Summary Basis of Decision for Zepzelca
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 Zepzelca is located below.
Recent Activity for Zepzelca
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.
The following table describes post-authorization activity for Zepzelca, a product which contains the medicinal ingredient lurbinectedin. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in PAATs.
For additional information about the drug submission process, refer to the 
Management of Drug Submissions and Applications Guidance.
Updated: 2023-08-30
Drug Identification Number (DIN):
DIN 02520834 - 4 mg lurbinectedin/vial, powder, intravenous administration
Post-Authorization Activity Table (PAAT)
| Activity/submission type, control number | Date submitted | Decision and date | Summary of activities |
|---|---|---|---|
| SNDS # 265287 | 2022-06-16 | Issued NOC 2022-12-13 | Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions, Adverse Reactions, and Dosage and Administration sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued. |
| SNDS # 259506 | 2021-12-16 | Issued NOC 2022-06-29 | Submission filed as a Level II – Supplement (Safety) to update the PM with new safety and administration information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Serious Warnings and Precautions Box, Warnings and Precautions, Adverse Reactions, and Dosage and Administration sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued. |
| PBRER-C # 261748 | 2022-02-22 | Filed 2022-04-04 | Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PBRER-C #1 for the period 2021-06-15 to 2021-12-14. The information was reviewed and found acceptable. |
| Drug product (DIN 02520834) market notification | Not applicable | Date of first sale: 2021-12-06 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| NDS # 247485 | 2020-12-16 | Issued NOC under NOC/c Guidance 2021-09-29 | NOC issued under the NOC/c Guidance for New Drug Submission. |
Summary Basis of Decision (SBD) for Zepzelca
Date SBD issued: 2022-01-04
The following information relates to the New Drug Submission for Zepzelca.
Lurbinectedin
Drug Identification Number (DIN):
- DIN 02520834 - 4 mg lurbinectedin/vial, powder, intravenous administration
Jazz Pharmaceuticals Ireland Ltd.
New Drug Submission Control Number: 247485
On September 29, 2021, Health Canada issued a Notice of Compliance under the Notice of Compliance with Conditions (NOC/c) Guidance to Jazz Pharmaceuticals Ireland Limited for the drug product Zepzelca. 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 Zepzelca is favourable for the treatment of adult patients with Stage III or metastatic small cell lung cancer who have progressed on or after platinum-containing therapy.
1 What was approved?
Zepzelca, an antineoplastic agent, was authorized for the treatment of adult patients with Stage III or metastatic small cell lung cancer (SCLC) who have progressed on or after platinum-containing therapy.
The marketing authorization with conditions was based on overall response rate and duration of response; no overall survival benefit has been demonstrated.
No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric (<18 years of age) use.
In patients with SCLC, no overall difference in effectiveness was observed between patients ≥65 years of age (35% of study population) and younger patients. However, there was a higher incidence of serious adverse reactions in patients ≥65 years of age than in patients <65 years of age (49% versus 26%, respectively)
Zepzelca (4 mg lurbinectedin/vial) is presented as a lyophilized power for intravenous infusion. In addition to the medicinal ingredient, the powder contains lactic acid, sodium hydroxide, and sucrose. Zepzelca is contraindicated in patients who are hypersensitive to this drug or to any drug ingredient in the formulation, including any non-medicinal ingredient, or component of the container.
Zepzelca 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. The Zepzelca 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 Zepzelca approved?
Health Canada considers that the benefit-harm-uncertainty profile of Zepzelca is favourable for the treatment of adult patients with Stage III or metastatic small cell lung cancer (SCLC) who have progressed on or after platinum-containing therapy. Zepzelca was authorized under the Notice of Compliance with Conditions (NOC/c) Guidance on the basis of the promising nature of the clinical evidence, and the need for further follow-up to confirm the clinical benefit.
