Summary Basis of Decision for Jemperli
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 Jemperli is located below.
Recent Activity for Jemperli
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 Jemperli
Date SBD issued: 2022-03-09
The following information relates to the new drug submission for Jemperli.
Dostarlimab
Drug Identification Number (DIN):
- DIN 02523434 - 50 mg/mL dostarlimab, solution, intravenous administration
GlaxoSmithKline Inc.
New Drug Submission Control Number: 251105
On December 23, 2021, Health Canada issued a Notice of Compliance under the Notice of Compliance with Conditions (NOC/c) Guidance to GlaxoSmithKline Inc. for the drug product Jemperli. 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-risk profile of Jemperli is favourable for use as monotherapy for the treatment of adult patients with mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) recurrent or advanced endometrial cancer that has progressed on or following prior treatment with a platinum-containing regimen.
1 What was approved?
Jemperli, an antineoplastic agent, was authorized for use as monotherapy for the treatment of adult patients with mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) recurrent or advanced endometrial cancer that has progressed on or following prior treatment with a platinum-containing regimen.
The marketing authorization with conditions is primarily based on tumour objective response rate and durability of response. An improvement in survival has not been established.
No data are available to Health Canada regarding use in pediatric patients (younger than 18 years of age); therefore, Health Canada has not authorized an indication in this population.
No overall differences in safety or efficacy were reported between elderly patients (65 years of age and over) and patients younger than 65 years of age.
Jemperli (50 mg/mL dostarlimab) is presented as a solution. In addition to the medicinal ingredient, the solution contains trisodium citrate dihydrate, citric acid monohydrate, L-arginine hydrochloride, sodium chloride, polysorbate 80, and water for injection.
The use of Jemperli 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.
The drug product was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with its administration. The Jemperli Product Monograph is available through the Drug Product Database.
For more information about the rationale for Health Canada's decision, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
2 Why was Jemperli approved?
Health Canada considers that the benefit-risk profile of Jemperli is favourable for use as monotherapy for the treatment of adult patients with mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) recurrent or advanced endometrial cancer that has progressed on or following prior treatment with a platinum-containing regimen.
The marketing authorization with conditions is primarily based on tumour objective response rate and durability of response. An improvement in survival has not been established.
Jemperli 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.
Endometrial cancer, which develops in the lining of the uterus, accounts for more than 90% of cases of gynecological malignancies diagnosed in Canadian women. It has a lifetime prevalence of 2-3%. Endometrial cancer is classified as either mismatch repair (MMR)-deficient (dMMR) or MMR‑proficient (MMRp), depending on the absence or presence of proteins which play critical roles in the MMR process. Defective deoxyribonucleic acid (DNA) mismatch repair results in genetic hypermutability, which is known as microsatellite instability (MSI). Microsatellites are repetitive DNA sequences (1 to 6 bases in length), and are present in both coding and noncoding regions throughout the genome. When mismatch repair is deficient, the resulting accumulation of base pair mismatches in the DNA interferes with its replication and drives genome instability. Genome instability can manifest within microsatellites, resulting in a condition referred to as microsatellite instability-high (MSI-H). In scientific literature and medical practice guidelines, the terms dMMR and MSI-H are used interchangeably. This biomarker (dMMR/MSI-H) has been observed at a high frequency (approximately 34%) in cases of endometrial cancer.
The standard of care for first-line treatment of advanced or metastatic endometrial cancer is carboplatin in combination with paclitaxel. However, there are no approved therapies or specific regimens recommended by international or national medical practice guidelines for patients who have progressed on or after treatment with a platinum-containing regimen. Patients are generally offered single-agent cytotoxic chemotherapy or hormonal therapy with low response rates. In Canada, a Notice of Compliance with conditions (NOC/c) was issued for pembrolizumab (an immune checkpoint inhibitor directed against programmed cell death protein-1 [PD-1]) for the treatment of various cancers including MSI-H cancers and endometrial carcinoma. There remains a need for new therapeutic options that have meaningful and durable effects in this patient population.
