Summary Basis of Decision for Polivy
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 Polivy is located below.
Recent Activity for Polivy
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 Polivy, a product which contains the medicinal ingredient polatuzumab vedotin. 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: 2023-09-28
Drug Identification Number (DIN):
DIN 02499614 - 140 mg/vial, polatuzumab vedotin, powder for solution, intravenous administration
DIN 02515431 - 30 mg/vial, polatuzumab vedotin, powder for solution, intravenous administration
Post-Authorization Activity Table (PAAT)
|
Activity/Submission Type, Control Number |
Date Submitted |
Decision and Date |
Summary of Activities |
|
SNDS-C # 261270 |
2022-02-04 |
Issued NOC 2023-01-20 |
Submission filed as a Level I – Supplement to remove the conditions from the NOC for NDS # 232303 for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma, not otherwise specified, who are not eligible for autologous stem cell transplant and have received at least one prior therapy. The submission provided a study report from study GO39942. The submission was reviewed and considered acceptable. An NOC was issued and the conditions were removed from the NOC. |
|
SNDS # 259726 |
2021-12-17 |
Issued NOC 2022-11-14 |
Submission filed as a Level I – Supplement for a new indication. The submission was reviewed and considered acceptable. The indication authorized was: Polivy (polatuzumab vedotin for injection) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (RCHP) is indicated for the treatment of adult patients with previously untreated large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS), high grade B-cell lymphoma, Epstein-Barr viruspositive (EBV+) DLBCL NOS, and T-cell/histiocyte rich LBCL. As a result of the SNDS, modifications were made to the Indications; Warnings and Precautions; Adverse Reactions; Dosage and Administration; Clinical Pharmacology; and Clinical Trials sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued and a Regulatory Decision Summary was published. |
|
SNDS # 249155 |
2021-01-29 |
Issued NOC under NOC/c Guidance 2021-12-24 |
Submission filed as a Level I – Supplement in response to commitments made as per the provisions of the NOC/c Guidance regarding the primary clinical study report for study GO29365. Based on the data provided in this SNDS, no new safety or efficacy issues were identified that impact the benefit-risk profile for Polivy for the authorized indications. The submission was reviewed and considered acceptable, and an NOC was issued under the NOC/c Guidance. |
|
SNDS # 243840 |
2020-09-10 |
Issued NOC 2021-04-27 |
Submission filed as a Level I – Supplement to add a new strength (30 mg/vial) and the addition of a drug product manufacturing facility. The submission was reviewed and considered acceptable, and an NOC was issued. A new DIN (02515431) was issued for the new presentation. A Regulatory Decision Summary was published. |
|
Drug product (DIN 02499614) market notification |
Not applicable |
Date of first sale: 2020-11-25 |
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
|
NDS # 232303 |
2019-10-07 |
Issued NOC under NOC/c Guidance 2020-07-09 |
NOC issued under the NOC/c Guidance for New Drug Submission. |
Summary Basis of Decision (SBD) for Polivy
Date SBD issued: 2020-10-08
The following information relates to the New Drug Submission for Polivy.
Polatuzumab vedotin
Drug Identification Number (DIN):
- DIN 02499614 ‑ 140 mg/vial, solution, intravenous administration
Hoffmann‑La Roche Ltd.
New Drug Submission Control Number: 232303
On July 9, 2020, Health Canada issued a Notice of Compliance under the Notice of Compliance with Conditions (NOC/c) Guidance to Hoffmann‑La Roche Limited for the drug product Polivy. 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 Polivy in combination with bendamustine and rituximab is favourable for the treatment of adult patients with relapsed or refractory diffuse large B‑cell lymphoma, not otherwise specified, who are not eligible for autologous stem cell transplant and have received at least one prior therapy.
1 What was approved?
Polivy, an antineoplastic agent, was authorized in combination with bendamustine and rituximab for the treatment of adult patients with relapsed or refractory diffuse large B‑cell lymphoma, not otherwise specified, who are not eligible for autologous stem cell transplant and have received at least one prior therapy.
Based on the data submitted to and reviewed by Health Canada, the safety and efficacy of Polivy in pediatric patients (<18 years of age) have not been established. Therefore, Health Canada has not authorized an indication for pediatric use.
