Summary Basis of Decision for Rybrevant
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 Rybrevant is located below.
Recent Activity for Rybrevant
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 Rybrevant
Date SBD issued: 2022-07-11
The following information relates to the new drug submission for Rybrevant.
Amivantamab
Drug Identification Number (DIN):
- DIN 02526182 - 350 mg/7 mL, solution, intravenous infusion
Janssen Inc.
New Drug Submission Control Number: 254440
On March 30, 2022, Health Canada issued a Notice of Compliance under the Notice of Compliance with Conditions (NOC/c) Guidance to Janssen Inc. for the drug product Rybrevant. 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 Rybrevant is favourable for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy.
Clinical effectiveness of Rybrevant is based on objective response rate (ORR) and duration of response (DOR) from a single-arm trial in patients with activating EGFR exon 20 insertion mutations.
A validated test is required to identify EGFR exon 20 insertion mutation-positive status prior to treatment.
1 What was approved?
Rybrevant, an antineoplastic monoclonal antibody, was authorized for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy.
Clinical effectiveness of Rybrevant is based on objective response rate and duration of response from a single-arm trial in patients with activating EGFR exon 20 insertion mutations.
A validated test is required to identify EGFR exon 20 insertion mutation-positive status prior to treatment.
Based on the data submitted and reviewed by Health Canada, the safety and efficacy of Rybrevant in pediatric patients (<18 years of age) has not been established; therefore, Health Canada has not authorized an indication for pediatric use.
No clinically relevant differences in effectiveness were observed between elderly patients (≥65 years of age) and younger patients. Evidence from the clinical study (EDI1001) suggests that the use of Rybrevant in the geriatric population is associated with differences in safety.
Rybrevant (350 mg/7 mL amivantamab) is presented as a solution for infusion. In addition to the medicinal ingredient, the solution contains ethylenediaminetetraacetic acid (EDTA), L-histidine, L-Histidine hydrochloride monohydrate, L-methionine, polysorbate 80, sucrose, and water for injection.
The use of Rybrevant 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 Rybrevant 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 Rybrevant approved?
Health Canada considers that the benefit-risk profile of Rybrevant is favourable for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy.
Clinical effectiveness of Rybrevant is based on objective response rate (ORR) and duration of response (DOR) from a single-arm trial in patients with activating EGFR exon 20 insertion mutations.
A validated test is required to identify EGFR exon 20 insertion mutation-positive status prior to treatment.
Rybrevant 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.
Lung cancer is the most commonly diagnosed cancer in Canada, with approximately 30,000 cases diagnosed annually. It is also the leading cause of cancer-related death, with close to 21,000 Canadians dying of lung cancer annually. In Canada, the 5-year net survival rate for lung cancer is estimated to be 19%. Survival is lower for patients with metastatic disease (approximately 10% worldwide).
Lung cancer is divided into two main subtypes, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Approximately 80 to 90% of lung cancers are classified as NSCLC. Aberrant activation of EGFR due to mutations has been implicated as a driver of tumour development and cell growth in lung cancer. It is estimated that 15 to 40% of NSCLC tumours harbor a mutation in the EGFR gene. Epidermal growth factor receptor exon 20 insertion (exon 20ins) mutations, classified as an uncommon mutation, are found in approximately 4–12% of patients with EGFR mutations. Tumours harbouring this mutation have had limited responses to currently authorized EGFR tyrosine kinase inhibitors (TKI). Platinum-based chemotherapy is a standard first-line treatment for patients with NSCLC harbouring an EGFR exon 20ins mutation. For patients who progress on, or after, platinum-based chemotherapy, there are no clear standard treatment options and no targeted therapies. Canadian clinical practice guidelines outline single agent chemotherapy, docetaxel, as an option in the second-line setting. However, reported response rates for docetaxel treatment are low for NSCLC patients, ranging from 8 to 13%. Other treatment options include chemotherapy regimens, TKI, and immunotherapy which have exhibited similarly low response rates. Therefore, a medical need exists in Canada for more effective therapies to treat patients with NSCLC harbouring EGFR exon 20ins mutations.
Rybrevant (amivantamab) is a bispecific, fully human antibody directed against the EGFR and mesenchymal-epithelial transition (MET) receptor. Amivantamab binds to the extracellular domain of EGFR and MET receptors, thereby disrupting the receptors' signaling functions by blocking ligand binding, and enhancing degradation of these receptors. The presence of EGFR and MET on the surface of tumour cells also allows for the targeting of these cells for destruction by immune effector cells, such as natural killer cells and macrophages, through antibody-dependent cellular cytotoxicity (ADCC) and trogocytosis mechanisms, respectively.