Dostarlimab (the medicinal ingredient in Jemperli) is a humanized monoclonal antibody. It is directed against PD-1, a receptor found on the surface of T cells. The upregulation of PD-1 in some tumours leads to increased signalling through this pathway, which can inhibit the immune surveillance of tumours conducted by T cells. Dostarlimab binds to PD-1 and blocks its interaction with the PD-1 ligands, programmed cell death-ligand (PD-L) 1 and PD-L2, thereby inhibiting T-cell proliferation and cytokine production.
Data from the ongoing pivotal study, GARNET, provided the primary evidence of the clinical efficacy and safety of Jemperli. The main efficacy results were based on data from 129 patients (in Cohort A1 of the study) with dMMR/MSI-H endometrial cancer who had progressed on or after a platinum-containing regimen. Patients received 500 mg Jemperli every 3 weeks for 4 cycles, followed by 1,000 mg every 6 weeks. Treatment continued until unacceptable toxicity or disease progression. The primary efficacy endpoints were the objective response rate (ORR) and the duration of response (DOR), as assessed by a blinded independent central review (BICR) according to the Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST v1.1).
In total, 108 of the 129 patients in Cohort A1 were evaluated for efficacy. Twenty-one patients were excluded from the evaluation due to insufficient follow-up time or having no measurable disease at baseline. Based on the primary efficacy results, the BICR-confirmed ORR was 43.5% (47 out of 108 patients; 95% confidence interval [CI] [34.0, 53.4]). A complete response (CR) was achieved by 10.2% of patients (11 out of 108), and a partial response (PR) was achieved by 33.3% of patients (36 out of 108).
At the time of data cut-off, the median DOR had not been reached, 78.3% of responders had a DOR of 6 months or longer, and 89.4% of responders had an ongoing response. In the context of available therapies, the ORR results supported by the DOR results are considered reasonably likely to predict clinical benefit. Therefore, the ORR and DOR results support the conditional approval of Jemperli for the intended indication.
The clinical safety of Jemperli was evaluated primarily in the 129 patients with dMMR/MSI-H endometrial cancer from Cohort A1 of the GARNET study. Supplementary safety data were collected from 515 patients with various advanced solid tumours who received Jemperli monotherapy in the other cohorts of the GARNET study.
The most commonly reported treatment-emergent adverse events (TEAEs), grade ≥3 adverse reactions, serious adverse events, and TEAEs leading to treatment interruption or discontinuation in patients with dMMR/MSI-H endometrial cancer (Cohort A1) are listed in the Clinical Safety section. Thirty-six patients (27.9%) with dMMR/MSI-H endometrial cancer died in the study, with disease progression as the primary or most commonly reported cause of death (31 patients; 24%). None of the patients treated with Jemperli in this cohort experienced an adverse reaction which led to death.
Jemperli is not recommended for pregnant women or women of childbearing potential not using contraception. Women of childbearing potential must use effective contraception during treatment and until four months after the last dose of Jemperli. Additionally, Jemperli should not be used while breastfeeding and breastfeeding should be avoided for at least four months after the last dose of Jemperli.
Important immune-related adverse reactions have been listed in the Warnings and Precautions section of the Jemperli Product Monograph. Infusion-related reactions are also identified as an important risk associated with Jemperli.
Overall, the preliminary efficacy data submitted from the pivotal study is indicative of promising clinical benefit, and the safety profile of Jemperli observed in this study was acceptable in the context of the recommended condition of use. The sponsor is expected to submit additional clinical data in order to confirm the benefit of Jemperli for the intended indication. Taking into account the disease setting, the limited treatment options available, and the magnitude and duration of the observed antitumoural effect, Jemperli is considered to provide a clinically relevant benefit in the target patient population.
A Risk Management Plan (RMP) for Jemperli was submitted by GlaxoSmithKline 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 Jemperli Product Monograph meet the necessary regulatory labelling, plain language, and design element requirements.
The sponsor submitted a brand name assessment that included testing for look-alike sound-alike attributes. Upon review, the proposed name Jemperli was accepted.
Jemperli 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 Jemperli Product Monograph to address the identified safety concerns. As described within the framework of the NOC/c Guidance, safety monitoring of the use of Jemperli 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 issued 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 Jemperli?