In Canada, lung cancer, which includes tumours of the bronchus, trachea, and lung, is the second most commonly diagnosed cancer and a leading cause of death. In 2020, approximately 29,800 Canadians are expected to have received a lung cancer diagnosis and 21,200 are expected to have died from the disease. Small cell carcinoma, which accounts for 20% of lung cancers, is an aggressive lung cancer related to smoking. It is characterised by early decimation to regional nodes and/or distant sites, particularly the brain. It typically is categorized according to the Veteran’s Administration Lung Cancer Study Group as limited stage SCLC (LS-SCLC) or as extensive stage SCLC (ES-SCLC). Approximately 30% to 40% of patients present with LS-SCLC at diagnosis.
Limited stage SCLC is defined as disease that is limited to the ipsilateral hemithorax and regional lymph nodes, and can be encompassed in a safe radiotherapy field. The median survival for patients with LS-SCLC and who do not receive treatment is 10 to 12 weeks. The median survival for patients treated with radiotherapy alone is 5 to 6 months, and 1% to 2% of patients are long-term survivors. Combined modality therapy increases the median survival to 18 to 24 months, and the probability of long-term (5-year) survival is 20% to 25%.
Extensive stage SCLC is disease that has spread beyond LS-SCLC and may include distant metastases, malignant pericardial or pleural effusions, and/or contralateral supraclavicular and contralateral hilar lymph node involvement. Patients with ES-SCLC are treated with palliative intent. Median survival is 8 to 10 weeks in the absence of chemotherapy. Thoracic radiotherapy can help improve local symptoms but does not prolong survival. The majority of patients (70% to 80%) respond to chemotherapy, with complete response in 15% to 20% of patients. Median survival ranges from 8 to 11 months. The majority of patients will, however, relapse and the 2-year survival rate is 5% to 10%.
Platinum-based chemotherapy is the standard first-line systemic therapy for patients with LS-SCLC and ES-SCLC. There are limited treatment options for patients with refractory disease or with disease progression after platinum-based chemotherapy. In the second-line setting, cisplatin combined with etoposide, followed by topotecan or cyclophosphamide, doxorubicin, and vincristine, is recommended for both patients with LS-SCLC and ES-SCLC who have progressed after more than 3 months of response to primary treatment. Second-line treatment is considered ineffective for patients who have progressed less than 3 months after completing first-line chemotherapy.
The medicinal ingredient in Zepzelca, lurbinectedin, is an alkylating drug that inhibits the oncogenic transcription process through (i) its binding to cytosine-guanine-rich sequences of deoxyribonucleic acid (DNA), mainly located around promoters of protein-coding genes; (ii) the eviction of oncogenic transcription factors from their binding sites; and (iii) the stalling of elongating ribonucleic acid polymerase II on those gene promoters and its specific degradation by the ubiquitin/proteasome machinery. These processes trigger a cascade of events that affect the activity of DNA binding proteins, including transcription factors, and DNA repair pathways leading to perturbation of the cell cycle and subsequent cellular apoptosis.
Lurbinectedin inhibits the transcription of selected cytokines by tumour-associated macrophages (TAMs) and reduces TAM infiltration in human tumours implanted in mice, reducing their tumour-supportive roles.
Zepzelca has shown a promising objective response rate (ORR) and duration of response (DOR) in the second line setting for patients with SCLC who have platinum-sensitive and platinum-resistant disease. The market authorization with conditions was based on the pivotal study (Study B-005), a multicentre, open-label, single-arm Phase II basket trial that aimed to assess the efficacy and safety of Zepzelca in nine cohorts of patients with advanced solid tumours, including a cohort of 105 patients with SCLC.
Among the 105 patients with SCLC enrolled in the pivotal study, Zepzelca administered as a 3.2 mg/m2 intravenous infusion over one hour resulted in an ORR of 35.2% (95% confidence interval [CI]: 26.2%, 45.2%), with a median DOR of 5.3 months (95% CI: 4.1, 6.4). All observed responses were partial responses. The ORR in patients with platinum-sensitive disease (defined as having a chemotherapy-free interval [CTFI] ≥90 days) was 45.0% (95% CI: 32.1%, 58.4%) with a DOR of 6.2 months (95% CI: 3.5, 7.3). The ORR in patients with platinum-resistant disease (CTFI <90 days) was 22.2% (95% CI: 11.2%, 37.1%), with a median DOR of 4.7 months (2.6, 5.6).
