlled trial, the methodological limitations of single-arm trials with small sample sizes mean the results should be interpreted based on clinical judgment. The clinical experts consulted by CADTH indicated that the response rates reported for entrectinib are clinically meaningful, particularly for those with CNS metastases at baseline, given that these patients typically have poor prognoses. The comparative evidence included in this review for entrectinib versus larotrectinib or standard therapies has important methodological limitations and is insufficient for drawing conclusions on comparative efficacy.

The clinical experts consulted by CADTH noted that patients would likely be screened and monitored for risk factors in accordance with the recommendations in the product monograph (e.g., risk of congestive heart failure) and that AEs would likely be managed in accordance with the dosage interruption and reduction scenarios reported in the product monograph. Overall, the clinical experts noted that the AE profile of entrectinib was acceptable and that entrectinib may be more tolerable than some alternatives (e.g., chemotherapy or radiation) for patients who have advanced diseases. Patient groups also noted a preference for targeted therapy and a desire to avoid systemic therapies that may be associated with greater toxicity. From a regulatory perspective, the sponsor is required to provide additional integrated safety analyses to Health Canada as part of the conditional market authorization (i.e., NOC/c); this will include further characterizing the off-target pharmacodynamics of entrectinib (given that it is not a selective inhibitor of TRK proteins), the cardiac risks, and the risks of fractures to identify risk factors and support labelling instructions for dose modification and monitoring.

Introduction

Disease Background

The NTRK genes encode the neurotrophin family of receptors. A recent study estimated the prevalence of NTRK gene fusion at 0.28% of all solid cancers. NTRK oncogenic fusions arise from exact intrachromosomal or interchromosomal rearrangements that juxtapose the kinase domain-containing 30 region of NTRK with the 50 region of NTRK gene partners. Preclinical data have demonstrated that chimeric oncogenic fusions may lead to the partial or complete deletion of the immunoglobulin-like domain of TRK, which has an inhibitory influence on downstream signalling pathways in the absence of activating ligands.² Available literature demonstrates that NTRK gene fusions are oncogenic drivers in various cancers¹² (refer to Appendix 3 for details).^12-15 Although reported to be prevalent in 0.28% of all solid cancers,¹⁶ NTRK oncogenic fusions are observed in variable frequencies across a spectrum of pediatric and adult cancers, with some uncertainty regarding exact frequencies (Figure 1).¹ Different studies have reported varying frequencies. The variation in frequency may be explained by the number of patients screened and the NTRK fusion detection techniques used.

Lung, colorectal, and breast cancer are the 3 most commonly diagnosed cancers in Canada (Table 4):

• In NSCLC, NTRK fusions (occurring in approximately 0.1% to 1% of cases)^4-6 are less common than other oncogenic gene rearrangements that involve the ALK, ROS1, and RET proto-oncogene and occur at frequencies of approximately 4% to 6%, 1% to 2%, and 1% to 2%, respectively.^17-19

• The NTRK mutation is also quite rare in breast cancer except in the rare subtype of secretory breast cancer, in which the prevalence of NTRK fusion has been reported to be 92%.

• NTRK gene fusions are also rare in sporadic CRCs (occurring in 2% to 3% of cases).⁴ These appear to be common in colorectal tumours with MSI-H and exclusive of RAS and BRAF mutations (which represent about 55% of mCRC cases).⁸

• The NTRK mutation is uncommon in adult sarcomas (1%); it is more frequently found in gastrointestinal stromal tumours (GISTs),²⁰ particularly wild-type GISTs (lacking mutations in KIT proto-oncogene [KIT] and PDGFRA).

• NTRK gene fusions are observed in 6% of adults with primary thyroid cancers.⁹

Although the frequency of NTRK fusions is low in common cancer types, NTRK3 fusions are nearly ubiquitous among rare cancer types, such as MASC and IFS.^4,10 In pediatric oncology, NTRK fusions are pathognomonic in specific, rare cancers, including IFS (91% to 100%)²¹ and cellular congenital mesoblastic nephroma (CMN) (83%).⁴ NTRK fusions are also commonly observed in several other very rare pediatric cancers, including secretory breast cancer (92%)²² and MASC of the salivary gland (100%).²³ In addition, there are significant numbers of NTRK fusion cancers among children with papillary thyroid carcinoma (9.4% to 25.9%),^24,25 undifferentiated sarcomas (1%; frequency in adult versus pediatric not specified),¹² high-grade gliomas (7.1%),⁴ inflammatory myofibroblastic tumours, and acute leukemia (rarely).²⁶

Table 4: Incidence and Mortality Associated With Solid Tumours Among People in Canada in 2019

ASIR = age-standardized incidence rate; ASMR = age-standardized mortality rate; CNS = central nervous system; NOS = not otherwise specified.

^aCanada totals include provincial and territorial estimates.

^bRates are age-standardized to the 2011 Canadian population and are per 100,000.

Source: Canadian Cancer Statistics Advisory Committee (2019).³

Figure 1: Incidence of NTRK Gene Fusions Across Multiple Solid Tumour Histologies

NTRK = neurotrophic tyrosine receptor kinase.

Source: Committee for Medicinal Products for Human Use assessment report.²⁷

Standards of Therapy

There is currently no reimbursed drug that targets the NTRK pathway. Among adult cancers, defining accepted clinical practice is difficult because NTRK gene fusions can be observed in a multitude of solid cancers. Patients with advanced solid tumours are largely treated with standard of care (i.e., chemotherapy, immunotherapy, and/or targeted therapy), as defined by their primary disease site.²⁸ Ultimately, many of these cancers have a poor prognosis, and patients who progress on upfront therapies will have limited subsequent therapeutic options.

NTRK-Targeted Therapy

Larotrectinib (Vitrakvi) is approved for use in Canada to treat adult and pediatric patients with locally advanced or metastatic solid tumours who have an NTRK gene fusion without a known acquired resistance mutation or in cases where surgical resection is likely to result in severe morbidity and patients have no satisfactory treatment options. Following a resubmission, CADTH issued a recommendation that larotrectinib be reimbursed with conditions. At the time of this review of entrectinib, larotrectinib is currently listed as under consideration for negotiation by the pan-Canadian Pharmaceutical Alliance.

Selected Disease Site–Specific Burden and Need Considerations

Secretory Breast Cancer

NTRK gene fusions are quite rare in breast cancer.^22,26 Currently, there a number of standard therapy options for patients with advanced breast cancer that have improved survival considerably,⁴ but many patients will ultimately go on to exhaust available therapies and be left with no suitable therapeutic options.²⁸ Secretory breast carcinoma is a very rare histologic subtype of breast cancer that is seen in fewer than 1% of patients with invasive breast cancer; this subtype is seen in children and adults and is associated with a generally favourable prognosis and a low likelihood of metastases.^22,26 However, for those patients with advanced, inoperable disease, treatments options are limited. Secretory breast carcinomas are also associated with a prevalence of NTRK gene fusions that is greater than 90%.⁴

Sarcoma and GIST

Sarcomas are a relatively rare tumour subtype representing more than 100 hundred subtypes. These are often categorized into soft tissue sarcomas (STSs) and bony sarcomas. STSs are associated with a less favourable prognosis, and in the adult population, these have a high risk of recurrence. Metastatic or unresectable STS is generally not curable. Limited effective cytotoxic therapies exist for STS, especially in the metastatic setting or upon relapse.²⁹

In adults with sarcoma and NTRK fusions, standard therapies include radiation and surgery as well as cytotoxic therapy (i.e., doxorubicin) for those with advanced disease. However, in the advanced setting, traditional chemotherapy has limited effectiveness.²⁸ The clinical exerts consulted for this review stated that there are examples of pediatric patients who were fusion-positive with locally advanced disease having enough response to the drug to facilitate curative surgical resection.

NTRK fusions are also seen in 3% to 4% of GIST tumours.²⁰ For GIST tumours with cKIT and PDGFRA mutations, targeted therapies represent the current standard of care. For 10% to 15% of GIST tumours that are classified as wild type with no KIT or PDFGFRA mutations, there is a significant unmet need for effective therapies.³⁰

Thyroid Cancer

For patients with advanced, inoperable thyroid cancer that has progressed on radioactive iodine therapy, current treatments include small-molecule tyrosine kinase inhibitors.²⁸ NTRK gene fusions may be identified in 6% of thyroid cancers.⁹

Gastrointestinal Cancers

For patients with advanced CRC, there is an unmet need for better therapies in patients with chemorefractory disease (i.e., have progressed on 2 or more prior lines of therapy). NTRK gene fusions are uncommon in CRC.^7,8 The clinical experts consulted by the review team noted that for patients with non-colorectal GI cancers, particularly pancreatic cancer and cholangiocarcinoma, there is a significant unmet need for better therapies.

Lung Cancer

Lung cancer remains the most common cancer in Canada.³¹ NTRK fusions are estimated in up to 1% of patients with NSCLC⁴ (compared to ALK fusions in 3% to 5%, ROS1 fusions in 1% to 2%, and epidermal growth factor receptor [EGFR] mutations in 20%).⁵ Systemic treatment options for advanced NSCLC include chemotherapy, immunotherapy, and combination and biomarker-directed targeted therapies, with response rates ranging from 45% to 60% in those without ALK, EGFR, ROS1, or BRAF-deranged lung cancer. While current therapies have improved outcomes for patients with NSCLC, patients will ultimately become refractory and/or intolerant; hence, there is a need for effective and tolerable therapies in pre-treated patients.³¹

Drug

Mechanism of Action

Entrectinib is an inhibitor of TRKA, TRKB, and TRKC (encoded by the NTRK1, NTRK2, and NTRK3 genes, respectively), ROS1 (encoded by the ROS1 gene), and ALK (encoded by the ALK gene). Fusion proteins that include TRK, ROS1, or ALK kinase domains drive tumorigenic potential by hyperactivating downstream signalling pathways, leading to unconstrained cell proliferation. Entrectinib potently inhibits TRK, ROS1, and ALK, leading to the inhibition of downstream signalling pathways and cell proliferation and the induction of tumour cell apoptosis.

Indication Under Review

Entrectinib is indicated for the treatment of adult patients who have unresectable, locally advanced or metastatic extracranial solid tumours (including brain metastases) with NTRK gene fusion without a known acquired resistance mutation and no satisfactory treatment options. The sponsor’s reimbursement request is per the indication. The product monograph states that a validated assay is required for the selection of patients with NTRK fusion–positive unresectable, locally advanced or metastatic extracranial solid tumours, including brain metastases. NTRK fusion–positive status should be established before initiation of entrectinib therapy.

Entrectinib received a NOC/c for this indication on February 10, 2020, pending the results of new information to verify its clinical benefit. Table 5 provides a summary of the status of the confirmatory studies required to address the conditions of the NOC/c.

Table 5: Update on Confirmatory Studies for Entrectinib NOC/c

BMD = bone mineral density; CR = complete response; DOR = duration of response; DXA = dual X-ray absorptiometry; EC50 = concentration of the drug that provides half the maximal response; IC50 = half-maximal inhibitory concentration; ICR = independent central review; M5 = major active metabolite of entrectinib; MASC = mammary analogue secretory carcinoma; NDS = new drug submission; NOC/c = Notice of Compliance with conditions; NSCLC = non–small cell lung carcinoma; NTRK = neurotrophic tyrosine receptor kinase; ORR = objective response rate; PR = partial response; Q2 = second quarter; SNDS-C = supplement to a new drug submission – confirmatory.

