Table 2, Responses to Questions From the Drug Programs - Entrectinib (Rozlytrek)

Implementation issues	Response
Relevant comparators
The pivotal entrectinib studies included patients with CNS metastases that were previously treated and/or asymptomatic. For patients with NTRK fusion–positive solid tumours and CNS metastases, is there a preferred NTRK inhibitor (e.g., larotrectinib vs. entrectinib)?	pERC noted that the clinical experts consulted by CADTH stated that, based on the limited available data, entrectinib may have more CNS penetration and promising intracranial activity for those patients with brain metastases. However, additional data and longer-term follow-up would be required to establish any conclusions regarding the comparative effectiveness of entrectinib and larotrectinib for patients with CNS metastases.
How do the efficacy and safety of entrectinib compare to best supportive care for patients with unresectable locally advanced or metastatic solid tumours with confirmed NTRK fusion–positive disease who have exhausted all other therapies?	pERC agreed with the clinical experts that entrectinib-treated adults with NTRK gene fusion–positive tumours had a clinically meaningful response rate that would not be expected in patients treated with best supportive care, although there is a lack of comparative efficacy data. Entrectinib is associated with manageable toxicities. Input from clinician groups and the clinical experts consulted by CADTH noted that entrectinib should be considered early during 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 as opposed to the NTRK fusion may be less effective and potentially more toxic than NTRK-targeting therapies, particularly for tumours for which the alternative is chemotherapy.
How do the efficacy and safety of entrectinib compare to existing systemic therapies used for treatment of unresectable locally advanced or metastatic solid tumours with confirmed NTRK fusion–positive disease in any line of therapy?	pERC noted that the clinical experts consulted by CADTH stated that entrectinib would be expected to act in a manner similar to other current histology-specific targeted agents (such as ALK or EGFR). This is based upon data that demonstrates that patients with NTRK-positive cancers do not have better outcomes compared with patients without the mutation, the very high response rates observed with entrectinib and larotrectinib in the presence of an NTRK gene fusion, and clinical expert opinion and experience, recognizing that the ORR reported for entrectinib and larotrectinib surpass expected response rates with alternate systemic therapies in advanced diseases.
Considerations for initiation of therapy
Patients with an ECOG performance status of 2 or less were eligible for the pivotal trials. Should eligibility for treatment with entrectinib be limited to patients with ECOG performance status of 2 or less?	The clinical experts suggested that patients with a higher ECOG performance status could be eligible for treatment with entrectinib if the oncologist believes that tumour-related symptoms are driving the performance status. The rationale is based on the high rate of response, duration of the responses, median time to response (i.e., approximately 1 month), and favourable toxicity profile. pERC appreciates that there are factors, including tumour-related symptoms, that may drive the deterioration in the patient’s performance status; however, enrolment in the clinical trials for entrectinib was limited to patients with good performance status.
What is an appropriate definition for “no satisfactory treatment options” for unresectable locally advanced or metastatic solid tumours with confirmed NTRK fusion–positive disease?	pERC noted that the clinical experts consulted by CADTH stated 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 and others may have several alternatives). 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 funding request for entrectinib is for use in adults with extracranial solid tumours only. Pediatric patients were not included in the funding request nor in the Health Canada approval. Patients with primary CNS solid tumours were not included in the funding request. Is there evidence to inform the use of entrectinib in: pediatric patients with NTRK fusion–positive solid tumours? in NTRK fusion–positive primary CNS tumours?	pERC noted that the sponsor initially sought regulatory approval for an indication that would include use in pediatric patients as well as those with primary CNS tumours. Health Canada did not approve usage in pediatric patients, citing the negative benefit vs. risk profile of entrectinib in the pediatric population, or for use in patients with primary CNS tumours, citing the lack of sufficient efficacy data to support benefit in primary brain tumours.
Considerations for continuation or renewal of therapy
The STARTRK-2, STARTRK-1, and ALKA trials performed on-treatment tumour assessments via CT or MRI scans at the end of cycle 1 (4 weeks) and at the end of alternate cycles thereafter (i.e., every 8 weeks), or whenever a clinical deterioration was observed, and at end of treatment if not done in the previous 4 weeks. What are clinically appropriate modalities and frequencies to assess therapeutic response to entrectinib?	pERC agreed with the clinical experts consulted by CADTH who advised that, in terms of outcomes that are used to determine whether a patient is responding to treatment in clinical practice, the typical metrics of treatment efficacy include disease evaluation by cross-sectional imaging modalities (MRI, CT, PET/CT) to assess response by RECIST (for solid tumours) or RANO (for CNS tumours), symptom improvement, treatment tolerability, and time to progression. pERC also agreed with the clinical experts that treatment response is typically assessed every 3 months; once response is established or remission is achieved, this interval may be prolonged.
Considerations for discontinuation of therapy
The STARTRK-2, STARTRK-1, and ALKA trials permitted dose reductions due to toxicity (up to a maximum of 2 dose reductions) and treatment interruption of up to 28 days due to treatment-related adverse effects. Treatment was discontinued if symptom resolution did not occur. Are the treatment interruption and discontinuation parameters used in the STARKTR-2, STARKTR-1, and ALKA trials applicable to clinical practice?	pERC noted that the product monograph for entrectinib provides detailed recommendations for the management of adverse events that require temporary interruption, dose reduction, or discontinuation of treatment with entrectinib. The clinical experts consulted by CADTH indicated that this is a reasonable reflection of how patients would be managed in clinical practice.

