Summary Basis of Decision for Gavreto

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.


Product type:

Drug

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Gavreto is located below.

Recent Activity for Gavreto

SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.

Summary Basis of Decision (SBD) for Gavreto

Date SBD issued: 2021-11-26

The following information relates to the new drug submission for Gavreto.

Pralsetinib

Drug Identification Number (DIN):

  • DIN 02517590 - 100 mg pralsetinib, capsule, oral administration

Hoffmann‑La Roche Ltd.

New Drug Submission Control Number: 243731

On June 30, 2021, Health Canada issued a Notice of Compliance under the Notice of Compliance with Conditions (NOC/c) Guidance to Hoffmann‑La Roche Limited for the drug product Gavreto. The product was authorized under the NOC/c Guidance on the basis of the promising nature of the clinical evidence, and the need for further follow‑up to confirm the clinical benefit. Patients should be advised of the fact that the market authorization was issued with conditions.

The market authorization was based on quality (chemistry and manufacturing), non‑clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada’s review, the benefit‑harm-uncertainty profile of Gavreto is favourable for the treatment of adult patients with rearranged during transfection (RET) fusion‑positive locally advanced unresectable or metastatic non‑small cell lung cancer (NSCLC).

A validated test is required prior to treatment to identify RET fusion‑positive status. Efficacy in patients with RET fusion‑positive NSCLC was based on objective response rate and duration of response in a single‑arm study.

1 What was approved?

Gavreto, a protein kinase inhibitor, was authorized for the treatment of adult patients with rearranged during transfection (RET) fusion‑positive locally advanced unresectable or metastatic non‑small cell lung cancer (NSCLC).

A validated test is required prior to treatment to identify RET fusion‑positive status. Efficacy in patients with RET fusion‑positive NSCLC was based on objective response rate and duration of response in a single‑arm study.

At the time of authorization, no data regarding the use of Gavreto in pediatric patients (less than 18 years of age) were available to Health Canada. Therefore, Health Canada has not authorized an indication for pediatric use.

In the pivotal efficacy and safety study (ARROW), 29.9% of the 438 patients who received the recommended dose of Gavreto (400 mg once daily), were 65 years or older. No overall differences were observed in pharmacokinetics or efficacy in these patients in comparison with younger patients. Patients 65 years of age and older were more likely to experience adverse events, serious adverse events, grade 3/4/5 adverse and serious adverse events, treatment interruptions, or treatment discontinuations.

Gavreto is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non‑medicinal ingredient, or component of the container.

Gavreto was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Gavreto (100 mg pralsetinib) is presented as a capsule. In addition to the medicinal ingredient, the capsule contains citric acid, FD&C blue #1 (Brilliant Blue FCF), hydroxypropyl methylcellulose (HPMC, hypromellose), magnesium stearate, microcrystalline cellulose (MCC), pharmaceutical grade printing ink, pregelatinized starch, sodium bicarbonate, and titanium dioxide.

For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Additional information may be found in the Gavreto Product Monograph, approved by Health Canada and available through the Drug Product Database.

2 Why was Gavreto approved?

Health Canada considers that the benefit-harm-uncertainty profile of Gavreto is favourable for the treatment of adult patients with rearranged during transfection (RET) fusion‑positive locally advanced unresectable or metastatic non‑small cell lung cancer (NSCLC).

Gavreto was authorized under the Notice of Compliance with Conditions (NOC/c) Guidance on the basis of the promising nature of the clinical evidence, and the need for further follow‑up to confirm the clinical benefit.

In Canada, there is a pronounced burden of disease related to lung cancer, and specifically to non‑small cell lung cancer (NSCLC). Approximately 80% to 85% of cases of lung cancer diagnosed in 2020 were cases of NSCLC. An estimated 1% to 2% of patients with NSCLC have gene fusions involving the rearranged during transfection (RET) gene (RET fusions). These RET fusions result in aberrant activation of the RET receptor tyrosine kinase pathway, and have been identified as disease‑driving oncogenes in NSCLC. Locally advanced unresectable or metastatic NSCLC are incurable diseases, and most patients have metastatic disease at the time of diagnosis.