Source: Sponsor-provided additional information.³²

Recommended Dosage

The recommended dose of entrectinib is 600 mg orally once daily. It is recommended in the product monograph that patients are treated until disease progression or unacceptable toxicity. The product monograph provides recommendations for the management of AEs that require temporary interruption, dose reduction, or discontinuation of treatment. From the starting dose of 600 mg once daily, the dose can be reduced twice: first to 400 mg once daily and then to 200 mg once daily. Treatment with entrectinib should be permanently discontinued if patients are unable to tolerate a dose of 200 mg once daily. The product monograph recommends that the use of concomitant strong or moderate cytochrome P450 3A (CYP3A) inhibitors and entrectinib should be avoided or limited to 14 days or less. If concomitant use of strong or moderate CYP3A inhibitors cannot be avoided, the dose of entrectinib should be reduced to 100 mg once daily with strong CYP3A inhibitors or to 200 mg once daily with moderate CYP3A inhibitors.

Health Canada has not authorized an indication for entrectinib for pediatric use, and there are no recommendations in the product monograph regarding dosing in pediatrics.

Table 6: Key Characteristics of Entrectinib and Larotrectinib

ALK = anaplastic lymphoma kinase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; NOC/c = Notice of Compliance with condition; NTRK = neurotrophic tyrosine receptor kinase; ROS1 = ROS proto-oncogene 1; TRK = tropomyosin receptor kinase.

^aHealth Canada–approved indications.

Source: Product monographs.^34,35

Stakeholder Perspectives

Patient Group Input

This section was prepared by CADTH staff based on the input provided by patient groups.

A total of 4 patient groups submitted input. The LHF is a charity that provides education (on tobacco cessation and prevention of respiratory illness), programs, and services for patients and health care providers. It also invests in research and policy improvement for lung health. LCC, a national charity and member of the Global Lung Cancer Coalition, serves as a resource for lung cancer education, patient support, research, and advocacy. CCC is a patient association dedicated to raising awareness of colon cancer prevention and treatment. It provides education, support, and advocacy for patients with colon cancer and their families to improve their quality of life. The CBCN, a member of Canadian Cancer Action Network, is a national charity engaged in education and advocacy to ensure the best quality of care for all people in Canada affected by breast cancer.

Lung cancer: Two organizations submitted survey responses. The OLA/LHF collected responses from 14 patients with lung cancer (1 of whom had experience with entrectinib) and caregivers through an online survey on or before December 18, 2021, as well as from 3 patients with lung cancer through phone interviews from September 2021, to October 2021. In addition, a registered nurse and a certified respiratory educator participated in the OLA/LHF survey. Another organization, LCC, conducted interviews with patients from January to February 2022 to collect their thoughts and experiences with lung cancer. (The total number of patients is unspecified; 8 patients had experiences with entrectinib and 1 patient has NTRK fusion mutation.)

According to the OLA/LHF survey results, patients found symptoms of lung cancer challenging, including shortness of breath (64%), fatigue (57%), cough (21%), chest tightness (14%), pain, and the psychosocial effects of receiving a poor diagnosis, such as depression (25%), worry about metastasis, concern about maintaining relationships with families and friends, feelings of isolation, and withdrawal from social activities due to stigma. These effects had great impacts on patients’ activities of daily living (60%), work (38%), leisure activities, and hobbies (28%) as well as on their emotional well-being (20%). Family members and caregivers also experienced psychosocial burden, fatigue, and emotional exhaustion due to caring for patients and the resulting impacts on their ability to work as well as their relationships, emotional well-being, and independence to travel and socialize.

The LCC survey results showed that patients with lung cancer want to better manage their symptoms, minimize side effects from treatments, improve quality of life, live longer while maintaining independence and functionality, minimize burden on their caregivers and loved ones, delay disease progression (i.e., achieve long-term remission), and prolong survival.

In addition, OLA/LHF survey respondents expressed the need for a therapy to treat brain metastases. Both OLA/LHF and LCC surveys highlighted the importance of biomarker testing, access to which is not routinely available across the country during diagnosis. However, patients acknowledged that new funding was announced in 2021 to expand next-generation sequencing (NGS) tests in many provinces. A number of patients from both surveys said they wished they had been screened for a biomarker sooner.

CRC: CCC conducted an online survey that was disseminated by the Canadian Cancer Society across pan-tumour forums and panels from December 7, 2021, to February 8, 2022. A total of 6 patients from Canada, the US, and Indonesia who have NTRK fusion mutation responded (2 patients with thyroid cancer, 2 patients with sarcoma, 1 patient with neuroendocrine tumours, and 1 patient with CRC at primary sites). Two out of 6 patients had experience with entrectinib.

Three out of 6 patients experienced symptoms from their cancers, such as pain, fatigue, cough, shortness of breath, and mobility issues, and 5 patients reported that the symptoms affected their daily lives. Some patients felt that the symptoms affected their work, daily activities, and ability to exercise. Three out of 6 patients also expressed psychological impacts, such as depression, stress, and fear of dying early. Five out 6 patients said that new therapy should improve their physical condition and quality of life. Five out of 6 patients also said they would take therapy to improve their quality of life even if it did not extend their OS. However, 2 patients said they would tolerate significant side effects if therapy could extend their survival by 2 months to 12 months. Patients expressed the need to carry on social activities without the burden of side effects from treatments. Lastly, patients emphasized that access to therapy and the option to be able to decide (along with physicians) which drug to take are important.

In terms of biomarker testing, 5 out of 6 patients had their testing done after diagnosis. One patient said she wished she had had the testing done earlier so she could have avoided unnecessary harmful treatments. Patients who responded to the CCC survey highlighted the importance of equitable access to biomarker testing so they can benefit from targeted therapy for their tumour profile.

Breast cancer: CBCN collated survey results from 2012 Lived Experience of Metastatic Breast Cancer Patients and Caregivers Survey Report and the 2017 Lived Experience Breast Cancer Patient Survey, both of which were conducted online, as well as a review of current studies and grey literature. A total of 146 patients in Canada with breast cancer (most of whom had metastatic breast cancer) participated in the surveys. None had experience with entrectinib.

In a 2012 survey, patients reported that fatigue (54%), insomnia (39%), and pain (37%) had a significant or debilitating impact. The 2017 survey showed similar results. In the 2012 survey, patients reported that cancer had a significant impact on social aspects of their lives, such as their ability to work (71%), caregiving responsibilities (21%), exercise (49%), hobbies and personal interests (42%), participation in social events and activities (41%), and spending time with loved ones (22%). Other challenges reported by the 2012 survey respondents included guilt, feeling like a burden to caregivers, fear of death, poor body image, not knowing what will happen to their children, and marital stress. Patients cited extended PFS, delayed progression, relief from cancer-related symptoms, improved quality of life, and minimal side effects from treatment as desirable outcomes. Also, patients wish to reduce the impact of cancer on their ability to care for children and dependents, continue working, spend time with loved ones, participate in social activities, travel, maintain friendships, and pursue personal interests. Lastly, patients said NTRK (fusion) gene testing is essential for optimal health outcomes and should be readily available and reimbursed appropriately. This testing is not currently part of routine breast cancer care.

Clinician Input

Input From Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise regarding the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol; assisting in the critical appraisal of clinical evidence; interpreting the clinical relevance of the results; and providing guidance on the potential place in therapy). In addition, as part of the entrectinib review, a panel of 3 clinical experts from across Canada was convened to characterize unmet therapeutic needs, assist in identifying and communicating situations where there were gaps in the evidence that could be addressed through the collection of additional data, promote the early identification of potential implementation challenges, gain further insight into the clinical management of patients living with a condition, and explore the potential place in therapy of the drug (e.g., potential reimbursement conditions). A summary of this panel discussion is presented in this section.

Unmet Needs

Similar to the input that was received during the CADTH review of larotrectinib, the clinicians felt that it was difficult to fully characterize the unmet need for patients who could be eligible for treatment with entrectinib. This is due to the breadth of potentially advanced solid tumours that may harbour NTRK fusion mutations and to variability in the availability and effectiveness of potential alternative therapies. However, they agreed that, in the case of metastatic solid malignancies, virtually all patients eventually progress on currently available therapies, with the possible exception of select patients receiving immunotherapies in select cancer types.

Overall, the clinicians felt that an ideal treatment would prolong survival, which was noted as the most important goal for adult patients with advanced, incurable disease. Additional important treatment goals included minimizing toxicity, decreasing cancer-related symptoms (i.e., pain and shortness of breath), maintaining or improving quality of life, delaying disease progression, improving PS, prolonging life, maintaining independence, and reducing burdens on caregivers.

Place in Therapy

The clinicians noted that the appropriateness of recommending that patients try other treatments before initiating treatment with entrectinib would depend on the cancer subtype and the efficacy of front-line therapy. However, it was agreed that entrectinib should be considered early in the course of NTRK fusion cancer treatment. This was based on the rationale that the NTRK fusion is the oncogenic driver in these tumours. Treatments targeting the tumour site as opposed to the TRK were perceived as likely to be less effective and having the potential to be more toxic than TRK-targeting therapies (i.e., entrectinib or larotrectinib), particularly for tumours where the alternative is chemotherapy. In addition, it was noted that therapies that do not target the TRK would be a poor use of patients’ time because patients endure side effects of treatments that are likely to be less efficacious than TRK-targeting treatments.

All clinicians noted that there is considerable variability in access to NTRK fusion testing across tumour sites and Canadian jurisdictions. Whether or not tumours are routinely tested for NTRK fusion, and the timing of such testing, would influence when targeted therapies such as entrectinib are identified as potential treatment options.

Patient Population

The clinicians indicated that entrectinib should be considered in adult patients with a good ECOG PS and advanced solid tumours that harbour an NTRK fusion. Entrectinib has not been approved by Health Canada for use in pediatric patients or patients with a primary CNS tumour.

The indication approved by Health Canada states that entrectinib should be limited to patients who have “no satisfactory treatment options.” The clinical experts consulted by CADTH noted that the definition of “no satisfactory treatment options” would depend on the tumour sites and reflect the range of alternative therapies available for those tumours (e.g., some have no alternatives, while others may have several). The clinical experts agreed that “no satisfactory treatment options” would be interpreted by clinicians to mean suboptimal treatment for the patient with respect to achieving treatment goals (e.g., improving survival and disease-free interval) or be associated with poor quality of life and/or significant toxicity.

The indication approved by Health Canada states that entrectinib should be limited to patients with unresectable or metastatic disease. The clinical experts noted that patients who have metastatic disease that is amenable to surgery (e.g., a patient with NTRK fusion–positive sarcoma who experiences a single lung metastasis at recurrence that is removed surgically with no other evidence of disease) should not be eligible for treatment with entrectinib. Rather, such patients would be eligible only at time of subsequent metastasis that is unresectable or if they develop multiple metastases that are not amenable to local control with stereotactic ablative radiotherapy or surgical resection.