Rybrevant has been shown to be efficacious in patients with locally advanced or metastatic NSCLC with activating EGFR exon 20ins mutations whose disease has progressed on or after platinum-based chemotherapy. The market authorization with conditions was based on the results of the CHRYSALIS Study, a Phase I, first-in-human, open-label study designed to evaluate the tolerability, safety, pharmacokinetics, and anti-tumour activity of Rybrevant. In the study, Rybrevant was administered by intravenous infusion at a dose of 1,050 mg for patients with a baseline body weight less than 80 kg and 1,400 mg for patients with a baseline body weight of 80 kg or greater. Administration was once weekly for the first 4 weeks (Cycle 1, 28 days/cycle) and then every 2 weeks in subsequent 28-day cycles starting at Week 5. The first infusion was administered as a split dose in Week 1 on Day 1 and Day 2.
The primary efficacy endpoint of the CHRYSALIS Study was the objective response rate (ORR). The primary efficacy population was comprised of 81 patients with locally advanced or metastatic NSCLC with activating EGFR exon 20ins mutations whose disease has progressed on or after platinum-based chemotherapy, who were treated with Rybrevant monotherapy. At the clinical cut-off date, these patients had undergone at least 3 scheduled post-baseline disease assessments to confirm a response. The confirmed ORR for the primary efficacy population, by blinded independent central review, was 39.5%. Three patients achieved a complete response. This was supported by a median duration of response of 11.14 months (range: 1.3 to 21.7 months). Of the 32 patients who achieved an objective response, 20 (62.5%) had a duration of response of 6 months or greater. In order to evaluate and confirm the effectiveness of the product, the sponsor is expected to submit the following data to Health Canada as part of the post-approval commitments: the results of a well-controlled Phase III clinical trial to confirm the efficacy of Rybrevant in patients with advanced NSCLC with EGFR exon 20ins mutations as well as further follow-up data for the CHRYSALIS Study, to allow for confirmation of the treatment effect observed, with respect to ORR and DOR.
Clinically important adverse reactions associated and observed with Rybrevant included rash (including dermatitis acneiform), infusion-related reactions (IRRs), interstitial lung disease/pneumonitis, and eye disorders. Other adverse reactions included paronychia, peripheral edema, and diarrhea. The most commonly reported treatment-emergent adverse events (TEAEs) that occurred in at least 20% of patients included rash (including dermatitis acneiform), IRRs, paronychia, musculoskeletal pain, dyspnea, nausea, hypoalbuminemia, fatigue, peripheral edema, stomatitis, cough, and constipation. Serious TEAEs occurred in 30.2% of patients with pulmonary embolism, dyspnea, pneumonitis and musculoskeletal pain being the most common events observed. There was also one incidence of toxic epidermal necrolysis reported. In 10.9% of patients in the target patient population, a TEAE led to treatment discontinuation. These were mainly due to pneumonia, pneumonitis, pleural effusion, and IRR.
No formal studies of Rybrevant have been conducted in patients with renal or hepatic impairment. Based on population pharmacokinetic analyses, no dosage adjustment is necessary for patients with mild or moderate renal impairment or for patients with mild hepatic impairment. No data are available in patients with severe renal impairment or in patients with moderate or severe hepatic impairment.
A Risk Management Plan (RMP) for Rybrevant was submitted by Janssen Inc. to Health Canada. 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. At the time of Notice of Compliance issuance, there were no RMP-related issues that would preclude the authorization of Rybrevant.
The submitted inner and outer labels, package insert, and Patient Medication Information section of the Rybrevant 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 Rybrevant was accepted.
Overall, the therapeutic benefits of Rybrevant therapy seen in the pivotal study are promising and are considered to outweigh the potential risks. Rybrevant 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 Rybrevant Product Monograph to address the identified safety concerns. As described within the framework of the NOC/c Guidance, safety monitoring of the use of Rybrevant 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 Rybrevant?
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 Rybrevant. The sponsor presented promising evidence of clinical effectiveness that Rybrevant has the potential to provide a significant increase in efficacy such that the overall benefit/risk profile is improved over existing therapies for a serious and life-threatening disease that is not adequately managed by a drug 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.
The New Drug Submission (NDS) for Rybrevant was reviewed under Project Orbis, an initiative of the United States Food and Drug Administration (FDA) Oncology Center of Excellence. The project is an international partnership designed to give cancer patients faster access to promising cancer treatments. The submission for Rybrevant was classified as a Project Orbis Type C submission, where the FDA had already issued a positive decision and subsequently shared their completed review documents with Health Canada.