Most patients (98.1%) experienced at least one treatment-emergent adverse event (TEAE; all grades) while on treatment. The most frequently observed (≥20%) TEAEs (all grades), including all laboratory abnormalities regardless of relationship with the study treatment, were anemia (95.2%), lymphopenia (85.7%), creatinine increase (82.7%), leukopenia (79.0%), hyperglycemia (77.7%), fatigue (77.1%), alanine aminotransferase increase (71.8%), neutropenia (71.4%), aspartate transaminase increase (44.7%), thrombocytopenia (43.8%), hyponatremia (40.4%), nausea (37.1%), hypoalbuminemia (34.0%), decreased appetite (33.3%), alkaline phosphatase increase (33.0%), constipation (31.4%), dyspnea (30.5%), vomiting (21.9%), hyperkalemia (20.2%), hypokalemia (20.2%), and diarrhea (20.0%).
Grade ≥3 TEAEs were observed in 59.0% of patients and Grade ≥4 TEAEs were observed in 23.8% of patients. The most frequently observed Grade ≥3 TEAEs included neutropenia (45.7%), lymphopenia (43.8%), leukopenia (28.6%), fatigue (12.4%), anemia (9.5%), hyponatremia (8.7%), thrombocytopenia (6.6%), dyspnea (5.7%), hyperglycemia (4.9%), febrile neutropenia (4.8%), pneumonia (4.8%), increased alanine aminotransferase (3.9%), diarrhea (3.8%), and upper respiratory tract infection (3.8%).
Treatment-emergent serious adverse events (SAEs) occurred in 34.3% of patients. The most common treatment-emergent SAEs (all grades) were neutropenia or decreased neutrophil count (5.7%), febrile neutropenia (4.8%), pneumonia (4.8%), anemia (3.8%), thrombocytopenia or decreased platelet count (3.8%), dyspnea (3.8%), general physical health deterioration (2.9%), and upper respiratory tract infection (2.9%).
Overall, in the context of a serious, life-threatening disease with limited treatment options, the benefit-risk-uncertainty profile Zepzelca is considered favourable in the target patient population.
Treatment with Zepzelca is associated with significant toxicity. Appropriate warnings and precautions are in place in the approved Zepzelca Product Monograph to address the identified safety concerns, including a Serious Warnings and Precautions box describing serious potential risks of embryo-fetal toxicity and myelosuppression associated with the use of Zepzelca. Zepzelca should be administered under the supervision of a physician who is experienced in the use of cancer chemotherapeutics.
A Risk Management Plan (RMP) for Zepzelca was submitted by Jazz Pharmaceuticals Ireland Limited 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 put in place to minimise risks associated with the product.
The submitted inner and outer labels, package insert and Patient Medication Information section of the Zepzelca 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 Zepzelca was accepted.
Zepzelca was authorized under the NOC/c Guidance. The efficacy data stem from the SCLC cohort of the pivotal Study B-005, which was a single-arm, multicentre trial. There remains uncertainty regarding the magnitude of the treatment effect and the potential for Zepzelca to prolong overall survival. As a condition for market authorization, the sponsor is expected to submit final data from this single-arm trial in addition to data from a Phase III trial to confirm the efficacy of Zepzelca in the indicated population.
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 Zepzelca?
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 Zepzelca. The sponsor presented promising clinical evidence that Zepzelca has the potential to provide effective treatment of a life-threatening disease for which no drug is presently marketed in Canada.
Subsequent review led to the decision to issue the sponsor market authorization under the NOC/c Guidance, in recognition of the promising but unconfirmed evidence of clinical effectiveness in the submission. In keeping with the provisions of the NOC/c Guidance, the sponsor agreed to provide additional information to confirm the clinical benefit of the product.