Geriatric patients (≥65 years of age) had higher incidences of Grade 3 or higher adverse events and discontinuation of treatment with Polivy compared with younger patients. There is insufficient evidence from clinical studies to determine if there are meaningful differences in response to Polivy in patients 65 years of age and older compared to a younger patient population.
Polivy 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.
Polivy 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.
Polivy (140 mg/vial polatuzumab vedotin) is presented as a lyophilised powder for solution. In addition to the medicinal ingredient, the powder contains polysorbate 20, sodium hydroxide, succinic acid, and sucrose.
For more information, refer to the Clinical, Non‑clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
Additional information may be found in the Polivy Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Polivy approved?
Health Canada considers that the benefit‑risk profile of Polivy in combination with bendamustine and rituximab is favourable for the treatment of adult patients with relapsed or refractory diffuse large B‑cell lymphoma, not otherwise specified, who are not eligible for autologous stem cell transplant and have received at least one prior therapy.
Polivy 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.
Non‑Hodgkin's lymphomas (NHLs) are a diverse group of malignancies, with more than 60 different subtypes. A significant proportion of NHLs (85‑90%) arise from B cells. Diffuse large B‑cell lymphoma (DLBCL) is an aggressive form of NHL, accounting for approximately 30% of lymphoma cases in Canada. It has both biological and clinical heterogeneity with respect to disease subtype and treatment. The standard treatment option for patients who have relapsed or refractory DLBCL and are not eligible for an autologous stem cell transplant include combination chemotherapy regimens, which may include rituximab. However, even with these therapies, the prognosis is poor for these patients.
Polivy (polatuzumab vedotin) is a CD79b‑targeted antibody‑drug conjugate that preferentially delivers monomethyl auristatin E (MMAE), a potent anti‑mitotic agent, to B cells. The polatuzumab vedotin molecule consists of MMAE covalently attached to polatuzumab, a humanized immunoglobulin G1 monoclonal antibody, via a cleavable linker. The monoclonal antibody binds with high affinity and selectivity to CD79b, a cell surface component of the B‑cell receptor. The CD79b molecule is expressed in both normal and malignant B cells, including over 95% of cases of DLBCL. Upon binding CD79b, polatuzumab vedotin is internalized. The linker is cleaved inside the cell, which releases MMAE. The unconjugated MMAE binds to microtubules, killing dividing cells by inhibiting cell division and inducing apoptosis.
Evidence of the clinical efficacy and safety of Polivy was primarily based on the pivotal Phase Ib/II study, GO29365. This study evaluated the efficacy, safety, and tolerability of Polivy in combination with bendamustine and rituximab (BR) relative to treatment with BR alone, and was ongoing at the time of the NOC/c issuance. Patients enrolled in this study had relapsed or refractory DLBCL, were not eligible to receive an autologous stem cell transplant, and had received at least one prior therapy.
The primary efficacy endpoint of the study was the complete response rate at the end of the treatment period, assessed by an independent review committee. The complete response rate was 40% (95% confidence interval [CI]: 24.9, 56.7) for patients treated with Polivy plus BR, and 17.5% (95% CI: 7.3, 32.8) for patients treated with BR alone. The difference in complete response rates between the two treatment groups was 22.5% (95% CI: 2.6, 40.2). This was also supported by secondary endpoints, including objective response rate, best overall response rate and duration of response. Due to the design of the pivotal trial, some uncertainty remains regarding the magnitude of the treatment effect. Nevertheless, in the context of conditional authorization, the observed treatment benefit serves as promising clinical evidence in the target patient population.
The primary safety population consisted of patients enrolled in the pivotal study, GO29365, who received at least one dose of Polivy plus BR or BR alone. Similar safety profiles were observed between the Polivy plus BR and BR treatment groups. The majority of adverse events were grade 1 or 2 in severity. Adverse events reported in over 10% of patients included neutropenia, thrombocytopenia, lymphopenia, anemia, diarrhea, abdominal pain, fatigue, pyrexia, pneumonia, infusion‑related reactions, decreased weight, decreased appetite, hypokalemia, hypoalbuminemia, hypocalcemia, peripheral neuropathy, dizziness, and pruritus. The incidence was higher in patients treated with Polivy plus BR for each of these adverse events.
