Summary Basis of Decision for Retevmo
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:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Retevmo is located below.
Recent Activity for Retevmo
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 Retevmo
Date SBD issued: 2021-11-09
The following information relates to the new drug submission for Retevmo.
Selpercatinib
Drug Identification Number (DIN):
- DIN 02516918 - 40 mg selpercatinib, capsule, oral administration
- DIN 02516926 - 80 mg selpercatinib, capsule, oral administration
Loxo Oncology, Inc.
New Drug Submission Control Number: 243748
On June 15, 2021, Health Canada issued a Notice of Compliance under the Notice of Compliance with Conditions (NOC/c) Guidance to Loxo Oncology, Inc. for the drug product Retevmo. 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 Retevmo, as monotherapy, is favourable for the treatment of the following cancers that harbour genetic alterations in the rearranged during transfection (RET) gene:
- metastatic RET fusion-positive non-small cell lung cancer in adult patients,
- RET-mutant medullary thyroid cancer in adult and pediatric patients 12 years of age and older with unresectable advanced or metastatic disease,
- RET fusion-positive differentiated thyroid carcinoma in adult patients with advanced or metastatic disease (not amenable to surgery or radioactive iodine therapy) following prior treatment with sorafenib and/or lenvatinib.
1 What was approved?
Retevmo, a protein kinase inhibitor, was authorized as monotherapy for the treatment of the following cancers that harbour genetic alterations in the rearranged during transfection (RET) gene:
- metastatic RET fusion-positive non-small cell lung cancer in adult patients,
- RET-mutant medullary thyroid cancer in adult and pediatric patients 12 years of age and older with unresectable advanced or metastatic disease,
- RET fusion-positive differentiated thyroid carcinoma in adult patients with advanced or metastatic disease (not amenable to surgery or radioactive iodine therapy) following prior treatment with sorafenib and/or lenvatinib.
Treatment with Retevmo should only be initiated following confirmation of a RET gene fusion or mutation using a validated test.
Promising clinical effectiveness of Retevmo for the above indications is based on objective response rates and duration of responses from LIBRETTO-001, a multicentre, multi-cohort, open-label, Phase I/II trial in patients with specific genetic alterations in RET.
Based on the data submitted to and reviewed by Health Canada, the promising clinical effectiveness of Retevmo has been established in adolescent patients 12 to 17 years of age with unresectable advanced or metastatic RET-mutant medullary thyroid cancer. The safety and efficacy of Retevmo have not been established in pediatric patients younger than 12 years of age.
Of 702 patients who received Retevmo in the LIBRETTO-001 study, 34% (239 patients) were 65 years of age or older and 10% (67 patients) were 75 years of age or older. No overall differences were observed in the safety or effectiveness of Retevmo between patients who were 65 years of age or older and patients younger than 65 years of age.
The use of Retevmo 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.
Retevmo 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.
Retevmo (40 mg or 80 mg selpercatinib) is presented as a capsule. In addition to the medicinal ingredient, the capsule contains black iron oxide, colloidal silicon dioxide, FD & C Blue No. 1 (80 mg capsule only), gelatin, microcrystalline cellulose, pharmaceutical grade printing ink, 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 Retevmo Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Retevmo approved?
Health Canada considers that the benefit-harm-uncertainty profile of Retevmo, as monotherapy, is favourable for the treatment of the following cancers that harbour genetic alterations in the rearranged during transfection (RET) gene:
- metastatic RET fusion-positive non-small cell lung cancer in adult patients,
- RET-mutant medullary thyroid cancer in adult and pediatric patients 12 years of age and older with unresectable advanced or metastatic disease,
- RET fusion-positive differentiated thyroid carcinoma in adult patients with advanced or metastatic disease (not amenable to surgery or radioactive iodine therapy) following prior treatment with sorafenib and/or lenvatinib.
Retevmo 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.
Rearranged during transfection (RET) kinase is a receptor tyrosine kinase that plays a critical role in the development of the enteric nervous system and kidney. Postnatally, it contributes to the maintenance of neural, neuroendocrine, hematopoietic, and male germ cell tissues. Genetic alterations in the RET gene (or ret proto-oncogene) have been implicated in the pathogenesis of several human cancers. The oncogenic activation of the RET gene may happen by chromosomal rearrangements (e.g., fusions) which result in endowing the RET receptor tyrosine kinase with constitutive activity, or by point mutations and insertions/deletions which directly or indirectly activate the RET kinase.
Fusions in the RET gene have been identified in 1% to 2% of cases of non-small cell lung cancer (NSCLC), particularly in younger patients (60 years of age or younger) with minimal or no prior tobacco exposure. Non-small cell lung cancer accounts for approximately 85% of all lung cancers. Histologically, NSCLC is generally divided into adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Most cases of RET fusion-positive NSCLC are adenocarcinoma, although cases of other histological types, including adenosquamous cell carcinoma and squamous cell carcinoma, have been reported in the literature. Patients with RET fusion-positive lung cancer commonly have brain metastases at rates similar to those in the overall NSCLC population (approximately 20% to 50% of patients).
The majority of patients with medullary thyroid cancer (MTC) have a RET mutation. Medullary thyroid cancer arises from the C cells (also called parafollicular cells) of the thyroid and accounts for 1% to 2% of all thyroid cancers. It occurs either sporadically (75% of cases) or is associated with familial syndromes (multiple endocrine neoplasia [MEN] type 2 syndromes, MEN2A and MEN2B, and familial MTC) in 25% of cases. Approximately 50% of sporadic cases of MTC carry a somatic RET mutation and at least 90% of familial cases have an identifiable germ line mutation. Sporadic disease typically occurs during the fourth to sixth decade of life, whereas hereditary disease may occur in very young children. Ten-year survival rates for patients with sporadic MTC at stage IV is 21%. However, the clinical course of sporadic MTC is highly heterogeneous, varying from indolent tumors that remain unchanged for many years to aggressive cancers associated with high mortality. Although surgery can be curative for the approximately 85% of patients who present with localized disease, recurrence develops in up to 50% of all patients after surgery. Metastatic MTC is considered incurable and MTC patients with distant metastases have a 5-year survival of 37%.