The Canadian regulatory decision on the Rybrevant New Drug Submission (NDS) was made independently. The review of the NDS for Rybrevant was based on a critical assessment of the data package submitted to Health Canada and of the reviews completed by the United States Food and Drug Administration as described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada. Method 3 was used for the review of the clinical efficacy, safety, and pharmacology. Method 2 was used for the review of non-clinical pharmacology and quality components of the submission.
For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.
Submission Milestones: Rybrevant
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting | 2021-05-05 |
| Advance Consideration under the Notice of Compliance with Conditions Guidance accepted | 2021-06-11 |
| New Drug Submission filed | 2021-07-05 |
| Screening | |
| Screening Acceptance Letter issued | 2021-07-30 |
| Review | |
| Quality evaluation completed | 2021-12-31 |
| Review of Risk Management Plan completed | 2022-01-13 |
| Non-clinical evaluation completed | 2022-02-04 |
| Clinical/medical evaluation completed | 2022-02-09 |
| Biostatistics evaluation completed | 2022-02-09 |
| Labelling review completed | 2022-02-14 |
| Notice of Compliance with Conditions Qualifying Notice issued | 2022-02-14 |
| Review of Response to Notice of Compliance with Conditions Qualifying Notice: | |
| Response filed (Letter of Undertaking) | 2022-02-22 |
| Clinical/medical evaluation completed | 2022-03-30 |
| Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate under the Notice of Compliance with Conditions Guidance | 2022-03-30 |
4 What follow-up measures will the company take?
In addition to the 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 the 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) as indicated below.
Study Papillion (61186372NSC3001)
Study Papillion is a randomized, open-label, Phase III confirmatory study of Rybrevant and carboplatin-pemetrexed combination therapy as compared with carboplatin-pemetrexed therapy alone, in patients with epidermal growth factor receptor (EGFR) exon 20 insertion mutated locally advanced or metastatic non-small cell lung cancer (NSCLC). The estimated study enrolment is 300 patients and the primary endpoint of the study is progression-free survival (PFS) based on blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumours guideline version 1.1 (RECIST v1.1). The key secondary endpoints of this study include objective response rate (ORR) per BICR, including duration of response, and overall survival (OS).
The approximate date of completion of this study is the fourth quarter of 2022 and the sponsor commits to filing the SNDS-c by the second quarter of 2023.
The Sponsor acknowledges that the indication for Rybrevant may be withdrawn if the results of this study do not demonstrate that Rybrevant in combination with carboplatin-pemetrexed is associated with a PFS that is both statistically significant and clinically meaningful over carboplatin-pemetrexed alone. Additionally, while OS is a secondary endpoint, it will be considered as a key element evaluated in the confirmation of benefit and assessment of benefit/risk for the indicated patient population.
Study CHRYSALIS (61186372EDI1001)
Study CHRYSALIS is a Phase I, first-in-human, open-label, dose escalation study of Rybrevant, a human bispecific EGFR and mesenchymal-epithelial transition factor (MET) antibody, in subjects with advanced NSCLC to further characterize the clinical benefit of Rybrevant for the treatment of patients with NSCLC with EGFR exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy. This study is being conducted to provide confirmation, and a more precise estimation of the ORR per BICR and duration of response in a high number of patients with longer follow-up. The data submitted will be an analysis after all responders in the target patient population (at least 129 patients with exon 20 insertion mutations and prior platinum-based chemotherapy) have been followed for at least 6 months from the date of initial response or until disease progression, whichever comes first. Safety will be evaluated for consistency.
The final report was ready in October, 2021. The Sponsor commits to filing the SNDS-c by the third quarter of 2022.
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 New Drug Submission (NDS) for Rybrevant was completed by Health Canada as part of an international partnership with the United States Food and Drug Administration as a Project Orbis Type C submission. The clinical review of the NDS for Rybrevant was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.
Clinical Pharmacology
Rybrevant (amivantamab) is a bispecific, fully human antibody directed against the epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition (MET) receptor. Amivantamab binds to the extracellular domain of the EGFR and MET receptors, thereby disrupting EGFR and MET receptor signaling functions by blocking ligand binding, and enhancing degradation of these receptors. The presence of EGFR and MET on the surface of tumour cells also allows for the targeting of these cells for destruction by immune effector cells, such as natural killer cells and macrophages, through antibody-dependent cellular cytotoxicity (ADCC) and trogocytosis mechanisms, respectively.
Pharmacodynamic responses of amivantamab in non-small cell lung cancer (NSCLC) patients with EGFR exon 20 insertion mutations have not been fully characterized.