At the time of authorization of Gavreto, there was limited availability in Canada of approved therapies specifically targeting RET fusion‑positive locally advanced unresectable or metastatic NSCLC. Until now, NSCLC has been treated as an oncogene‑negative condition, which results in a non‑targeted approach to therapy. Some multikinase inhibitors have RET inhibitory activity, but trials with NSCLC patients have not provided sufficiently vigorous results for these inhibitors to be utilized as early therapeutic options in RET fusion‑positive NSCLC. Additionally, some published studies have reported that immune checkpoint inhibitors appear less effective in RET fusion‑positive disease.

Pralsetinib, the medicinal ingredient in Gavreto, is a kinase inhibitor that targets RET fusions, including known disease‑driving fusion partners, and gatekeeper mutations associated with resistance to the multikinase inhibitors.

The clinical efficacy of Gavreto was demonstrated through interim results of the pivotal Phase II study, ARROW. Patients enrolled in this study had locally advanced unresectable or metastatic NSCLC with measurable disease assessed by the Response Evaluable Criteria in Solid Tumors (RECIST) version 1.1 (v1.1), and a RET fusion confirmed by a validated test. Patients previously treated with platinum‑based chemotherapy were placed in Cohort 1. Treatment‑naïve patients, all of whom were deemed not eligible for platinum‑based chemotherapy, were placed in Cohort 2. The dose for patients in both cohorts was 400 mg Gavreto once daily and continued until progression of disease or unacceptable toxicity.

The major efficacy outcome measures were the overall response rate (ORR) according to RECIST v1.1, and the duration of response (DOR) as evaluated by a blinded independent central review (BICR). In patients previously treated with platinum‑based chemotherapy (Cohort 1), the ORR was 57.5% (95% confidence interval [CI]: 46.4, 68.0), with a median DOR of 17.1 months (95% CI: 15.2, 17.1). In patients with treatment‑naïve RET fusion‑positive NSCLC (Cohort 2; not eligible for platinum‑based chemotherapy), the ORR was 70.4% (95% CI: 49.8, 86.2), with a median DOR of 9.0 months (95% CI: 6.3, not estimable).

These findings were generally consistent regardless of previous lines of therapy, which supports a line‑agnostic indication. An extrapolation from the metastatic stage (99% of patients) to the locally advanced unresectable stage was considered reasonable based on baseline disease characteristics of the population with advanced NSCLC and the current understanding of oncogene‑driven NSCLC.

The clinical safety of Gavreto was evaluated based on data from the pooled safety population of 438 patients enrolled in the pivotal Phase II study, ARROW. All patients in this population had solid tumours and were treated with 400 mg Gavreto once daily until progression of disease or unacceptable toxicity. The safety of Gavreto at a starting dose of 400 mg once daily was evaluated in a subset of 220 patients with locally advanced unresectable or metastatic NSCLC. These patients were treated for a median of 4.7 months (range: 0.1 to 20.3 months).

Treatment‑emergent adverse events (TEAEs) were reported in 99.1% of patients, and serious adverse reactions were reported in 34.1% of patients. Dose reductions due to adverse reactions were required in 32.7% of patients, and adverse reactions led to permanent discontinuation of treatment with Gavreto for 10.9% of patients. The most frequently reported adverse events and adverse reactions which led to these outcomes are listed in the Clinical Safety section.

A Serious Warnings and Precautions box in the Gavreto Product Monograph highlights the risks of interstitial lung disease/pneumonitis, hypertension, hepatotoxicity, and hemorrhage. Based on its mechanism of action and findings from animal studies, Gavreto may cause fetal harm when administered to pregnant women. Additionally, treatment with Gavreto may impair or slow wound healing as it has the ability to inhibit the vascular endothelial growth factor (VEGF) pathway through off‑target activity.

Fatal adverse reactions (Grade 5) occurred in 4.1% of patients in the pivotal study, including one fatal case of pneumonitis in the pooled safety population (438 patients) and one fatal case of hemorrhage. While metastatic disease can increase the risk of hemorrhage, there may be an increased risk of hemorrhage during treatment with Gavreto.