The NDS for Zepzelca was reviewed under Project Orbis, a framework for concurrent submission and review of oncology products, as well as information sharing among regulators from multiple jurisdictions. The submission for Zepzelca was reviewed as a Type C collaboration between Health Canada, the United States Food and Drug Administration (FDA), and Australia’s Therapeutic Goods Administration. Although the review of the submission was collaborative, each jurisdiction made its regulatory decision independently. The Canadian regulatory decision on the review of Zepzelca was based on a critical assessment of the data package submitted to Health Canada. The foreign review completed by the United States FDA was used as an added reference as 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: Zepzelca
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting | 2020-10-14 |
| Advance Consideration under the Notice of Compliance with Conditions Guidance accepted | 2020-11-30 |
| New Drug Submission filed | 2020-12-16 |
| Screening | |
| Screening Deficiency Notice issued | 2021-01-15 |
| Response to Screening Deficiency Notice filed | 2021-01-20 |
| Screening Acceptance Letter issued | 2021-01-21 |
| Review | |
| Biostatistics evaluation completed | 2021-06-01 |
| Review of Risk Management Plan completed | 2021-07-02 |
| Non-clinical evaluation completed | 2021-07-28 |
| Quality evaluation completed | 2021-08-05 |
| Labelling review completed | 2021-08-05 |
| Clinical/medical evaluation completed | 2021-08-06 |
| Notice of Compliance with Conditions Qualifying Notice (NOC/c-QN) issued | 2021-08-06 |
| Review of Response to NOC/c-QN: | |
| Response filed (Letter of Undertaking) | 2021-09-02 |
| Labelling review completed | 2021-09-27 |
| Clinical/medical evaluation completed | 2021-09-28 |
| Notice of Compliance (NOC) issued by Director General, Therapeutic Products Directorate under the Notice of Compliance with Conditions (NOC/c) Guidance | 2021-09-29 |
4 What follow-up measures will the company take?
Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations, and in the Notice of Compliance with Conditions (NOC/c) Guidance. In addition, the sponsor has agreed to confirm the clinical benefits and risks of Zepzelca by providing the following:
- The final report for the small cell lung cancer (SCLC) cohort in Study B-005 (PM1183-B-005-14), a multicentre Phase II clinical trial of Zepzelca in selected advanced solid tumours-SCLC cohort.
- The final report of a confirmatory Phase III, randomized, multicentre study comparing Zepzelca as a single agent, or the combination of Zepzelca with irinotecan, versus investigator’s choice (topotecan or irinotecan) in patients with relapsed SCLC after failure of one prior platinum-containing chemotherapy line. The study will include an analysis of patients with resistant disease (chemotherapy-free interval <90 days) and with sensitive disease (chemotherapy-free interval ≥90 days). The results of the primary efficacy endpoint of overall survival and the secondary endpoints of progression free survival, overall response rate, and duration of response will be used to confirm the improved clinical benefit.
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 Zepzelca was completed by Health Canada as part of an international partnership with the United States Food and Drug Administration (FDA) and Australia’s Therapeutic Goods Administration as a Project Orbis Type C submission. The foreign review completed by the United States FDA was used as an added reference as described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.
Clinical Pharmacology
The medicinal ingredient in Zepzelca, lurbinectedin, is an alkylating drug that inhibits the oncogenic transcription process through (i) its binding to cytosine-guanine-rich sequences of deoxyribonucleic acid (DNA), mainly located around promoters of protein-coding genes; (ii) the eviction of oncogenic transcription factors from their binding sites; and (iii) the stalling of elongating ribonucleic acid (RNA) polymerase II on those gene promoters and its specific degradation by the ubiquitin/proteasome machinery. These processes trigger a cascade of events that affect the activity of DNA binding proteins, including transcription factors, and DNA repair pathways leading to perturbation of the cell cycle and subsequent cellular apoptosis. Lurbinectedin inhibits the transcription of selected cytokines by tumour-associated macrophages (TAMs) and reduces TAM infiltration in human tumours implanted in mice, reducing their tumour-supportive roles.
In pharmacodynamic studies, increased incidences of Grade 4 neutropenia and Grade ≥3 thrombocytopenia were observed with increased lurbinectedin exposure.
The potential for QTc prolongation with lurbinectedin at a therapeutic dose was evaluated in 39 patients with advanced cancer. Large effects (>10 ms) on the QTc interval were not detected at doses of 3.2 mg/m2 lurbinectedin every three weeks.
