Summary Basis of Decision for Vitrakvi

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 Vitrakvi is located below.

Recent Activity for Vitrakvi

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 Vitrakvi

Date SBD issued: 2019-12-18

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

Larotrectinib (supplied as larotrectinib sulfate)

Drug Identification Number (DIN):

  • DIN 02490315 - 25 mg capsule, oral administration
  • DIN 02490323 - 100 mg capsule, oral administration
  • DIN 02490331 - 20 mg/mL solution, oral administration

Bayer Inc.

New Drug Submission Control Number: 219998

On July 10, 2019, Health Canada issued a Notice of Compliance under the Notice of Compliance with Conditions (NOC/c) Guidance to Bayer Inc. for the drug product Vitrakvi. 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 Vitrakvi is favourable for the treatment of adult and pediatric patients with solid tumours that:

  • have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion without a known acquired resistance mutation,
  • are metastatic or where surgical resection is likely to result in severe morbidity, and
  • have no satisfactory treatment options.

1 What was approved?

Vitrakvi, an antineoplastic agent, was authorized for the treatment of adult and pediatric patients with solid tumours that:

  • have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion without a known acquired resistance mutation,
  • are metastatic or where surgical resection is likely to result in severe morbidity, and
  • have no satisfactory treatment options.

The safety and efficacy of Vitrakvi in pediatric patients (28 days to <18 years of age) were established based on data from three open-label, single-arm clinical studies. There are no data in pediatric patients less than one month of age.

The safety and efficacy of Vitrakvi in geriatric patients (≥65 years of age) were established based on data from three open-label, single-arm clinical studies. The number of patients aged 65 and over were not sufficient to determine whether geriatric patients respond to Vitrakvi differently than younger patients.

Vitrakvi 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.

Vitrakvi 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.

Vitrakvi (25 mg, 100 mg, and 20 mg/mL larotrectinib, supplied as larotrectinib sulfate) is presented as capsules (25 mg and 100 mg strengths) and as an oral solution (20 mg/ml strength). In addition to the medicinal ingredient larotrectinib, the capsules also contain ammonia solution, dimethicone, FD&C Blue #2 aluminum lake, gelatin, propylene glycol, shellac, and titanium dioxide. As for the oral solution, in addition to the medicinal ingredient, the solution also contains citric acid, hydroxypropyl betadex, glycerol, methylparahydroxybenzoate, natural flavour, potassium sorbate, propylene glycol, purified water, sodium citrate, sodium dihydrogen phosphate, sorbitol, and sucrose.

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 Vitrakvi Product Monograph, approved by Health Canada and available through the Drug Product Database.

2 Why was Vitrakvi approved?

Health Canada considers that the benefit-harm-uncertainty profile of Vitrakvi is favourable for the treatment of adult and pediatric patients with solid tumours that:

  • have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion without a known acquired resistance mutation,
  • are metastatic or where surgical resection is likely to result in severe morbidity, and
  • have no satisfactory treatment options.

Vitrakvi 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.

Tropomyosin receptor kinase (TRK) fusion cancer is defined by the presence of a specific type of genomic alteration rather than the site of origin of the tumour or its histology. It is characterized by the presence of a neurotrophic tyrosine receptor kinase (NTRK) gene fusion, in which a chromosomal rearrangement causes an NTRK gene to become fused with an unrelated gene. These oncogenic NTRK gene fusions lead to the overexpression and constitutive activation of TRK proteins with subsequent activation of downstream cell signalling pathways involved in cell proliferation and survival, leading to TRK fusion cancer.

Current estimates indicate that an NTRK gene fusion is present in approximately 1% of all solid tumour malignancies. Prevalence varies considerably across different tumour types. These gene fusions are present at low frequencies in some common adult cancers, such as non-small cell lung cancer (NSCLC), colorectal cancer, and melanoma. In some very rare forms of cancer, such as infantile fibrosarcoma, secretory breast carcinoma, mammary analogue secretory cancer of the salivary glands, and congenital mesoblastic nephroma, NTRK gene fusions are either very common or may be present in 100% of cases.