Overall, the safety profile of the pooled safety population (438 patients) was consistent with and supportive of that of the NSCLC‑specific population (220 patients), with the exception of patients 65 years of age and older. Patients in this age group were more likely to experience adverse events, serious adverse events, grade 3/4/5 adverse events or serious adverse events, treatment interruptions, or treatment discontinuations. Based on the review of the safety and efficacy information of the product, the benefit‑harm‑uncertainty profile of Gavreto was determined to be acceptable.

A Risk Management Plan (RMP) for Gavreto was submitted by Hoffmann-La Roche Limited to Health Canada. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product. At the time of authorization, there were no RMP-related issues that would preclude the authorization of Gavreto.

The submitted inner and outer labels, package insert and Patient Medication Information section of the Gavreto Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.

A review of the submitted brand name assessment was conducted, including testing for look‑alike sound‑alike attributes, and the proposed name Gavreto was accepted.

Gavreto has an acceptable safety profile based on the non‑clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Gavreto Product Monograph to address the identified safety concerns. As described within the framework of the NOC/c Guidance, safety monitoring on the use of Gavreto will be ongoing. Further evaluation will take place upon the submission of the requested studies after they become available.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

3 What steps led to the approval of Gavreto?

The sponsor filed a request for Priority Review Status under the Priority Review Policy for the review of the new drug submission (NDS) for Gavreto. An assessment was conducted, which determined that substantial evidence of clinical effectiveness had not been provided for the use of Gavreto for the intended indication. Therefore, the NDS did not meet the criteria for Priority Review Status.

The sponsor then submitted a request for Advance Consideration of the NDS for Gavreto under the Notice of Compliance with Conditions (NOC/c) Guidance, for which an assessment was conducted. The findings indicated that there was promising evidence of clinical effectiveness for the use of Gavreto for the intended indication, and that the NDS met the criteria for acceptance into review under this pathway.

Subsequent review of the NDS led to the decision to issue the sponsor market authorization under the NOC/c Guidance, in recognition of the promising but unconfirmed evidence of clinical effectiveness in the submission. In keeping with the provisions of the NOC/c Guidance, the sponsor agreed to provide additional information to confirm the clinical benefit.

The NDS for Gavreto was reviewed under Project Orbis, an international partnership designed to give cancer patients faster access to promising cancer treatments. The submission for Gavreto was classified as a Project Orbis Type C submission, where the United States Food and Drug Administration (FDA) has already issued a positive decision and subsequently shared the completed review documents with Health Canada. The Canadian regulatory decision on the review of Gavreto was made independently and was based on a critical assessment of the data package submitted to Health Canada. The foreign multidisciplinary review completed by the United States FDA was used as an added reference.

Submission Milestones: Gavreto

Submission MilestoneDate
Request for priority status filed2020-06-18
Rejection issued by Director, Bureau of Medical Sciences2020-07-24
Pre-submission meeting2020-08-05
Acceptance of Advance Consideration under the NOC/c Guidance2020-09-04
New drug submission filed2020-09-08
Screening
Screening Deficiency Notice issued2020-09-30
Response to Screening Deficiency Notice filed2020-10-08
Screening Acceptance Letter issued2020-11-03
Review
Review of Risk Management Plan complete2021-03-04
Non-Clinical Evaluation complete2021-04-22
Quality Evaluation complete2021-05-18
Clinical/Medical Evaluation complete2021-05-20
Labelling Review complete2021-05-20
Notice of Compliance with Conditions Qualifying Notice (NOC/c-QN) issued2021-06-11
Review of Response to NOC/c-QN:
Response filed (Letter of Undertaking)2021-06-15
Clinical/Medical Evaluation complete2021-06-29
Notice of Compliance (NOC) issued by Director General, Therapeutic Products Directorate under the Notice of Compliance with Conditions (NOC/c) Guidance2021-06-30

For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.

4 What follow-up measures will the company take?

Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.