Following a dose of 3.2 mg/m2 lurbinectedin administered as a one-hour intravenous infusion, geometric means of the total plasma maximum plasma concentration and the area under the concentration-time curve from time zero to infinity were 107 μg/L and 551 μg*h/L, respectively. No accumulation of lurbinectedin was observed in plasma upon repeated administrations every three weeks.
The typical volume of distribution of lurbinectedin at steady state is 504 L. Binding to plasma proteins is approximately 99%, to both albumin and α-1-acid glycoprotein. In vitro studies with human liver microsomes and supersomes indicate that cytochrome P450 (CYP) 3A4 is the main CYP enzyme responsible for the hepatic metabolism of lurbinectedin.
The terminal half-life of lurbinectedin is 51 hours. Total plasma clearance of lurbinectedin is 11 L/h. The major route of lurbinectedin-related radioactivity excretion was via the feces (89% of the administered dose). The most abundant metabolite found in feces accounted for 1% of the dose and only traces of unchanged lurbinectedin were detected in feces (<0.2% of the administered dose). Excretion in urine was the minor route (6% of the administered dose), mainly as unchanged compound (1% of the administered dose) and one metabolite (up to 1% of the administered dose).
Population pharmacokinetics analyses showed that weight, age, and sex do not have a clinically meaningful influence on the systemic exposure of lurbinectedin. Further, no apparent pharmacokinetic difference was observed in patients with mild hepatic impairment who received 3.2 mg/m2 of lurbinectedin every three weeks as compared to patients with normal hepatic function. The pharmacokinetic characteristics of lurbinectedin in patients with moderate to severe hepatic impairment are unknown. No apparent pharmacokinetic difference was observed in patients with mild, moderate, or severe renal impairment who received 3.2 mg/m2 of lurbinectedin every three weeks as compared to patients with normal renal function. The pharmacokinetic characteristics of lurbinectedin in patients with a creatinine clearance (i.e., CrCl) <30 mL/min or patients on dialysis are unknown.
Overall, the clinical pharmacology data support the use of Zepzelca for the recommended indication.
For further details, please refer to the Zepzelca Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The clinical efficacy of Zepzelca was evaluated in the pivotal Study B-005 (PM1183-B-005-14), a multicentre, open-label, single-arm Phase II basket trial designed to assess the efficacy and safety of Zepzelca in nine cohorts of advanced, difficult-to-treat solid tumours, including a cohort of 105 previously treated patients with small cell lung cancer (SCLC). Zepzelca was administered as a one-hour intravenous infusion every three weeks at a dose of 3.2 mg/m2. Most of the patients were male (60.0%), white (75.2%), had a history of smoking (92.4%), and had a median age of 60 years (range: 40 to 83). A total of 35.2% of the patients were aged 65 years or older. Most patients had an Eastern Cooperative Oncology Group Performance Status of 0 (36.2%) or 1 (56.2%).
The primary objective of the trial was to determine the investigator-assessed (IA) objective response rate (ORR; complete or partial response). Among the 105 enrolled patients with SCLC, the IA-ORR was 35.2% (95% confidence interval [CI]: 26.2%, 45.2%) with a median duration of response (DOR) of 5.3 months (95% CI: 4.1, 6.4). All observed responses were partial responses.
The results from the primary analysis were supported by key secondary endpoints. The ORR assessed by an independent review committee (IRC) was 30.5% (95% CI: 21.9%, 40.2%) with a median DOR of 5.1 months (95% CI: 4.9, 6.4). All observed responses were partial responses.
The median progression-free survival (PFS) rates determined by the investigator and the IRC were 3.5 months (95% CI: 2.6, 4.3) and 3.5 months (95% CI: 2.6, 4.2), respectively. The median overall survival (OS) was 9.3 months (95% CI: 6.3, 11.8). However, the endpoints of PFS and OS are considered exploratory as Study B-005 did not have comparator arms for each cohort, including the SCLC cohort.
