Indication: Brentuximab vedotin in combination with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide in previously untreated high-risk Hodgkin lymphoma (HL) in the pediatric population. Brentuximab vedotin in combination with doxorubicin, vinblastine, and dacarbazine for the treatment of previously untreated patients with advanced stage HL.
Sponsors: BC Cancer Agency and Pediatric Oncology Group of Ontario
Final recommendation: Reimburse with conditions
Summary
What Is the CADTH Reimbursement Recommendation for Adcetris?
CADTH recommends that Adcetris be reimbursed by public drug plans for the treatment of patients with previously untreated advanced stage Hodgkin lymphoma (HL) if certain conditions are met.
Which Patients Are Eligible for Coverage?
Adcetris should only be covered to treat adults aged 18 years or older with advanced stage classical HL or children and adolescents aged 2 years or older with high-risk HL who are in relatively good health. Adcetris should not be covered to treat patients with nodular lymphocyte-predominant HL, severe sensory or motor peripheral neuropathy, cerebral or meningeal disease, or a neurologic disease that affects their daily activities.
What Are the Conditions for Reimbursement?
Adcetris should only be reimbursed if it is prescribed by a clinician with experience treating HL and its cost is reduced. In the pediatric population, the prescribing clinician should also have expertise in pediatric oncology. Brentuximab vedotin (BV) should be used in combination with doxorubicin (Adriamycin), vinblastine, and dacarbazine (AVD) in adults or doxorubicin (Adriamycin), vincristine, etoposide, prednisone, and cyclophosphamide (AVEPC) in pediatric patients.
Why Did CADTH Make This Recommendation?
Evidence from a clinical trial demonstrated that Adcetris plus AVD was better than doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD) in delaying disease progression and prolonging survival in adults with previously untreated advanced stage (Ann Arbor stage III and IV) classical HL. Evidence from another clinical trial demonstrated that Adcetris plus AVEPC was better than doxorubicin (Adriamycin), bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (ABVE-PC) in delaying disease progression or relapse, second malignancy, or death in patients aged 2 years or older and younger than 22 years with high-risk classical HL.
Patients need new treatments for HL that control symptoms, prolong remission, prolong survival, and improve quality of life. In addition, there is a need to avoid further therapies and late effects in the pediatric population. Adcetris meets some of these needs because it prolongs disease remission, prolongs survival, and may delay the need for further therapies.
Based on CADTH’s assessment of the health economic evidence in a population of adults with previously untreated advanced stage HL, Adcetris does not represent good value to the health care system at the public list price. A price reduction is therefore required. As no health economic information was submitted on the use of Adcetris in pediatric patients with advanced stage HL, the cost-effectiveness of Adcetris in this population is unknown.
Based on public list prices, Adcetris is estimated to cost the public drug plans approximately $35 million over the next 3 years. However, the budget impact is uncertain because pediatric patients were assumed to receive the same chemotherapy backbone and comparator treatment as adults, which is contradictory to the feedback provided by the clinical experts consulted for this review.
Additional Information
What Is HL?
HL is a type of blood cancer that originates from white blood cells called lymphocytes. In 2022, an estimated 1,050 new cases of HL occurred in Canada overall. In 2019, 25 children in Canada aged 0 to 14 years were diagnosed with HL.
Unmet Needs in HL
Patients need new treatments for HL that control disease symptoms, prolong remission, prolong survival, and improve quality of life.
How Much Does Adcetris Cost?
In the adult population, treatment with Adcetris plus AVD is expected to cost approximately $21,584 per patient per 28 days. In the pediatric population, treatment with Adcetris plus AVEPC is expected to cost approximately $21,110 per patient per 28 days, depending on patient weight and body surface area.
The pCODR Expert Review Committee (pERC) recommends that BV be reimbursed for the treatment of previously untreated patients with advanced stage HL only if the conditions listed in Table 1 are met.
This recommendation supersedes the pERC recommendation for BV for the treatment of previously untreated patients with stage IV HL in combination with AVD, dated December 3, 2020.