In addition to requirements outlined in the Food and Drugs Act and Regulations, and in keeping with the provisions outlined in the Notice of Compliance with Conditions (NOC/c) Guidance, the sponsor has agreed to provide the following reports:

Confirmatory Studies

The sponsor has committed to submitting the final reports and datasets from the pivotal Phase II study, ARROW, to confirm and further characterize the clinical benefit of pralsetinib for the treatment of adult patients with rearranged during transfection (RET) fusion‑positive locally advanced or metastatic non‑small cell lung cancer (NSCLC) with treatment‑naïve RET fusion‑positive NSCLC and with RET fusion‑positive NSCLC who have previously received platinum chemotherapy. These reports are expected to provide a more precise estimation of the overall response rate and duration of response assessed by blinded independent central review (BICR). At this point, all responders in the population of patients with treatment‑naïve NSCLC (approximately 120 patients) will have been followed for at least 12 months from the date of initial response (or until disease progression, whichever comes first), and all responders in the population of patients with NSCLC previously treated with platinum therapy (87 patients) will have been followed for at least 6 months. This study is expected to end in April 2022, with the final report to be submitted in October 2022.

The sponsor has also committed to submitting the final report and datasets from the AcceleRET‑Lung study. This study compares pralsetinib to the physician’s choice of platinum‑based chemotherapy treatment regimens based on standard of care treatment for the first‑line treatment of RET fusion‑positive, metastatic NSCLC. The results from this study may inform product labelling. The study is expected to end in December 2025, with the final report to be submitted in June 2026.

The sponsor has also committed to submitting annual progress reports of the confirmatory studies.

Additional Studies

The sponsor has committed to conducting a comprehensive analysis evaluating and characterizing the incidence, clinical presentation, management, and outcome of the potential serious risk of pralsetinib‑associated gastrointestinal perforations and fistulas. The sponsor is expected to submit an integrated final report containing data from patient‑level and pooled analyses of ongoing and completed clinical trials, post‑marketing reports and/or literature reports and a comprehensive pharmacovigilance assessment for this potential serious risk. The final report is to be submitted in August 2026, and results from this report may inform product labelling.

Post‑Market Safety Monitoring Studies

Periodic Benefit‑Risk Evaluation Reports ‑ Confirmatory (PBRER‑Cs) or Periodic Safety Update Reports ‑ Confirmatory (PSUR‑Cs) are to be submitted annually to Health Canada until all conditions for market authorization under the NOC/c Guidance have been removed. The PBRER‑Cs or PSUR‑Cs are expected to comply with International Council for Harmonisation (ICH) guidelines and to include cumulative data on relevant unlisted adverse reactions from the date of marketing to the time of the report.

The sponsor is also expected to comply with the requirements for reporting on specific issues of concern, reporting all serious adverse drug reactions occurring in Canada, all serious unexpected adverse drug reactions occurring outside of Canada, and risk management measures, in accordance with the current Food and Drug Regulations (C.01.017) and guidance documents. The sponsor has also committed to providing copies of several post‑market study reports requested by the United States Food and Drug Administration (FDA) to Health Canada when available.

5 What post-authorization activity has taken place for Gavreto?

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada’s decisions were negative or positive. The PAAT will continue to be updated during the product life cycle.

At this time, no PAAT is available for Gavreto. When available, the PAAT will be incorporated into this SBD.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

6 What other information is available about drugs?

Up-to-date information on drug products can be found at the following links:

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision

Clinical Pharmacology

Pralsetinib, the medicinal ingredient in Gavreto, is a tyrosine kinase inhibitor that targets oncogenic fusions and mutations involving the rearranged during transfection (RET) gene, including V804 gatekeeper mutations associated with resistance to other therapies. Gene fusions involving the RET gene (RET fusions), which result in aberrant activation of the RET receptor tyrosine kinase pathway, have been found to be disease‑driving oncogenes in non‑small cell lung cancer (NSCLC). Activating point mutations and RET fusion proteins can drive tumorigenic potential through the hyperactivation of downstream signalling pathways, leading to uncontrolled cell proliferation.