Subgroup analysis according to the chemotherapy-free interval (CTFI) indicated that the IA-ORR in patients with platinum-sensitive disease (defined as having a CTFI ≥90 days) was 45.0% (95% CI: 32.1%, 58.4%) with a median DOR of 6.2 months (95% CI: 3.5, 7.3). The ORR in patients with platinum-resistant disease (CTFI <90 days) was 22.2% (95% CI: 11.2%, 37.1%), with a median DOR of 4.7 months (95% CI: 2.6, 5.6).
Overall, results from the pivotal study demonstrate a promising ORR and DOR in the second line setting for SCLC patients with platinum-sensitive and platinum-resistant disease.
The efficacy data are derived from the SCLC cohort of the pivotal Study B-005, which was a single-arm, multicentre trial and there remains uncertainty regarding the magnitude of the treatment effect and the potential for Zepzelca to prolong OS. 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. As a condition for market authorization, the sponsor is expected to submit final data from the single-arm trial and data from a Phase III trial to confirm the efficacy of Zepzelca in the indicated population.
Indication
The New Drug Submission for Zepzelca was filed by the sponsor with the following indication:
Treatment of adult patients with small cell lung cancer (SCLC) who have progressed on or after prior platinum-containing therapy.
To adequately represent the patient population enrolled in the SCLC cohort in the pivotal study, Health Canada approved the following indication:
Treatment of adults with Stage III or metastatic small cell lung cancer (SCLC) who have progressed on or after platinum-containing therapy.
For more information, refer to the Zepzelca Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The clinical safety of Zepzelca relied on the safety data stemming from 105 patients with SCLC in the pivotal Study B-005 described in the Clinical Efficacy section. This safety analysis is supported by an integrated safety analysis which includes pooled safety data derived from 554 patients treated with 3.2 mg/m2 Zepzelca from Study B-005 (335 patients from nine cohorts, including the 105 SCLC patients) and the lurbinectedin arm of Study C-004, a Phase III trial involving 219 patients with platinum-resistant ovarian cancer.
At the cut-off date of January 15, 2019, a total of 618 cycles were administered to the 105 patients with SCLC. The median time on treatment was 14.0 weeks (range: 1.1 to 85.0). The median cumulative dose was 12.8 mg/m2 (range: 3.2 to 73.8) and the median relative dose intensity was 97.4% (range: 65.2% to 104.3%).
Most patients (98.1%) experienced at least one treatment-emergent adverse event (TEAE; all grades) while on treatment. The most frequently observed (≥20%) TEAEs (all grades), including all laboratory abnormalities regardless of relationship with the study treatment, were anemia (95.2%), lymphopenia (85.7%), increased creatinine (82.7%), leukopenia (79.0%), hyperglycemia (77.7%), fatigue (77.1%), increased alanine aminotransferase (71.8%), neutropenia (71.4%), increased aspartate transaminase (44.7%), thrombocytopenia (43.8%), hyponatremia (40.4%), nausea (37.1%), hypoalbuminemia (34.0%), decreased appetite (33.3%), increased alkaline phosphatase (33.0%), constipation (31.4%), dyspnea (30.5%), vomiting (21.9%), hyperkalemia (20.2%), hypokalemia (20.2%), and diarrhea (20.0%).
Grade ≥3 TEAEs were observed in 59.0% of patients and Grade ≥4 TEAEs were observed in 23.8% of patients. The most frequently observed Grade ≥3 TEAEs included neutropenia (45.7%), lymphopenia (43.8%), leukopenia (28.6%), fatigue (12.4%), anemia (9.5%), hyponatremia (8.7%), thrombocytopenia (6.6%), dyspnea (5.7%), hyperglycemia (4.9%), febrile neutropenia (4.8%), pneumonia (4.8%), increased alanine aminotransferase (3.9%), diarrhea (3.8%), and upper respiratory tract infection (3.8%).
Treatment-emergent serious adverse events (SAEs) occurred in 34.3% of patients. The most common treatment-emergent SAEs (all grades) were neutropenia or decreased neutrophil count (5.7%), febrile neutropenia (4.8%), pneumonia (4.8%), anemia (3.8%), thrombocytopenia or decreased platelet count (3.8%), dyspnea (3.8%), general physical health deterioration (2.9%), and upper respiratory tract infection (2.9%).