The follicular cell-derived, differentiated cancers of the thyroid (papillary thyroid cancer and follicular thyroid cancer) are the most common thyroid cancers, representing 80% to 85% and 10% to 15% of all thyroid cancer cases, respectively. Poorly differentiated subtypes (poorly differentiated thyroid cancer and anaplastic thyroid cancer), which are characterized by less differentiated histologic features and more aggressive clinical behaviour than the differentiated subtypes, account for 5% to 10% of thyroid cancers. Fusions in the RET gene have been identified in approximately 6% to 9% of papillary thyroid cancers and in approximately 6% of poorly differentiated thyroid cancers. Neither follicular thyroid cancer nor anaplastic thyroid cancer are frequently associated with RET gene fusions. Differentiated thyroid cancer can occur in children and adolescents, and accounts for 1.4% of all pediatric malignancies. Most cases of differentiated thyroid cancer occurring in children and adolescents are papillary thyroid carcinomas. Rearrangements in the RET gene in papillary thyroid carcinomas are more commonly detected in children than adults. Localized well-differentiated thyroid tumors are usually curable with total thyroidectomy or lobectomy, followed by postoperative treatment with radioactive iodine therapy for patients at high risk of persistent disease or disease recurrence after total thyroidectomy. Up to 30% of patients with differentiated thyroid carcinoma may have recurrence of disease. Sixty-six percent of these recurrences occur within the first decade after initial therapy. In patients with distant metastases, 5-year survival is 50%, regardless of tumor histology.
Selpercatinib, the medicinal ingredient in Retevmo, is an orally available, small-molecule kinase inhibitor that inhibits RET receptor tyrosine kinase (wild type and mutant/fusion isoforms) with good efficacy and selectivity. It can also inhibit other kinases such as vascular endothelial growth factor receptor (VEGFR) 3 (VEGFR3 [FLT4]) and VEGFR1 (FLT1) kinases. Selpercatinib treatment resulted in significant cytotoxicity in human cancer cell lines that harbour endogenous RET gene alterations and minimal cytotoxicity in human cancer cell lines without an endogenous RET gene alteration.
The market authorization of Retevmo was based on efficacy and safety data derived from a Phase I/II, multicentre, open-label, multi-cohort clinical trial (LIBRETTO-001) in patients with advanced RET fusion-positive NSCLC, RET-mutant MTC, and RET fusion-positive thyroid cancer. The Phase I portion of LIBRETTO-001 identified the recommended Phase II dose. Patients in the Phase II portion of the study received Retevmo 160 mg orally twice daily until unacceptable toxicity or disease progression. The major efficacy outcome measures were overall response rate and duration of response, as determined by an independent review committee according to the Response Evaluation Criteria in Solid Tumors (RECIST) guideline, version 1.1.
The efficacy results indicate that monotherapy with Retevmo induces clinically meaningful, durable responses in patients with metastatic RET fusion-positive NSCLC who have previously been treated with one or more lines of platinum-based chemotherapy. An overall response rate of 63.8% (95% confidence interval [CI]: 53.9%, 73.0%) was observed in the primary analysis set of 105 patients with RET fusion-positive NSCLC previously treated with platinum-based chemotherapy. These patients had received a median of 3 prior systemic therapies (range: 1 to 15). The median duration of response was 17.5 months (95% CI: 12.0 months, not estimable). In addition, the results for overall response rate and duration of response suggest potential benefit in patients with metastatic RET fusion-positive NSCLC who have received prior systemic therapies other than platinum-based chemotherapy (anti-programmed death 1 [anti-PD-1] therapy, anti-programmed death ligand 1 [anti-PD-L1] therapy, and multikinase inhibitors) and in treatment-naïve patients with metastatic RET fusion-positive NSCLC.
A clinically meaningful overall response rate of 69.1% (95% CI: 55.2%, 80.9%) was observed in the primary analysis set of 55 patients with advanced or metastatic RET-mutant MTC previously treated with cabozantinib and/or vandetanib. The median duration of response was not reached at the time of data cut-off. Similarly, among 88 patients with RET-mutant medullary thyroid cancer not previously treated with cabozantinib or vandetanib, the overall response rate was 72.7% (95% CI: 62.2%, 81.7%). The median duration of response was 21.95 months (95% CI: not estimable, not estimable). This median result is highly immature, given the inability to evaluate the confidence interval. Nevertheless, these results provide evidence of potential efficacy of Retevmo for the treatment of patients with RET-mutant MTC, irrespective of prior treatments. The clinical benefit of Retevmo treatment has not been demonstrated for patients with resectable disease.
Three patients younger than 18 years of age (15, 16 and 17 years of age) were included in the RET-mutant MTC group of the LIBRETO-001 trial: one patient in the cohort with prior cabozantinib or vandetanib treatment and two patients in the cohort not previously treated with cabozantinib or vandetanib. Two of them achieved a partial response (one in each group) with an observed duration of response of 12.8 months and 14.6 months, and one patient had a stable disease lasting longer than 16 weeks. As of the data cut-off date, the three adolescent patients remained on treatment. Although limited, these results represent promising evidence of clinical effectiveness of Retevmo as a treatment of RET-mutant MTC in adolescent patients.
For the primary efficacy set of 19 patients with RET fusion-positive thyroid cancer who had been previously treated with systemic therapy other than radioactive iodine, the observed overall response rate was 78.9% (15/19; 95% CI: 54.4%, 93.9%) and the median duration of response was 18.4 months (95% CI: 7.6 months, not estimable). Despite the relatively small number of patients, the overall response rate results are considered of sufficient magnitude and durability to provide promising evidence of clinical benefit in patients with papillary thyroid cancer (a subtype of differentiated thyroid cancer). However, this potential benefit needs to be confirmed with results from a larger number of patients.
There are no data on the efficacy of Retevmo for the treatment of adolescent patients with RET fusion-positive thyroid cancer, as no pediatric patients were enrolled in the RET fusion-positive thyroid cancer group of LIBRETTO-001. The results from the LIBRETTO-001 trial provide evidence of potential efficacy of Retevmo for the treatment of adult patients with metastatic RET fusion-positive papillary thyroid cancer who have received prior treatment. In the patient population with RET fusion-positive thyroid cancer, the benefit of Retevmo has not been established for: (i) patients who are systemic therapy-naïve; (ii) patients with advanced disease that is resectable or patients with stable or indolent advanced disease; (iii) patients with histology subtypes other than papillary thyroid cancer; and (iv) patients younger than 18 years of age.
In order to confirm the effectiveness of Retevmo, the final reports of ongoing confirmatory trials will be submitted for evaluation to Health Canada as part of the post-approval commitments.
The safety profile of Retevmo was generally consistent across patients with RET fusion-positive NSCLC (number of patients [n] = 329) and patients with RET-mutant MTC (n = 299). Most patients (99.0%) experienced at least one treatment-emergent adverse event during treatment with Retevmo. The most commonly reported (in at least 25% of patients) adverse reactions, including laboratory abnormalities, are listed in order of decreasing frequency: increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), decreased lymphocytes, increased glucose, decreased leukocytes, decreased albumin, decreased calcium, dry mouth, increased creatinine, diarrhea, increased alkaline phosphatase, hypertension, decreased platelets, increased total cholesterol, fatigue, decreased sodium, rash, and constipation. Thirty-three percent of patients treated with Retevmo experienced serious adverse events. Deaths due to an adverse event occurred in 3% of patients. Fatal adverse events that occurred in more than one patient included sepsis (n = 3), cardiac arrest (n = 3), respiratory failure (n = 3), and hemorrhage (n = 3).