The incidences of grade 3 or higher neutropenia, thrombocytopenia, anemia, lymphopenia, pancytopenia, and pneumonia were also higher in patients treated with Polivy plus BR. Other adverse events that occurred at a higher incidence in patients treated with Polivy plus BR include infusion‑related reactions, hepatic toxicity, gastrointestinal toxicity, arthralgia, and skeletal pain. Infections, which were observed at similar incidences in the two treatment groups, were a leading cause of serious adverse events and death. Four fatal infections occurred in each treatment group.
Discontinuations of the study drug due to adverse events were more frequent in the Polivy plus BR treatment group than in the BR treatment group (31.1% and 15.4%, respectively). The observed increase was attributed to higher incidences of neutropenia and thrombocytopenia.
Overall, the data from this study indicate that the risks associated with Polivy are tolerable and manageable, and the safety profile of Polivy is acceptable for its intended indication.
The supportive studies GO27834 and GO29044 were both ongoing at the time of the NOC/c issuance for Polivy, whereas study DCS4968g was completed. The findings from these studies described a safety profile for Polivy as a single agent and in combination with other regimens in DLBCL patients that was consistent with other similar MMAE‑antibody conjugates. The main adverse events of clinical relevance were neutropenia, peripheral neuropathy, and infection. Collectively, the data from the three supportive studies indicated that the 1.8 mg/kg dose of Polivy (the recommended dose) has a manageable safety profile in patients with DLBCL.
A Serious Warnings and Precautions box has been included in the Polivy Product Monograph to highlight the risk of fatal, life‑threatening, or serious infections, including opportunistic infections. These have been reported in patients and are clinically significant. Serious and severe myelosuppression, including neutropenia, febrile neutropenia, thrombocytopenia, and anemia have also been listed in this section.
A Risk Management Plan (RMP) for Polivy was submitted by Hoffmann‑La Roche 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 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 Polivy Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.
A Look‑alike Sound‑alike brand name assessment was performed and the proposed name Polivy was accepted.
Polivy 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 Polivy Product Monograph to address the identified safety concerns. As described within the framework of the NOC/c Guidance, safety monitoring of the use of Polivy will be ongoing. Further evaluation will take place upon the submission of the requested studies after they become available.
This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non‑clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
3 What steps led to the approval of Polivy?
Initially, the sponsor filed a request for Priority Review status under the Priority Review Policy for the review of the new drug submission (NDS) for Polivy. Following review of the submitted clinical assessment package, it was determined that the sponsor's request did not fulfill the eligibility criteria set out in the Priority Review Policy. The clinical study data did not provide substantial evidence of effectiveness for the proposed indication. Additionally, the number of patients included in the study was not large enough to appropriately assess the efficacy and safety of Polivy under the Priority Review pathway. The request for Priority Review status was therefore rejected.
The sponsor subsequently filed a request for Advance Consideration under the Notice of Compliance with Conditions (NOC/c) Guidance for the review of the NDS for Polivy. An assessment was conducted, which showed that the criteria for filing under the NOC/c Guidance had been met. The evidence of clinical effectiveness was promising. Additionally, the drug has the potential to provide an effective treatment of a disease that is not adequately managed by other drugs marketed in Canada.
In keeping with the provisions of the NOC/c Guidance, the sponsor agreed to provide additional information, including the results of a randomized controlled Phase III confirmatory study, to confirm the clinical benefit of Polivy.
