Summary Basis of Decision for Vitrakvi

 

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 (t_½) 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 (C_max) 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 C_max was 36% higher with the oral solution than with the capsules. The C_max 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 C_max 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 indication	Health 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.