Based on the available data, Retevmo is associated with the serious risks of embryo-fetal toxicity, hemorrhage, hepatotoxicity, hypersensitivity, hypertension, and heart rate-corrected QT (QTc) interval prolongation, all of which have been highlighted in the Serious Warnings and Precautions box of the Retevmo Product Monograph. The identified risks can be mitigated by monitoring and dose modification strategies, as it is conveyed in the Retevmo Product Monograph.
Limited data are available on the safety profile of Retevmo in adolescent patients. There were only three patients aged 15 to 17 years enrolled in the LIBRETTO-001 trial, all of whom had RET-mutant MTC. No additional safety risks were identified in these three adolescent patients compared to the adult patient population. Based on the safety profile established in adult patients, Retevmo is expected to be associated with significant toxicity in adolescents, such as serious hemorrhage, hepatotoxicity, hypersensitivity, hypertension, and QTc interval prolongation. Furthermore, based on animal studies, delayed growth and impaired sexual development may occur in adolescent patients treated with Retevmo. However, the submitted clinical studies were not appropriately designed to evaluate these potential long-term risks in adolescent patients.
The initially proposed Retevmo dose was 160 mg twice daily irrespective of the patient’s weight. However, this dose is considered high for patients with lower weights, as it may be associated with increased toxicity due to increased exposure of selpercatinib. In order to mitigate the risk of QTc interval prolongation, while maintaining adequate antitumor efficacy of the drug, a dose of 120 mg twice daily was recommended for patients weighing less than 50 kg.
Additional safety data will be assessed when the requested final reports of confirmatory studies are submitted, as part of the conditions under the NOC/c Guidance.
A Risk Management Plan (RMP) for Retevmo was submitted by Loxo Oncology, 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 Retevmo Product Monograph meet the necessary regulatory labelling, plain language, and design element requirements.
A review of the submitted brand name assessment, including testing for look-alike sound-alike attributes, was conducted and the proposed name Retevmo was accepted.
Overall, the benefits of Retevmo therapy seen in the LIBRETTO-001 trial are promising and are considered to outweigh the potential risks for the intended patient populations. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Retevmo Product Monograph to address the identified safety concerns. As described within the framework of the NOC/c Guidance, monitoring the safety of the drug will be ongoing. Further evaluation will take place upon the submission of the requested study reports.
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 Retevmo?
At the pre-submission meeting of June 11, 2020, the sponsor requested Advance Consideration under the Notice of Compliance with Conditions (NOC/c) Guidance for the New Drug Submission (NDS) for Retevmo. Upon assessment of the presented information, Health Canada determined that the eligibility criteria were met for the NDS to be filed and reviewed under the NOC/c policy. There was promising evidence of clinical effectiveness that the drug would provide effective treatment of metastatic RET fusion-positive non-small cell lung cancer, advanced or metastatic RET-mutant medullary thyroid cancer, and advanced or metastatic RET fusion-positive thyroid cancer, which are serious and life-threatening diseases with unmet medical needs (i.e., no therapies or not adequately managed by a drug marketed in Canada).
The review of the NDS led to the decision to issue a market authorization for Retevmo under the Notice of Compliance with Conditions (NOC/c) Guidance, in recognition of the promising but unconfirmed evidence of clinical effectiveness presented 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 of the product.
The NDS for Retevmo was reviewed under Project Orbis, an international partnership designed to give cancer patients faster access to promising cancer treatments. The submission for Retevmo was classified as a Project Orbis type C submission, where the United States Food and Drug Administration (FDA) had already issued a positive decision and subsequently shared its completed review documents with Health Canada. The Canadian regulatory decision on the review of Retevmo was made independently and was based on a critical assessment of the data package submitted to Health Canada. The foreign reviews completed by the European Medicines Agency (EMA) and the FDA were used as added references.
Submission Milestones: Retevmo
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting | 2020-06-11 |
| Acceptance of Advance Consideration under the Notice of Compliance with Conditions (NOC/c) Guidance | 2020-08-06 |
| Submission filed | 2020-09-10 |
| Screening | |
| Screening Deficiency Notice issued | 2020-10-07 |
| Response filed | 2020-10-16 |
| Screening Acceptance Letter issued | 2020-10-19 |
| Review | |
| Biostatistics Evaluation completed | 2021-03-12 |
| Biopharmaceutics Evaluation completed | 2021-03-31 |
| Non-Clinical Evaluation completed | 2021-04-22 |
| Quality Evaluation completed | 2021-05-04 |
| Clinical/Medical Evaluation completed | 2021-05-04 |
| Review of Risk Management Plan completed | 2021-05-04 |
| Labelling Review completed | 2021-05-04 |
| Notice of Compliance with Conditions Qualifying Notice (NOC/c-QN) issued | 2021-05-05 |
| Review of Response to NOC/c-QN: | |
| Response filed (Letter of Undertaking) | 2021-05-13 |
| Labelling Review completed | 2021-05-27 |
| Clinical/Medical Evaluation completed | 2021-06-10 |
| Notice of Compliance (NOC) issued by Director General, Therapeutic Products Directorate, under the Notice of Compliance with Conditions (NOC/c) Guidance | 2021-06-15 |
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?
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 reports of ongoing confirmatory trials of Retevmo (selpercatinib, also known as LOXO-292), as follows:
- The final reports of study LIBRETTO-001 (LOXO-RET-17001): “A Phase 1/2 Study of Oral LOXO-292 in Patients with Advanced Solid Tumors, Including RET Fusion-Positive Solid Tumors, Medullary Thyroid Cancer and Other Tumors with RET Activation”, for patients with:
- RET fusion-positive metastatic non-small cell lung cancer (NSCLC). The report will include:
- Blinded independent central review (BICR)-assessed overall response rate and duration of response after all responders in the population of at least 180 patients have been followed for at least 12 months from the date of initial response (or until disease progression, whichever comes first) in patients with NSCLC previously treated with platinum therapy.
- BICR-assessed overall response rate and duration of response after all responders in the population of at least 65 patients have been followed for at least 12 months from the date of initial response (or until disease progression, whichever comes first) in patients with treatment-naïve NSCLC.