One phase III, multicentre randomized controlled trial (RCT) (ECHELON-1) demonstrated that treatment with BV in combination with doxorubicin (Adriamycin), vinblastine, and dacarbazine (BV + AVD) resulted in a benefit in overall survival (OS), modified progression-free survival (mPFS), and progression-free survival (PFS) per investigator compared to ABVD in adults who were diagnosed with advanced stage (i.e., Ann Arbor stage III and IV) classical HL and had not received treatment. As of the data cut-off date of March 11, 2023, with a median follow-up of approximately 88 months, the hazard ratio (HR) was 0.61 (95% confidence interval [CI], 0.414 to 0.892) and there was a 3% absolute reduction in number of OS events between the BV + AVD group and the ABVD group, favouring BV + AVD, in the intention-to-treat (ITT) population. Results for mPFS per independent review facility (data cut-off date of April 20, 2017; HR = 0.770; 95% CI, 0.603 to 0.982) and PFS per investigator-assessment (data cut-off date of June 1, 2021; HR for PFS = 0.678; 95% CI, 0.532 to 0.863) in the ITT population also favoured the BV + AVD group.
Another phase III, multicentre RCT (AHOD1331) demonstrated that BV in combination with doxorubicin (Adriamycin), vincristine, etoposide, prednisone, and cyclophosphamide (BV + AVEPC) provides a clinically meaningful benefit in event-free survival (EFS) compared to ABVE-PC in patients aged 2 years or older and younger than 22 years with high-risk classical HL defined as Ann Arbor stage IIB with bulk tumour, stage IIIB, stage IVA, or stage IVB HL. After a median follow-up time of 42.1 months, the proportion of patients who had not experienced an EFS event (disease progression or relapse, second malignancy, or death) and thus were censored for the 3-year EFS analysis was 92.1% (95% CI, 88.4 to 94.7) in the BV + AVEPC group and 82.5% (95% CI, 77.4 to 86.5) in the ABVE-PC group. The HR for 3-year EFS was 0.41 (95% CI, 0.25 to 0.67; P < 0.001) favouring the BV + AVEPC group.
Patients identified a need for new treatments for HL that control disease symptoms, prolong remission, prolong survival, and improve quality of life. In addition, clinicians indicated there is a need to avoid further therapies and late effects in the pediatric population. Given the totality of the evidence, pERC concluded that BV met some of the needs identified by patients because it prolongs disease remission, prolongs survival, and may delay the need for further therapies.
Using the manufacturer-submitted price for BV and publicly listed prices for all other drug costs, the incremental cost-effectiveness ratio for BV + AVD was $115,865 per quality-adjusted life-year (QALY) gained compared with ABVD in adults. At this incremental cost-effectiveness ratio, BV + AVD is not cost-effective at a $50,000 per QALY gained willingness-to-pay threshold for adults with previously untreated advanced stage HL. A price reduction is required for BV + AVD to be considered cost-effective at a $50,000 per QALY gained threshold.
As the manufacturer used data from the ECHELON-1 trial to inform clinical effectiveness, and because the trial data excluded pediatric patients, the results of the economic evaluation represent the cost-effectiveness of BV + AVD for the treatment of patients with previously untreated advanced stage HL. As such, the clinical and cost-effectiveness of BV + AVD compared with most relevant comparators for those aged younger than 18 years is unknown. Additionally, as CADTH was unable to incorporate data from the AHOD1331 trial into the manufacturer’s model, we were unable to estimate the cost-effectiveness of BV + AVEPC compared with ABVE-PC.