Prior to treatment with Vitrakvi, the presence of an NTRK gene fusion should be confirmed in a tumour specimen using a validated test. In Canada, currently available methods for the detection of an NTRK gene fusion include next-generation sequencing (NGS), fluorescence in situ hybridization (FISH), and reverse-transcription polymerase chain reaction (RT-PCR).

Initial treatment for patients with advanced TRK fusion cancer is based on the standard of care for the tumour site of origin. Treatment options comprise limited or toxic systemic therapies, or for some tumours, surgery with significant morbidity. Overall, there are few, if any, treatment options available for this patient population if standard treatment has failed. Vitrakvi (larotrectinib) targets and inhibits the TRK family of proteins.

The efficacy analysis was based on data from three ongoing single-arm clinical studies, which contributed a total of 73 adult and pediatric patients to a pooled efficacy analysis set, the extended Primary Analysis Set (ePAS). All patients had advanced cancer, with unresectable or metastatic solid tumours harbouring an NTRK gene fusion. The presence of an NTRK gene fusion was confirmed in a tissue sample using a validated method. All patients also experienced disease progression following systemic therapy for their disease, if available, or would have required surgery with significant morbidity. The most common of the 14 tumour types represented in the ePAS were soft tissue sarcoma, salivary gland tumour, and infantile fibrosarcoma, all of which are rare cancers.

Efficacy endpoints were evaluated by a blinded independent review committee (IRC) according to the Response Evaluation Criteria in Solid Tumours, version 1.1 (RECIST v1.1). The primary efficacy endpoint was the overall response rate (ORR). In the ePAS (number of patients [n] = 73), the ORR was 75%, which was considered clinically meaningful. The ORR in the adult sub-population (n = 52) was 69%, and was 90% in the pediatric sub-population (n = 21). The duration of response (DOR) was a secondary endpoint. With a median duration of follow-up of 10.2 months, the median DOR was not yet estimable.

The safety analysis was based on data from 176 patients with heterogeneous advanced cancers, with or without an NTRK gene fusion, across the same three single-arm clinical studies. Pediatric patients comprised 25% (n = 44) of the safety analysis population.

Vitrakvi was generally well-tolerated in the safety analysis population. Almost all patients (98%) experienced at least one treatment-emergent adverse event (TEAE), regardless of attribution. The most commonly reported TEAEs (in ≥20% of patients) were fatigue, nausea, dizziness, vomiting, anemia, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), cough, constipation, and diarrhea. The most common serious TEAEs (reported in ≥2% of patients) included pyrexia, diarrhea, sepsis, abdominal pain, cellulitis, dehydration, and vomiting.

The safety profile observed in the pediatric subpopulation was generally consistent with the safety profile observed in the adult population. However, long-term safety data are limited. While NTRK genes are predominantly expressed in the nervous system, these genes are also expressed in a variety of other body systems. The potential consequences of TRK inhibition in developing children compared with adults is not completely understood.

There are no clinical data available on the use of Vitrakvi in pregnant or breastfeeding women. However, the risk of fetal harm was identified during the non-clinical review.

Overall, the data reviewed provide promising evidence of the clinical effectiveness of Vitrakvi for the approved indication, when administered according to the recommended dosing regimen. The results of ongoing and additional studies and post-market safety update reports will be submitted to verify the clinical benefit of Vitrakvi.

A Risk Management Plan (RMP) for Vitrakvi was submitted by Bayer Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. 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.

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

A Look-alike Sound-alike brand name assessment was performed and the proposed name Vitrakvi was accepted.

Vitrakvi 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 Vitrakvi Product Monograph to address the identified safety concerns. As described within the framework of the NOC/c Guidance, safety monitoring on the use of Vitrakvi 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 Vitrakvi?