- RET-mutant advanced or metastatic medullary thyroid cancer (MTC). The report will include:
- BICR-assessed overall response rate and duration of response in at least 125 patients with RET-mutant MTC who received one or more lines of prior cabozantinib and/or vandetanib, after all patients have been followed for at least 24 months from first dose of selpercatinib or until disease progression, whichever comes first.
- BICR-assessed overall response rate and duration of response in at least 125 patients with RET-mutant MTC naïve to cabozantinib and vandetanib after all patients have been followed for at least 24 months from first dose of selpercatinib or until disease progression, whichever comes first.
- BICR-assessed overall response rate and duration of response in three adolescent patients who have been followed for at least 24 months from first dose of selpercatinib.
- RET fusion-positive advanced or metastatic thyroid cancer. The report will include:
- BICR-assessed overall response rate and duration of response in at least 50 patients after all responding patients have been followed for 12 months following onset of response or until disease progression, whichever comes first, in patients with RET fusion-positive thyroid cancer who have received radioactive iodine (if appropriate for their tumor histology).
- The final report of study LIBRETTO-431 (J2G-MC-JZJC): “A Multicenter, Randomized, Open-Label, Phase 3 Trial Comparing Selpercatinib to Platinum-Based and Pemetrexed Therapy with or without Pembrolizumab as Initial Treatment of Advanced or Metastatic RET Fusion-Positive Non-Small Cell Lung Cancer”, to provide substantial evidence for confirming that Retevmo is associated with an improved clinical benefit compared to currently marketed therapies in Canada for patients with metastatic RET fusion-positive NSCLC.
Based on the similarity of the underlying biology driving both RET fusion-positive thyroid cancers and RET fusion-positive NSCLC, the results from LIBRETTO-431 in patients with RET fusion-positive NSCLC could provide data to support the clinical benefit of selpercatinib in patients with RET fusion-positive thyroid cancer.
- The final report of study LIBRETTO-531 (J2G-MC-JZJB): “A Multicenter, Randomized, Open-label, Phase 3 Trial Comparing Selpercatinib to Physicians Choice of Cabozantinib or Vandetanib in Patients with Progressive, Advanced, Kinase Inhibitor Naïve, RET-Mutant Medullary Thyroid Cancer”
- To provide substantial evidence for confirming that Retevmo is associated with an improved clinical benefit compared to currently marketed therapies in Canada for patients with advanced or metastatic RET-mutant MTC. The results of the efficacy endpoints “progression-free survival” and “overall survival” will be used to confirm the improved clinical benefit.
- To provide confirmatory results supporting the clinical benefit of Retevmo for the treatment of adolescent patients with advanced or metastatic RET-mutant MTC.
- The final report of study LIBRETTO-121 (LOXO-RET-18036): “A Phase 1/2 Study of the Oral RET Inhibitor LOXO 292 in Pediatric Patients with Advanced RET-Altered Solid or Primary Central Nervous System Tumors”, to support the clinical benefit of Retevmo for the treatment of adolescent patients with advanced or metastatic RET-mutant MTC.
- An integrated analysis of the clinical benefit of Retevmo in pediatric patients 12 years of age and older from LIBRETTO-001, LIBRETTO-531, and LIBRETTO-121 that further characterizes the efficacy of Retevmo and its potential serious risk of long-term adverse effects of selpercatinib on growth and development.
6 What other information is available about drugs?
Up-to-date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision
Clinical Pharmacology
The clinical pharmacology data support the use of selpercatinib, the medicinal ingredient in Retevmo, for the specified indications. Selpercatinib is an orally available, small-molecule kinase inhibitor that inhibits RET receptor tyrosine kinase (wild type and mutant/fusion isoforms) with good efficacy and selectivity. It can also inhibit other kinases such as vascular endothelial growth factor receptor (VEGFR) 3 (VEGFR3 [FLT4]) and VEGFR1 (FLT1) kinases.
The pharmacokinetics of selpercatinib was comparable between healthy volunteers and cancer patients. Limited data are available on the pharmacokinetics of selpercatinib in pediatric patients 12 to17 years of age.
Steady state was reached by approximately 7 days and the median accumulation ratio after oral administration of selpercatinib 160 mg twice daily was 3.4-fold for the area under the concentration-time curve (AUC) and 2.66-fold for the maximum observed concentration (Cmax). At steady state, the mean selpercatinib Cmax was 2,980 ng/mL, AUC in a dosing interval of 24 hours (AUC0-24 h) was 51,600 ng*h/mL, half-life was 24.5 hours and apparent total body clearance was 6 L/h after oral administration of selpercatinib 160 mg twice daily in cancer patients.
Selpercatinib is metabolized predominantly by cytochrome P450 (CYP) 3A4 (CYP3A4) enzymes. Unchanged selpercatinib constituted 86% of the radioactive drug components in plasma. Approximately 69% of the administered selpercatinib dose was recovered in feces and 24% was recovered in urine. Exposure-response analysis demonstrated that selpercatinib 160 mg twice daily was the optimal clinical dose.
In clinical trials, selpercatinib caused concentration-dependent prolongation of the heart rate-corrected QT (QTc) interval. A prolonged QTc interval predisposes the patient to torsade de pointes. Torsade de pointes can be asymptomatic or experienced by the patient as dizziness, palpitations, syncope, or seizures. If sustained, torsade de pointes can progress to ventricular fibrillation and sudden cardiac death.
In the LIBRETTO-001 trial (described in the Clinical Efficacy section), in patients in whom Retevmo was initiated at the dose of 160 mg twice daily, the mean change from baseline in the QT interval corrected for heart rate according to the Fredericia formula (QTcF) averaged from 18 ms to 22 ms at 2 hours after dosing from day 8 of treatment onward. Treatment-emergent QTcF interval prolongation values higher than 480 ms and higher than 500 ms were reported in 16.9% and 6.1% of patients, respectively. Increases of more than 60 ms from baseline QTcF interval values were reported in 15.4% of patients.
In a randomized, double-blind, placebo- and positive-controlled, 4-way crossover electrocardiogram (ECG) assessment study in 32 healthy subjects (LOXO-RET-18032), selpercatinib at single supratherapeutic doses of 320 mg and 640 mg was associated with a concentration-dependent prolongation of the QTcF interval. The maximum difference from placebo in mean change from baseline QTcF interval was 8.1 ms (90% confidence interval [CI]: 4.28, 11.87) at 12 hours post dosing in the 320 mg arm and 9.7 ms (90% CI: 6.98, 12.47) at 2.5 hours post dosing in the 640 mg treatment arm. The mean Cmax values were 2,024 ng/mL and 2,356 ng/mL after the single 320 mg and 640 mg doses, respectively, which are lower than the mean Cmax value for the recommended therapeutic dose of 160 mg twice daily at steady state.