Table 1: Reimbursement Conditions and Reasons
Reimbursement condition | Reason | Implementation guidance |
|---|---|---|
Initiation | ||
1. Brentuximab vedotin should only be initiated in patients with previously untreated advanced stage HL who meet either of the following: 1.1. adults aged 18 years or older with advanced stage classical HL, defined as stage III and IV according to the Ann Arbor staging system 1.2. children and adolescents aged 2 years or older with high-risk HL, defined as stage IIB with bulk tumour or stage IIIB, IVA, or IVB according to the Ann Arbor staging system | Evidence from the ECHELON-1 trial demonstrated that treatment with BV + AVD has a beneficial effect compared to ABVD in adults with previously untreated advanced stage (i.e., Ann Arbor stage III or stage IV) HL. Evidence from the AHOD1331 trial demonstrated that treatment with BV + AVEPC has a beneficial effect on EFS compared to ABVE-PC in patients aged ≥ 2 years and < 22 years who were previously untreated for high-risk classical HL (i.e., Ann Arbor stage IIB with bulk tumour, stage IIIB, stage IVA, stage IVB). | — |
2. Patients must have good PS. | The ECHELON-1 trial included patients with an ECOG PS of 0 to 2. | — |
3. Brentuximab vedotin should not be used in patients who have any of the following: 3.1. nodular lymphocyte-predominant HL 3.2. severe sensory or motor peripheral neuropathy 3.3. cerebral or meningeal disease 3.4. neurologic disease affecting activities of daily living. | Patients with nodular lymphocyte-predominant HL; cerebral or meningeal disease, including signs or symptoms of progressive multifocal leukoencephalopathy; neurologic disease requiring medication or compromising normal activities of daily living; and peripheral sensory or motor neuropathy were excluded from the ECHELON-1 trial. | — |
Discontinuation | ||
4. Treatment should be continued until disease progression, unacceptable toxicity, or completion of the maximum number of treatment cycles, whichever comes first. | BV + AVD was given for 6 cycles in the ECHELON-1 trial. Patients in the ECHELON-1 trial discontinued treatment if they experienced progressive disease, unsatisfactory therapeutic response, or unacceptable toxicity. In the AHOD1331 trial, BV + AVEPC was given for 5 cycles unless patients met the criteria for removal from protocol therapy such as progressive disease, physician’s determination, or development of a second malignancy. | In adults, treatment with BV + AVD should be for a maximum of 6 cycles. The dose of brentuximab vedotin is the same for stage III and stage IV disease in adults. In pediatric patients, treatment with BV + AVEPC should be for a maximum of 5 cycles. |
Prescribing | ||
5. BV + AVD should be prescribed by a clinician with expertise and experience in the treatment of HL. In pediatric patients, BV + AVEPC should be prescribed by a clinician with expertise in pediatric oncology. | This is to ensure brentuximab vedotin is prescribed only for appropriate patients and adverse effects are managed in an optimized and timely manner. | — |
6. Brentuximab vedotin should be used in combination with AVD in adults or AVEPC in pediatric patients. | The ECHELON-1 trial provided evidence for BV + AVD and the AHOD1331 trial provided evidence for BV + AVEPC. pERC did not review evidence supporting the use of brentuximab vedotin in combination with other chemotherapy drugs. | — |
Pricing | ||
7. A reduction in price | In a population of adults with previously untreated advanced stage HL, the ICER for BV + AVD is $115,865 per QALY gained when compared with ABVD. A 55% reduction in the price of BV would be required for BV + AVD to achieve an ICER of $50,000 per QALY compared to ABVD. In a population of pediatric patients with advanced stage HL, the cost-effectiveness of BV is unknown. | — |
ABVD = doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine; ABVE-PC = doxorubicin (Adriamycin), bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide; AVD = doxorubicin (Adriamycin), vinblastine, and dacarbazine; AVEPC = doxorubicin (Adriamycin), vincristine, etoposide, prednisone, and cyclophosphamide; BV + AVD = brentuximab vedotin in combination with doxorubicin (Adriamycin), vinblastine, and dacarbazine; BV + AVEPC = brentuximab vedotin in combination with doxorubicin (Adriamycin), vincristine, etoposide, prednisone, and cyclophosphamide; ECOG = Eastern Cooperative Oncology Group; EFS = event-free survival; HL = Hodgkin lymphoma; ICER = incremental cost-effectiveness ratio; PS = performance status; QALY = quality-adjusted life-year.