The pharmacokinetics of intravenous amivantamab (as a monotherapy) was characterized in patients with advanced NSCLC enrolled in the Phase I CHRYSALIS Study. The details of this study are provided in the Clinical Efficacy section below. Of the 362 patients, 187 had an EGFR exon 20 insertion mutation. The pharmacokinetic parameters and potential covariate effect on the pharmacokinetics of amivantamab was determined by population modelling analysis (based on a total of 8,756 serum concentration data obtained from 362 patients).
Following intravenous administration, amivantamab demonstrated linear pharmacokinetics over the dose range of 350 mg to 1,750 mg and could be described by a two-compartment model. The population modelling analysis estimated (mean ± standard deviation) total volume of distribution, clearance, and half-life were 5.13 L ± 1.78 L, 360 mL/day ± 144 mL/day, and 11.3 days ± 4.53 days, respectively. The volume of distribution and clearance of amivantamab increased with increased body weight. At a given dose, amivantamab exposure was approximately 30 to 40% lower in patients with a body weight 80 kg or higher compared to patients who were less than 80 kg. Clearance was estimated to be 24% higher in men than in women, corresponding to a 34% higher exposure (measured by area under the concentration-time curve [AUC] from 0 to 14 days, steady state) in women than in men. The patients' age (range: 32 to 87 years), race (Asian, total number [n] = 217; Caucasian, n = 108; others, n = 37), creatinine clearance (29 to 276 mL/min), or mild hepatic impairment (total bilirubin less than or equal to the upper limit of normal [ULN] and aspartate aminotransferase [AST] greater than the ULN, or total bilirubin less than or equal to 1.5 times the ULN and any AST) were not found to have a significant impact on the exposure of amivantamab.
Comparable amivantamab exposure was observed following the proposed recommended Phase II dosing regimen, i.e., 1,050 mg for patients with a body weight less than 80 kg and 1,400 mg for patients with a body weight greater than or equal to 80 kg, every week for 4 weeks and every two weeks thereafter. Amivantamab concentration reached steady state by Cycle 4 (9th dose) during the stage in which doses were administered every two weeks, with a mean accumulation ratio of approximately 2.4.
The clinical pharmacology data support the use of Rybrevant for the recommended indication. For further details, please refer to the Rybrevant Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The efficacy and safety of Rybrevant for the authorized indication was evaluated based on data from the pivotal, Phase I CHRYSALIS Study (EDI1001). This study was a first-in-human, open-label, multicentre, multi-cohort, two-part study designed to investigate Rybrevant in the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). At the time of authorization, the study was ongoing. The end point of the study is specified as the point in time when all patients have completed therapy and have had at least 6 months of follow-up or have discontinued the study.
The CHRYSALIS Study has two parts. Part 1 of the study was a dose escalation phase with the primary objective of identifying the maximum tolerated dose of Rybrevant monotherapy and determining the recommended Phase II dose (RP2D) to be used in the dose expansion phase, Part 2. The objective of Part 2 was to assess the safety and pharmacokinetics of amivantamab monotherapy at the RP2D, and to examine its clinical activity within molecularly defined tumour subgroups.
For Part 1, a total of 77 patients with advanced NSCLC were enrolled in one of six dosing cohorts ranging from 140 mg to 1,750 mg Rybrevant. All doses were tolerable through all dosing cohorts with no maximum tolerated dose identified. Based on the tolerability, safety, antitumour activity, and pharmacokinetic results, a weight-based regimen was identified as the RP2D regimen. Patients having a baseline body weight less than 80 kg received a 1,050 mg dose and patients having a baseline body weight greater than or equal to 80 kg received a 1,400 mg dose. Rybrevant was administered intravenously once weekly for the first four weeks (Cycle 1, 28 days/cycle) and then every two weeks in subsequent cycles starting at Week 5. The first infusion was administered as a split dose in Week 1 on Day 1 and Day 2. At the time of authorization, this dosing regimen of Rybrevant monotherapy was included in the Rybrevant Product Monograph.
The primary objective of the dose expansion phase (Part 2) was to determine the safety, tolerability, and antitumor activity (efficacy) of Rybrevant monotherapy at the RP2D in patients with advanced NSCLC. Patients in this part of the study were enrolled into single-arm, molecularly defined cohorts by tumour EGFR and/or MET receptor alteration/mutation status. This included the pivotal cohort, which was comprised of patients with locally advanced or metastatic NSCLC whose tumours harboured a previously diagnosed epidermal growth factor receptor (EGFR) exon 20 insertion (exon 20ins) mutation (the target patient population for the proposed indication). These patients made up Cohort D and had a median age of 62 years (range: 36 to 84 years), with 41.1% of patients 65 years of age or older, 61.2% female, 55.0% Asian, and 34.9% Caucasian. Eighty-two percent of patients had a baseline body weight less than 80 kg and 18% were 80 kg or greater. The majority of patients had adenocarcinoma (96.1%) that was considered to be Stage IV disease at initial diagnosis (79.1%). All patients had received prior platinum-based chemotherapy. Prior to enrollment in this cohort, confirmation was required of EGFR exon 20ins mutation status by certified local testing using tissue and/or plasma samples.