According to a pharmacokinetic-pharmacodynamic model, the predicted magnitude of QTcF interval prolongation at the mean steady-state Cmax value of 2,980 ng/mL reported for the 160 mg therapeutic dose in cancer patients was 10.7 ms (90% CI: 9.3, 12.2).
The Cmax values of selpercatinib are increased in the presence of moderate to strong CYP3A4 inhibitors, which would be expected to lead to an exaggerated QTc interval prolongation effect.
Based on a population pharmacokinetic analysis, in subjects with body weights lower than 50 kg, the AUC and the maximal concentrations of selpercatinib were approximately 50% and 70% higher than in subjects with body weights of 70 kg to 80 kg. Therefore, dosing adjustment of selpercatinib to 120 mg twice daily is required in subjects who weigh under 50 kg to minimize the risk of adverse events, including QTc interval prolongation.
In patients with severe hepatic impairment, selpercatinib dose must be reduced to 80 mg twice daily (irrespective of a patient’s weight). No dosage adjustment is necessary in patients with mild or moderate hepatic impairment. Similarly, no dosage adjustment is required in patients with mild, moderate or severe renal impairment. The effect of end-stage renal disease on the pharmacokinetics and safety of selpercatinib has not been evaluated. Therefore, the use of selpercatinib is not recommended in patients with end-stage renal disease.
A list of established or potential drug-drug interactions and relevant recommendations to avoid coadministration of Retevmo with drugs that may increase selpercatinib plasma concentrations (strong and moderate CYP3A4 inhibitors) and with drugs that may decrease selpercatinib plasma concentrations (strong and moderate CYP3A4 inducers, and proton pump inhibitors), have been included in the Retevmo Product Monograph.
For further details, please refer to the Retevmo Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The efficacy of Retevmo in patients with advanced RET fusion-positive non-small cell lung cancer, RET-mutant medullary thyroid cancer, and RET fusion-positive thyroid cancer was evaluated in a Phase I/II, multicentre, open-label, multi-cohort clinical trial (LIBRETTO-001). The Phase I portion of LIBRETTO-001 identified the recommended Phase II dose. Patients in the Phase II portion of the study received Retevmo 160 mg orally twice daily until unacceptable toxicity or disease progression.
The major efficacy outcome measures were overall response rate and duration of response, as determined by an independent review committee according to the Response Evaluation Criteria in Solid Tumors (RECIST) guideline, version 1.1.
Patients with RET fusion-positive non-small cell lung cancer (NSCLC)
A clinically meaningful overall response rate of 63.8% (95% confidence interval [CI]: 53.9%, 73.0%) was observed in the primary analysis set of 105 patients with RET fusion-positive NSCLC previously treated with platinum-based chemotherapy. These patients had received a median of 3 prior systemic therapies (range: 1 to 15). The median duration of response was 17.5 months (95% CI: 12.0 months, not estimable).
The overall response rate results derived from an integrated analysis set of 184 patients previously treated with platinum-based chemotherapy were consistent with the results of the primary analysis set. This larger set included the 105 patients from the primary analysis set.
An exploratory subgroup analysis of 58 patients who had received an anti-programmed death 1 (anti-PD-1) or anti-programmed death ligand 1 (anti-PD-L1) therapy, either sequentially or concurrently with platinum-based chemotherapy, showed an overall response rate of 66% (95% CI: 52%, 78%). The median duration of response was not reached (95% CI: 12.0 months, not estimable).
Among the 105 previously treated patients of the primary analysis set, 11 had measurable central nervous system (CNS) metastases at baseline and had not received radiation therapy to the brain within 2 months prior to study entry. Responses in intracranial lesions were observed in 10 of these 11 patients (90.9% [95% CI: 58.7%, 99.8%]). The median CNS duration of response for patients with measurable CNS disease at baseline was 10.1 months (95% CI: 6.7 months, not estimable).
In the analysis set of 39 treatment-naïve patients (i.e., patients who have not received any prior anticancer therapy), the overall response rate was 85% (33/39) (95% CI: 69.5%, 94.1%). After median follow-up of 7.4 months, the median duration of response was not yet reached (95% CI: 12.0 months, not estimable).
In the LIBRETTO-001 trial, 98% of the previously treated patients and all of the treatment-naïve patients with RET fusion-positive NSCLC had metastatic disease. Accordingly, locally advanced RET fusion-positive NSCLC is not included in the Retevmo indications.
Due to limited clinical data, the efficacy of Retevmo in patients with RET fusion-positive NSCLC of squamous histology has not been fully evaluated. Only one patient with RET fusion-positive NSCLC of squamous histology was enrolled and treated with Retevmo in the LIBRETTO-001 trial. The patient achieved partial response based on the independent review committee assessment and stable disease as per the investigator assessment.
The overall response rate and duration of response analyzed by fusion partners were consistent across patients with cancers harbouring a KIF5B-RET fusion, a CCDC6-RET fusion, or an unknown RET fusion partner (i.e., the molecular test reported a RET fusion but did not specify the fusion partner). These efficacy endpoints were difficult to characterize for the small number of patients with tumors harbouring other fusion partners.
Patients younger than 18 years of age were not included in the efficacy population for RET fusion-positive NSCLC. Consequently, the indication of Retevmo for patients with metastatic RET fusion-positive NSCLC is restricted to adult patients.
Overall, the efficacy results indicate that monotherapy with Retevmo induces clinically meaningful, durable responses in patients with metastatic RET fusion-positive NSCLC who have previously been treated with one or more lines of platinum-based chemotherapy. In addition, the results for overall response rate and duration of response suggest potential benefit in patients who have received prior systemic therapies other than platinum-based chemotherapy (anti-PD/PD-L1 therapy or multikinase inhibitors) and in treatment-naïve patients. Further follow-up is needed to confirm the clinical benefit.
Patients with RET-mutant medullary thyroid cancer (MTC)
The results from LIBRETTO-001 indicate that monotherapy with Retevmo induces clinically meaningful responses in patients with RET-mutant MTC who had previously received cabozantinib and/or vandetanib and in patients with RET-mutant MTC who were naïve to treatment with cabozantinib and vandetanib.
An overall response rate of 69.1% (95% CI: 55.2%, 80.9%) was observed in the primary analysis set of 55 patients with advanced or metastatic RET-mutant MTC previously treated with cabozantinib and/or vandetanib. Notably, 53% of these heavily pretreated patients had received two or more multikinase inhibitors prior to enrollment in the study. The median duration of response was not reached at the time of data cut-off.