Although other systemic therapies may be available, treatments like entrectinib are selected for patients based on molecular findings to target the oncogene that is driving their cancer. These treatments are more attractive and potentially more beneficial in the context of personalized or precision medicine. Unless the potential alternative treatment is known to be safe and highly effective, entrectinib would ideally be considered before exhausting other systemic therapy options because:

• Compared to alternatives, entrectinib may be associated with higher response rates, have a better safety profile, and be more tolerable.

• Given entrectinib’s mechanism of action and the available evidence for it, the clinical experts believed that it would be efficacious in patients with NTRK gene fusions and advanced disease regardless of the number of prior therapies.

• Patients may no longer be fit for any systemic therapy after receiving alternative treatments (e.g., they may have poor ECOG PS).

• The presence of NTRK fusion mutations is clinically actionable, and the Canadian consensus guidelines recommend the use of TRK inhibitors as the preferred option for patients with NTRK fusion tumours.

The clinicians noted that entrectinib or other similar drugs targeting an oncogene driving the cancer may change the existing treatment paradigm as precision medicine approaches are adopted in clinical practice.

When asked how to identify the patients best suited for treatment with entrectinib, the clinicians noted that NTRK fusions are relatively rare in common cancers; therefore, a diagnostic testing algorithm would be required. Given the rarity, tumour NTRK assessment in enriched populations may also be required. Specifically, routine clinical testing (i.e., fluorescence in situ hybridization [FISH]) establishes NTRK fusion status in classic histologies (e.g., IFS and CMN). Fusion panels in NGS are routinely used for other STS cases at diagnosis and include NTRK coverage. In patients with glioma who lack BRAF (V600E) or BRAF fusion, H3K27M mutations will require NGS testing that includes NTRK1, NTRK2, and NTRK3 gene fusions. Patients with differentiated thyroid cancer that is either unresectable or progressive and/or symptomatic after surgery and refractory to radioactive iodine therapy will receive NGS screening. Reflex testing should also be considered. The clinicians noted that patients with poor ECOG PS, who are unable to tolerate oral therapies, who lack NTRK gene fusions, and who have resectable disease would be least suitable for treatment with entrectinib. In adult patients, the clinicians were not aware of any additional predictive biomarkers of efficacy for entrectinib beyond the presence of NTRK gene fusion.

The clinicians also noted that a potential acquired resistance can be identified on a new biopsy or circulating tumour DNA analysis. It should not affect the testing strategy upfront because it happens after treatment initiation and affects subsequent therapy.

Assessing Response to Treatment

In terms of outcomes that are used to determine whether a patient is responding to treatment in clinical practice, the clinicians indicated that typical metrics of treatment efficacy include disease evaluation by cross-sectional imaging modalities (MRI, CT, PET/CT) to assess response by RECIST 1.1 (for solid tumours) or Response Assessment in Neuro-Oncology (for CNS tumours), symptom improvement, treatment tolerability, and TTP. In addition, for patients with differentiated thyroid cancer, thyroglobulin levels are monitored.

The clinicians noted that in adults, objective response, non-progression, patient-reported improvements in ability to perform activities, improved survival, stabilization, improvement or reduced severity of symptoms, and improvement or no deterioration in quality of life would all be considered clinically meaningful outcomes. Clinicians noted that treatment response is typically assessed every 3 months and that once response is established or remission is achieved, this interval may be prolonged.

Discontinuing Treatment

The clinicians noted that treatment failure would be determined by disease progression, treatment intolerability, poor quality of life (e.g., poor ECOG PS), or patient request to discontinue treatment.

Prescribing Conditions

The clinicians reported that all treatment settings are appropriate for entrectinib administration in adults, given that it is an oral therapy. The clinicians also noted the requirement for the NTRK fusion status of the tumour to be documented. This can be done through FISH (which is routine in IFS or CMN) or NGS panels (for non-IFS, STS, glioma, and differentiated thyroid tumours). Immunohistochemistry can be used for screening in non-CNS histologies, but NTRK fusion must be confirmed using NGS or FISH.

Entrectinib has only be studied as monotherapy and should not be given in combination with other systemic anti-cancer therapies. There is insufficient evidence to evaluate the efficacy of sequential usage of entrectinib or larotrectinib for disease progression on 1 of the 2 drugs. The clinical experts noted that a patient who experiences intolerance to 1 of the TRK inhibitors could be given a trial with the other to determine if tolerability improves.

Clinician Group Input

This section was prepared by CADTH staff based on the input provided by clinician groups.

The following clinician groups have provided input:

• OH-CCO Lung Cancer DAC: 5 clinician members held joint discussions through meetings and email.

• LCC: 22 clinicians gathered information from publicly available sources, published manuscripts, conference presentations, and members’ experiences.

• OH-CCO GI Cancer DAC: 3 clinicians held joint discussions at a committee meeting.

• OH-CCO Breast Cancer DAC: 2 clinician members held joint discussions at a committee meeting.

• OH-CCO HNT DAC: 2 clinician members held joint discussions through email.

The OH-CCO DACs provide clinical and health system guidance on drug-related issues in support of CCO’s mandate, including the Provincial Drug Reimbursement Programs and the Systemic Treatment Program. LCC is a national charity that increases awareness of lung cancer, supports and educates patients with lung cancer and their families, and engages in research and advocacy for patient access to best care. The LCC Medical Advisory Committee is made up of clinicians and key opinion leaders across Canada.

Unmet Needs

Lung cancer: The OH-CCO Lung Cancer DAC and LCC have identified improved survival (efficacy) and ease of administration or improved compliance as goals of therapy. In addition, OH-CCO Lung Cancer stated that improved quality of life and delayed time to chemotherapy are treatment goals; LCC mentioned improved response and tolerability as treatment goals. Both groups said that patients who are refractory to chemotherapy and/or immunotherapy, such as those with NTRK fusion–positive mutation without targeted therapy options, are a subset of patients with NSCLC who have unmet needs.

GI cancer: According to the OH-CCO GI Cancer DAC, treatment goals include prolonging life, delaying disease progression, improving quality of life, and decreasing cancer symptoms. This group stated that there is an unmet need for patients with all subtypes of GI cancer who are considered palliative.

Breast cancer: The OH-CCO Breast Cancer DAC identified improved OS with acceptable toxicity as the treatment goal. This group cited a prevalence rate of more than 90% for NTRK fusion mutation in a subset of patients with breast cancer (i.e., secretory breast cancer, which is the current unmet need) as well as any other patients with NTRK fusion–positive breast cancer.

HNT cancer: The OH-CCO HNT DAC listed cancer shrinkage, improvement in the severity of cancer-related symptoms, ability to maintain and/or improve quality of life, and delayed disease progression as treatment goals. The group stated that the unmet needs are in patients with salivary gland tumours (for which chemotherapy associated with a poor response rate and significant toxicity is available) and thyroid cancers (for which multi-tyrosine kinase inhibitors with toxicity and short DORs are available).

Place in Therapy

Lung cancer: The OH-CCO Lung Cancer DAC stated that entrectinib would displace first-line treatments (i.e., chemotherapy and immunotherapy combinations or pembrolizumab as a single drug) to second-line treatment, and second-line treatment (i.e., docetaxel) to third-line treatment. In contrast, LCC said that entrectinib would most likely be tried after chemotherapy and/or immunotherapy as the first-line option(s), and as the first-line option when these therapies are contraindicated (e.g., due to comorbidities or poor ECOG PS). LCC also added that while it is reasonable to try chemotherapy and/or immunotherapy before entrectinib, it should not be mandated. Lastly, LCC mentioned that entrectinib would be an additional option or an alternative to larotrectinib (e.g., when intolerant to larotrectinib).

GI cancer: The OH-CCO GI Cancer DAC stated that entrectinib would not affect the sequencing of current therapies because it is recommended that patients try other treatments first; therefore, entrectinib would be an additional line of treatment (i.e., the indication would fall between any line of therapies). The group added that NTRK mutation testing should be added to an NGS panel for patients with GI cancer.

Breast cancer: According to the OH-CCO Breast Cancer DAC, because very few patients with breast cancer have NTRK mutation and NTRK gene testing is not routine, it remains unclear where entrectinib would fit into the current treatment paradigm. (Note: the clinical experts consulted by CADTH identified secretory breast cancer as an area where entrectinib may be beneficial.) OH-CCO Breast Cancer said entrectinib would be an additional line of therapy where many treatments for metastatic breast cancer are palliative.

HNT cancer: The OH-CCO HNT DAC stated that ideally, entrectinib would be used as a first-line therapy if NTRK mutation was identified before treatment initiation or as a later line if a patient is already on a different systemic therapy at the time of disease progression or intolerance (thereby pushing back the currently available treatments to later lines). OH-CCO HNT does not believe it would be appropriate to recommend other treatments before entrectinib.

Patient Population

Lung cancer: The OH-CCO Lung Cancer DAC stated that patients with metastatic NSCLC containing an NTRK fusion mutation are a subset of patients for whom the new treatment is needed. The group pointed out that ideally, these patients should be identified by reflex gene testing on lung cancer biopsies; however, some patients are missed due to lack of testing and/or problems with the availability of testing. LCC agreed that all patients with NSCLC and NTRK fusion mutation identified by NGS (or 2-part process of immunohistochemistry confirmed by NGS) should be offered entrectinib if they have not already received larotrectinib and if it is not otherwise contraindicated. LCC added that if NGS panels are limited, NTRK gene testing should be reserved for those who have tested negative for other driver mutations, given that NTRK mutation is mutually exclusive with these. Both groups agreed that patients without NTRK fusion mutation should not be treated with entrectinib. OH-CCO Lung Cancer added that patients with extremely poor ECOG PS should not be treated with entrectinib. In addition, LCC said that patients with ROS1 and NSCLC respond well to entrectinib.

GI cancer: The OH-CCO GI Cancer DAC said that suitable patients should be identified by NTRK gene testing and the least suitable patients would be those without NTRK fusion mutation and/or with poor ECOG PS.

Breast cancer: The OH-CCO Breast Cancer DAC stated that patients with NTRK fusion–positive breast tumours are suitable for entrectinib. The group added that ideally, all patients with metastatic breast cancer should be tested for NTRK fusion mutation; however, given its low prevalence in breast cancer overall and its higher prevalence in secretory breast cancer, identifying this subset is helpful.

HNT cancer: The OH-CCO HNT DAC reported that patients with NTRK mutations (found most commonly in salivary gland tumours and thyroid cancers) are most suitable for entrectinib treatment, while those without NTRK mutations and/or who have early stage or resectable cancers are the least suitable. The group expressed that, as with other types of solid tumours, molecular testing should be routinely performed on advanced and/or metastatic salivary and thyroid cancers to identify NTRK mutation.

Assessing Response to Treatment

Lung cancer: The OH-CCO Lung Cancer DAC said that treatment responses (i.e., stabilization, no deterioration in symptoms, or reduction in the frequency or severity of symptoms such as cough, shortness of breath, fatigue, anorexia, or pain) should be assessed every 4 weeks to 8 weeks and CT imaging should be done every 3 months to 4 months. LCC stated that clinical assessment of tolerability, symptoms, and tumour response by imaging (CT or MRI) should be done every 6 weeks to 12 weeks, depending on patient factors, with frequency and specific measurement tool determined by local practice. LCC added that meaningful improvement would be indicated by reduced or improved symptoms, prolonged life, and good quality of life, such as independent living and the ability to achieve personal life goals.