The pharmacokinetics of pralsetinib was assessed through a non‑compartmental analysis of data obtained in the pivotal study, ARROW (described in the Clinical Efficacy section). Following the administration of a single oral dose, pralsetinib was rapidly absorbed into the systemic circulation (median time to peak concentration [Tmax] of 2 to 4 hours), followed by monophasic elimination. At steady state, the maximum plasma concentration (Cmax) ranged from 1,610 to 2,830 ng/mL and the area under the plasma concentration‑time curve (AUC) from time 0 extrapolated to infinity (AUC0‑inf) ranged from 33,800 to 43,900 ng•h/mL. Following the administration of a single dose of 400 mg, the half‑life of pralsetinib was 14.7 hours. After multiple dose administration at 400 mg daily, the half‑life of pralsetinib was 22.2 hours at steady state, which provided support for 400 mg daily as the recommended dosing regimen. Dose‑dependent increases in systemic pralsetinib exposure were observed over the dose range of 60 mg to 600 mg daily (0.15‑ to 1.5‑times the recommended dose). However, dose proportionality could not be concluded due to the low number of patients receiving doses outside the 400 mg daily dosing regimen.

An exposure‑response analysis was conducted for pralsetinib which assessed the model‑predicted primary exposure metrics for exposure‑efficacy and exposure‑safety. Overall, the exposure‑response analyses in patients with non‑small cell lung cancer (NSCLC) revealed no relevant or consistent relationships between increasing exposure to pralsetinib and efficacy or safety endpoints.

Cardiovascular safety was evaluated and data from the pivotal study indicated that pralsetinib had no clinically relevant or statistically significant effects on QT prolongation.

Studies were also conducted to assess the effects of the co‑administration of certain drugs on the pharmacokinetics, safety, and tolerability of pralsetinib in healthy adult subjects. Co‑administration of pralsetinib with esomeprazole (which alters gastric pH) appeared to be generally safe and well tolerated by healthy adult subjects. The co‑administration of pralsetinib with itraconazole (a combined P‑glycoprotein [P‑gp] and strong cytochrome P450 [CYP]3A inhibitor) or rifampin (a combined P‑gp and strong CYP3A inducer) were also evaluated. Based on findings from these studies, it is recommended to avoid the co‑administration of pralsetinib with strong CYP3A inhibitors or combined P‑gp and strong CYP3A inhibitors and if this is not possible, to reduce the dose of pralsetinib to half of the recommended dose. Additionally, it is recommended to avoid the co‑administration of pralsetinib with strong CYP3A inducers and if this is not possible, to increase the starting dose of pralsetinib.

A pooled population pharmacokinetic analysis was conducted using data from four Phase I studies in healthy volunteers (193 subjects in total) and one Phase I/II study in patients with NSCLC (161 patients). The covariate analysis of the population pharmacokinetic model predicted statistically significant increases in exposure to pralsetinib in patients with NSCLC (43% higher exposure than in healthy subjects), in the elderly (≤15% increase in exposure in patients ≥80 years of age compared with patients ≥60 years of age), and in individuals with Asian ethnicity (7% increase in Cmax compared with individuals with non‑Asian ethnicity).

No statistically significant effects were observed on pharmacokinetic parameters with respect to markers of hepatic function in patients with mild hepatic impairment and markers of renal function in patients with mild to moderate renal impairment. Therefore, no therapeutic individualization is needed for patients with these conditions. The effects of pralsetinib in patients with moderate or severe hepatic impairment or patients with severe renal impairment are unknown.

The effect of food on the pharmacokinetics, safety and tolerability of pralsetinib was evaluated in 20 healthy adult subjects. A clinically significant increase was observed in oral bioavailability in subjects who received pralsetinib under fed conditions, relative to the levels observed in subjects who received pralsetinib under fasted conditions. The median Tmax of pralsetinib was 4.0 hours under fasted conditions and 8.5 hours under fed conditions, which indicates that food delays the absorption of pralsetinib. The dosing instructions state that pralsetinib is to be taken on an empty stomach (no food intake for at least two hours before and at least one hour after taking pralsetinib).

For further details, please refer to the Gavreto Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

Evidence of the clinical efficacy of Gavreto was provided through interim results of the pivotal Phase II study, ARROW. To meet the enrollment criteria, patients were required to have locally advanced unresectable or metastatic NSCLC with measurable disease evaluated using the Response Evaluable Criteria in Solid Tumors (RECIST) version 1.1 (v1.1), and a RET fusion determined by a validated test. Patients with asymptomatic central nervous system (CNS) metastases, including patients with stable or decreasing steroid use within two weeks prior to study entry, were enrolled.