Subgroup analyses by disease stage: pERC recognized the uncertainty around the magnitude of benefit in the stage III population versus the stage IV population given that the ECHELON-1 trial was not stratified or designed to detect treatment effects within subgroups according to stage. Potentially small treatment effects (and an uncertain benefit to risk ratio) were identified by Health Canada in 2019 as restricting the approved indication to stage IV disease. pERC discussed that although subgroup analyses of the OS and mPFS results signalled that BV + AVD might be more effective in patients with stage IV classical HL than those with stage III classical HL, conclusions regarding subgroup differences between patients who are stage III versus stage IV are uncertain because of the limitations of trial design and subgroup analyses. The consulted clinical experts highlighted that the approach to treatment, especially with their experience using ABVD, is to treat stage III and stage IV classical HL in the same manner. The manufacturer’s submitted model structure did not allow for the exploration of the treatment effect of BV + AVD by disease stage. As such, the cost-effectiveness of BV + AVD by disease stage is unknown.
Health-related quality of life (HRQoL): Patient group input highlighted the importance of improved HRQoL. In the ECHELON-1 trial, HRQoL outcome measures (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 [EORTC QLQ-C30] and EQ-5D-3L visual analogue scale [VAS]) showed improvements in both treatment groups and similar scores between the BV + AVD and ABVD groups. However, interpretation of these results is complicated by the analyses being exploratory and no formal between-group comparisons were done for the EQ-5D-3L VAS. Results for HRQoL outcomes were not reported in the publication for the AHOD1331 trial.
Pediatric population: pERC noted that there remains an evidence gap with respect to the clinical efficacy and safety of BV + AVD in the pediatric population as all participants in the ECHELON-1 trial were required to be aged 18 years or older. Furthermore, pERC acknowledged input from clinician groups and clinical experts that BV would be used in combination with a pediatric chemotherapy backbone (i.e., AVEPC) instead of AVD in the pediatric patient population. To address the unmet needs in the pediatric patient population, pERC considered evidence from the AHOD1331 trial, which demonstrated that BV + AVEPC is more effective than ABVE-PC for EFS in pediatric patients with high-risk classical HL. The manufacturer’s model did not assess the cost-effectiveness of BV in a pediatric population. Given all participants of ECHELON-1 (used to populate the clinical effects of BV + AVD in the economic model) were required to be aged 18 years or older, the clinical- and cost-effectiveness of BV + AVD in pediatric patients is unknown. CADTH was unable to incorporate data from the AHOD1331 trial into the manufacturer’s model. As such, the cost-effectiveness of BV + AVEPC is unknown.
Adverse events: The safety profile of BV + AVD is consistent with the known AEs for the individual components of the regimen, but it was notable that more patients treated with BV + AVD experienced serious AEs than in the ABVD group of the ECHELON-1 trial. pERC acknowledged that BV + AVD had notable side effects such as neuropathy and risk of febrile neutropenia; however, these were manageable and no significant detriment to quality of life was observed in the ECHELON-1 trial. pERC noted that later in the trial, primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) was used in 83 patients in the BV + AVD arm and 43 patients in the ABVD arm to prevent neutropenia or febrile neutropenia. This resulted in lower rates of neutropenia and febrile neutropenia compared to those who had not received G-CSF prophylaxis, though these rates remained higher than the rates in patients in the ABVD group who also received G-CSF prophylaxis. However, pERC noted that fewer patients in the BV + AVD arm experienced pulmonary-related toxicity than in the ABVD arm.
Gaps in the evidence: pERC acknowledged that PET-adapted bleomycin, etoposide, doxorubicin (Adriamycin), cyclophosphamide, vincristine (Oncovin), procarbazine, and prednisone (BEACOPP) and PET-adapted ABVD are relevant comparators as they are commonly used as first-line treatments for patients with advanced HL in Canada. However, pERC could not draw conclusions regarding the relative efficacy and safety of BV + AVD compared with PET scan–guided approaches given the lack of comparative data.