Submission Milestones: Polivy
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2019-01-23 |
| Request for priority status | |
| Request for priority review status filed: | 2019-03-08 |
| Rejection issued by Director, Centre for Evaluation of Radiopharmaceuticals and Biotherapeutics: | 2019-04-05 |
| Pre‑submission meeting: | 2019-08-06 |
| Acceptance of Advance Consideration under the Notice of Compliance with Conditions (NOC/c) Guidance: | 2019-10-02 |
| Submission filed: | 2019-10-07 |
| Screening | |
| Screening Acceptance Letter issued: | 2019-11-08 |
| Review | |
| Review of Risk Management Plan complete: | 2020-04-24 |
| Quality Evaluation complete: | 2020-05-14 |
| Clinical/Medical Evaluation complete: | 2020-05-22 |
| Labelling Review complete, including Look-alike Sound-alike brand name assessment: | 2020-05-25 |
| Notice of Compliance with Conditions Qualifying Notice (NOC/c‑QN) issued: | 2020-05-26 |
| Review of Response to NOC/c‑QN: | |
| Response filed (Letter of Undertaking): | 2020-06-16 |
| Clinical/Medical Evaluation complete: | 2020-06-30 |
| Notice of Compliance (NOC) issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate under the Notice of Compliance with Conditions (NOC/c) Guidance: | 2020-07-09 |
The Canadian regulatory decision on the review of Polivy 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 United States Food and Drug Administration (FDA) were consulted as added references.
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
4 What follow-up measures will the company take?
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 several conditions, including (but not limited to) those listed below.
During the review of the pivotal study, GO29365, the sponsor committed to submitting the primary clinical study report as a Supplement to a New Drug Submission (SNDS) if the outcomes of the study have an impact on the benefit/risk profile of Polivy.
Confirmatory Studies
The sponsor is expected to file a Supplement to a New Drug Submission ‑ Confirmatory (SNDS‑C) to submit the final report from the primary analysis of the confirmatory study, GO39942. The estimated number of patients enrolled in the study is 875. The primary efficacy endpoint is progression‑free survival. Key secondary endpoints include the complete remission rate as assessed by an independent review committee, and overall survival. The expected completion date for the primary analysis is December 2021. The sponsor has committed to filing the SNDS‑C by September 2022.
The sponsor has also acknowledged that the indication approved for Polivy under the NOC/c policy may be withdrawn if the confirmatory study does not demonstrate an improvement in progression‑free survival and an overall positive benefit/risk profile as compared to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R‑CHOP).
In accordance with the NOC/c Guidance, the sponsor has agreed to submit status reports on the progress of the ongoing confirmatory study. The reports are to be submitted annually, within 60 calendar days of the anniversary of the market authorization.
Post‑Marketing Safety Monitoring
The sponsor has committed to including pulmonary toxicity (including but not limited to pneumonitis) as an important risk within the Canadian Risk Management Plan.
The sponsor has also committed to providing analyses of any new cases of gastrointestinal complications (including but not limited to colitis and perforation), pancreatitis, and serious infections (including but not limited to reactivated viral and opportunistic infections) through Periodic Benefit‑Risk Evaluation Reports (PBRERs). The PBRERs are to be submitted every six months, and are expected to include clinical exposure data.
The sponsor is expected to report all serious adverse reactions that occur in Canada and all serious unexpected adverse reactions that occur outside of Canada to Health Canada within 15 days of occurrence. Additionally, the sponsor is expected to comply with notification and reporting guidelines for specific issues of concern as outlined in the NOC/c Guidance.
Additional Information
The sponsor has committed to submitting a report regarding the development and validation of a sensitive assay to evaluate the neutralizing capacity of anti‑drug antibodies (ADA) in confirmed ADA‑positive patient samples.
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
Polatuzumab vedotin, the medicinal ingredient in Polivy, is a CD79b‑targeted antibody‑drug conjugate that preferentially delivers an anti‑mitotic agent (monomethyl auristatin E [MMAE]) to B cells, resulting in the killing of malignant B cells. The polatuzumab vedotin molecule consists of MMAE covalently attached via a cleavable linker to a humanized immunoglobulin G1 monoclonal antibody. The antibody is produced by recombinant deoxyribonucleic acid (DNA) technology in Chinese hamster ovary (CHO) cells. It binds with nanomolar affinity and selectivity to CD79b, a cell surface component of the B‑cell receptor. Expression of CD79b is restricted to normal cells within the B‑cell lineage (with the exception of plasma cells) and malignant B cells. Notably, CD79b is expressed in over 95% of cases of diffuse large B‑cell lymphoma (DLBCL). Upon binding CD79b, polatuzumab vedotin is rapidly internalized by the B cell. The linker is cleaved by lysosomal proteases within the cell to enable intracellular delivery of MMAE. Unconjugated MMAE then binds to microtubules and kills dividing cells by inhibiting cell division and inducing apoptosis.