GI cancer: The OH-CCO GI Cancer DAC stated that the outcomes used to determine response are improvement in cancer symptom control and objective response by tumour markers. Reduction in the frequency or severity of symptoms as well as response on imaging assessed as per standard GI cancer practice (i.e., every 2 months to 4 months) are considered meaningful.

Breast cancer: The OH-CCO Breast Cancer DAC stated that OS is the outcome used to determine response to treatment, and tumour response within the breast is considered a clinically meaningful response, with frequency of assessment as per the study protocol.

HNT cancer: The OH-CCO HNT DAC mentioned that cancer-related or clinical symptoms, physical exam findings related to the cancer (i.e., lymphadenopathy), and imaging assessed approximately every 3 months are the outcomes used to determine response. In addition, OH-CCO HNT listed improved cancer-related symptoms and shrinkage or stabilization of cancer as clinically meaningful responses.

Discontinuing Treatment

Lung cancer: Both the OH-CCO Lung Cancer DAC and LCC stated that intolerance or toxicity (especially ≥ grade 3), patient wish, and unequivocal disease progression (clinical or radiographic) not amenable to control with targeted radiation are criteria for discontinuing treatment.

GI, breast, and HNT cancer: According to the 3 clinician groups representing these cancer types, unequivocal disease progression and/or intolerance should guide decisions about treatment discontinuation.

Prescribing Conditions

Lung cancer: Both the OH-CCO Lung Cancer DAC and LCC said that home is an appropriate setting for the treatment. OH-CCO Lung Cancer added that it is appropriate to start and administer entrectinib in certain hospitalized patients. LCC added that entrectinib should be prescribed only by a specialist, most commonly a medical or pediatric oncologist; however, in some jurisdictions where respirologists oversee systemic therapy, it is appropriate for them to prescribe entrectinib.

GI cancer: The OH-CCO GI Cancer DAC mentioned that an outpatient cancer centre with a medical oncologist is the appropriate setting for treatment with entrectinib.

Breast cancer: The OH-CCO Breast Cancer DAC stated that a cancer centre with expertise in toxicity management is the appropriate setting for this treatment.

HNT cancer: The OH-CCO HNT DAC said entrectinib should be prescribed by a specialist (i.e., a medical oncologist) and can be taken at home as an oral therapy.

Additional Considerations

The OH-CCO GI Cancer DAC said that NTRK gene testing is currently funded only for patients with CRC. It recommends expanding testing to include all GI cancers and to expand access to provincial pathology lab reports with NTRK testing results, which are currently not available to clinicians.

The OH-CCO Breast Cancer DAC said that NTRK fusion mutation is rare in breast cancer, but that a third of patients in the clinical trial (N = 6) had a CR with entrectinib; therefore, a different paradigm (i.e., a disease-agnostic perspective) is needed for evaluating these treatments.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may affect the programs’ abilities to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CADTH are summarized in Table 7.

Table 7: Summary of Drug Plan Input and Clinical Expert Response

ALK = anaplastic lymphoma kinase; CNS = central nervous system; ECOG PS = Eastern Cooperative Oncology Group Performance Status; EGFR = epidermal growth factor receptor; NTRK = neurotrophic tyrosine receptor kinase; ORR = objective response rate; RANO = Response Assessment in Neuro-Oncology; RECIST 1.1 = Response Evaluation Criteria In Solid Tumours Version 1.1; TRK = tropomyosin receptor kinase; vs. = versus.

Clinical Evidence

Systematic Review (Pivotal and Protocol Selected Studies)

Objectives

To perform a systematic review of the beneficial and harmful effects of entrectinib (100 mg and 200 mg) for the treatment of adult patients who have unresectable, locally advanced or metastatic extracranial solid tumours (including brain metastases) with NTRK gene fusion without a known acquired resistance mutation and no satisfactory treatment options.

Methods

The studies selected for inclusion in the systematic review include pivotal studies provided in the sponsor’s submission to CADTH and Health Canada as well as those meeting the selection criteria presented in Table 8. Outcomes included in the CADTH review protocol reflect outcomes considered to be important to patients, clinicians, and drug plans.

Table 8: Inclusion Criteria for the Systematic Review

AE = adverse event; BSC = best supportive care; CNS = central nervous system; ECOG PS = Eastern Cooperative Oncology Group Performance Status; HRQoL = health-related quality of life; NTRK = neurotrophic tyrosine receptor kinase; OS = overall survival; PFS = progression-free survival; SAE = serious adverse event; WDAE = withdrawal due to adverse event.

The literature search for clinical studies was performed by an information specialist using a peer-reviewed search strategy according to the PRESS Peer Review of Electronic Search Strategies checklist.³⁶

Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946–) through Ovid and Embase (1974–) through Ovid. All Ovid searches were run simultaneously as a multi-file search. Duplicates were removed using Ovid deduplication for multi-file searches, followed by manual deduplication in Endnote. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concept was Rozlytrek (entrectinib). Clinical trials registries were searched: the US National Institutes of Health’s clinicaltrials.gov, WHO’s International Clinical Trials Registry Platform search portal, Health Canada’s Clinical Trials Database, and the European Union Clinical Trials Register.

No filters were applied to limit the retrieval by study type. Retrieval was not limited by publication date or by language. Conference abstracts were excluded from the search results. Refer to Appendix 1 for the detailed search strategies.

The initial search was completed on February 23, 2022. Regular alerts updated the search until the meeting of the CADTH pan-Canadian Oncology Drug Review Expert Committee on July 13, 2022.

Grey literature (literature that is not commercially published) was identified by searching relevant websites from the CADTH Grey Matters: A Practical Tool For Searching Health-Related Grey Literature checklist.³⁷ Included in this search were the websites of regulatory agencies (US FDA and European Medicines Agency). Google was used to search for additional internet-based materials. Refer to Appendix 1 for more information on the grey literature search strategy.

These searches were supplemented by reviewing bibliographies of key papers and through contacts with appropriate experts. In addition, the drug sponsor was contacted for information regarding unpublished studies.

Two CADTH clinical reviewers independently selected studies for inclusion in the review based on titles and abstracts, according to the predetermined protocol. Full-text articles of all citations considered potentially relevant by at least 1 reviewer were acquired. Reviewers independently made the final selection of studies to be included in the review, and differences were resolved through discussion.

Findings From the Literature

A total of 320 studies were identified from the literature for inclusion in the systematic review (Figure 2). The included studies are summarized in Table 9. There were no excluded studies.

Figure 2: Flow Diagram for Inclusion and Exclusion of Studies

Table 9: Details of Individual Included Studies

AE = adverse event; ALCL = anaplastic large-cell lymphoma; ALK = anaplastic lymphoma kinase; BICR = blinded independent central review; BM = brain metastases; BR = best response; CBR = clinical benefit rate; CHF = coronary heart failure; CNS = central nervous system; CTCAE = Common Terminology Criteria for Adverse Events; DLT = dose-limiting toxicity; DOR = duration of response; DVT = deep vein thrombosis; ECOG PS = Eastern Cooperative Oncology Group Performance Status; EIAED = enzyme-inducing anti-epileptic drug; EMA = European Medicines Agency; HRQoL = health-related quality of life; GI = gastrointestinal; MI = myocardial infarction; MTD = maximum tolerated dose; NA = not applicable; NCI = National Cancer Institute; NSCLC = non–small cell lung cancer; NTRK = neurotrophic tyrosine receptor kinase; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; PD = progressive disease; PK = pharmacokinetic; q.d. = once a day; RANO = Response Assessment in Neuro-Oncology; RECIST = Response Evaluation Criteria in Solid Tumours; ROS1 = ROS proto-oncogene 1; RP2D = recommended phase II dose; SD = stable disease; TKI = tyrosine kinase inhibitor; TRK = tropomyosin receptor kinase; TTR = time to response.

Note: Eight additional reports were included: FDA Multidisciplinary Review⁴⁵; Health Canada Pharmaceutical Safety and Efficacy Assessment⁴⁶; EMA European Public Assessment Report²⁷; Clinical Study Reports for ALKA, STARTRK-1, and STARTRK-2^47-49; and the Integrated Reports for Safety and Efficacy.⁵⁰

Source: Drug reimbursement review sponsor submission.⁵⁰

Table 10: Details of Integrated Analysis

BOR = best objective response; CBR = clinical benefit rate; CCOD = clinical cut-off date; CNS = central nervous system; DOR = duration of response; NA = not applicable; NTRK = neurotrophic tyrosine receptor kinase; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; q.d. = once a day; TRK = tropomyosin receptor kinase.

Source: Demetri et al. (2022).⁵¹

Description of Studies

The CADTH systematic review included 3 open-label, single-group trials (ALKA, STARTRK-1, and STARTRK-2) and a pooled analysis of entrectinib in adult patients with advanced or metastatic solid tumours.

ALKA-372 to 001 Study

ALKA-372 to 001 was an open-label, multi-centre, non-randomized, single-group, phase I dose escalation trial in adult patients with advanced and/or metastatic solid tumours with NTRK1, NTRK2, NTRK3, ROS1, or ALK genetic alterations.⁴⁵ Patients were enrolled from October 26, 2012 to March 27, 2018. The trial was conducted at 2 sites in Milan, Italy.⁵⁴ Three dosing schedules were investigated using a conventional 3 plus 3 patient enrolment scheme. All patients had to be observed for 1 cycle before subsequent patients were enrolled at the next (higher) dose level.⁴⁵

STARTRK-1 Study

STARTRK-1 was an open-label, multi-centre, phase I trial in adult patients with locally advanced or metastatic solid tumours.⁴⁵ STARTRK-1 and ALKA-372 to 001 were conducted concurrently and were interdependent; i.e., dose escalation decisions in 1 study affected the conduct of the other.⁵⁵ Patients were enrolled from August 7, 2014 to May 10, 2018. The trial was conducted at 10 sites in 3 countries (8 sites in the US, 1 in Spain, and 1 in South Korea).⁵⁴ The trial included a dose escalation and a dose expansion phase; molecular alterations were required only for enrolment in the dose expansion phase (NTRK1, NTRK2, NTRK3, ROS1, or ALK by local testing). Dose escalation was investigated using a conventional 3 plus 3 enrolment scheme with an accelerated titration design. Eligible patients enrolled in the dose expansion phase were grouped into molecularly-defined cohorts under a Simon’s 2-stage (minmax) design determined by the type of molecular alteration harboured by the patient’s tumour.⁴⁵

STARTRK-2 Study

STARTRK-2 is an open-label, multi-centre, phase II basket trial in adult patients with locally advanced or metastatic solid tumours with an NTRK1, NTRK2, NTRK3, ROS1, or ALK molecular alteration.⁴⁵ STARTRK-2 is ongoing and is being conducted at more than 150 sites in 15 countries.⁵⁴ Patients are assigned to different baskets according to tumour type and gene fusion (Figure 3). NTRK1, NTRK2, and NTRK3 are treated as a combined NTRK1, NTRK2, and NTRK3 gene rearrangement basket. Broadly, the baskets of patients are NTRK1, NTRK2, and NTRK3; ROS1; and ALK.⁴⁵ Depending on the patient population sub-basket, prior systemic treatment is allowed; however, prior treatment with inhibitors of TRK, ROS1, or ALK are not allowed in patients with tumours harbouring those respective gene rearrangements except in patients with ALK or ROS1-rearranged NSCLC with CNS-only progression who were previously treated with crizotinib. Sub-baskets include patients who are or have: ALK-positive NSCLC with CNS progression post-crizotinib; ALK-positive non-NSCLC solid tumours; NTRK fusion–positive solid tumours; ROS1-positive NSCLC; ROS1-positive NSCLC CNS progression post-crizotinib; ROS1-positive non-NSCLC solid tumours; or who are enrolled in the Japan recommended phase II dose (RP2D) safety and tolerability substudy.⁵⁶ Patients are enrolled in a non-evaluable basket if they are not assessable for the primary end point (i.e., did not have measurable disease or co-dual oncogenic drivers) but contribute to the assessment of safety and pharmacokinetics (PK).⁴⁵ Treatment is continued until progression, patient withdrawal, or the occurrence of unacceptable toxicity.⁵⁴