The efficacy analysis focused on the patients enrolled in Cohort D. The primary efficacy population was comprised of 81 patients who were treated with the RP2D, and who had at least three scheduled post-baseline disease assessments to allow for confirmation of response, as per the study protocol. As of the clinical cut-off date for analysis of October 8, 2021, the median follow-up for the primary efficacy population was 9.7 months. The confirmed objective response rate (ORR) by blinded independent central review (BICR) was 39.5% (95% confidence interval [CI]: 28.8%, 51.0%). Three patients achieved a complete response. The lower bound of the 95% CI for this analysis was greater than 12%, thus exceeding the pre-determined threshold for a meaningful treatment effect. The median duration of response (DOR), based on BICR assessment, was 11.14 months (range: 1.3 to 21.7 months). Of the 32 responders, 20 (62.5%) had a DOR greater than or equal to 6 months as of the clinical cut-off date.
Indication
One change was made to the proposed indication filed by the sponsor as part of the New Drug Submission for Rybrevant. Health Canada requested the specification of use in adult patients. Accordingly, Health Canada approved the following indication:
Rybrevant (amivantamab for injection) is indicated for:
- The treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy.
The clinical effectiveness of Rybrevant is based on objective response rate (ORR) and duration of response (DOR) from a single-arm trial in patients with activating epidermal growth factor receptor (EGFR) Exon 20 insertion mutations.
A validated test is required to identify EGFR Exon 20 insertions mutation-positive status prior to treatment.
Overall Analysis of Efficacy
A medical need exists for more effective treatment options for patients with locally advanced or metastatic NSCLC with activating EGFR exon 20ins mutations whose disease has progressed on, or after, prior platinum-based chemotherapy. The magnitude of the treatment effect observed in the CHRYSALIS Study demonstrates promising evidence of a clinically meaningful benefit in the target patient population; however, given the design of the pivotal study, confirmation of the treatment effect is required. As a condition of authorization for Rybrevant, the sponsor has committed to the following confirmatory conditions:
- The submission of the results of a well-controlled Phase III clinical study to confirm the efficacy of Rybrevant in patients with advanced NSCLC with EGFR exon 20ins mutations.
- The submission of further follow-up data for the CHRYSALIS Study to allow for confirmation and further characterization of the treatment effect observed, with respect to ORR and DOR.
For more information, refer to the Rybrevant Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The clinical safety of Rybrevant was evaluated based on data from the pivotal, Phase I CHRYSALIS Study described in the Clinical Efficacy section.
The primary safety population included 129 patients from the CHRYSALIS Study with EGFR exon 20ins mutations who had progressed on, or after, prior platinum-based chemotherapy and who were treated with at least one dose of Rybrevant monotherapy at the RP2D. Patients received Rybrevant 1,050 mg (for patients <80 kg) or 1400 mg (for patients ≥80 kg) by intravenous infusion once weekly for 4 weeks, then every 2 weeks thereafter, until disease progression or unacceptable toxicity. The median treatment duration was 5.6 months (range: 0.03 to 23.9 months), with 44.2% of patients treated for at least 6 months.
Clinically important adverse reactions associated and observed with Rybrevant included rash (including dermatitis acneiform), infusion-related reactions (IRRs), interstitial lung disease/pneumonitis, and eye disorders. Other adverse reactions included paronychia, peripheral edema, and diarrhea.
The majority of patients experienced at least one treatment-emergent adverse event (TEAE). Most events were low grade (Grades 1 or 2), with 41.1% of patients experiencing a Grade 3 or higher TEAE. Grade 5 TEAEs occurred in 9 (7.0%) patients. The most commonly reported (≥20%) TEAEs included rash (including dermatitis acneiform), infusion-related reactions (IRR), paronychia, musculoskeletal pain, dyspnea, nausea, hypoalbuminemia, fatigue, peripheral edema, stomatitis, cough, and constipation. Serious TEAEs occurred in 30.2% of patients, with pulmonary embolism, dyspnea, pneumonitis and musculoskeletal pain being the most common events observed. There was also one reported incidence of toxic epidermal necrolysis. Treatment-emergent adverse events leading to treatment discontinuation occurred in 10.9% of patients in the target patient population. These were mainly due to pneumonia, pneumonitis, pleural effusion, and IRR.