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 Jemperli. The sponsor presented promising evidence of clinical effectiveness that Jemperli has the potential to provide effective treatment of a serious, life-threatening disease that is not adequately managed by a drug marketed in Canada.
A subsequent review led to the decision to issue the sponsor a market authorization for Jemperli under the NOC/c Guidance, in recognition of the promising but unconfirmed evidence of clinical effectiveness in the submission. In keeping with the provisions of the NOC/c Guidance, the sponsor agreed to provide additional information to confirm the clinical benefit
The regulatory decision regarding the NDS for Jemperli was based on a critical assessment of the quality, non-clinical, and clinical data submitted to Health Canada. The reviews completed by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) were used as added references, as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.
For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.
Submission Milestones: Jemperli
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting | 2020-11-24 |
| Advance Consideration under the Notice of Compliance with Conditions Guidance accepted | 2021-01-27 |
| New Drug Submission filed | 2021-03-26 |
| Screening | |
| Screening Acceptance Letter issued | 2021-04-23 |
| Review | |
| Review of Risk Management Plan completed | 2021-09-17 |
| Non-clinical evaluation completed | 2021-10-26 |
| Quality evaluation completed | 2021-11-03 |
| Clinical/medical evaluation completed | 2021-11-03 |
| Labelling review completed | 2021-11-08 |
| Notice of Compliance with Conditions Qualifying Notice issued | 2021-11-08 |
| Review of Response to Notice of Compliance with Conditions Qualifying Notice | |
| Response filed (Letter of Undertaking) | 2021-12-02 |
| Clinical/medical evaluation completed | 2021-12-13 |
| Labelling review completed | 2021-12-13 |
| Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate under the Notice of Compliance with Conditions Guidance | 2021-12-23 |
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 results from studies listed below.
Confirmatory Studies
Results from the following studies are expected to be submitted in a Supplement to a New Drug Submission – Confirmatory (SNDS-C) by December 2022:
RUBY Part 1 (Confirmatory Study 4010-03-001)
The sponsor has committed to providing the results of the RUBY study, which is expected to serve as the confirmatory study. This Phase III, randomized, double-blind study will be conducted in patients with mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) recurrent or advanced endometrial cancer who have not received prior systemic anticancer therapy for recurrent or advanced disease. The study is designed to compare the efficacy and safety of treatment with Jemperli in combination with chemotherapy to treatment with chemotherapy alone.
GARNET (Ongoing Study 4010-01-001)
Additional data and updated results from Cohort A1 of the ongoing GARNET study (described in the Clinical Efficacy section) are anticipated in the SNDS-C. Enrolment in the study is expected to increase to include additional patients with measurable disease, to be followed for at least 12 months from the onset of response.
Additional Studies
The sponsor has committed to monitoring and analyzing certain clinical pharmacology parameters. The immunogenicity of Jemperli in clinical trials will be monitored, along with the safety of Jemperli in patients with moderate or severe hepatic impairment or severe renal impairment. In the next appropriate regulatory submission, the sponsor is expected to provide an integrated exposure-response analysis for all patients with liver and kidney impairment, if data become available from clinical trials.
Post-Market Safety Monitoring
The sponsor has agreed to submit annual status reports on the progress of the confirmatory studies (RUBY Part 1 and GARNET) until such time that the clinical study reports have been submitted to Health Canada. These reports are to be submitted within 60 days of the market authorization anniversary. Additionally, Periodic Benefit-Risk Evaluation Reports are to be submitted biannually for 2 years.
The sponsor is expected 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:
- 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
As described above, the review of the clinical component of the New Drug Submission for Jemperli was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.
Clinical Pharmacology
Dostarlimab, the medicinal ingredient in Jemperli, is a humanized immunoglobulin G4 (IgG4) monoclonal antibody. It is directed against programmed cell death protein-1 (PD-1), a receptor found on the surface of T cells. The upregulation of PD-1 in some tumours leads to increased signalling through this pathway, which can inhibit the immune surveillance of tumours conducted by T cells. Dostarlimab binds to PD-1 and blocks its interaction with the PD-1 ligands, programmed cell death-ligand (PD-L) 1 and PD-L2, thereby inhibiting T-cell proliferation and cytokine production.