Integrated Analysis

The regulatory and reimbursement submissions for entrectinib are based on the pooled analyses of efficacy and safety data from patients enrolled in the 3 trials who were NTRK fusion–positive. The sponsor made the decision to pool efficacy and safety data from these trials based on early guidance from the FDA and European Medicines Agency. This decision was deemed justified due to the rarity of the tumours with NTRK gene fusion, the challenges involved in identifying and enrolling patients with rare diseases in clinical trials, and the lack of an established comparator in this disease population. Additionally, the eligibility criteria and trial conduct (including patient population, study end points, dosing schedules, and tumour assessment methodology and frequency) were similar across the 3 trials, further supporting the pooled efficacy and safety analyses.⁵⁷

Figure 3: Schematic Showing the Design of the STARTRK-2 Basket Trial

ALK = anaplastic lymphoma kinase; CLIA = Clinical Laboratory Improvement Amendments; MD = medical doctor; NGS = next-generation sequencing; NTRK = neurotrophic tyrosine receptor kinase; ROS1 = ROS proto-oncogene 1; RT-PCR = reverse transcriptase polymerase chain reaction.

Populations

Inclusion and Exclusion Criteria

ALKA-372 to 001 Study

The ALKA-372 to 001 study included adult patients greater than or equal to 18 years of age with histologically or cytologically confirmed diagnoses of advanced and/or metastatic solid tumours with ALK-positive alterations and ALK-negative patients with TRKA or ROS1 alterations. The trial was expanded to include ALK-negative patients with TRKB or TRKC genetic alterations (as per amendment 6), with all molecular alterations confirmed by local testing only. Patients for whom no alternative effective standard therapy was available, for whom standard therapy was considered unsuitable, or who had been refused therapy (per protocol amendment 8) were eligible for the study.

Other main eligibility criteria included: an ECOG PS score of less than or equal to 2 and life expectancy of at least 3 months; controlled asymptomatic CNS involvement in the absence of therapy with an anticonvulsant (up to protocol amendment 7) or in the presence of therapy with non–enzyme-inducing anti-epileptic drugs (per protocol amendment 8) or requiring steroids at a stable dose (dexamethasone ≤ 4 mg/day or equivalent) for at least 2 weeks. The study had an accelerated dose escalation phase per cohort until a predetermined level of toxicity was observed. At that point, the dose escalation followed a modified Fibonacci scheme (50%, 40%, or 33% increments). Dose escalation was planned to continue until the RP2D was determined.⁴⁵ Treatment was continued until progression, patient withdrawal, or the occurrence of unacceptable toxicity.⁵⁴ There was no limit to how many cycles a patient could receive.⁵⁸ Dose modifications were permitted for toxicities, and doses could be maintained or reduced after recovery from toxicities if patients recovered within a maximum of 2 weeks.⁴⁵

STARTRK-1 Study

The STARTRK-1 trial included adult patients greater than or equal to 18 years of age with any locally advanced or metastatic tumours (dose escalation only) or histologically or cytologically confirmed diagnosis of locally advanced or metastatic solid tumours with an NTRK1, NTRK2, NTRK3, ROS1, or ALK molecular alteration (dose expansion). Patients must have had measurable disease according to RECIST 1.1, a life expectancy of at least 3 months, and an ECOG PS of less than or equal to 2. Prior cancer therapy was allowed, including crizotinib, ceritinib, investigational drugs, and radiotherapy. Patients with controlled asymptomatic CNS involvement were allowed. Resolution of any acute toxic effects (excluding alopecia) of any prior anti-cancer therapy (National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 grade ≤ 1) was required.⁵⁴

STARTRK-2 Study

The STARTRK-2 trial includes adult patients greater than or equal to 18 years of age with locally advanced or metastatic solid tumours harbouring an NTRK1, NTRK2, NTRK3, ROS1, or ALK molecular alteration based on central testing, or based on local testing if a nucleic acid–based method is used and the local laboratory is Clinical Laboratory Improvement Amendments certified or equivalently accredited. (Patients enrolled based on local testing are required to submit a tissue sample for central confirmation.)⁵⁴ Patients are required to have an ECOG PS of less than or equal to 2 and a minimum life expectancy of 4 weeks.⁴⁹ Prior cancer therapy is allowed, excluding approved or investigational TRK, ROS1, or ALK inhibitors (non-NSCLC patients only) in patients with tumours that harbour the respective gene arrangements. Patients with CNS involvement — including leptomeningeal carcinomatosis that is asymptomatic or previously treated and controlled — are allowed.⁵⁴

Integrated Analyses of NTRK Fusion–Positive Solid Tumours

The pooled analysis for the August 31, 2020 CCOD consisted of the following datasets:

• NTRK safety-evaluable population (N = 193; 97% from STARTRK-2): all patients with an NTRK fusion–positive tumour who received at least 1 dose of entrectinib

• NTRK efficacy-evaluable population (N = 121; 98% from STARTRK-2): all patients with NTRK fusion–positive extracranial primary tumours who received at least 1 dose of entrectinib and had measurable disease at baseline and at least 12 months of follow-up

• NTRK efficacy-evaluable population with CNS metastases at baseline (N = 19 based on BICR assessment): subpopulation used for the evaluation of the “intracranial efficacy” end points.

The following procedures were employed to confirm that patients had solid tumours harbouring NTRK gene fusions:

• confirmation that a Clinical Laboratory Improvement Amendments certified or equivalently accredited nucleic acid–based local test was used (several different assay methods were used in patients across the trials)

• adequate nucleic acid specimen for producing a reliable test result

• presence of an NTRK fusion known to result in oncogenic drive activity

  • gene fusions predicted to translate into a fusion protein with a functional kinase domain were considered positive gene fusions

  • other molecular alterations, such as rearrangements, deletions, or over-expression, were not considered positive for a gene fusion

• lack of co-occurrence with other strong onco-driver mutations likely to confer resistance

  • patients with other oncogenic drivers, such as KRAS and EGFR, were not considered evaluable for efficacy because they did not meet the criteria (outlined previously) with respect to having a sole (NTRK fusion) known onco-driver.^51,59

The criteria to molecularly define eligibility for inclusion in the NTRK-positive, efficacy-evaluable population were applied consistently to all 3 study populations so that all patients who were NTRK-positive in the integrated dataset met the molecular criteria determined as per the STARTRK-2 protocol.⁵⁹ A total of 193 adult patients were included in the updated, integrated safety analysis, and 121 adults were included in the updated efficacy analysis. Reasons for exclusion from the efficacy analysis population were not reported for the August 31, 2020 CCOD. As shown in Table 16, the NTRK efficacy-evaluable analysis population was further subdivided into those with CNS metastases (n = 26, based on investigator assessment; n = 19, based on BICR) and those without CNS metastases (N = 95, based on investigator assessment; N = 102, based on BICR).

Baseline Characteristics

Baseline characteristics for the ALKA, STARTRK-1, and STARTRK-2 trials and the integrated analysis are summarized in Table 11. The NTRK efficacy-evaluable analysis set (N = 121) included 59 male patients (48.8%) and 62 female patients (51.2%). The mean age was 55.9 years (standard deviation [SD] = 15.6), with a larger proportion of patients less than 65 years of age (64.5%) versus greater than or equal to 65 years of age (35.5%). The majority of patients were White (60.3%). Most patients had an ECOG PS of 0 (43.8%) or 1 (47.1%); a minority had an ECOG PS of 2 (9.1%). The mean body mass index of patients was 24.80 (SD = 5.15). Approximately 39% of patients reported a history of smoking.

The solid tumour types that were reported in at least 5% of the patients included sarcoma (n = 26; 21.5%), MASC (n = 24; 19.8%), NSCLC (n = 22; 18.2%), thyroid cancer (n = 13; 10.7%), colon cancer (n = 10; 8.3%), and breast cancer (n = 7; 5.8%). Nearly all patients (96.7%) had metastatic disease at baseline. The most common metastatic sites were lung (61.2%) and lymph nodes (55.4%). The majority of patients had NTRK3 fusions (n = 67; 55.4%), followed by NTRK1 (n = 48; 39.7%) and NTRK2 fusions (n = 6; 5.0%).

The majority of patients had received some form of prior anti-cancer therapy (n = 97; 80.2%): 74 patients (61.2%) had received any prior radiotherapy and 103 patients (85.1%) had previous cancer surgery. Overall, 30.6% of patients (n = 37) did not have prior systemic anti-cancer therapy, whereas 28.9% (n = 35) had 1 prior systemic therapy, 21.5% (n = 26) had 2 prior systemic therapies, 9.9% (n = 12) had 3 prior systemic therapies, 5.8% (n = 7) had 4 prior systemic therapies, and 3.3% (n = 4) had more than 4 lines of prior systemic therapy. The most frequent systemic prior anti-cancer therapy was chemotherapy (n = 88; 72.7%), followed by targeted therapy (n = 24; 19.8%), immunotherapy (n = 13; 10.7%), and hormonal therapy (n = 10; 8.3%).

There were 19 patients (17.2%) with CNS metastases at baseline as assessed by a BICR, with 17 patients (14.0%) reporting prior radiotherapy of the brain.

Figure 4: Safety and Efficacy Analysis Populations (CCOD: August 31, 2020)

ALK = anaplastic lymphoma kinase; CNS = central nervous system; CCOD = clinical cut-off date; ECOG PS = Eastern Cooperative Oncology Group Performance Status; NSCLC = non–small cell lung carcinoma; NTRK = neurotrophic tyrosine receptor kinase; RECIST v1.1 = Response Evaluation Criteria in Solid Tumours Version 1.1; ROS1 = ROS proto-oncogene 1; TRK = tropomyosin receptor kinase.

Source: Drug reimbursement review sponsor submission.⁵⁰

Table 11: Summary of Baseline Characteristics

BICR = blinded independent central review; BMI = body mass index; BSA = body surface area; CNS = central nervous system; CRC = colorectal cancer; CUP = carcinoma of unknown primary; ECOG = Eastern Cooperative Oncology Group; GI = gastrointestinal; GIST = gastrointestinal stromal tumour; IQR = interquartile range; MASC = mammary analogue secretory carcinoma; MPNST = malignant peripheral nerve sheath tumour; NE = not estimable; NOS = not otherwise specified; NSCLC = non–small cell lung carcinoma; NTRK = neurotrophic tyrosine receptor kinase; Std = standard deviation.