The sponsor filed a request for Advance Consideration under the Notice of Compliance with Conditions (NOC/c) Guidance for the review of the new drug submission (NDS) for Vitrakvi. An assessment was conducted, and showed that the criteria for filing under the NOC/c Guidance had been met. The evidence of clinical effectiveness was promising. Additionally, this drug is intended to treat a patient population with a life-threatening disease, for which no drug is presently marketed in Canada.

In keeping with the provisions of the NOC/c Guidance, the sponsor agreed to provide additional information to verify the clinical benefit.

Submission Milestones: Vitrakvi

Submission MilestoneDate
Pre-submission meeting:2018-06-06
Request for priority status
Filed:2018-06-06
Acceptance of Advance Consideration under the Notice of Compliance with Conditions (NOC/c) Guidance:2018-08-10
Submission filed:2018-09-18
Screening
Screening Deficiency Notice issued:2018-10-12
Response filed:2018-10-24
Screening Acceptance Letter issued:2018-11-05
Review
Biostatistics Evaluation complete:2019-04-25
Quality Evaluation complete:2019-05-24
Labelling Review complete, including Look-alike Sound-alike brand name assessment:2019-06-03
Clinical/Medical Evaluation complete:2019-06-13
Review of Risk Management Plan complete:2019-06-14
Notice of Compliance with Conditions Qualifying Notice (NOC/c-QN) issued:2019-06-14
Review of Response to NOC/c-QN:
Response filed (Letter of Undertaking):2019-06-17
Clinical/Medical Evaluation complete:2019-07-03
Notice of Compliance (NOC) issued by Director General, Therapeutic Products Directorate under the Notice of Compliance with Conditions (NOC/c) Guidance:2019-07-10

The Canadian regulatory decision on the review of Vitrakvi was based on a critical assessment of the data package submitted to Health Canada. The foreign review completed by the United States Food and Drug Administration (FDA) was consulted for relevant supplementary information.

For additional information about the drug submission process, refer to the Management of Drug Submissions 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 committed to provide the following reports:

Confirmatory studies

The sponsor has committed to submit the final report from the 73 patients with neurotrophic tyrosine receptor kinase (NTRK) fusion solid tumours in the extended Primary Analysis Set. These 73 patients were enrolled across three single-arm clinical studies. The final report will further characterize the duration of response in patients who achieved a complete or partial response to larotrectinib (the medicinal ingredient in Vitrakvi). All responding patients will be followed for at least two years from the onset of response, and duration of response will be assessed by independent central review.

The sponsor has also committed to submit the final report from other ongoing and proposed studies conducted to verify and expand upon the clinical benefit of larotrectinib by providing more precise estimates of the overall response rate (ORR) and mature response duration. These studies include additional patients with several different types of common cancers in which NTRK gene fusions occur at low frequencies, patients with central nervous system tumours, and patients with various tumour types that have not been well represented to date. All responding patients will be followed for at least 12 months from the onset of response. The ORR and the duration of response will be evaluated by independent central review. Completion of all confirmatory studies is expected by August 2024, and submission of the final reports is expected in August 2025.

Additional studies

The sponsor has committed to providing the results of a long-term study in pediatric patients with solid tumours harbouring the NTRK gene fusion. This study will examine the long-term safety effects of larotrectinib and identify potential adverse events associated with treatment, particularly in relation to growth and development. Completion of this study is expected by August 2027, and submission of the final report is expected in August 2028.

Post-market safety monitoring

A conditional Periodic Benefit-Risk Evaluation Report (PBRER-C) or Periodic Safety Update Report (PSUR-C) is to be submitted annually to Health Canada until all the conditions for market authorization have been removed, or for a minimum of three years following marketing in Canada (whichever occurs later). The annual PBRER-C or PSUR-C must comply with International Council for Harmonisation (ICH) guidelines, and include cumulative data on relevant unlisted adverse reactions from the date of marketing to the time of the report.