Patients previously treated with platinum‑based chemotherapy were placed in Cohort 1. Patients not previously treated with platinum‑based chemotherapy, including patients who had not received any systemic therapy (treatment naïve) were placed in Cohort 2. Patients in both cohorts were given 400 mg Gavreto once daily until progression of disease or unacceptable toxicity.

The efficacy analysis included 125 patients with confirmed RET fusion‑positive NSCLC who received a starting dose of 400 mg Gavreto. Seventy‑eight (78.4%) of these patients had prior systemic therapy, 87 patients (69.6%) had prior platinum‑based therapy, and 27 patients (21.6%) had received no prior systemic therapy (treatment naïve). The major efficacy outcome measures were the overall response rate (ORR) according to RECIST v1.1, and the duration of response (DOR) as evaluated by a blinded independent central review (BICR).

In patients previously treated with platinum‑based chemotherapy (Cohort 1), the efficacy assessment was based on 87 patients with a median age of 60 years (range: 28 to 85 years), with 37% of patients aged 65 years or older. At baseline, the majority of patients had an Eastern Oncology Cooperative Group (ECOG) performance status of 0 (36%) or 1 (59%). In this population, 99% of patients had metastatic disease and 1% of patients had locally advanced unresectable disease. The predominant histology was adenocarcinoma (in 95% of patients). Forty‑three percent (43%) of patients had a history of brain metastases. The ORR for Cohort 1 was 57.5% (95% confidence interval [CI]: 46.4, 68.0), with a median DOR of 17.1 months (95% CI: 15.2, 17.1).

In patients with treatment‑naïve RET fusion‑positive NSCLC who were not eligible for platinum-based chemotherapy (Cohort 2), the efficacy assessment was based on 27 patients with a median age of 65 years (range: 30 to 87 years), with 52% of patients aged 65 years or older. At baseline, the majority of patients had an ECOG performance status of 0 (41%) or 1 (56%). All patients had metastatic disease and adenocarcinoma histology. Thirty‑seven percent (37%) of patients had a history of brain metastases or current brain metastases. The ORR for Cohort 2 was 70.4% (95% CI: 49.8, 86.2), with a median DOR of 9.0 months (95% CI: 6.3, not estimable).

Central nervous system anti‑tumour activity was evaluated as a prespecified secondary endpoint, as Gavreto crosses the blood brain barrier. Eight patients previously treated with platinum‑based chemotherapy (Cohort 1) had CNS metastases at baseline. Four of these patients had a confirmed response (two complete responses and two partial responses). In a subset of 77 patients who did not have CNS metastases at baseline and who received 400 mg Gavreto daily, no new occurrences of brain metastases were observed during the specified study period.

Consistent results were obtained regardless of previous lines of therapy, which were supportive of a line agnostic indication. An extrapolation from the metastatic stage (99% of patients) to the locally advanced unresectable stage was considered reasonable based on baseline disease characteristics of the population with advanced NSCLC and the current understanding of oncogene‑driven NSCLC.

Indication

Sponsor's proposed indicationHealth Canada-approved indication
Gavreto is a kinase inhibitor indicated for the treatment of patients with rearranged during transfection (RET)‑positive locally advanced or metastatic non‑small cell lung cancer (NSCLC).Gavreto (pralsetinib) is indicated for the treatment of adult patients with rearranged during transfection (RET) fusion‑positive locally advanced unresectable or metastatic non‑small cell lung cancer (NSCLC).

A validated test is required prior to treatment to identify RET fusion‑positive status.

Efficacy in patients with RET fusion‑positive NSCLC was based on objective response rate and duration of response in a single‑arm study.

For more information, refer to the Gavreto Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

Evidence of the clinical safety of Gavreto is based on data from the pooled safety population of 438 patients enrolled in the pivotal Phase II study, ARROW (described in the Clinical Efficacy section). All patients in this population had solid tumours and were treated with 400 mg Gavreto once daily. The safety of Gavreto at a starting dose of 400 mg once daily was evaluated in a subset of 220 patients with locally advanced unresectable or metastatic NSCLC. These patients were treated for a median of 4.7 months (range: 0.1 to 20.3 months).