Source: Supplemental Efficacy Results (clinical cut-off date: August 31, 2020).¹¹

Interventions

ALKA-372 to 001 Study

In the ALKA-372 to 001 study, 3 entrectinib dosing schedules were investigated as follows:

• schedule A: 4 days on, 3 days off for 3 weeks, followed by a 7-day rest period in a 4-week cycle; fasted condition; once or twice daily dosing

• schedule B: continuous daily dosing in a 4-week cycle; fed condition; once-daily dosing

• schedule C: 4 days on, 3 days off in a 4-week cycle; fed condition; once or twice daily dosing.

The dose escalation for all schedules was planned to continue until the RP2D was determined or until the study was terminated at the discretion of the sponsor. For all schedules, a conventional 3 plus 3 patient enrolment scheme was followed during dose escalation. The study had an initial 100% accelerated escalation phase until a predetermined level of toxicity was encountered. At that point, escalation was to follow a modified Fibonacci scheme. Dose escalation continued until a dose-limiting toxicity (DLT) was observed in 2 of 3 or 2 of 6 patients in cycle 1. If 2 of 3 patients experienced a DLT, then enrolment into the cohort ceased. If a dose level was deemed safe (i.e., 0 of 3 or 1 of 6 patients experienced a DLT), then additional patients (at least 15 total patients per cohort) could have been enrolled at the sponsor’s discretion to obtain additional safety, tolerability, and PK data. A DLT was defined as an AE occurring during the first treatment cycle that fulfilled pre-specified criteria and grading (generally grade ≥ 3 in severity) and for which a causal relationship to entrectinib could not be excluded. Failure to recover (excluding alopecia) after delaying the initiation of next treatment administration by a maximum of 14 days — and failure to complete the first-cycle treatment with at least 75% of the planned doses because of a drug-related toxicity — also met the criteria for a DLT.

STARTRK-1 Study

In the STARTRK-1 dose escalation phase, each cycle consisted of 28 days in repeated 4-week cycles (cycle 1 was 42 days until it was reduced to 28 days in amendment 5 for all patients). The starting dose was 100 mg/m² once daily in the fed condition. (Doses of 200 mg/m², 400 mg/m², 600 mg, and 800 mg were also studied.) Dose escalation followed an accelerated phase in which the dose was doubled in successive cohorts until 1 patient experienced DLT in the first cycle or 2 patients experienced AEs at least possibly related to entrectinib that were grade 2 or greater severity (but not considered to be DLTs) and that occurred during the first cycle, whichever came first. If these situations occurred, dose escalation followed a modified Fibonacci scheme (i.e., 50%, 40%, or 33% increments). RP2D was to be determined based on available safety, tolerability, and PK and pharmacodynamic data from different dose levels and schedules tested; once determined, administration of a flat dose was to be considered for a subgroup of patients if data supported the decision. In dose expansion, patients received entrectinib orally in repeat 28-day cycles at a fixed dose of 600 mg once daily determined as the RP2D from dose escalation. Treatment was continued until progression, patient withdrawal, or the occurrence of unacceptable toxicity. Treatment could continue beyond progression after discussion with the sponsor.⁴⁵ There was no limit to how many cycles during which a patient could receive treatment.⁶⁰ Dose modifications were permitted for toxicities, and doses could be maintained or reduced (up to 2 dose levels) unless a patient was receiving the starting dose of 100 mg/m²/day (in which case, the patient would be instructed to stop treatment); dose interruptions were allowed for a maximum of 28 days for recovery.^45,54

STARTRK-2 Study

In STARTRK-2, entrectinib is administered at a dose of 600 mg orally as capsules on a continuous daily dosing regimen in 28-day cycles. Doses can be reduced by 2 dose levels (400 mg and 200 mg) to manage AEs if these are considered related to entrectinib, or doses can be resumed at the initial dose if AEs are considered unrelated to entrectinib (and treatment is interrupted until the AE stabilizes). Dose escalation to 800 mg once daily is allowed for patients with CNS disease if they have been on treatment for at least 2 cycles with a best response of stable disease and without grade 2 or greater AEs.⁴⁵ Treatment is continued until progression, patient withdrawal, or the occurrence of unacceptable toxicity.⁵⁴

Outcomes

A list of efficacy end points identified in the CADTH review protocol that were assessed in the clinical trials included in this review is provided in Table 12. These end points are further summarized here. A detailed discussion and critical appraisal of the outcome measures are provided in Appendix 3.

Table 12: Summary of Outcomes of Interest Identified in the CADTH Review Protocol

BOR = best overall response; CBR = clinical benefit rate; DLT = dose-limiting toxicity; DOR = duration of response; mCRC = metastatic colorectal cancer; MTD = maximum tolerated dose; NA = not applicable; NSCLC = non–small cell lung carcinoma; ORR = overall response rate; OS = overall survival; PD = pharmacodynamic; PFS = progression-free survival; PK = pharmacokinetic; QLQ-C30 = Quality of Life Questionnaire Core 30; QLQ-CR29 = Quality of Life Questionnaire Colorectal Cancer 29; QLQ-LC13 = Quality of Life Questionnaire Lung Cancer 13; RP2D = recommended phase II dose; TTR = time to tumour response.

Source: Clinical Study Reports and Common Technical Document, Section 2.7.3.^47-49,61

Tumour Response Assessment

Tumour responses were assessed using CT or MRI by investigator (local) assessment and by BICR and evaluated using RECIST 1.1. Screening assessments were performed within 30 days before the first administration of entrectinib, and on-treatment tumour assessments were performed at the end of every odd cycle (starting with cycle 1) or when clinical deterioration was observed, and at end of treatment (if not done in the previous 4 weeks). Tumour assessments could be performed outside of protocol-defined time points at the discretion of the investigator. For patients who experienced a CR or PR, response confirmation was performed no fewer than 4 weeks from when response criteria were first met. Tumour response was reassessed at the time of study drug continuation unless a tumour assessment had been performed within the previous 4 weeks. BICR assessment of tumour scans was conducted prospectively for patients enrolled in STARTRK-2 and retrospectively for patients in ALKA or STARTRK-1.^61,62

Figure 5: Dose Modifications for Entrectinib-Related Adverse Events

CNS = central nervous system; G = grade of adverse event based on NCI CTCAE v4.0; NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events.

Source: Clinical Study Report.⁴⁹

Objective Response Rate

ORR was defined as the proportion of patients with confirmed CR or PR. A confirmed response is a response that persists on repeat imaging greater than or equal to 4 weeks after the initial documentation of the response. Non-responders included:

• patients without a confirmed objective response

• patients without a post-baseline tumour assessment

• patients who received at least 1 dose of entrectinib and discontinued for any reason before undergoing 1 post-baseline response evaluation.⁶²

Duration of Response

DOR (in months) is calculated only for responders (as defined previously). It is measured from the date of first objective response (CR or PR) to the first documentation of radiographic disease progression or the date of death due to any cause, whichever is earlier. For patients without disease progression or death, DOR was censored at the last tumour assessment date.⁶²

Best Overall Response

BOR was the best radiologic overall response recorded from the start of the study treatment until disease progression and was based on RECIST 1.1. A BOR status of CR or PR required confirmation no earlier than 4 weeks from the first response. Stable disease can be assigned only after a patient meets stable disease criteria for at least 5 weeks (i.e., ≥ 35 days) following the first dose of the study treatment. Otherwise, the best response will not be evaluable. Other cases of a best response that are not evaluable include no post-baseline scans available and missing subsets of scans at all time points. Patients with only non-target lesions can be assessed only as CR, non-CR/non-PD, PD, or not evaluable. All other determinations of BOR are specified in the RECIST 1.1 guidelines.⁶²

Clinical Benefit Rate

CBR is the proportion of patients meeting 1 of the following criteria: confirmed CR or confirmed PR; stable disease for no fewer than 6 months following the start of entrectinib. Patients without a post-baseline tumour assessment or patients who received at least 1 dose of entrectinib and discontinue for any reason before undergoing 1 post-baseline response evaluation were counted as not achieving clinical benefit.⁶²

Progression-Free Survival

PFS was defined as time (months) from first dose of entrectinib to first documentation of radiographic disease progression or death due to any cause. PFS data for patients without progression or death were censored on the date of the last tumour assessment (or, if no tumour assessment was performed after the baseline visit, at the date of first dose of entrectinib).⁶²

Time to CNS Progression

Time to CNS progression was defined as time (months) from first dose of entrectinib to first documentation of radiographic CNS disease progression or death due to any cause. Radiographic CNS disease progression is defined as an occurrence of a new CNS lesion or progression in any CNS lesion per RECIST 1.1 criteria. Censoring rules similar to those defined previously were applied: patients without radiographic CNS progression or death were censored on the date of the last tumour assessment. (Note: patients without CNS lesions present at baseline, per investigator assessment, were not required to have scheduled brain scans every 8 weeks.)

Overall Survival

OS was defined as the time (months) from the first dose of entrectinib to the date of death due to any cause. Patients who were alive at the time of the analysis were censored on the last known date that they were alive. In addition, the following censoring rules apply:

• Patients with no post-baseline information were censored on the date of first dose of entrectinib.

• Patients who were lost to follow-up or withdrew consent for further follow-up were censored on the last known date on which they were alive.⁶²

Intracranial Objective Response Rate

Selecting only CNS lesion(s) (target, non-target, or both, as determined by BICR) for each patient, the RECIST 1.1 algorithms for time point response and BOR assessment were used to determine intracranial response. Patients with confirmed CR or confirmed PR in the CNS lesion(s) were referred to as intracranial responders. A confirmed intracranial response is a CNS response that persists on repeat imaging greater than or equal to 4 weeks after initial documentation of CNS response. This analysis was performed for patients presenting with measurable CNS lesions at baseline as well as for patients with only non-measurable CNS lesions at baseline.⁶²

Intracranial Duration of Response

IC-DOR was calculated only for intracranial responders and is measured from the date of first intracranial response to first documentation of radiographic CNS disease progression or date of death due to any cause, whichever is earlier. For patients without CNS disease progression who have not died within 30 days of the last dose of study treatment, IC-DOR was censored at the last tumour assessment date before any date of subsequent anti-cancer therapy, including surgery or radiotherapy to the brain.⁶²

Intracranial Progression-Free Survival

IC-PFS was defined as the time (months) from the first dose of entrectinib to the first documentation of radiographic CNS disease progression or death due to any cause. Radiographic CNS disease progression is defined as an occurrence of a new CNS lesion or progression in any CNS lesion per RECIST 1.1 criteria. Similar censoring rules, as defined previously in this review, were applied: patients without radiographic CNS progression or death were censored on the date of the last tumour assessment.⁶²

Safety Analyses

Safety analyses were performed on the safety population analysis sets, as previously described. These were performed separately for patients with and without CNS disease at baseline. Summary statistics on AEs, treatment-emergent AEs, serious AEs, dose modifications (reductions and interruptions), discontinuations due to AEs, and deaths were reported.⁶³

Health-Related Quality of Life

Data on patient-reported HRQoL and health status were collected in the STARTRK-2 trial through self-administered questionnaires that included the EORTC QLQ-C30, the EORTC QLQ-LC13, and the EORTC QLQ-CR29.^45,64 HRQoL assessments were administered before the first dose of entrectinib at cycle 1 (day 1) and for each subsequent cycle (day 1), as well as at the end of treatment. The EORTC QLQ-C30 is a validated questionnaire that comprises 30 questions to assess global health status (GHS), functioning, and symptoms using multi-item and single-item measures.⁴⁵ Each domain and item of the QLQ-C30 was linear-transformed to standardize the raw score to a range from 0 to 100. A clinically meaningful change from baseline was defined as an improvement or worsening of greater than or equal to 10 points. A higher score on the functional scales represents a higher and/or healthy level of functioning; similarly, a higher score for GHS represents higher HRQoL. Conversely, a higher score on symptom scales represents higher severity of the symptom. The average scores and mean changes from baseline for each item in the QLQ-C30 were presented in tabular and graphical format.⁴⁵

Statistical Analysis

Clinical Cut-Off Dates

As shown in Table 13, the sponsor conducted a series of analyses with longer-term follow-ups and increasing sample sizes (largely through the accrual of additional patients in the ongoing STARTRK-2 trial).