Safety was also assessed in the population of all patients with locally advanced or metastatic NSCLC regardless of EGFR or MET receptor mutation status treated with at least one dose of Rybrevant monotherapy at the RP2D (n = 302). The safety profile observed in this larger population was found to be consistent and comparable to the observed safety profile for the primary safety population.
Infusion-related reactions (IRRs) were identified as a clinically important TEAE associated with Rybrevant. These reactions occurred in 64.3% of patients treated with Rybrevant at the RP2D. The majority of IRRs were Grade 1 or 2 in severity, with Grade 3 IRRs reported by 4 (3.1%) patients, and no reported Grade 4 or 5 events. Most IRRs (>90%) occurred during the Day 1, Cycle 1 infusion, and were Grade 2 in severity. A substantial reduction in the incidence of IRRs was observed with the Cycle 1, Day 2 infusion and with subsequent treatment cycles. To address the risk of IRRs, clear communication has been included in the Rybrevant Product Monograph including a recommended dosing regimen for Rybrevant, instructions for an initial split dose, and pre-medications and dose modifications in the event of an IRR. Other clinically significant reactions observed with Rybrevant included skin disorders, interstitial lung disease/pneumonitis, and eye disorders. These reactions, including dose management, have been adequately described in the Product Monograph.
Eye disorders, including keratitis (0.7%), occurred in 13.2% of patients treated with Rybrevant. Other reported adverse reactions included dry eye, blurred vision, eye pruritus, increased lacrimation, visual impairment, ocular hyperemia, eyelid ptosis, aberrant eyelash growth, and uveitis. All events were Grade 1 to 2 in severity.
Administration of other EGFR and MET inhibitor molecules to pregnant animals has resulted in an increased incidence of impairment of embryo-fetal development, embryolethality, and abortion. Therefore, based on its mechanism of action and findings in animal models, Rybrevant could cause fetal harm when administered to a pregnant woman. Due to this risk, female patients of reproductive potential are advised to use effective contraception during treatment and for 3 months after the last dose of Rybrevant. Male patients must use effective contraception and not donate or store semen during treatment and for 3 months after the last dose of Rybrevant.
No studies have been conducted to determine if Rybrevant is excreted in human or animal milk or if it affects milk production. Rybrevant is a fully human IgG1-based bispecific antibody. In general, human IgGs are known to be excreted in breast milk during the first few days after birth, and decrease to lower concentrations soon afterwards. Because of the potential for serious adverse reactions from Rybrevant in breastfed infants, breastfeeding is not advised during treatment with Rybrevant and for 3 months following the last dose.
Interstitial lung disease (ILD) or ILD-like adverse reactions (e.g., pneumonitis) occurred in 3.3% of patients treated with Rybrevant, with 0.7% of patients experiencing Grade 3 ILD. Three patients (1%) discontinued Rybrevant due to ILD/pneumonitis.
Skin rash (including dermatitis acneiform) (73.5%), pruritis (17.9%) and dry skin (10.9%) occurred in patients treated with Rybrevant. Most cases were Grade 1 or 2 in severity, with Grade 3 events occurring in 3.6% of patients. Rash leading to dose reduction occurred in 5% of patients and Rybrevant discontinuation due to rash occurred in 0.7% of patients. Rash usually developed within the first 4 weeks of therapy, with a median time to onset of 14 days (range: 1 to 276 days). Paronychia occurred in patients treated with Rybrevant. Most events were Grade 1 or 2, with Grade 3 paronychia occurring in 1.4% of patients. Toxic epidermal necrolysis (TEN) occurred in one patient (0.3%) treated with Rybrevant.
No formal studies of Rybrevant in patients with renal or hepatic impairment have been conducted. Based on population pharmacokinetic analyses, no dosage adjustment is necessary for patients with mild or moderate renal impairment or for patients with mild hepatic impairment. No data are available in patients with severe renal impairment or in patients with moderate or severe hepatic impairment.
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). The immunogenicity assay used to detect ADAs was validated and fit for purpose. The sensitivity of the assay was well within the acceptable range for detection of ADAs and the tolerance of the assay was acceptable.
Overall, the immunogenicity of Rybrevant was low. Of the 286 patients assessed for ADAs in the CHRYSALIS Study, 3 patients (1.0%) tested positive and had low ADA titers. The low immunogenicity precludes drawing definitive conclusions on the impact of ADAs on efficacy or safety.