Treatment‑emergent adverse events (TEAEs) were reported in 99.1% of patients. The most common adverse reactions (in 25% of patients or greater) reported in the safety analysis set of 220 patients were anemia, leukopenia, neutropenia, constipation, edema, fatigue, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), musculoskeletal pain, and hypertension.

Serious adverse reactions were reported in 34.1% of patients who received Gavreto. The most common serious adverse reactions (in 2% of patients or greater) reported in Gavreto‑treated patients were pneumonia (11.4%), pneumonitis (5.0%), hemorrhage (4.1%), dyspnoea (2.3%), sepsis (3.2%), neutropenia (2.3%), urinary tract infection (2.3%) and pyrexia (2.3%). Fatal adverse reactions (Grade 5) occurred in nine (4.1%) patients, including four cases of pneumonia (the only fatal adverse reaction which occurred in more than one patient).

Dose reductions due to adverse reactions occurred in 32.7% of patients treated with Gavreto. The most common adverse reactions resulting in dose reductions (reported in 2% of patients or greater) were neutropenia (10.5%), anemia (6.8%), pneumonitis (4.5%), fatigue (3.6%), leukopenia (3.2%), thrombocytopenia (2.7%), hypertension (2.7%), and pneumonia (2.7%).

Adverse reactions led to permanent discontinuation of Gavreto for 10.9% of patients. The most common adverse reactions (reported in more than one patient) that led to permanent discontinuation were pneumonia (2.3%), pneumonitis (1.8%), and sepsis (0.9%).

Measurements for certain abnormal laboratory findings worsened from baseline to the end of the study, including increased AST, increased ALT, increased alkaline phosphatase (ALP), decreased albumin, decreased calcium corrected, decreased phosphate, increased creatinine, decreased sodium, decreased neutrophils, decreased hemoglobin, decreased lymphocytes, and decreased platelets.

A Serious Warnings and Precautions box in the Gavreto Product Monograph highlights the risks of interstitial lung disease/pneumonitis, hypertension, hepatotoxicity, and hemorrhage. Based on its mechanism of action and findings from animal studies, Gavreto may cause fetal harm when administered to pregnant women. Additionally, treatment with Gavreto may impair or slow wound healing, as it has the ability to inhibit the vascular endothelial growth factor (VEGF) pathway through off‑target activity.

Fatal adverse reactions (Grade 5) occurred in 4.1% of patients in the pivotal study. Deaths due to pneumonia or other infections are common in patients with NSCLC undergoing treatment. Pneumonitis is a common adverse reaction to treatment with protein kinase inhibitors, and one fatal case of pneumonitis (0.2%) was reported in the pivotal study in the pooled safety population (438 patients). One fatal case of hemorrhage (0.5%) also occurred in the pivotal study in the NSCLC safety population (subset of 220 patients). While metastatic disease can increase the risk of hemorrhage, there may be an increased risk of hemorrhage during treatment with Gavreto.

Overall, the safety profile of the pooled safety population (438 patients) was consistent with and supportive of that of the NSCLC‑specific population (220 patients), with the exception of patients 65 years of age and older. Patients in this age group were more likely to experience adverse events, serious adverse events, grade 3/4/5 adverse events, grade 3/4/5 serious adverse events, treatment interruptions, or treatment discontinuations. Based on the review of the safety and efficacy information of the product, the benefit‑harm‑uncertainty profile of Gavreto was determined to be acceptable.

For more information, refer to the Gavreto Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.2 Non-Clinical Basis for Decision

Pralsetinib, the medicinal ingredient in Gavreto, exhibited in vivo anti‑tumor activity in mice with subcutaneously‑implanted tumor xenografts bearing RET‑activating mutations. Additionally, pralsetinib improved survival in mice implanted intracranially with tumour models expressing the RET fusions KIF5B‑RET or CCDC6‑RET. Both outcomes suggest potential activity against RET‑dependent CNS metastases. A wide distribution was observed in rats following a single administration of (14C) pralsetinib, which was detected especially in the walls of the small intestine, liver, adrenal gland, uveal tract, and pigmented skin. Pralsetinib did not inhibit in vitro human ether‑a‑go‑go‑related gene (hERG) potassium currents at relevant concentrations or induce prolongation of the corrected QT (QTc) interval in a 13‑week repeat‑dose toxicity study in monkeys.