Table 13: Integrated Analyses for Entrectinib for Adults With NTRK Fusion Tumours

CCOD = clinical cut-off date; ECOD = enrolment cut-off date; EMA = European Medicines Agency; NTRK = neurotrophic tyrosine receptor kinase.

Source: Sponsor’s Clinical Summary.⁵⁹

Power Calculation

For the integrated analysis, a proportion of responding patients that exceeded 30% was considered to be clinically meaningful; thus, assuming a true ORR of 60%, a sample size of 56 patients was required to yield a 95% CI with plus or minus 14% precision that would exclude a lower limit of 30%.^61,62 Based on a summary of treatment options for common tumours that harbour NTRK fusions (including salivary gland cancer, secretory breast cancer, sarcoma, thyroid cancer, CRC, lung cancer, and glioblastoma), it was determined that expected rates of response to later lines of treatment in the refractory setting for metastatic and locally advanced unresectable solid tumours are typically less than 30%, and a median DOR is generally less than 10 months across available approved drugs.

Statistical Analysis

The primary efficacy outcomes were ORR and DOR, as per the BICR assessment. Secondary outcomes included CBR, PFS, time to CNS progression, and OS. Additional secondary outcomes focused on patients with CNS metastases at baseline and included IC-ORR, IC-DOR, and IC-PFS.

BICR-assessed ORR, CBR, and IC-ORR were presented as an efficacy summary (number and proportion of patients with confirmed CR or PR) and corresponding 2-sided 95% Clopper-Pearson exact CIs.⁴⁵ For time-to-event end points, which included DOR, PFS, OS, IC-DOR, and IC-PFS, the median, 25th and 75th percentiles were presented using the Kaplan–Meier method, and 2-sided 95% CIs were calculated using the Brookmeyer and Crowley (1982) and Klein and Moeschberger (1997) methods. For DOR and PFS, landmark analyses at 6 months, 9 months, and 12 months with corresponding 95% CIs were also calculated using the Kalbfleisch and Prentice method (1980).

Formal statistical significance testing was not performed; thus, no P values were reported. Point estimates with 95% CIs were reported to estimate the magnitude of treatment effect. The sponsor reported that no statistical adjustments for multiplicity were made due to the rarity of the patient population and expectation of significant clinical benefit; and no statistical adjustments were made to account for subgroup effects associated with the pooling of data in the analysis.^61,62 Pre-specified sensitivity analyses to evaluate the robustness of therapeutic efficacy included ORR and DOR for the enrolled population (i.e., the analyses were not limited to patients who were NTRK fusion-gene positive), as well as ORR and DOR, including the NTRK efficacy non-evaluable analysis set.

Subgroup Analyses

Subgroup analyses for BICR-assessed ORR by sex, age group, ECOG PS, any prior systemic therapy, number of prior systemic therapies, and tumour histology were pre-specified; graphic displays of efficacy end points (waterfall and swimmer plots) were provided to depict each patient’s best tumour response and time on study, including time to first objective response and DOR. Additional subgroups were identified for analyses, but were not reported.

Analysis Populations

The analysis sets used in the integrated evaluations efficacy and safety are summarized in Table 15.

Table 14: Statistical Analyses of Efficacy End Points

CBR = clinical benefit rate; CI = confidence interval; DOR = duration of response; ECOG PS = Eastern Cooperative Oncology Group Performance Status; IC = intracranial; NTRK = neurotrophic tyrosine receptor kinase; ORR = overall response rate; OS = overall survival; PFS = progression-free survival.

Source: Statistical Analysis Plan.⁶²

Table 15: Analysis Sets in the Integrated Evaluations of Efficacy and Safety

BIRC = blinded independent central review; CNS = central nervous system; NTRK = neurotrophic tyrosine receptor kinase; RECIST 1.1 = Response Evaluation Criteria in Solid Tumours Version 1.1; TRK = tropomyosin receptor kinase.

Source: Statistical Analysis Plan.⁶²

Results

Patient Disposition

Table 16 provides a summary of the patient disposition for those included in the NTRK efficacy-evaluable population (N = 121). ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Eighty-five patients (70.2%) discontinued treatment with entrectinib. Disease progression (56 out of 85; 65.9%) and AEs (17 out of 85; 20.0%) were the most frequently cited reasons.

Exposure to Study Treatments

Treatment with Entrectinib

Exposure to entrectinib was reported only for the NTRK safety-evaluable population (Table 17). The mean and median durations of therapy were 11.54 months (SD = 11.49) and 8.34 months (interquartile range = 2.73 to 17.25), respectively.¹¹

Table 16: Patient Disposition (NTRK Efficacy-Evaluable Analysis Set; August 2020 CCOD)

AE = adverse event; CCOD = clinical cut-off date; NTRK = neurotrophic tyrosine receptor kinase.

Source: Sponsor-provided additional information.⁶⁵

Table 17: Summary of Exposure (NTRK Safety-Evaluable Population; August 2020 CCOD)

CCOD = clinical cut-off date; IQR = interquartile range; NE = not estimable; NTRK = neurotrophic tyrosine receptor kinase; Std = standard deviation.

Source: Supplemental Efficacy Results (clinical cut-off date: August 31, 2020).¹¹

Concomitant Medications

Across all 3 trials included in the efficacy analysis, seizure prophylaxis and non–enzyme-inducing anti‐epileptic drugs were allowed during the study for patients with controlled asymptomatic CNS involvement. Prophylactic use of granulocyte colony-stimulating factor or erythropoietin could be initiated according to American Society of Clinical Oncology guidelines in patients who were having difficulty with severe neutropenia or anemia. Palliative radiotherapy was allowed to specific sites if medically necessary.^60,66-68 In STARTRK-1 and STARTRK-2, it was recommended that moderate to strong inhibitors and inducers of cytochrome P450 CYP3A be used with caution, as well as cytochrome P450 substrates.^60,68

Subsequent Medications

Following BICR assessment of PD, 6 patients (11.1%) received subsequent anti-cancer treatment, most frequently with systemic drugs (n = 5; 9.3%) and 1 patient received a radiopharmaceutical treatment (Yttrium). Systemic anti-cancer drugs included doxorubicin (n = 2), bevacizumab (n = 1), everolimus (n = 1), irinotecan (n = 1), nivolumab (n = 1), and others. One additional patient received doxorubicin after discontinuation of entrectinib but before PD.⁶⁹ A total of 18 patients (33.3%) continued treatment with entrectinib beyond the BICR assessment of PD.⁷⁰

Efficacy

Only those efficacy outcomes and analyses of subgroups identified in the review protocol are reported in this section.

Table 18: Summary of Efficacy End Points (NTRK Efficacy-Evaluable Analysis Set; August 2020 CCOD)

CCOD = clinical cut-off date; CI = confidence interval; CNS = central nervous system; CR = complete response; DOR = duration of response; NE = not estimable; NR = not reported; NTRK = neurotrophic tyrosine receptor kinase; ORR = overall response rate; OS = overall survival; PD = progressive disease; PFS = progression-free survival; PR = partial response; SD = stable disease; TTR = time to response.

Source: Supplemental Efficacy Results (clinical cut-off date: August 31, 2020).¹¹

Objective Response Rate

A summary of the primary and secondary efficacy analyses is shown in Table 18. The ORR by BICR was 61.2% (95% CI, 51.87 to 69.88), which met the sponsor’s predefined threshold for a clinically meaningful ORR, given that the lower limit of the 95% CI excluded 30% (in accordance with the sponsor’s statistical analysis plan).⁶² A total of 19 patients (17.7%) demonstrated a BOR of CR and 55 patients (45.5%) demonstrated a PR.⁵⁰ There were 13 patients (10.7%) who had stable disease and 13 patients (10.7%) who had PD. There were 6 patients (5.0%) with non-CR or non-PD (i.e., patients with non-target lesions as assessed by BICR, but measurable disease at baseline as assessed by the investigator) and 15 patients (12.4%) who were missing or non-evaluable. The median times to objective response were 1.0 month (95% CI, 0.9 to 1.0) for the overall population and 1.3 months (95% CI, 0.9 to 2.8) for patients with CNS metastases at baseline.

As shown in Table 19, the point estimates for ORR ranged widely across tumour types, and the CIs reflected a high degree of uncertainty for many tumour types. In light of the small sample sizes and the wide CIs, no meaningful conclusions can be drawn about the efficacy of entrectinib in different types of solid tumours. As noted in CADTH’s review of larotrectinib for NTRK-positive tumours, it is not methodologically meaningful to evaluate the ORR (and by extension, the effectiveness) of TRK inhibitors on different cancer types separately. At least 1 patient demonstrated a response to treatment in each of the tumour types, with the exception of neuroblastoma (n = 1). The ORRs for the larger subgroup populations were generally consistent with the results for the overall population; however, a higher proportion of patients with salivary MASC tumours experienced tumour response (20 patients out of 24 patients [83.3%], 95% CI, 62.6 to 95.3), while a lower proportion of those with colorectal carcinoma experienced tumour response (2 patients out of 10 patients [20%], 95% CI, 2.5 to 55.6). A waterfall plot for the baseline change in tumour sum for all patients is illustrated in Figure 6.

As shown in Table 7, the drug programs that participate in the CADTH reimbursement review process noted that efficacy data based on prior lines of systemic cancer therapy are of particular interest from an implementation perspective. Upon request from CADTH, the sponsor provided subgroup analyses from the updated efficacy dataset (N = 121) based on prior exposure to systemic cancer therapies. The ORR for patients who had not received any prior systemic cancer therapies was 81.1% (95% CI, 65.8 to 90.5); for those who had received 1 prior systemic therapy, it was 57.1% (95% CI, 40.9, 72.0); for 2 prior systemic therapies, 57.7% (95% CI, 38.9, 74.5); for 3 prior systemic therapies, 50.0% (95% CI, 25.4, 74.6); and for 4 prior systemic therapies, it was 42.9% (95% CI, 5.8, 75.0) (summarized in Table 19).³² The sponsor provided a further breakdown, with ORRs separated by tumour type and number of prior systemic therapies (Table 38 on page 125).