The review of the clinical pharmacology data included a comprehensive review of the pivotal population pharmacokinetic report, as well as examining the submitted foreign review reports. The pharmacokinetic profile of dostarlimab was assessed using non-compartmental analysis and a population pharmacokinetics-based approach (in 546 subjects) for single-agent dostarlimab. Dostarlimab exhibited linear, dose-proportional pharmacokinetics over the dose range of 1 to 10 mg/kg. Following intravenous infusion, the mean maximum serum concentrations of dostarlimab were generally reached shortly after the end of the infusion. The pharmacokinetics of dostarlimab was described by a two-compartment model, with a time-dependent linear elimination from the central compartment.
Both weight-based and fixed dosing regimens were examined in the pivotal GARNET study (described in the Clinical Efficacy section). The results of the pharmacokinetic simulation indicated that the relative differences in the minimum, maximum, and average plasma concentrations between the weight-based and fixed regimens were within a zone of similarity with respect to efficacy and safety. The fixed dose was selected as the recommended dose in the post-market setting.
The incidence of treatment-emergent anti-drug antibodies (ADAs) was low (2.1%). Neutralizing antibodies were detected in 1.0% of patients. The impact of ADAs on the pharmacokinetics, efficacy, and safety of dostarlimab is unknown due to the limited number of patients with ADAs.
Based on a population pharmacokinetic analysis, no dose adjustment is needed in patients with mild hepatic impairment, or those with mild or moderate renal impairment. Data are not sufficient to draw any conclusions regarding dose adjustments in patients with moderate hepatic impairment or severe renal impairment, and no data are available in patients with severe hepatic impairment.
A Phase I, open-label, single-arm study was conducted, in which the recommended dose of Jemperli was administered to patients with multiple tumour types. No large mean increases were observed in the heart rate-corrected QT (QTc) interval relative to baseline, when assessed at 0.5 hours after administration.
For further details, please refer to the Jemperli Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
Evidence of the clinical efficacy of Jemperli was provided primarily through the pivotal study, GARNET (study 4010-01-001). The GARNET study is an ongoing, multinational, uncontrolled, multiple parallel cohort, open-label, Phase I dose-escalation study. This study also included expansion cohorts in patients with recurrent or advanced solid tumours who have limited available treatment options.
The main efficacy results were based on data from 129 patients in Cohort A1 with mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) endometrial cancer who had progressed on or after a platinum-containing regimen. Local diagnostic assays (immunohistochemistry, polymerase chain reaction, or next-generation sequencing) were used to confirm dMMR/MSI-H tumour status.
Patients received 500 mg Jemperli every 3 weeks for 4 cycles, followed by 1,000 mg every 6 weeks. Treatment continued until unacceptable toxicity or disease progression that was symptomatic, rapidly progressive, required urgent intervention, or occurred with a decline in performance status. The median duration of treatment was 26 weeks, with a minimum of 3 weeks and a maximum of 139 weeks. The primary efficacy endpoints were the objective response rate (ORR) and the duration of response (DOR), as assessed by a blinded independent central review (BICR) according to the Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST v1.1).
The efficacy population was defined as patients who had measurable disease at baseline, and had either a minimum of 24 weeks of follow-up or had less than 24 weeks of follow-up and discontinued due to adverse events or disease progression. Twenty-one patients were excluded from the evaluation due to insufficient follow-up time or having no measurable disease at baseline. Therefore, 108 patients (all 18 years or older) were evaluated for efficacy in the GARNET study.
Based on the primary efficacy results, the BICR-confirmed ORR was 43.5% (47 out of 108 patients; 95% confidence interval [CI] [34.0, 53.4]). A complete response (CR) was achieved by 10.2% of patients (11 out of 108), and a partial response (PR) was achieved by 33.3% of patients (36 out of 108).