Implementation issues

Response

Relevant comparators

The pivotal entrectinib studies included patients with CNS metastases that were previously treated and/or asymptomatic. For patients with NTRK fusion–positive solid tumours and CNS metastases, is there a preferred NTRK inhibitor (e.g., larotrectinib vs. entrectinib)?

pERC noted that the clinical experts consulted by CADTH stated that, based on the limited available data, entrectinib may have more CNS penetration and promising intracranial activity for those patients with brain metastases. However, additional data and longer-term follow-up would be required to establish any conclusions regarding the comparative effectiveness of entrectinib and larotrectinib for patients with CNS metastases.

How do the efficacy and safety of entrectinib compare to best supportive care for patients with unresectable locally advanced or metastatic solid tumours with confirmed NTRK fusion–positive disease who have exhausted all other therapies?

pERC agreed with the clinical experts that entrectinib-treated adults with NTRK gene fusion–positive tumours had a clinically meaningful response rate that would not be expected in patients treated with best supportive care, although there is a lack of comparative efficacy data. Entrectinib is associated with manageable toxicities. Input from clinician groups and the clinical experts consulted by CADTH noted that entrectinib should be considered early during 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 as opposed to the NTRK fusion may be less effective and potentially more toxic than NTRK-targeting therapies, particularly for tumours for which the alternative is chemotherapy.

How do the efficacy and safety of entrectinib compare to existing systemic therapies used for treatment of unresectable locally advanced or metastatic solid tumours with confirmed NTRK fusion–positive disease in any line of therapy?

pERC noted that the clinical experts consulted by CADTH stated that entrectinib would be expected to act in a manner similar to other current histology-specific targeted agents (such as ALK or EGFR). This is based upon data that demonstrates that patients with NTRK-positive cancers do not have better outcomes compared with patients without the mutation, the very high response rates observed with entrectinib and larotrectinib in the presence of an NTRK gene fusion, and clinical expert opinion and experience, recognizing that the ORR reported for entrectinib and larotrectinib surpass expected response rates with alternate systemic therapies in advanced diseases.

Considerations for initiation of therapy

Patients with an ECOG performance status of 2 or less were eligible for the pivotal trials. Should eligibility for treatment with entrectinib be limited to patients with ECOG performance status of 2 or less?

The clinical experts suggested that patients with a higher ECOG performance status could be eligible for treatment with entrectinib if the oncologist believes that tumour-related symptoms are driving the performance status. The rationale is based on the high rate of response, duration of the responses, median time to response (i.e., approximately 1 month), and favourable toxicity profile. pERC appreciates that there are factors, including tumour-related symptoms, that may drive the deterioration in the patient’s performance status; however, enrolment in the clinical trials for entrectinib was limited to patients with good performance status.

What is an appropriate definition for “no satisfactory treatment options” for unresectable locally advanced or metastatic solid tumours with confirmed NTRK fusion–positive disease?

pERC noted that the clinical experts consulted by CADTH stated 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 and others may have several alternatives). 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 funding request for entrectinib is for use in adults with extracranial solid tumours only. Pediatric patients were not included in the funding request nor in the Health Canada approval. Patients with primary CNS solid tumours were not included in the funding request. Is there evidence to inform the use of entrectinib in:

pediatric patients with NTRK fusion–positive solid tumours?
in NTRK fusion–positive primary CNS tumours?

pERC noted that the sponsor initially sought regulatory approval for an indication that would include use in pediatric patients as well as those with primary CNS tumours. Health Canada did not approve usage in pediatric patients, citing the negative benefit vs. risk profile of entrectinib in the pediatric population, or for use in patients with primary CNS tumours, citing the lack of sufficient efficacy data to support benefit in primary brain tumours.

Considerations for continuation or renewal of therapy

The STARTRK-2, STARTRK-1, and ALKA trials performed on-treatment tumour assessments via CT or MRI scans at the end of cycle 1 (4 weeks) and at the end of alternate cycles thereafter (i.e., every 8 weeks), or whenever a clinical deterioration was observed, and at end of treatment if not done in the previous 4 weeks. What are clinically appropriate modalities and frequencies to assess therapeutic response to entrectinib?

pERC agreed with the clinical experts consulted by CADTH who advised that, in terms of outcomes that are used to determine whether a patient is responding to treatment in clinical practice, the typical metrics of treatment efficacy include disease evaluation by cross-sectional imaging modalities (MRI, CT, PET/CT) to assess response by RECIST (for solid tumours) or RANO (for CNS tumours), symptom improvement, treatment tolerability, and time to progression. pERC also agreed with the clinical experts that treatment response is typically assessed every 3 months; once response is established or remission is achieved, this interval may be prolonged.

Considerations for discontinuation of therapy

The STARTRK-2, STARTRK-1, and ALKA trials permitted dose reductions due to toxicity (up to a maximum of 2 dose reductions) and treatment interruption of up to 28 days due to treatment-related adverse effects. Treatment was discontinued if symptom resolution did not occur. Are the treatment interruption and discontinuation parameters used in the STARKTR-2, STARKTR-1, and ALKA trials applicable to clinical practice?

pERC noted that the product monograph for entrectinib provides detailed recommendations for the management of adverse events that require temporary interruption, dose reduction, or discontinuation of treatment with entrectinib. The clinical experts consulted by CADTH indicated that this is a reasonable reflection of how patients would be managed in clinical practice.

From: Entrectinib (Rozlytrek)

Entrectinib (Rozlytrek): CADTH Reimbursement Recommendation: Indication: For the treatment of adults with unresectable locally advanced or metastatic extracranial solid tumours, including brain metastases, that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion without a known acquired resistance mutation and with no satisfactory treatment options [Internet].

Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2022 Nov.

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Table 2Responses to Questions From the Drug Programs