The sponsor has committed to comply with the requirements for reporting on specific issues of concern, reporting adverse drug reactions occurring in Canada and internationally, and risk management measures as described in the NOC/c Guidance.

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

Larotrectinib is a highly selective tyrosine receptor kinase inhibitor. It targets the tropomyosin receptor kinase (TRK) family of proteins, inclusive of TRKA, TRKB, and TRKC, which are encoded by the neurotrophic tyrosine receptor kinase (NTRK) genes NTRK1, NTRK2, and NTRK3 genes, respectively.

Chromosomal rearrangements can result in the fusion of NTRK1, NTRK2, or NTRK3 with other genes. These gene fusions give rise to oncogenic TRK fusion proteins with constitutive kinase activity. This in turn activates cell signalling pathways involved in cell proliferation and survival, promoting the development of tumours.

Larotrectinib has been shown to inhibit TRK fusion proteins, as well as the proliferation of cell lines containing NTRK gene fusions, in a concentration-dependent manner. In mouse xenograft models of TRK fusion cancer, exposure to larotrectinib significantly inhibited tumour growth.

In adult cancer patients, larotrectinib is absorbed quickly (within approximately one hour) and has a short half-life (t½) of approximately three hours. With twice daily dosing of 100 mg Vitrakvi, the exposure to larotrectinib (as measured by the area under the concentration-time curve [AUC]) was 5,410 ± 3,813 ng*h/mL. The maximum plasma concentration (Cmax) of larotrectinib was 914 ± 445 ng/mL. Higher exposures were observed in cancer patients than in healthy subjects.

In healthy adult subjects, the mean absolute bioavailability of larotrectinib was 34% after a single 100 mg dose. The AUC of larotrectinib was similar between the oral solution formulation and the capsules of Vitrakvi. The Cmax was 36% higher with the oral solution than with the capsules. The Cmax and AUC were dose-proportional in healthy subjects who received the capsule formulation up to a dose of 400 mg, and slightly higher than proportional at doses from 600 mg to 900 mg.

Larotrectinib is metabolized mainly by the cytochrome P450 (CYP) 3A4/5 enzymes. Co-administration of larotrectinib with strong CYP 3A4 inhibitors or CYP 3A4 inducers should therefore be avoided. If this is not possible, the dose of larotrectinib should be reduced by 50% if administered with a strong CYP 3A4 inhibitor, or doubled if administered with a strong CYP 3A4 inducer.

A study in subjects with end-stage renal disease indicated that dose adjustments are not needed for patients with renal impairment of any severity. Dose adjustments are also not needed for patients with mild hepatic impairment (Child-Pugh A). However, the starting dose of larotrectinib should be reduced by 50% for patients with moderate (Child-Pugh B) to severe (Child-Pugh C) hepatic impairment.

The results of population pharmacokinetic analyses indicate that children between 3 months and <18 years of age achieve similar exposure to adults. However, AUC and Cmax were three-fold higher in patients 1 to 3 months of age than in adults. The relevance of this observation is difficult to assess, as there were only four patients in this age group, and the variability was high.

The effects of larotrectinib on the QT interval were examined through concentration-response modelling of the QTc data. The results indicate that larotrectinib does not prolong the QT interval to any clinically relevant extent.

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

Clinical Efficacy

Data from three ongoing clinical studies were submitted in support of the clinical efficacy of Vitrakvi. Collectively, these studies contributed 73 patients to a pooled efficacy analysis set, the extended Primary Analysis Set (ePAS). All three are open-label, single-arm studies in patients with advanced cancers, who have unresectable or metastatic solid tumours with an NTRK gene fusion.