Intracranial Objective Response Rate

The intracranial efficacy of entrectinib in patients with baseline CNS metastases is highlighted in Table 20. The BICR-assessed IC-ORRs were 52.6% (95% CI, 28.86 to 75.55) and 63.6% (95% CI, 30.8 to 89.1) for all patients with baseline CNS disease (10 patients out of 19 patients responded) and those with measurable disease at baseline (7 patients out of 11 patients responded), respectively. The sponsor reported the results of a subgroup analysis based on prior brain radiotherapy, and the ORRs were similar between those who had no prior brain radiotherapy or had brain radiotherapy greater than or equal to 6 months before the initiation of treatment (55.6%; 95% CI, 21.2 to 86.3 [n = 9]) versus those who had brain radiotherapy within 6 months of initiating treatment with entrectinib (50.0%; 95% CI, 18.7 to 81.3 [n = 10]).

Table 19: Subgroup Analyses (NTRK Efficacy-Evaluable Analysis Set)

CCOD = clinical cut-off date; CI = confidence interval; CNS = central nervous system; CUP = carcinoma of unknown primary; DOR = duration of response; ECOG PS = Eastern Cooperative Oncology Group Performance Status; GI = gastrointestinal; MASC = mammary analogue secretory carcinoma; NA = not applicable; NE = not estimable; NR = not reported; NSCLC = non–small cell lung carcinoma; NTRK = neurotrophic tyrosine receptor kinase; ORR = objective response rate; OS = overall survival; PFS = progression-free survival.

^aThe subgroup analyses for the October 31, 2018 CCOD included the following: sarcoma (n = 16); NSCLC (n = 1); salivary (MASC) (n = 1); thyroid cancer (n = 7); colorectal carcinoma (n = 7); breast cancer (n = 6); neuroendocrine tumours (n = 4); pancreatic cancer (n = 3); gynecologic (n = 2); cholangiocarcinoma (n = 1); upper GI tract adenocarcinoma (n = 1); neuroblastoma (n = 1).

Source: Demetri et al. (2022)⁵¹; drug reimbursement review sponsor submission⁵⁰; sponsor-provided additional information.³²

Figure 6: Waterfall Plot of Best Percentage Change From Baseline in Tumour Sum as per BICR Assessment (NTRK Efficacy-Evaluable Analysis Set; CCOD: August 2020; N = 121)

BICR = blinded independent central review; CCOD = clinical cut-off date; CNS = central nervous system; CR = complete response; CRC = colorectal cancer; CUP = carcinoma of unknown primary; GI = gastrointestinal; MASC = mammary analogue secretory carcinoma; ND = not determined; NE = not estimable; NSCLC = non–small cell lung cancer; NTRK = neurotrophic tyrosine receptor kinase; PD = progressive disease; PR = partial response; SD = stable disease; SLD = sum of the longest diameter.

Source: Drug reimbursement review sponsor submission.⁵⁰

Table 20: Intracranial Efficacy (BICR-Assessed) in Patients With NTRK Fusion–Positive Solid Tumours and BICR-Assessed CNS Metastases at Baseline

BICR = blinded independent central review; CI = confidence interval; CNS = central nervous system; CR = complete response; NE = not estimable; NTRK = neurotrophic tyrosine receptor kinase; PD = progressive disease; PR = partial response; SD = stable disease.

Source: Supplemental Efficacy Results (clinical cut-off date: August 31, 2020).¹¹

Figure 7: Kaplan–Meier Plots for DOR and Intracranial DOR (CCOD: August 2020)

BICR = blinded independent central review; CCOD = clinical cut-off date; CI = confidence interval; DOR = duration of response; No. = number.

Source: Supplemental Efficacy Results (clinical cut-off date: August 31, 2020).¹¹

Duration of Response

The DOR among responders was 20.0 months (95% CI, 13.0 to 38.2) at the August 31, 2020 data cut-off. For the patients who demonstrated a CR or PR with entrectinib, responses of at least 6 months, 12 months, 18 months, 24 months, 30 months, and 36 months were reported for 58 patients (78%), 46 patients (62%), 32 patients (43%), 20 patients (27%), 10 patients (14%), and 4 patients (5%). The event-free probabilities were 0.82 (95% CI, 0.73 to 0.91) at 6 months, 0.66 (95% CI, 0.55 to 0.77) at 12 months, 0.49 (95% CI, 0.37 to 0.61) at 24 months, and 0.39 (95% CI, 0.24 to 0.53) at 36 months.

Intracranial Duration of Response

The IC-DORs among responders were 17.2 months (95% CI, 7.4 to NE) and 22.1 months (95% CI, 7.4 to NE) for all patients with baseline CNS disease and those with measurable disease at baseline, respectively.

Figure 8: Kaplan–Meier Plots for DOR and Intracranial DOR (CCOD: August 2020)

BICR = blinded independent central review; CCOD = clinical cut-off date; CI = confidence interval; DOR = duration of response; NE = not estimable; No. = number.

Source: Supplemental Efficacy Results (clinical cut-off date: August 31, 2020).¹¹

Table 21: DOR, PFS, and OS for Overall Efficacy Population and Patients With Baseline CNS Metastases

CI = confidence interval; CNS = central nervous system; DOR = duration of response; NA = not applicable; NE = not estimable; OS = overall survival; PFS = progression-free survival.

Source: Supplemental Efficacy Results (clinical cut-off date: August 31, 2020).¹¹

Figure 9: Kaplan–Meier Plots for Intracranial Progression-Free Survival (CCOD: August 2020)

BICR = blinded independent central review; CCOD = clinical cut-off date; CI = confidence interval; No. = number.

Source: Supplemental Efficacy Results (clinical cut-off date: August 31, 2020).¹¹

Overall Survival

A total of 49 patients (40.5%) had died by the time of the August 2020 CCOD. The median OS was 33.8 months (95% CI, 23.4 to 46.4). A total of 10 patients (50.2%) with baseline CNS metastases had died by the time of the August 2020 CCOD. The median OS was 19.9 months (95% CI, 7.9 to NE). The OS event-free rates from 6 months through 48 months are summarized in Table 21. Updated subgroup analyses for OS were not reported for the August 31, 2020 CCOD⁷²; therefore, the results for the October 2018 CCOD are reported in Table 19.

The EORTC QLQ-C30

Results for the QLQ-C30 from August 2020 (N = 110) are summarized in Table 22. Study STARTRK-2 evaluated patient-reported outcomes (PROs) of the treatment impact on functioning and HRQoL based on the QLQ-C30. A change from baseline of greater than or equal to 10 points on a scale of 1 to 100 was considered clinically meaningful by the sponsor, with higher scores reflecting better functioning and HRQoL. The sponsor reported that cycle 10 was selected as the last time point providing representative information, noting that by then, less than 50% of the PRO evaluable population was still in the STARTRK-2 study. At baseline, patients reported moderate to high baseline values on HRQoL and functioning scales. Mean scores at baseline were 65.4 (SD = 23.3) for GHS; 66.8 (SD = 33.9) for role functioning; 75.9 (SD = 25.2) for physical functioning; and 82.9 (SD = 19.6) for cognitive functioning. Based on the October 31, 2018 CCOD, the product monograph reports that from cycle 2 to cycle 10, 20% to 31% of patients met the criteria for a clinically meaningful improvement in GHS, while 25% to 41% of patients met the criteria for a clinically meaningful worsening. Across the functioning scales, 19% to 48% of patients met the criteria for a clinically meaningful improvement in role and physical functioning, while 33 to 46% of patients met the criteria for a clinically meaningful worsening in cognitive functioning.

Figure 10: Kaplan–Meier Plots for OS for Overall Population and Patients with Baseline CNS Metastases (CCOD: August 2020)

CCOD = clinical cut-off date; CI = confidence interval; CNS = central nervous system; NE = not estimable; No. = number; OS = overall survival.

Source: Supplemental Efficacy Results (clinical cut-off date: August 31, 2020).¹¹

The EORTC QLQ-C29

Updated results for the EORTC QLQ-C29 were not available for the updated August 2020 CCOD; therefore, the results from the October 2018 CCOD are summarized in Table 22. The ability to interpret changes from baseline for these questionnaires is limited by the small number of patients who completed questionnaires initially and the rate of patient drop-off at later cycles. The sponsor reported that among the 7 mCRC patients, baseline results for the QLQ-CR29 showed low abdominal symptom burden (abdominal pain [mean = 27.8], bloating [mean = 33.3], and stool frequency [mean = 13.9]). The scores were variable throughout the study and followed no trend, but remained low overall at most study visits throughout the study.⁵⁹

The EORTC QLQ-LC13

Updated results for the EORTC QLQ-LC13 were not available for the updated August 2020 CCOD; therefore, the results from the October 2018 CCOD are summarized in Table 22. The ability to interpret changes from baseline for these questionnaires is limited by the small number of patients who completed questionnaires initially and the rate of patient drop-off at later cycles. The sponsor reported that patients with NSCLC (n = 12) showed moderate lung symptom burden at baseline (chest pain [mean = 5.6], coughing [mean = 38.9], and dyspnea [mean score = 26.9]) and at most study visits throughout the study.⁵⁹

Table 22: EORTC QLQ-C30, QLQ-C29, and QLQ-LC13 (STARTRK-2)

CCOD = clinical cut-off date; EORTC = European Organisation for Research and Treatment of Cancer; IQR = interquartile range; QLQ-C30 = Quality of Life Questionnaire Core 30; QLQ-CR29 = Quality of Life Questionnaire Colorectal Cancer 29; QLQ-LC13 = Quality of Life Questionnaire Lung Cancer 13; QoL = quality of life; Std = standard deviation.

Source: Supplementary Results Report (clinical cut-off date: 31 October 2018).⁵⁰

Harms

Table 23 provides a summary of AEs reported in the safety-evaluable population (N = 193). Nearly all patients who were NTRK fusion–positive experienced at least 1 AE (99.5%); ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||¹¹

Adverse events

Table 24 provides a summary of AEs reported in the safety-evaluable population (N = 193).

Serious Adverse Events

Table 25 provides a detailed summary of the ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.

Withdrawals Due to Adverse Events

Table 26 provides a detailed summary of withdrawals due to AEs that were reported for adult patients in the NTRK safety-evaluable population for the August 31, 2020 CCOD. The overall proportion of patients who withdrew from the study treatment as a result of AEs was |||||||.

Mortality

Deaths in the NTRK safety-evaluable population from the October 31, 2018 CCOD (N = 113) are summarized in Table 27. ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||⁷³||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||⁴⁶

Adverse Events of Special Interest

AEs of special interest identified by the sponsor included adverse CNS events, weight changes, congestive heart failure, increases in blood creatinine, QTc prolongation, vision disorders, hematologic events, hepatotoxicity, and pneumonitis events. In addition to these, Health Canada noted that skeletal fractures and hyperuricemia were of special interest in its review of entrectinib. Table 28 provides a summary of the AEs of special interest based on a pooled dataset of 355 patients.

Table 23: Summary of Adverse Events (NTRK Safety-Evaluable Population; August 2020 CCOD; N = 193)

AE = adverse event; CCOD = clinical cut-off date; NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; NTRK = neurotrophic tyrosine receptor kinase; SAE = serious adverse event.

Source: Supplemental Efficacy Results (clinical cut-off date: August 31, 2020).¹¹

Table 24: Treatment-Emergent Adverse Events Reported in ≥ 10% of Patients or With ≥ 1 Grade 3 or Grade 4 Event (NTRK Safety-Evaluable Population; August 2020 CCOD)