Exposures to antibody‑conjugated MMAE or unconjugated MMAE increased dose proportionally following administration of polatuzumab vedotin, over the range of 0.1 to 2.4 mg/kg. Plasma exposures of unconjugated MMAE (the cytotoxic component of Polivy) were less than 3% of the exposure to antibody‑conjugated MMAE.
Population pharmacokinetic studies were conducted to evaluate a wide range of covariates. Weight was identified as the most influential covariate, and the results of the studies support weight‑based dosing for Polivy.
Mild hepatic impairment was associated with increased exposure to unconjugated MMAE, as measured by the area under the concentration‑time curve (AUC) and the maximum concentration (Cmax). In patients with mild hepatic impairment, the AUC and Cmax were 40% and 34% greater, respectively, than in patients with normal hepatic function. Patients with moderate or severe hepatic impairment could be at increased risk of experiencing adverse reactions, and the data available in this population are limited. Treatment with Polivy should be avoided in patients with moderate or severe hepatic impairment.
Physiologically based pharmacokinetic model simulations of MMAE released from polatuzumab vedotin indicate that strong cytochrome P450 (CYP) 3A inhibitors may increase the AUC of unconjugated MMAE by 48%. Patients receiving strong CYP3A inhibitors concomitantly with Polivy should be monitored closely for signs of toxicities. Strong CYP3A inducers may decrease the AUC of unconjugated MMAE.
Polatuzumab vedotin had no significant impact on the population pharmacokinetics of rituximab when both drugs were used in combination.
At the recommended dose of 1.8 mg/kg, polatuzumab vedotin did not have a clinically meaningful effect on the QT interval.
For further details, please refer to the Polivy Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
Evidence of the clinical efficacy of Polivy was primarily based on the pivotal study, GO29365, which was ongoing at the time when the Notice of Compliance with Conditions (NOC/c) was issued.
The pivotal study GO29365 was a Phase Ib/II, randomized, open‑label study designed to evaluate the efficacy, safety, and tolerability of Polivy in combination with bendamustine and rituximab (BR), relative to treatment with BR alone. Patients enrolled in this study had relapsed or refractory diffuse large B‑cell lymphoma (DLBCL). At the time of the NOC/c issuance, this study was ongoing and was planned to continue until all patients have had two years of follow‑up or have discontinued the study.
Phase Ib of this study was a safety assessment to confirm the tolerability of the Polivy plus BR regimen. Six patients with relapsed or refractory DLBCL were included and treated in this cohort.
The Phase II portion of the study included a cohort of 80 patients with relapsed or refractory DLBCL, who were not eligible to receive an autologous stem cell transplant and who had received at least one prior therapy. Patients in this cohort were randomized 1:1 to receive either Polivy plus BR, or BR alone (40 patients in each treatment group). Randomization was stratified based on the duration of response to prior therapy. The median age of patients in this study was 69 years, and the median number of prior lines of therapy was 2 (range: 1‑7). Polivy was administered by intravenous infusion at a dose of 1.8 mg/kg in addition to BR, once every 21 days, for 6 cycles of treatment.
The primary efficacy endpoint of the study was the complete response rate at the end of treatment, as assessed by an independent review committee (IRC). The end of treatment was defined as 6‑8 weeks after Day 1 of Cycle 6, or the date of the last study treatment. The complete response rate was 40% (95% confidence interval [CI]: 24.9, 56.7) for patients treated with Polivy plus BR, and 17.5% (95% CI: 7.3, 32.8) for patients treated with BR alone. The difference in complete response rates between the two treatment groups was 22.5% (95% CI: 2.6, 40.2). It was noted that the 95% CIs for complete response rates overlapped for the two treatment groups.
Key secondary endpoints included the IRC‑assessed objective response rate at the end of treatment and the best overall response rate. Both endpoints counted complete and partial responses. The objective response rate was 45.0% for patients treated with Polivy plus BR, and 17.5% for patients treated with BR alone. The best overall response rate was 62.5% in the Polivy plus BR treatment group, and 25.0% in the BR treatment group. Duration of response was estimated to be 12.6 months in the Polivy plus BR treatment group and 7.7 months in the BR treatment group.