Dose reductions were required in 27.4% of patients. Treatment-emergent adverse events leading to dose reductions in >2% of patients included neutropenia (20.0%), febrile neutropenia (4.2%), fatigue (4.2%), thrombocytopenia (2.1%), and pneumonia (2.1%).
Dose interruptions due to TEAEs occurred in 48.4% of patients. Treatment-emergent adverse events requiring dose interruption in ≥3% of patients were neutropenia (13.7%) and hypoalbuminemia (5.3%).
Treatment discontinuation due to TEAEs occurred in 1.9% of patients, with peripheral neuropathy and myelosuppression observed in one patient each.
Appropriate warnings and precautions are in place in the approved Zepzelca Product Monograph to address the identified safety concerns, including a Serious Warnings and Precautions box describing serious potential risks of embryo-fetal toxicity and myelosuppression associated with the use of Zepzelca. Zepzelca should be administered under the supervision of a physician who is experienced in the use of cancer chemotherapeutics.
Overall, in the context of a serious life-threatening disease with limited treatment options, the benefit-risk-uncertainty profile of Zepzelca is considered favourable in the target patient population with an unmet medical need.
For more information, refer to the Zepzelca 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 Zepzelca was completed by Health Canada as part of an international partnership with the United States Food and Drug Administration (FDA) and Australia’s Therapeutic Goods Administration as a Project Orbis Type C submission. The foreign review completed by the United States FDA was used as an added reference as described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.
Lurbinectedin, the medicinal ingredient in Zepzelca, is a small molecule with an established pharmacological class of alkylating drug. It consists of two fused tetrahydroisoquinoline rings linked to an additional tetrahydro-β-carboline ring. The drug binds covalently to the exocyclic amino group of guanines in the minor groove of cytosine-guanine-rich deoxyribonucleic acid (DNA) sequences. Binding results in adduct formation and bends DNA. The formation of adducts results in eventual double strand breaks, ultimately leading to cell death.
Data was presented showing an association between lurbinectedin adducts and degradation of phosphorylated ribonucleic acid (RNA) polymerase II, leading to decreased transcription. Consistent with its mechanism of action, lurbinectedin had antiproliferative and cytotoxic activity in multiple tumour cell lines with half-maximal inhibitory concentration values in the low nanomolar range. This activity was enhanced in cell lines with defects in DNA mismatch repair machinery. Incubation with lurbinectedin also resulted in increased cell death of human monocytes and, at lower concentrations, decreased migration and chemokine production.
In in vivo studies, administration of lurbinectedin to athymic mice implanted with various human tumour cell lines inhibited tumour growth in an array of human tumour models, including small cell lung cancer (SCLC). Investigators also showed enhanced anti-tumour activity in an in vivo SCLC implantation model following treatment with a combination of lurbinectedin and doxorubicin compared to either drug alone. In other models, the administration of lurbinectedin to mice implanted with several tumour cell lines also resulted in reductions in blood- and tumour-infiltrating macrophages.
The toxicological assessment of lurbinectedin was mainly conducted in Sprague Dawley rats, beagle dogs, and cynomolgus monkeys. While dogs were utilized in the initial 4-week toxicology studies, monkeys were utilized in the 13-week non-rodent toxicology study due to metabolic data suggesting that monkey metabolism was more similar to human metabolism than other tested non-rodent species.
There were no unique human metabolites for lurbinectedin compared to metabolites observed in animals. Two metabolites, M1 and PM030047, were present in humans at approximately 14% and 10% of the parent exposure, respectively. Although PM030047 was present in rats, exposure levels were uncertain. In vivo exposure levels in monkeys appeared to be lower for both metabolites. Additionally, the highest doses and exposures in these studies were all at levels lower than the human dose of 3.2 mg/m2, therefore, there is not a full toxicological coverage of these metabolites. However, given that each of these main metabolites represent less than 15% of the parent compound and toxicity profiles in humans are similar to those in animals, the disparity in metabolite exposure does not represent a significant safety concern for the intended patient population. There were no clear acute effects on cardiovascular, central nervous system, or respiratory parameters in any species.