At the time of data cut-off, the median DOR had not been reached, 78.3% of responders had a DOR of 6 months or longer, and 89.4% of responders had an ongoing response. The ORR was durable and of sufficient magnitude to serve as an endpoint earlier than improved survival over that of available therapies. This endpoint is considered reasonably likely to predict clinical benefit, and thus supports the conditional approval of Jemperli for the intended indication.
Treatment with Jemperli was associated with promising clinical benefit, based on the preliminary efficacy data submitted from Cohort A1 of the GARNET study. However, the clinical study was limited by its uncontrolled design, sample size, and the immaturity of the data, which must be taken into consideration when evaluating clinical effectiveness. For this reason, the sponsor is expected to submit additional clinical data in order to confirm the benefit of Jemperli for the intended indication. Taking into account the disease setting, the limited treatment options available, and the size and duration of the observed antitumoural effect, Jemperli is considered to provide a clinically relevant benefit in the targeted patient population.
Indication
Health Canada approved the following indication:
Jemperli (dostarlimab for injection) is indicated as a monotherapy for the treatment of adult patients with mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) recurrent or advanced endometrial cancer (EC) that has progressed on or following prior treatment with a platinum-containing regimen.
For more information, refer to the Jemperli Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The clinical safety of Jemperli was evaluated primarily in 129 patients from Cohort A1 of the GARNET study (described in the Clinical Efficacy section) with dMMR/MSI-H endometrial cancer. Supplementary safety data were collected from patients with various advanced solid tumours who received Jemperli monotherapy in the other cohorts of the GARNET study, for a total of 515 evaluated patients.
In patients with dMMR/MSI-H endometrial cancer (Cohort A1; 129 patients) the most commonly reported treatment-emergent adverse events (TEAEs; reported in ≥10% of patients) were nausea (32.6%), diarrhea (27.9%), anemia (27.1%), fatigue (24.8%), vomiting (18.6%), pyrexia (10.9 %), arthralgia (15.5%), pruritus (14.0%), back pain (14.7%), rash (10.1%), myalgia (10.9%), cough (16.3%), peripheral edema (10.1%), constipation (19.4%), abdominal pain (16.3%), urinary tract infection (15.5%), decreased appetite (12.4%), and asthenia (21.7%). The grade ≥3 adverse reactions that occurred in more than one patient were anemia (14.7%), diarrhea (2.3%), increased alanine transaminase (2.3%), increased transaminases (1.6%), and colitis (1.6%). The only Grade 4 TEAE reported in more than 1% of patients with dMMR/MSI-H endometrial cancer was sepsis (3 patients; 2.3%).
Serious adverse events (SAEs) were reported in 44 patients (34.1%) with dMMR/MSI-H endometrial cancer. The most frequently reported SAEs (in over 2% of patients) were abdominal pain, acute kidney injury, sepsis, pulmonary embolism, pyrexia, and urinary tract infection. In 10 of the 44 patients, the SAEs were considered to be immune-related.
Thirty-six patients (27.9%) with dMMR/MSI-H endometrial cancer died during the study, with disease progression as the primary or most commonly reported cause of death (31 patients; 24%). None of the 129 patients treated with Jemperli experienced an adverse reaction which led to death.
Treatment-emergent adverse events led to treatment interruption in 24.0% of patients with dMMR/MSI-H endometrial cancer. Anemia and diarrhea were the most frequently reported TEAEs leading to treatment interruption, and were each reported in over 2% of patients (3.1% and 2.3%, respectively). Treatment-emergent adverse events led to permanent discontinuation in 15 patients (11.6%). Increased alanine aminotransferase and increased transaminases each led to permanent discontinuation in two patients (1.6% each), and were the only TEAEs observed in more than one patient.
Treatment with Jemperli is associated with immune-mediated adverse events (AEs). Immune-mediated AEs were reported in 34.9% of patients. The most frequently observed immune-mediated AEs, reported in over 5% of patients, were diarrhea (8.5%) and hypothyroidism (7.0%). Six patients discontinued treatment due to immune-related adverse reactions, the majority of which were immune-related hepatic events. Increased alanine aminotransferase and increased transaminases each led to permanent discontinuation in two patients (1.6% each), and were the only immune-related AEs observed in more than one patient.