Due to the design of the pivotal trial, there is some residual uncertainty regarding the magnitude of the treatment effect. Although the 95% CIs for the primary endpoint overlapped for the two treatment groups, the observed treatment effect serves as promising clinical evidence in the target patient population in the context of conditional authorization.
Indication
Health Canada approved the following indication for Polivy:
Polivy (polatuzumab vedotin) in combination with bendamustine and rituximab is indicated for the treatment of adult patients with relapsed or refractory diffuse large B‑cell lymphoma, not otherwise specified, who are not eligible for autologous stem cell transplant and have received at least one prior therapy.
The proposed indication was for adult patients with DLBCL. This was revised slightly to specify adult patients with relapsed or refractory DLBCL, to reflect the patient population in the pivotal study.
For more information, refer to the Polivy Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The primary safety population consisted of patients with relapsed or refractory DLBCL, who received at least one dose of Polivy plus BR (45 patients), or BR alone (39 patients). The patients in this population were enrolled in the pivotal study, GO29365, which is described in the Clinical Efficacy section. Additional safety data were derived from the supportive studies GO27834, GO29044, and DCS4968g.
Pivotal Study: GO29365
Similar safety profiles were observed between the Polivy plus BR and BR treatment groups. The majority of adverse events were grade 1 or 2 in severity. The incidence of serious adverse events reported in the two treatment groups was comparable (64.4% and 61.5%, respectively). A higher incidence of Grade 3 or higher adverse events was observed in patients treated with Polivy plus BR (84.4%) compared to patients treated with BR alone (74.4%). A lower incidence of death was observed in patients treated with Polivy plus BR (55.6%) compared to patients treated with BR alone (71.8%), with disease progression as the most common reason for death in both treatment groups. The incidence of deaths due to adverse events was 20.0% in patients treated with Polivy plus BR, and 28.2% in patients treated with BR alone.
The most common adverse events, reported in over 10% of patients, included neutropenia, thrombocytopenia, lymphopenia, anemia, diarrhea, abdominal pain, fatigue, pyrexia, pneumonia, infusion‑related reactions, decreased weight, decreased appetite, hypokalemia, hypoalbuminemia, hypocalcemia, peripheral neuropathy, dizziness, and pruritus. The incidence was higher in patients treated with Polivy plus BR for each of these adverse events. The incidences of Grade 3 or higher neutropenia, thrombocytopenia, anemia, lymphopenia, pancytopenia, and pneumonia were also higher in patients treated with Polivy plus BR. Other adverse events that occurred at a higher incidence in patients treated with Polivy plus BR include infusion‑related reactions, hepatic toxicity, gastrointestinal toxicity, arthralgia, and skeletal pain. Infections, which were observed at similar incidences in the two treatment groups, were a leading cause of serious adverse events and death. Four fatal infections occurred in each treatment group.
Discontinuations of the study drug due to adverse events were more frequent in the Polivy plus BR treatment group than in the BR treatment group (31.1% and 15.4%, respectively). The observed increase was attributed to higher incidences of neutropenia and thrombocytopenia.
Treatment with any therapeutic protein is accompanied by the risk of immunogenicity (the development of anti‑drug antibodies [ADAs], which have the potential to neutralize the biological activity of the drug). Serum samples from 134 patients enrolled in the pivotal study were examined for ADAs against polatuzumab vedotin using validated methods. Five patients (3.7%) had ADAs at baseline, and eight patients (6.0%) were found to have treatment‑emergent ADAs. The number of patients in which ADAs were detectable was too small to determine their impact on the safety and efficacy of Polivy. Patient samples were not assessed for neutralizing antibodies.
A Serious Warnings and Precautions box has been included in the Polivy Product Monograph to highlight the risk of fatal, life‑threatening, or serious infections, including opportunistic infections, which have been reported in patients treated with Polivy and are considered clinically significant. Serious and severe myelosuppression, including neutropenia, febrile neutropenia, thrombocytopenia, and anemia have also been included in this section.
Overall, the data from this study indicate that the risks associated with Polivy are tolerable and manageable, and the safety profile of Polivy is acceptable for its intended use. The identified risks have been appropriately addressed and communicated in the Product Monograph.