The overall response rate (67.7% [95% CI: 58.8%, 75.9%]) derived from an integrated analysis set of 124 patients previously treated with cabozantinib and/or vandetanib was consistent with the results of the primary analysis set. This larger set included the 55 patients from the primary analysis set.
The overall response rates were also consistent among the analyzed subgroups (by age, sex, race, Eastern Cooperative Oncology Group [ECOG] performance status, RET mutation type, type of RET molecular assay, number of prior therapies, and type of prior systemic therapy).
Among 88 patients with RET-mutant MTC not previously treated with cabozantinib or vandetanib, the overall response rate was 72.7% (95% CI: 62.2%, 81.7%). The median duration of response was 21.95 months (95% CI: not estimable, not estimable). This median result is highly immature, given the inability to evaluate the confidence interval.
Overall, these results provide evidence of potential efficacy of Retevmo for the treatment of patients with RET-mutant MTC, irrespective of prior treatments. Further follow-up is needed to confirm the clinical benefit. The RET-mutant MTC indication was revised to exclude patients with resectable disease, for whom the clinical benefit of Retevmo treatment has not been demonstrated.
Pediatric patients with RET-mutant MTC
Three patients younger than 18 years of age (15, 16 and 17 years of age) were included in the RET-mutant MTC group of the LIBRETTO-001 trial: one patient in the cohort with prior cabozantinib or vandetanib treatment and two patients in the cohort not previously treated with cabozantinib or vandetanib. Two of them achieved a partial response (one in each group) with an observed duration of response of 12.8 months and 14.6 months, and one patient had a stable disease lasting longer than 16 weeks. As of the data cut-off date, the three adolescent patients remained on treatment. Although limited, these results represent promising evidence of clinical effectiveness of Retevmo as a treatment of RET-mutant MTC in adolescent patients.
An ongoing trial of Retevmo, LIBRETTO-531, recruiting patients with RET-mutant MTC, is expected to provide more data regarding the clinical benefit of Retevmo for the treatment of adolescent patients with advanced or metastatic RET-mutant MTC. Assuming an enrollment rate of 2% for pediatric patients with RET-mutant MTC (as observed in LIBRETTO-001) and an expected overall enrollment of 400 patients with RET-mutant MTC, approximately eight pediatric patients could be enrolled in LIBRETTO-531. In conjunction with data from the continued follow-up of pediatric patients from LIBRETTO-001, the results derived from pediatric patients in LIBRETTO-531 may be sufficient to confirm the benefit of Retevmo in this patient population.
Another Phase I/II trial of Retevmo, LIBRETTO-121, is underway in pediatric patients with advanced solid or primary CNS tumors and may also provide data for confirming the clinical benefit of Retevmo in adolescent patients with RET-mutant MTC.
Patients with RET fusion-positive thyroid cancer
The results from LIBRETTO-001 trial indicate that treatment with single-agent Retevmo induces clinically meaningful responses in patients with RET fusion-positive thyroid cancer who have had disease progression following prior systemic treatment.
For the primary efficacy set of 19 patients with RET fusion-positive thyroid cancer who had been previously treated with systemic therapy other than radioactive iodine, the observed overall response rate was 78.9% (95% CI: 54.4%, 93.9%) and the median duration of response was 18.4 months (95% CI: 7.6 months, not estimable).
Among these 19 patients, tumor histological types included papillary thyroid cancer (number of patients [n] = 13), poorly differentiated thyroid cancer (n = 3), anaplastic thyroid cancer (n = 2), and Hürthle cell thyroid cancer (n = 1). Patients were radioactive iodine-refractory (if radioactive iodine was an appropriate treatment option) and had received a median of 3 (range: 1 to 7) prior therapies. Two of the 19 patients (10.5%) had achieved a best response of “partial response” to their last systemic treatment.
Despite the relatively small number of patients, the overall response rate results are considered of sufficient magnitude and durability to provide promising evidence of clinical benefit in patients with papillary thyroid cancer (a subtype of differentiated thyroid cancer). However, this potential benefit needs to be confirmed with results from a larger number of patients.
While responses were observed in four patients with tumor histological subtypes other than papillary thyroid cancer, the limited number of these patients precluded assessment of the median duration of response. The initially proposed indication was revised to be restricted to patients with differentiated thyroid cancer, which encompasses papillary and follicular thyroid cancers. As the follicular thyroid cancer does not commonly harbour RET fusions, by restricting the indication to patients with differentiated thyroid cancer, the vast majority of the targeted patients are expected to be those with RET-fusion positive papillary thyroid cancer. This approach is consistent with the approved indications of sorafenib and lenvatinib, multikinase inhibitors authorized for the treatment of patients with differentiated thyroid cancer refractory to radioactive iodine. Patients with RET fusion-positive differentiated thyroid cancer whose disease relapses or becomes refractory following treatment with sorafenib or lenvatinib would be eligible for Retevmo treatment.
The initially proposed indication for RET fusion-positive thyroid cancer included patients with advanced disease. However, all patients with RET fusion-positive thyroid cancer enrolled in the LIBRETTO-001 trial had metastatic disease at baseline. Patients with advanced RET fusion-positive thyroid cancer may have resectable or relatively indolent disease. For this category of patients, the study results did not indicate that the potential benefit of Retevmo treatment would outweigh its associated risks. Consequently, the indication was restricted to patients with advanced or metastatic disease (not amenable to surgery or radioactive iodine therapy) following prior treatment with sorafenib and/or lenvatinib.
The sponsor has also provided the efficacy results from eight patients comprising the analysis set referred to as “systemic therapy-naïve patients”. Given that this analysis set was not prespecified in the statistical analysis plan and the patients included were not accounted for in the demographic data, the overall response rate results derived from this analysis set were not considered sufficiently reliable to support the potential efficacy of Retevmo in treatment-naïve patients with RET fusion-positive thyroid cancer. In addition, although sorafenib and lenvatinib are not specifically marketed for patients with RET fusion-positive thyroid cancer, there is no evidence that the patient subpopulation with RET fusion-positive thyroid cancer would respond differently to these drugs. The submission does not contain any promising evidence of an improved benefit-risk profile with Retevmo over these existing therapies for the treatment of systemic therapy-naïve patients with thyroid cancer. Moreover, the proposed confirmatory approach will not be able to confirm that Retevmo is associated with an improved benefit over marketed drugs in Canada for patients with RET fusion-positive thyroid cancer who have not received prior systemic therapies.