  • LOXO-TRK-14001 (Study 1) is a Phase I dose-finding study which contributed eight adult patients
  • NAVIGATE (Study 2) is a Phase II basket study which contributed 44 adult and pediatric patients
  • SCOUT (Study 3) is a Phase I/II dose-finding/efficacy and safety study which contributed 21 pediatric patients

All patients were required to have progressed following systemic therapy for their disease, if available, or to have required surgery with significant morbidity. The most common of the 14 tumour types (>10%) represented in the ePAS were soft tissue sarcoma (25%), salivary gland tumours (18%), and infantile fibrosarcoma (14%), all of which are rare cancers. Gene fusions involving NTRK1 (44%), NTRK2 (3%), and NTRK3 (48%) were represented. Sixteen unique upstream fusion partners were represented. Next-generation sequencing (NGS) was used to confirm 90.4% of NTRK gene fusions. A small number of fusions were identified using fluorescence in situ hybridization (FISH), and one case was confirmed by reverse transcription polymerase chain reaction (RT-PCR).

The starting dose in the majority of adult patients was 100 mg Vitrakvi administered orally, twice per day. The starting dose in the majority of pediatric patients was 100 mg/m2 up to a maximum of 100 mg twice daily. Treatment with Vitrakvi was continued until the patient experienced disease progression or an unacceptable level of toxicity.

The primary efficacy endpoint was the overall response rate (ORR). Ruling out a lower limit of 30% for the ORR was predefined as a clinically meaningful response. Response endpoints were evaluated by a blinded independent review committee (IRC) according to the Response Evaluation Criteria in Solid Tumours, version 1.1 (RECIST v1.1). The ORR was 75% (95% confidence interval [CI]: 64, 85) in the ePAS (number of patients [n] = 73). This includes a complete response in 16 patients (22%), a surgical complete response in one patient (1%), and a partial response in 38 patients (52%). The ORR was 69% in the adult subpopulation (n = 52) and 90% in the pediatric subpopulation (n = 21). Overall, responses were deep, that is, the maximal reduction in tumour size well exceeded 30% in many individual patients.

The duration of response (DOR) was a secondary endpoint. The median duration of follow-up was 10.2 months. At this time, the median DOR was not yet estimable. The median time to first response, another secondary endpoint, was 1.8 months (range: 1.0 to 14.6 months). Responses were typically seen by the time of the first protocol specified disease assessment at the end of the second cycle of treatment (cycles were in 28-day increments).

The study protocols were amended to exclude patients with prior disease progression on approved or investigational tyrosine kinase inhibitors with anti-TRK activity, including entrectinib, crizotinib and lestaurtinib. This change was made because these patients could potentially harbour acquired resistance to Vitrakvi, a tropomyosin receptor kinase inhibitor targeting the TRK family of proteins. However, three patients who had prior exposure to crizotinib were enrolled to two of the clinical studies before the change was implemented. Treatment durations for these patients were 1.0, 3.7, and 4.1 months. Progressive disease was documented by the IRC. An acquired resistance mutation was detected in one patient.

Overall, the data reviewed provide promising evidence of the clinical effectiveness of Vitrakvi for the approved indication, when administered according to the recommended dosing regimen. The results of additional studies and post-market safety update reports will be submitted to verify the clinical benefit of Vitrakvi.

Indication

Sponsor's proposed indicationHealth Canada-approved indication
Vitrakvi (larotrectinib) is indicated for:
  • the treatment of adult and pediatric patients with locally advanced or metastatic solid tumours harbouring a neurotrophic tyrosine receptor kinase (NTRK) gene fusion.
Vitrakvi (larotrectinib) is indicated for the treatment of adult and pediatric patients with solid tumours that:
  • have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion without a known acquired resistance mutation,
  • are metastatic or where surgical resection is likely to result in severe morbidity, and
  • have no satisfactory treatment options.

The indication proposed by the sponsor was revised to state that Vitrakvi should only be used in patients with no other satisfactory treatment options in order to reflect limitations in the available data at the time of approval. Revisions were also made to highlight the need to confirm the presence of an NTRK gene fusion before treatment is initiated, and to communicate that Vitrakvi is not indicated for patients in whom a known acquired resistance mutation in the NTRK gene fusion has been identified.