Immune-related adverse reactions including immune-related pneumonitis, colitis, endocrinopathies, immune-related skin adverse reactions, and nephritis, were reported with Jemperli treatment and are considered important identified risks. Symptoms can manifest during treatment or after treatment discontinuation, may occur in any organ or tissue, and may affect more than one body system simultaneously. Important immune-related adverse reactions have been listed in the Warnings and Precautions section of the Jemperli Product Monograph.
Infusion-related reactions are also considered an important identified risk. Although none were reported in patients with dMMR/MSI-H endometrial cancer, infusion-related reactions including hypersensitivity occurred in 7 patients (1.4%), including Grade 2 (1.2%) and Grade 3 (0.2%) reactions in the monotherapy dataset. All patients recovered from the infusion-related reactions.
There are no available data on the use of Jemperli in pregnant women. Human immunoglobulins are known to cross the placental barrier, and as an immunoglobulin G4 (IgG4), dostarlimab has the potential to be transmitted from the mother to the developing fetus. Therefore, Jemperli is not recommended for pregnant women or women of childbearing potential not using contraception. Women of childbearing potential should use effective contraception during treatment with Jemperli and until 4 months after the last dose of Jemperli. It is unknown whether dostarlimab or its metabolites are secreted in human milk, and for this reason, a risk to the newborn child cannot be excluded. Jemperli should not be used while breastfeeding, and breastfeeding should be avoided for at least 4 months after the last dose of Jemperli.
Overall, similar safety profiles were observed for Jemperli in the 129 patients with dMMR/MSI-H endometrial cancer (Cohort A1 of the GARNET study) and the 386 patients with various advanced solid tumours in the other cohorts of the study. No new safety signals were identified in patients with dMMR/MSI-H endometrial cancer relative to patients with other advanced solid tumours. The safety profile of Jemperli is therefore considered acceptable, with generally manageable toxicities. Adequate risk minimization measures are in place in the approved Product Monograph to manage the risks associated with Jemperli, including the important risk of immune-related adverse reactions. However, some uncertainties remain due to the limited size of the safety database, the lack of direct controls, and the need for long-term data.
For more information, refer to the Jemperli Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
As described above, the review of the non-clinical component of the New Drug Submission for Jemperli was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.
General toxicology studies included one single-dose study and two repeat-dose studies (conducted for 4 weeks and 13 weeks) in cynomolgus monkeys, in which dostarlimab was administered intravenously. Dostarlimab was generally well tolerated in the single-dose and 4 week repeat-dose toxicity studies. The no-observed-adverse-effect level (NOAEL) in both studies was considered to be 100 mg/kg, the highest dose evaluated. The NOAEL could not be determined in the 13-week repeat-dose toxicity study.
A study was conducted in which dostarlimab was administered intravenously to cynomolgus monkeys (4 animals of each sex per group) at dose levels of 0 (control) 10, 30, and 100 mg/kg once weekly over 13 weeks, for a total of 14 doses. Following the dosing period, 2 animals of each sex from the control and high dose groups were assigned to an 8-week treatment-free recovery period. One male monkey in the group receiving 10 mg/kg doses was euthanized on Day 89 due to chronic, unresolved generalized skin findings (initially recorded on Day 5) and secondary swollen and firm inguinal lymph nodes. The skin findings were indicative of an immune reaction, and considering the mechanism of action of dostarlimab, may be exaggerated pharmacological effects. Liquid feces was observed in all groups including the control, and was considered a possible drug-related effect at doses ≥30 mg/kg/week based on the increased incidence compared to controls and the timing relative to dosing. However, there were no correlated changes observed in body weight and food consumption, or associated pathology findings, and therefore it was not considered an adverse effect. Immune-mediated findings were observed in the skin, kidney, liver, or heart of 12 animals per group in groups that received dostarlimab. These findings were sporadic and could be anticipated pharmacological effects or drug-related exacerbation of background findings.