Supportive Studies: GO27834, GO29044, and DCS4968g
At the time of the NOC/c issuance for Polivy, the studies GO27834 and GO29044 were both ongoing and DCS4968g was completed.
GO27834 was a Phase II open‑label and randomized study, which aimed to evaluate the safety and activity of Polivy combined with rituximab, or pinatuzumab vedotin combined with rituximab. A non‑randomized Phase Ib/II portion of the study evaluated the safety and activity of Polivy combined with obinutuzumab.
GO29044 was a Phase Ib/II open‑label dose escalation study, which assessed the safety, tolerability, and activity of Polivy in combination with cyclophosphamide, doxorubicin, and prednisone, as well as rituximab or obinutuzumab, in patients with B‑cell non‑Hodgkin's lymphoma (NHL).
DCS4968g was a Phase I open‑label dose‑escalation study, which assessed the safety of Polivy as a single agent in patients with relapsed or refractory B‑cell NHL and chronic lymphocytic leukemia, or in combination with rituximab in patients with relapsed or refractory B‑cell NHL.
The findings from these studies described a safety profile for Polivy as a single agent and in combination with other regimens in DLBCL patients that was consistent with other similar MMAE‑antibody conjugates. The main adverse events of clinical relevance were neutropenia, peripheral neuropathy, and infection. Overall, the data from the three supportive studies indicated that the 1.8 mg/kg dose of Polivy (the recommended dose) has a manageable safety profile in patients with DLBCL.
For more information, refer to the Polivy Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
In non‑clinical pharmacodynamic studies, polatuzumab vedotin exhibited antitumour activity in vitro in CD79b‑expressing human Burkitt lymphoma cells and in vivo in xenograft models of diffuse large B‑cell lymphoma (DLBCL). The addition of an anti‑CD20 antibody (rituximab or obinutuzumab) and chemotherapy (bendamustine or cyclophosphamide, doxorubicin, and prednisone [CHP]) to polatuzumab vedotin enhanced the antitumour activity.
Polatuzumab vedotin does not bind to CD79b of non‑clinical species. Toxicology studies were conducted with a surrogate antibody‑drug conjugate (ADC) that binds to cynomolgus monkey CD79b, as well as polatuzumab vedotin and monomethyl auristatin E (MMAE). No adverse effects were observed on cardiovascular, neurologic, or respiratory safety pharmacology endpoints in rats or monkeys following repeated dosing of polatuzumab vedotin or the surrogate ADC. The primary target organs of polatuzumab vedotin, as identified in the repeat‑dose toxicity studies, were the bone marrow, lymphoid tissues, liver and male reproductive organs, consistent with the expected activity of MMAE. All target organ toxicities were reversible except for the testicular toxicity in male rats.
No carcinogenicity studies were conducted with polatuzumab vedotin or MMAE. Monomethyl auristatin E was found to be genotoxic in a rat bone marrow micronucleus study, through an aneugenic mechanism. This is consistent with the pharmacological effect of MMAE as a microtubule disrupting agent. It was not found to be mutagenic in vitro in the Ames test or the L5178Y mouse lymphoma forward mutation assay. No genotoxicity studies were conducted with polatuzumab vedotin.
Although no dedicated fertility studies were conducted with polatuzumab vedotin, signs of toxicity were observed in repeat‑dose studies in male rats. These effects impaired reproductive function and fertility, and were non‑reversible.
In the embryo‑fetal developmental study, MMAE induced embryo‑fetal deaths and fetal malformations in rats at exposures below the clinical exposure. No teratogenicity studies have been performed with polatuzumab vedotin.
Overall, the non‑clinical pharmacology and toxicology profile of polatuzumab vedotin supports its proposed clinical use. The results of the non‑clinical studies as well as the potential risks to humans have been included in the Polivy Product Monograph. Considering the intended use of Polivy, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Polivy Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
Characterization of the Drug Substance
Polatuzumab vedotin, the drug substance, is an antibody‑drug conjugate. It consists of the potent anti‑mitotic agent monomethyl auristatin E (MMAE) covalently attached to polatuzumab, a monoclonal antibody.
The drug portion, MMAE, is a synthetic analogue of the antineoplastic natural product dolastatin 10. Its linking to polatuzumab is achieved through a protease‑cleavable linker. Together, MMAE and the linker form the drug substance intermediate SGD‑1006.