The indication was approved based on ORR and DOR in a pooled patient population. Most patients had rare cancers. In some of the tumour types represented in the ePAS, including some common cancers with limited representation, a response was not observed. Thus, the tumour agnostic indication was approved based in part on an extrapolation of efficacy findings to some tumour types and NTRK gene fusion partners. Additionally, the indication is accompanied by instructions to promote the safe and effective use of Vitrakvi. Treatment should only be initiated if an NTRK gene fusion is confirmed in a tumour specimen using a validated test. Vitrakvi should only be administered under the supervision of a health professional experienced in the use of antineoplastic agents.

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

Clinical Safety

The safety analysis was based on data from 176 patients with heterogeneous advanced cancers, across the same three single-arm clinical studies. Patients with and without the NTRK gene fusion were included in the safety analysis set. A pediatric subpopulation of patients (n = 44 [25%]) included 12 patients (27%) aged 1 month to <2 years, 19 patients (43%) aged 2 to <12 years, and 13 patients (30%) aged 12 to <18 years.

Overall, Vitrakvi was well-tolerated in the safety analysis population. Almost all patients (98%) experienced at least one treatment-emergent adverse event (TEAE), regardless of attribution. The most commonly reported TEAEs (in ≥20% of patients), in order of decreasing frequency, were fatigue, nausea, dizziness, vomiting, anemia, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), cough, constipation, and diarrhea. The most common serious TEAEs (reported in ≥2% of patients) included pyrexia, diarrhea, sepsis, abdominal pain, cellulitis, dehydration, and vomiting.

Doses were modified (interrupted or reduced) due to a TEAE in 37% of patients. The TEAEs which most often resulted in dose modification (in ≥3% of patients) were increased ALT, increased AST, and dizziness. Treatment was permanently discontinued in 13% of patients as a result of TEAEs. Dehydration, fatigue, increased ALT and increased AST all led to the discontinuation of more than one patient.

Increased ALT and increased AST of any grade were each reported in 26% of patients. The maximum grades observed were Grade 4 increased ALT in one patient (<1%) and Grade 3 increased ALT and increased AST in five patients each (3% each).

Neurologic or psychiatric TEAEs of any grade were reported in 65% of patients, including Grade 3 events in 6% of patients and Grade 4 events in <2% of patients.

Neutropenia was reported as a TEAE in 10% of patients, with Grade 3 events accounting for 5%.

Weight increase was reported as a TEAE in 15% of patients, with Grade 3 events accounting for 4%. Weight increase was more frequently reported as a TEAE in pediatric patients (23%) compared with adult patients (12%). Given that weight gain was reported as an adverse effect in non-clinical studies and that published reports of individuals with congenital mutations in TRK pathway proteins suggest that decreases in TRK-mediated signaling are correlated with obesity, the TEAE of weight increase was of clinical concern.

The safety profile observed in the pediatric subpopulation was generally consistent with the safety profile observed in the adult population. Grade 3-4 TEAEs which occurred more frequently in the pediatric subpopulation than in the general patient population include increased weight (3% vs. 1%) and neutropenia (5% vs. <1%). One pediatric patient discontinued treatment due to Grade 3 increased ALT.

At the time of approval, the available data regarding the long-term safety of Vitrakvi were limited, particularly in relation to its potential effects on growth and the achievement of developmental milestones in pediatric patients. The results of a population pharmacokinetic analysis indicated that in pediatric patients from 1 to 3 months of age, drug exposure following the recommended dose was three-fold higher than in adults. However, the clinical relevance of this is unknown.

There are no clinical data available on the use of Vitrakvi in pregnant or breastfeeding women. However, the risk of fetal harm was identified during the non-clinical review.

Warnings and precautions are in place in the approved Vitrakvi Product Monograph to address the identified safety concerns.

Post-Approval Conditions

As a product authorized under the Notice of Compliance with Conditions (NOC/c) Guidance, further studies are required to verify the clinical benefit and safety of Vitrakvi.