Animal reproductive or fertility studies have not been conducted with dostarlimab. The PD1/PDL1 pathway is thought to be involved in maintaining tolerance to the fetus throughout pregnancy. In murine models of pregnancy, inhibition of PD-L1 signalling has been shown to disrupt tolerance to the fetus, resulting in an increase in fetal loss. Therefore, the administration of dostarlimab during pregnancy could cause fetal harm, including increased rates of abortion or stillbirth.
No immunotoxicity, juvenile animal toxicity, or local tolerance studies have been conducted with dostarlimab. No tissue cross-reactivity was observed in studies conducted with human and cynomolgus monkey tissues.
No studies have been conducted to evaluate the carcinogenic or genotoxic potential of dostarlimab.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Jemperli Product Monograph. Considering the intended use of Jemperli, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Jemperli Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
As described above, the review of the quality component of the New Drug Submission for Jemperli was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.
Characterization of the Drug Substance
Detailed characterization studies were performed to provide evidence that dostarlimab consistently exhibits the desired structure and biological activity. Primary and higher-order structures, physicochemical properties, heterogeneity, biological activity, immunochemical properties, and degradation pathways were all examined. Process validation outcomes indicated that process-related and product-related impurities are reduced to levels below the acceptable limits.
Manufacturing Process of the Drug Substance and Drug Product and Process Controls
Dostarlimab, the drug substance, is produced in Chinese hamster ovary (CHO) cells which have been genetically engineered to express this protein. A cell culture is initiated with a thawed vial of cells from a working cell bank, and allowed to expand to commercial scale in bioreactors. Dostarlimab is purified from the clarified harvest through a series of chromatography, viral inactivation, filtration, and formulation steps.
The manufacturing process for Jemperli, the drug product, involves pooling and mixing the formulated drug substance, bioburden reduction filtration, and sterile filtration. The bulk drug product is then filled into sterile vials, stoppered, and capped. The vials are visually inspected, and then stored at 5 ± 3 °C until they are shipped to the labelling and packaging sites.
The commercial drug substance and drug product manufacturing processes include controls that are derived from product and process understanding gained throughout process development, process characterization, and process performance qualification. These controls are suitable to deliver consistent process performance, to produce a drug substance and drug product of consistent quality which reliably complies with established specifications.
None of the non-medicinal ingredients (excipients, described earlier) found in the drug product are prohibited by the Food and Drug Regulations. The compatibility of dostarlimab with the excipients is supported by the stability data provided.
Control of the Drug Substance and Drug Product
Jemperli is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program before sale as per the Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs. Through this program, final product lots were tested using a subset of release methods. The testing process confirmed that the methods used in-house are acceptable for their intended use and positively support the quality review recommendation.
The release and stability specifications for both the drug substance and drug product are considered suitable to demonstrate safety, identity, strength, purity, and quality. The release and shelf life test methods were appropriately validated or qualified. The primary reference material and the working reference material used in commercial release and stability testing have been appropriately qualified.
Stability of the Drug Substance and Drug Product
Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed 30 month shelf life at 5 ± 3 °C for Jemperli is considered acceptable.
The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.
Facilities and Equipment
A Virtual Evaluation of the Product and Facility (VEPF) was conducted for the drug substance manufacturing site, as an on-site evaluation (OSE) was not feasible due to the coronavirus disease 2019 (COVID-19) pandemic. No observations were made. Along with additional information assessed, the outcome of the VEPF supported the issuance of a Notice of Compliance with Conditions (NOC/C).
Based on a risk assessment score determined by Health Canada, an OSE was not warranted for the drug product manufacturing site.
Adventitious Agents Safety Evaluation
The drug substance manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. Microbial and endotoxin levels are controlled through the design of the manufacturing facilities, as well as in-process and release testing. The risk of contamination with adventitious agents is controlled through raw materials testing, cell line testing, and microbial testing of the unprocessed bulk. The chromatography, viral filtration, and viral inactivation steps were shown to be capable of clearing viruses.
The biologic raw materials used during manufacturing originate from sources with no or minimal risk of contamination with transmissible spongiform encephalopathy agents or other human pathogens.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| JEMPERLI | 02523434 | GLAXOSMITHKLINE INC | DOSTARLIMAB 50 MG / ML |