Overall Analysis of Safety
The safety profile of Rybrevant monotherapy, given the life-threatening nature of advanced NSCLC, was considered tolerable and manageable based on the assessed information. Overall, the risks associated with Rybrevant, and appropriate risk management strategies, have been adequately addressed and communicated in the Rybrevant Product Monograph.
As part of the marketing authorization, to confirm the clinical benefit of Rybrevant, the sponsor has agreed to provide the final clinical study report for the CHRYSALIS Study as well as the results of a well-controlled Phase III clinical study of Rybrevant in patients with advanced NSCLC with EGFR exon 20ins mutations.
For more information, refer to the Rybrevant 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 New Drug Submission (NDS) for Rybrevant was completed by Health Canada as part of an international partnership with the United States Food and Drug Administration as a Project Orbis Type C submission. The review of the non-clinical component of the NDS for Rybrevant was conducted as per Method 2 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.
The pharmacological mechanism of action of amivantamab in the treatment of patients with non-small cell lung cancer (NSCLC) with exon 20 insertion mutated epidermal growth factor receptor (EGFR) involves significant inhibition of EGFR and mesenchymal-epithelial transition (MET) receptor signaling. This leads to decreased cellular proliferation, induction of cell death, and antitumour activity.
The submitted non-clinical studies supported the proposed mechanism of action of amivantamab. In vitro studies conducted in both human and monkey tissues demonstrated that amivantamab has high avidity to both the EGFR and MET receptor. Amivantamab also competitively inhibited the binding of the ligands epidermal growth factor (EGF) and hepatocyte growth factor (HGF) to EGFR and MET receptors. This inhibited downstream cell signaling, thereby inhibiting cell proliferation and the induction of cell death. In addition, further data demonstrated that amivantamab induces trogocytosis in macrophages and monocytes and elicits antibody-dependent cellular cytotoxicity. Finally, amivantamab was shown to significantly inhibit tumour growth in an implanted patient-derived xenograft model in mice with exon 20 insertion mutated EGFR.
In repeat-dose toxicity studies conducted in cynomolgus monkeys, amivantamab was well tolerated at weekly intravenous doses of up to 120 mg/kg for 3 months and subcutaneous doses of up to 125 mg/kg for 2 weeks. There were no effects on cardiovascular, respiratory, or nervous system function. Overall, amivantamab exhibited an acceptable safety profile and tolerability in this non-human primate model.
No reproductive or developmental studies were conducted to evaluate whether amivantamab affects fertility or reproduction. Based on its mechanism of action, amivantamab could cause fetal harm or developmental abnormalities when administered to a pregnant woman. Evidence from published literature shows that inhibition of EGFR and/or MET signaling pathways during pregnancy can cause impaired embryo-fetal development, embryo lethality, and abortions in mice, rats, and non-human primates. It is therefore reasonable to expect that amivantamab may cause adverse effects on embryo-fetal and postnatal development in humans. Appropriate warnings and precautionary measures are in place in the Rybrevant Product Monograph.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Rybrevant Product Monograph. In view of the intended use of Rybrevant, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Rybrevant Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
As described above, the New Drug Submission (NDS) for Rybrevant was completed by Health Canada as part of an international partnership with the United States Food and Drug Administration as a Project Orbis Type C submission. The review of the quality component of the NDS for Rybrevant was conducted as per Method 2 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.
Characterization of the Drug Substance
Rybrevant contains the medicinal ingredient amivantamab, an immunoglobulin G1 (IgG1) subclass monoclonal antibody manufactured in Chinese hamster ovary cells. Rybrevant is a low fucose, fully human IgG1 bispecific antibody with immune-cell directing activity targeting the epidermal growth factor (EGF) and hepatocyte growth factor (HGF) receptors (epidermal growth factor receptor [EGFR] and mesenchymal-epithelial transition factor [MET], respectively). By targeting both EGFR and MET simultaneously, amivantamab blocks signalling pathways and inhibits cell proliferation. The proposed mechanism of action also includes Fc-dependent functions. The binding of amivantamab to EGFR and MET receptors on the surface of tumour cells also induces antibody-dependent cell-mediated cytotoxicity (ADCC) and trogocytosis mechanisms (antibody-mediated transfer of the membrane fragments and the target receptor from tumour cells to effector cells such as monocytes, macrophages and neutrophils).
Detailed characterization studies were performed to provide assurance that amivantamab consistently exhibits the desired characteristic structure and biological activity.
The drug substance manufacturing process has been optimized and scaled up during development. The process changes introduced at each generation of the process were adequately described and comparatively addressed. Lot release, stability, and characterization data have also been used to support the comparability assessment.