The sponsor has committed to submit the final report from the 73 patients with NTRK fusion solid tumours who were enrolled across the three single-arm clinical studies and then included in the ePAS. The sponsor has also committed to submitting the final reports from other ongoing or proposed confirmatory studies conducted to verify and expand upon the clinical benefit of larotrectinib by providing more precise estimates of the ORR and mature response duration in adult and pediatric patients with solid tumours harbouring an NTRK gene fusion, including results for additional tumour types.

The sponsor has additionally committed to providing the results of a long-term study in pediatric patients with solid tumours with an NTRK gene fusion. This study will examine the long-term safety of larotrectinib and identify potential adverse events associated with treatment, with a focus on growth and the achievement of developmental milestones.

As part of the sponsor's post-market monitoring commitments, a Periodic Benefit-Risk Evaluation Report (PBRER) or Periodic Safety Update Report (PSUR) must be submitted annually until all of the conditions for market authorization have been lifted.

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

7.2 Non-Clinical Basis for Decision

The indication approved for Vitrakvi is tumour agnostic, as it is based on the presence of a specific genomic alteration rather than on the type of tissue affected. This was supported by the non-clinical data submitted, which provided evidence that larotrectinib inhibits TRK fusion proteins, which led to suppressed cell proliferation and tumour growth inhibition. These effects were observed across three TRK fusion cancer cell lines in vitro and in vivo (animal models).

Larotrectinib was not found to be mutagenic in the bacterial reverse mutation (Ames) or the in vitro mammalian mutagenesis assays. The in vivo mouse micronucleus test also resulted in a negative outcome.

General toxicity studies were conducted in rats and monkeys, and involved repeat dosing for up to 13 weeks. Adverse effects associated with larotrectinib included skin lesions (in rats only), emesis (in monkeys only), weight gain, increased liver serum enzymes, and decreased albumin concentration.

Although there were no dedicated fertility studies, effects of larotrectinib on certain fertility-related parameters were examined in other studies. No effects on spermatogenesis (in rats) or on the histopathology of male reproductive organs (in rats and monkeys) were observed in the general studies. These observations were made at doses corresponding to approximately seven times (in rats) and ten times (in monkeys) the maximum human exposure at the recommended clinical dose. A four-week study in female rats revealed signs of reproductive toxicity, including fewer corpora lutea, increased incidence of anestrus, and decreased uterine weight with uterine atrophy. These effects were observed at doses corresponding to eight times the maximum human exposure at the recommended clinical dose. The effects were reversible.

The effects of larotrectinib on embryo-fetal development were studied in pregnant rats and rabbits during the period of organogenesis. Relative to the exposure in humans at the recommended clinical dose, the maternal exposure levels in rats and rabbits were approximately 9.0 and 0.6 times higher, respectively. Malformations were detected in the offspring at these exposure levels. Additionally, larotrectinib was found to cross the placenta in both species, as it was detected in blood samples obtained from fetuses at termination.

A juvenile toxicity study was conducted in rats, in which significant toxic effects were observed with repeated dosing of larotrectinib. These occurred at exposures lower than those expected with the proposed clinical dose in pediatric patients, and included increased mortality, neuronal effects, growth retardation, and delayed sexual development. Lower fertility was observed in animals at three times the recommended clinical exposure.

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

For more information, refer to the Vitrakvi 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 Vitrakvi 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 in-use shelf life of 30 days is acceptable for the oral solution, if stored at 2°C to 8°C. The oral solution must not be frozen, and must be discarded 30 days after the container is first opened. The capsules must be stored at room temperature (15°C to 30°C).

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

All non-medicinal ingredients found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. Gelatin used in the production of Vitrakvi capsules is sourced from healthy animals, and the sponsor has provided documentation confirming that it is not considered a risk for transmitting bovine spongiform encephalopathy (BSE) or transmissible spongiform encephalopathy (TSE). The oral solution does not contain any materials of animal origin.