In vitro studies of the metabolism of pralsetinib were conducted in human primary hepatocytes and liver microsomes. Metabolism was mediated mainly by CYP3A4 (Phase I) and uridine 5'‑diphospho‑glucuronosyltransferase (UGT) 1A4 (Phase II). The major metabolite observed in human primary hepatocytes, M709, was generated from the direct N‑glucuronidation of pralsetinib. Pralsetinib was a direct inhibitor of CYP2C8, CYP2C9, and CYP3A4/5, a time‑dependent inhibitor of CYP3A4/5, and an inducer of CYP2C8, CYP2C9, and CYP3A4/5. In vitro, pralsetinib was a dual substrate of P‑gp and breast cancer resistance protein (BCRP), and an inhibitor of P‑gp, BCRP, organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, multidrug and toxin extrusion (MATE) 1, and MATE2‑K.

No mortalities were observed in 13‑week repeat‑dose studies in which doses up to 20 mg/kg/day and up to 10 mg/kg/day were administered to rats and monkeys, respectively. Findings in the rat included toxicities in the bone marrow, kidney, and lung. Hyperphosphatemia and tissue mineralization were also common findings in animals, and were related to fibroblast growth factor receptor (FGFR) inhibition. In 28‑day rat and monkey toxicology studies, adverse effects on the heart (necrosis and hemorrhage) were observed at exposures ≥2.6 times greater and ≥1.1 times greater, respectively, than the human exposure based on the AUC at the clinical dose of 400 mg. In monkeys, necrosis and hemorrhage were attributed to sepsis. Evidence of liver toxicity was observed in rats. In monkeys, adverse effects were observed in the gastrointestinal tract, including intussusception in the 13‑week study and in a 28‑day study. Extensive gastrointestinal inflammation and/or ulceration leading to bacterial sepsis and death were also observed in the 28‑day study at doses of 15 mg/kg and higher.

Adverse effects were observed in the bones and teeth of rats following exposures approximately 0.9‑times the clinical exposure (as measured by the AUC), which are expected to be related to vascular endothelial growth factor receptor (VEGFR)/FGFR inhibition. Physeal dysplasia in the femur was also noted in the 28‑day repeat‑dose toxicity studies.

Pralsetinib was not found to be genotoxic in in vitro and in vivo genotoxicity studies. The results of several in vitro mutagenicity assays indicated that pralsetinib was negative for mutagenic activity. Carcinogenicity studies have not been conducted, as they are not needed to support the registration of a drug intended for the treatment of patients with advanced cancer. Following the oral administration of pralsetinib in general toxicology studies, dose‑related effects were observed in the reproductive organs which may impair male and female fertility. These effects include degeneration of the corpus luteum in the ovary, cellular debris and reduced sperm in the epididymis, tubular degeneration in the testis correlating with small/soft testis, and reduced epididymis and testis weights.

The developmental toxicity of pralsetinib was evaluated in an embryo‑fetal study in rats, in which pralsetinib was administered during the period of organogenesis. At dose levels ≥20 mg/kg (approximately 1.5‑times the exposure based on AUC at the human dose of 400 mg), embryo‑fetal mortality due to post‑implantation loss (early resorptions) occurred in 100% of cases, and was accompanied by reduced gravid uterine weight. At dose levels ≥5 mg/kg (approximately 0.2‑times the exposure based on AUC at the human dose of 400 mg), increases were observed in a wide range of fetal visceral and skeletal malformations/variations. The observed renal malformations and variations were consistent with the role of RET in renal organogenesis.

The results of the non‑clinical studies as well as the potential risks to humans have been included in the Gavreto Product Monograph. Considering the intended use of Gavreto, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Gavreto Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.3 Quality Basis for Decision

The Chemistry and Manufacturing information submitted for Gavreto has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 24 months is acceptable when the drug product is stored at room temperature (15 ºC to 30 ºC).

Proposed limits of drug-related impurities are considered adequately qualified (i.e. within International Council for Harmonisation [ICH] limits and/or qualified from toxicological studies).

All sites involved in production are compliant with Good Manufacturing Practices.

All non-medicinal ingredients (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.

None of the excipients used in the formulation of Gavreto is of human or animal origin.

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