Results from process validation studies indicate that the processing steps adequately control the levels of product- and process-related impurities. The impurities that were reported and characterized were found to be within established limits.
Manufacturing Process of the Drug Substance and Drug Product and Process Controls
The drug substance manufacturing process is based on a master and working cell bank system, where the cell banks have been thoroughly characterized and tested for adventitious contaminants and endogenous viruses in accordance with International Council for Harmonisation (ICH) guidelines. Results from genetic characterization studies also demonstrated stability of these cell banks.
Amivantamab is a bispecific antibody with each parental antibody manufactured in separate processes and then combined in a single bispecific antibody manufacturing process. Each parental antibody is produced through the thawing of a single working cell bank vial corresponding to each parental antibody which then goes through a series of cell growth, harvesting, and purification steps, resulting in a concentrated pool of drug substance intermediates for each antibody. The drug substance intermediates are filtered, bottled, and frozen until further processing to form the bispecific antibody.
The manufacturing process for the amivantamab drug substance starts with the thawing of drug substance intermediates which are then pooled prior to reduction, diafiltration and oxidation reactions to obtain the heterodimer antibody. The heterodimer antibody undergoes a series of viral inactivation, chromatography, viral filtration, and purification steps. It is then filled into polycarbonate containers. The final drug substance contains a target of 50 mg/mL amivantamab as well as the following excipients: histidine, sucrose, polysorbate 80, methionine, and ethylenediaminetetraacetic acid (EDTA).
The manufacturing process for the drug product starts with thawing the drug substance which is then gently swirled and prefiltered into a sanitized pooling vessel. The drug substance is sterile-filtered and filled into vials. After filling, vials are stoppered and then capped prior to inspection and storage at 2 to 8 °C. All changes that occurred throughout process development were supported by comparability data.
The materials used in the manufacture of the drug substance and drug product are considered suitable and/or meet standards appropriate for their intended use. The method of manufacturing and the controls used during the manufacturing process for both the drug substance and drug product are validated and considered to be adequately controlled within justified limits. The proposed drug product manufacturing process is able to consistently manufacture Rybrevant drug product of acceptable quality.
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 the amivantamab with the excipients is supported by the stability data provided.
Control of the Drug Substance and Drug Product
The drug substance and drug product are tested against suitable reference standards to verify that they meet approved specifications and analytical procedures are validated and in compliance with International Council for Harmonisation (ICH) guidelines.
Each lot of Rybrevant drug product is tested for appearance, content, identity, potency, purity, and impurities. Established test specifications and validated analytical test methods are considered acceptable.
Testing through Health Canada's lot release testing and evaluation program of consecutive manufactured final product lots was not conducted for this submission. The proposed testing sites have significant depth of manufacturing and testing experience with other monoclonal antibody products authorized by Health Canada. In addition, the complete quality report from the United States Food and Drug Administration was available to Health Canada for review and no issues were found that would support the need to conduct lot release testing for any of the methods.
The results for all of the batches were within the proposed specification limits.
Rybrevant 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.
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 5 ± 3 °C for Rybrevant is considered acceptable when the product is protected from light.
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
The design, operations, and controls of the facility and equipment that are involved in the production are considered suitable for the activities and products manufactured.
Based on a risk assessment score determined by Health Canada, an on-site evaluation of the drug substance intermediate manufacturing facility was not deemed necessary. An OSE was previously conducted at this site in 2014 and no major issues were identified.
The drug substance manufacturing site received a risk assessment score suggesting that an OSE should be conducted, however, the site has a significant depth of experience with monoclonal antibody purification for other products authorized by Health Canada. As such, an OSE was not recommended based on this mitigating factor. In addition, an inspection report from the United States Food and Drug Association (FDA) was provided to Health Canada, and no major issues were identified during inspection.
Based on a risk assessment score determined by Health Canada, an on-site evaluation of the drug product manufacturing facility was not deemed necessary.
All sites involved in production are compliant with Good Manufacturing Practices.
Adventitious Agents Safety Evaluation
The amivantamab manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. Pre-harvest culture fluid from each lot is tested to ensure freedom from adventitious microorganisms (bioburden, mycoplasma, and viruses) and appropriate limits are set. Purification process steps designed to remove and inactivate viruses are adequately validated.
Raw materials and product contact materials used for the manufacturing of Rybrevant present no bovine spongiform encephalopathy (BSE) or transmissible spongiform encephalopathy (TSE) transmission risk.
The excipients used in the drug product formulation are not of animal or human origin.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| RYBREVANT | 02526182 | JANSSEN INC | AMIVANTAMAB 350 MG / 7 ML |