The drug substance intermediate polatuzumab is a recombinant, humanized monoclonal antibody directed against human CD79b, a component of the B‑cell receptor. Detailed characterization studies were carried out to provide assurance that the intermediate polatuzumab and its derived drug substance polatuzumab vedotin consistently exhibit the expected structure and biological activity. The physicochemical, biological, and immunological properties of polatuzumab vedotin, its purity and stability, were all examined using appropriate analytical methods and were found to be satisfactory. Analysis of the primary structure confirmed that conjugation occurs at the expected site.
Manufacturing Process and Process Controls of the Drug Substance and Drug Product
Polatuzumab vedotin, the medicinal ingredient in Polivy, is an antibody‑drug conjugate. The antibody intermediate and the drug intermediate are manufactured separately, and are joined by a cleavable linker through a conjugation reaction.
The drug portion, SGD‑1006, consists of MMAE attached to a protease‑cleavable linker. This intermediate is manufactured through convergent, solution-phase, fragment-based peptide synthesis.
The antibody portion, polatuzumab, is manufactured using recombinant deoxyribonucleic acid (DNA) technology in Chinese hamster ovary (CHO) cells. The cell culture in which polatuzumab is expressed is allowed to expand to commercial scale through a fed‑batch process. Purification of polatuzumab from the cell culture involves a series of chromatography, viral inactivation, and filtration steps. The purified antibody intermediate is stored frozen at ‑20°C.
The drug substance, polatuzumab vedotin, is produced through a conjugation reaction which covalently links SGD‑1006 to polatuzumab. This is followed by formulation and filtration steps, after which the drug substance is stored frozen at ‑20°C.
The drug product, Polivy, is produced from the thawed drug substance through a series of steps including bioburden reduction filtration, mixing, sterile filtration, aseptic filling, and partial stoppering. Following lyophilization, the vials are fully stoppered and capped, visually inspected, and stored at 2‑8°C.
The data from process validation studies indicate that the manufacturing processes for the intermediates and the drug substance are capable of consistently manufacturing these components to an acceptable standard.
All non‑medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of polatuzumab vedotin with the excipients is supported by the stability data provided.
Control of the Drug Substance and Drug Product
The control strategies for manufacturing the drug substance intermediates (SGD‑1006 and polatuzumab), drug substance, and drug product were found to be acceptable. Process validation and batch analysis data indicate that the manufacturing processes operate consistently and yield a product of acceptable quality. All analytical procedures used for testing were validated and qualified in accordance with the relevant International Council for Harmonisation (ICH) guidelines.
Polivy is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program before sale as per Health Canada's Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs. As part of this program, final product lots were tested for purity and potency using a subset of release methods. Test results were found acceptable. For post-approval monitoring, Polivy was classified as a low‑risk product. The risk level assigned to a drug product is determined by factors including the nature of the product, its indication and target patient population, and the manufacturer's production.
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 24‑month shelf life at 2‑8°C for Polivy is considered acceptable. The vial should be stored in its outer carton to protect it from light, and must not be frozen or shaken.
Facilities and Equipment
On‑site evaluations (OSEs) were not conducted in connection with this drug submission. Based on risk assessment scores determined by Health Canada, OSEs were not warranted for the three facilities manufacturing polatuzumab, polatuzumab vedotin, or Polivy at the time of review.
Adventitious Agents Safety Evaluation
The cell banks used in the manufacture of Polivy were characterized according to relevant ICH guidelines and were found to be free from viral contaminants and other adventitious agents. The manufacturing process for the polatuzumab drug substance intermediate has shown robust and effective clearance of potential viral contaminants and it incorporates adequate control measures to prevent contamination and maintain microbial control.
The biologic raw materials used during manufacturing originate from sources with no or minimal risk of transmissible spongiform encephalopathy or other human pathogens.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| POLIVY | 02515431 | HOFFMANN-LA ROCHE LIMITED | POLATUZUMAB VEDOTIN 30 MG / VIAL |
| POLIVY | 02499614 | HOFFMANN-LA ROCHE LIMITED | POLATUZUMAB VEDOTIN 140 MG / VIAL |