The major toxicological findings in all three tested species were injection site findings including hemorrhage, edema, inflammation, thrombosis, and necrosis and bone marrow effects leading to transient leukopenia and mild anemia with decreased cellularity in the bone marrow.
Decreases in reticulocytes of at least 90% occurred after dosing at high dose levels in all three species. Gastrointestinal tract toxicity was also common at high dose levels, with soft/liquid feces in all species and vomiting in non-rodent species; transient inappetence and weight loss following dosing also occurred in rats and monkeys. In the 8-cycle study in rats there were also signs of male reproductive toxicity (testicular atrophy and hypospermia) at the high dose of 0.06 mg/kg (0.36 mg/m2; exposure approximately 24 times lower than the human exposure of 551 ng*hr/mL at the 3.2 mg/m2 dose as measured by the area under the concentration-time curve [AUC]). No findings were reported in monkeys. In rats, the maximum tolerated dose was estimated as 0.06 mg/kg (0.36 mg/m2) for males and 0.03 mg/kg (0.18 mg/m2) for females.
The starting clinical dose of 0.02 mg/m2 for the first-in-human clinical trial was derived by calculating 10% of the maximum tolerated dose of approximately 0.2 mg/m2 in the most sensitive species, female rats.
Dogs showed signs of testicular tubular cell degeneration at doses ≥0.01 mg/kg (0.2 mg/m2; exposure approximately 90 times lower than the human exposure at the 3.2 mg/m2 dose as measured by the AUC). Finally, in the 4-week rat study, there were signs of liver toxicity at the high dose in both sexes (0.18 mg/kg in males/0.09 mg/kg in females) characterized by large increases in liver enzymes and bilirubin as well as hepatocyte necrosis, hemorrhage, and thrombi. Bone marrow suppression, gastrointestinal toxicity, and liver toxicity are common clinical findings as well. The highest doses used in the rat and monkey 8-cycle studies resulted in exposures approximately 8 times lower than the human exposure at the recommended dose of 3.2 mg/m2 once every 3 weeks.
Lurbinectedin was negative in the in vitro Ames assay but induced mutations in the mouse TK lymphoma assay, confirming that, as expected based on its mechanism of action, lurbinectedin is genotoxic. Consistent with the principles discussed in International Council for Harmonisation guidance for industry, the sponsor did not conduct fertility or pre- and post-natal development studies. Given its mechanism of action as a genotoxic agent targeting rapidly dividing cells, an embryo-fetal development study would not be needed, however, the sponsor did conduct a preliminary single-dose level embryo-fetal development study in rats. No viable fetuses were observed when six pregnant rats received a single lurbinectedin dose of 0.1 mg/kg (0.6 mg/m2). Lurbinectedin did not demonstrate the potential for phototoxicity in an in vitro study. Studies investigating the presence of lurbinectedin in breast milk or the carcinogenicity of lurbinectedin in the proposed patient population were not conducted.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Zepzelca Product Monograph, including a Serious Warnings and Precautions box describing serious potential risks of embryo-fetal toxicity and myelosuppression associated with the use of Zepzelca. In view of the intended use of Zepzelca, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product for the treatment of patients with metastatic SCLC who have progressed after platinum-containing therapy.
For more information, refer to the Zepzelca 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 Zepzelca was completed by Health Canada as part of an international partnership with the United States Food and Drug Administration (FDA) and Australia’s Therapeutic Goods Administration as a Project Orbis Type C submission. The foreign review completed by the United States FDA was used as an added reference as described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.
The Chemistry and Manufacturing information submitted for Zepzelca 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 48 months is acceptable when the drug product is stored at 5 °C ± 3 °C.
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.
None of the non-medicinal ingredients (excipients, described earlier) found in the drug product are prohibited by the Food and Drug Regulations.
None of the excipients used in the formulation of Zepzelca is of human or animal origin.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| ZEPZELCA | 02520834 | JAZZ PHARMACEUTICALS IRELAND LIMITED | LURBINECTEDIN 4 MG / VIAL |