The initially proposed indication for RET fusion-positive thyroid cancer included pediatric patients 12 years of age and older. However, no pediatric patients were enrolled in the RET fusion-positive thyroid cancer group of the LIBRETTO-001 trial. Consequently, there are no data on the efficacy of Retevmo for the treatment of adolescent patients with RET fusion-positive thyroid cancer. The proposed extrapolation of the efficacy data from adult to adolescent patients was not considered appropriate in the absence of demonstrated similarity in clinical behaviour of RET fusion-positive thyroid cancer in adult and adolescent patients. Furthermore, the sponsor has not provided an acceptable strategy for confirming the benefit of Retevmo in adolescent patients with advanced or metastatic thyroid cancer. It is therefore unknown if the potential benefit outweighs the risks associated with Retevmo in adolescent patients. Due to this uncertainty, the indication for the treatment of advanced or metastatic RET fusion-positive thyroid cancer has been restricted to adult patients.
Overall, the results from the LIBRETTO-001 trial provide evidence of potential efficacy of Retevmo for the treatment of adult patients with metastatic RET fusion-positive papillary thyroid cancer who have received prior treatment. Further follow-up is needed to confirm the clinical benefit.
In the patient population with RET fusion-positive thyroid cancer, the benefit of Retevmo has not been established for: (i) patients who are systemic therapy-naïve; (ii) patients with advanced disease that is resectable or patients with stable or indolent advanced disease; (iii) patients with histology subtypes other than papillary thyroid cancer; and (iv) patients younger than 18 years of age.
Indications
The New Drug Submission for Retevmo was filed by the sponsor with the following proposed indications:
Retevmo (selpercatinib) is indicated as monotherapy for the treatment of:
- metastatic RET fusion-positive non-small cell lung cancer (NSCLC) in adult patients,
- advanced or metastatic RET-mutant medullary thyroid cancer (MTC) in adult and pediatric patients 12 years of age and older who require systemic therapy,
- advanced or metastatic RET fusion-positive thyroid cancer in adult and pediatric patients 12 years of age and older who require systemic therapy and are radioactive iodine (RAI)-refractory (if RAI is appropriate).
Upon review of the submitted data, Health Canada revised the proposed indications to reflect a more accurate representation of the studied patient populations with RET-mutant medullary thyroid cancer and RET fusion-positive thyroid cancer in the LIBRETTO-001 trial. Rationales for the revisions are elaborated in the Clinical Efficacy section. Accordingly, Health Canada approved the following indications:
Retevmo (selpercatinib) is indicated as monotherapy for the treatment of:
- metastatic RET fusion-positive non-small cell lung cancer (NSCLC) in adult patients,
- RET-mutant medullary thyroid cancer (MTC) in adult and pediatric patients 12 years of age and older with unresectable advanced or metastatic disease,
- RET fusion-positive differentiated thyroid carcinoma in adult patients with advanced or metastatic disease (not amenable to surgery or radioactive iodine therapy) following prior treatment with sorafenib and/or lenvatinib.
For more information, refer to the Retevmo Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The safety of Retevmo was evaluated in the first-in-human Phase I/II trial of Retevmo, LIBRETTO-001, which had an open-label, single-arm design (see the Clinical Efficacy section). As of the data cut-off, 702 patients had received at least one dose of Retevmo.
The uncontrolled design of the study did not allow a clear distinction to be made between the signs/symptoms of the underlying diseases and Retevmo-related adverse events. In addition, there was a significant heterogeneity between the studied populations in terms of age, type of malignancy, and dose administered (from 20 mg once daily to 240 mg twice daily). Among the 702 patients, 667 (95%) received the recommended dose of 160 mg twice daily, which represented a starting dose for 609 (86.8%) patients and a protocol-specified dose adjustment for 58 (8.3%) patients. Patients were treated with Retevmo for a median period of 8.7 months (range: 0.1 to 31.0 months). Median dose intensity (i.e., the median total amount of drug delivered over the total time course of treatment) for the overall study population was 96.7%.
The safety profile of Retevmo was generally consistent across patients with RET fusion-positive non-small cell lung cancer (number of patients [n] = 329) and patients with RET-mutant medullary thyroid cancer (n = 299).
Most patients (99.0%) experienced at least one treatment-emergent adverse event during treatment with Retevmo.
The most commonly reported adverse reactions (in at least 25% of patients), including laboratory abnormalities, are listed in order of decreasing frequency: increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), decreased lymphocytes, increased glucose, decreased leukocytes, decreased albumin, decreased calcium, dry mouth, increased creatinine, diarrhea, increased alkaline phosphatase, hypertension, decreased platelets, increased total cholesterol, fatigue, decreased sodium, rash, and constipation.
Thirty-three percent of patients treated with Retevmo experienced serious adverse events. Deaths due to an adverse event occurred in 3% of patients. Fatal adverse events that occurred in more than one patient included sepsis (n = 3), cardiac arrest (n = 3), respiratory failure (n = 3), and hemorrhage (n = 3).
Permanent discontinuation of Retevmo due to an adverse event occurred in 5% of patients. Adverse events resulting in permanent treatment discontinuation included increased ALT (0.4%), sepsis (0.4%), increased AST (0.3%), drug hypersensitivity (0.3%), fatigue (0.3%), and thrombocytopenia (0.3%).
Dosage interruptions due to an adverse event occurred in 42% of patients treated with Retevmo. Adverse events requiring dosage interruption in more than 2% of patients included increased ALT, increased AST, hypertension, diarrhea, pyrexia, and QT interval prolongation.
Dose reductions due to an adverse event occurred in 31% of patients who received Retevmo. Adverse events requiring dose reductions in more than 2% of patients included increased ALT, increased AST, QT interval prolongation, and fatigue.
Based on the available data, Retevmo is associated with the serous risks of embryo-fetal toxicity, hemorrhage, hepatotoxicity, hypersensitivity, hypertension, and QTc interval prolongation, all of which have been outlined in the Serious Warnings and Precautions box of the Retevmo Product Monograph. The identified risks can be mitigated by monitoring and dose modification strategies, as it is conveyed in the Retevmo Product Monograph.
There are no available data regarding the use of Retevmo in pregnant women. It is unknown whether Retevmo is excreted in human milk. Similarly, no human data are available on the effect of Retevmo on fertility.
No clinically relevant differences in the treatment-emergent adverse event profile were observed between patients younger than 65 years of age and patients 65 years of age or older, or between males and females.
Pediatric patients
There are limited data on the safety profile of Retevmo in pediatric patients. The safety of Retevmo has been evaluated in only three patients aged 15 to 17 years enrolled in LIBRETTO-001. They all had RET-mutant MTC. No additional safety risks were identified in these three adolescent patients compared to the adult population. All but one of the treatment-emergent adverse events were Grade 1 (mild) or Grade 2 (moderate) in severity. Based on the safety profile established in adult patients, Retevmo is expected to be associated with significant toxicity in adolescents, such as serious hemorrhage, hepatotoxicity, hypersensitivity, hypertension, and QTc interval prolongation.
Additional safety summary information was provided for six pediatric patients (1 to 10 years old) who received Retevmo via single-patient protocols. These patients had different types of RET-altered solid tumors. Two of these pediatric patients had events of QTc interval prolongation related to Retevmo, which appeared to have been temporally associated with elevated maximum concentration (Cmax) values. The first patient was 8 years old (weight unknown) and received Retevmo 80 mg twice daily. The Cmax of Retevmo was 4,970 ng/mL on the day of the observed QTc interval prolongation. The second patient was 1 year old and received Retevmo 90 mg/m2 twice daily. The Cmax was 5,289 ng/mL on the day of the observed QTc interval prolongation. These clinical observations suggest that there is a correlation between the risk of QTc interval prolongation and the Cmax values. No other unexpected safety findings were observed in these pediatric patients.
The patients from the single-patient protocols ranged in age from 1 to 10 years old and were therefore younger than the age range for the proposed indications. Therefore, there is a gap in the evidence of safety for patients aged 11 to 14 years. However, since there were no unexpected safety findings in the age group of 1 to 10 years and in the age group of 15 to 17 years, it is likely that the safety profile of Retevmo in patients aged 11 to 14 years will be similar. Nevertheless, due to the limited total number of pediatric patients treated with Retevmo, the safety profile of Retevmo in adolescent patients (12 to 17 years old) has not been fully characterized.
Of note, non-clinical studies showed epiphyseal growth plate thickening in rats and minipigs exposed to selpercatinib. This non-clinical effect on growth was partially reversible in rats and it was considered reversible in minipigs. The non-clinical studies also showed that spermatogenesis and estrous cycling of animals were affected at clinically relevant exposures. The impact on long-term fertility was not assessed.
Based on animal studies, delayed growth and impaired sexual development may occur in adolescent patients treated with Retevmo. However, the submitted clinical studies were not appropriately designed to evaluate these potential long-term risks in adolescent patients.
The initially proposed Retevmo dose was 160 mg twice daily regardless of a patient’s weight. However, this dose may be high for patients with lower weights, as it may be associated with increased toxicity. Therefore, to mitigate the risk of QTc interval prolongation, while maintaining adequate antitumor efficacy of the drug, a dose of 120 mg twice daily is recommended for patients weighing less than 50 kg.
As part of the conditions under the NOC/c Guidance, an integrated analysis of data from pediatric patients will be provided along with the final reports of confirmatory studies, in order to confirm the clinical benefit of Retevmo in adolescent patients.
Appropriate warnings and precautions are in place in the approved Retevmo Product Monograph to address the identified safety concerns.
For more information, refer to the Retevmo Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
Selpercatinib, the medicinal ingredient in Retevmo, is a small-molecule kinase inhibitor. In enzyme assays, selpercatinib inhibited the rearranged during transfection (RET) receptor tyrosine kinase, vascular endothelial growth factor receptor (VEGFR) 3 (VEGFR3 [FLT4]) and VEGFR1 (FLT1) kinases with half-maximal inhibitory concentration (IC50) values ranging from 0.92 nM to 67.6 nM.
In vitro, selpercatinib demonstrated inhibition of human cancer cell lines derived from multiple tumor types harbouring RET gene fusions and mutations.
In mouse studies, selpercatinib demonstrated inhibition of tumor growth in RET fusion and RET mutant cancer cell allografts, patient-derived RET fusion xenograft models, and a patient-derived RET fusion xenograft model harbouring a RET V804M mutation. Selpercatinib also exhibited antitumor activity in mice intracranially implanted with patient-derived RET fusion xenograft tumors
The IC50 values at which selpercatinib inhibits both mutated RET kinase isoforms and VEGFR kinases are similar (ranging from 0.92 nM to 67.6 nM). Inhibition of the VEGF signalling pathway can cause side effects, including hypertension, rashes, and impaired wound healing.
Repeat-dose toxicity studies were conducted in rats and minipigs. Target organs of toxicity were the hematopoietic system, lymphoid tissues, tongue, pancreas, epiphyseal growth plate, and male reproductive tissues. In general, toxicities observed in these organs were reversible, with the exception of testicular toxicity. Reversible toxicity was observed in the ovaries and gastrointestinal tract in minipigs only. At high doses, gastrointestinal toxicity caused morbidity in minipigs at exposures that were generally lower than exposures determined in humans at the recommended dose. Minipigs also showed signs of minimal to marked increases in tongue, esophagus, and stomach atrophy at a high dose (approximately 0.3 times the human exposure at the 160 mg twice daily clinical dose).
Based on findings in animal studies, treatment with selpercatinib may impair fertility in men and women of reproductive potential. The potential for impaired sexual development has not been fully evaluated in the non-clinical studies. There is a potential risk for impaired sexual development in adolescent humans as they are still in the reproductive development phase.
In repeat-dose toxicity studies, animals showed signs of physeal hypertrophy and tooth dysplasia at doses resulting in exposures of selpercatinib equal to or higher than approximately 3 times (for rats) and approximately 0.3 times (for minipigs) the human exposure at the clinical dose of 160 mg twice daily. There is a potential risk for delayed growth in pediatric patients, as adolescent humans are still in the skeletal growth development phase. The reversibility of this potential risk has not been fully evaluated.
Carcinogenicity studies have not been conducted with selpercatinib. Based on data from in vitro genotoxicity tests, selpercatinib is considered to be non-genotoxic at the recommended human therapeutic dose of 160 mg twice daily. In vivo, in a micronucleus assay in rats, selpercatinib exhibited genotoxicity at concentrations higher than 7 times the Cmax at the human dose of 160 mg twice daily.
Based on data from the embryo-fetal development studies and its mechanism of action, selpercatinib can cause fetal harm when administered to a pregnant woman.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Retevmo Product Monograph. In view of the intended use of Retevmo, there are no pharmacological or toxicological issues within this submission to preclude authorization of the product.
For more information, refer to the Retevmo 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 Retevmo 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 limits and/or qualified from toxicological studies).
All sites involved in production are compliant with Good Manufacturing Practices.
All non-medicinal ingredients (i.e., excipients, described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. There are no excipients of human origin. The only excipient of animal origin is the gelatin used in the capsule shells. Satisfactory information has been provided to establish that this excipient does not pose a risk of contamination with transmissible spongiform encephalopathy agents.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| RETEVMO | 02516918 | LOXO ONCOLOGY INC | SELPERCATINIB 40 MG |
| RETEVMO | 02516926 | LOXO ONCOLOGY INC | SELPERCATINIB 80 MG |