Budget impact is uncertain: In CADTH’s base-case estimate of the budget impact of introducing BV, pediatric patients were included and it was assumed that the chemotherapy backbone and comparator treatment they would receive is identical to what adults would receive, which is contradictory to feedback provided by the clinical experts for this review. CADTH did not address this in reanalyses as it is beyond the scope of a CADTH review. The results of a CADTH scenario analysis estimated that there are approximately 13 pediatric patients per year in the pan-Canadian budget impact analysis (39 pediatric patients over 3 years). The 28-day cycle costs of treating pediatric patients with BV + AVEPC is $21,110, or $105,551 for 5 cycles of treatment. As such, the cost of treating pediatric patients with HL with BV + AVEPC would be approximately $1,372,165 per year (assuming 13 patients are treated per year).
HL is a B-cell malignancy that originates in the lymphocytes. Classical HL accounts for 95% of all HL cases. The estimated incidence in Canada in 2022 was 2.6 cases per 100,000. Based on 2018 Canadian cancer statistics, which reported cancer incidence by stage, approximately 23.3% of patients in Canada presenting with HL have stage III disease and 22.7% have stage IV disease. Childhood HL represents 6% of all cancers and has an incidence rate of 12 cases per million (1.2 cases per 100,000) per year in the 0 to14 year age group. In 2019, 25 children in Canada in this age group were diagnosed with HL.
The goal of therapy in patients with advanced HL is curative. The clinical experts consulted by the review team noted that patients with advanced HL are treated the same, regardless of stage. Current first-line treatment regimens for adults with advanced stage HL rely on chemotherapy. For adults with stage IV HL, the preferred regimen is BV + AVD. For patients with advanced HL, treatment approaches also include ABVD for up to 6 cycles with PET response after 2 cycles of chemotherapy (PET2)-directed treatment adaptation, as well as based on upfront PET2-driven treatment adaptation with BEACOPP. For pediatric patients, the clinical experts consulted by the review team also noted that most clinical centres in Canada use ABVE-PC for 5 cycles with radiation therapy determined by PET2, while relatively fewer centres use vincristine (Oncovin), etoposide, prednisone, and doxorubicin (Adriamycin) (OEPA) or cyclophosphamide, vincristine (Oncovin), prednisone, and dacarbazine (COPDAC).
BV has been approved by Health Canada for the treatment of patients with previously untreated stage IV HL, in combination with AVD. BV is an antibody-drug conjugate that is available as lyophilized powder for reconstitution and the dosage recommended in the product monograph for previously untreated stage IV HL is 1.2 mg/kg up to a maximum of 120 mg in combination with AVD as an IV infusion over 30 minutes, administered every 2 weeks for a maximum of 12 doses (i.e., administered on days 1 and 15 of each 28-day cycle up to a maximum of 6 cycles) or until disease progression or unacceptable toxicity.
BV + AVD was previously reviewed by CADTH and received a recommendation to reimburse with conditions for the treatment of patients with previously untreated stage IV HL from pERC (issued on December 3, 2020). The original CADTH review of BV + AVD included the ECHELON-1 trial. pERC made this recommendation because it was satisfied that BV + AVD may have a net clinical benefit compared with ABVD for patients with previously untreated stage IV HL based on clinically meaningful improvements in mPFS in the ITT population and the prespecified subgroup of patients with stage IV disease. However, pERC recognized the uncertainty around the magnitude of the mPFS benefit with BV in combination with AVD in the subgroup of patients with stage IV disease given that the ECHELON-1 trial was not designed nor powered to detect specific treatment effects or test specific hypotheses within individual subgroups. In the 2020 recommendation, pERC noted that current practice in Canada is to offer the same treatments to patients with stage III and IV disease; however, pERC highlighted that the Health Canada–approved indication was limited to patients with stage IV HL. pERC noted that updated clinical and economic data comparing BV in combination with AVD with currently available treatments in Canada for patients with previously untreated stage III HL, could form the basis of a new submission to CADTH pending a submission for regulatory approval.
In the present review, pERC considered the following unlabelled indications:
BV + AVD for the treatment of patients with previously untreated advanced stage HL (an expansion of the labelled indication for stage IV disease to also include stage III)
BV + AVEPC in previously untreated high-risk HL in the pediatric population.
This tumour group submission is based on updated data from the ECHELON-1 trial and a new trial conducted in the pediatric population, the AHOD1331 trial. Of note, this review is based on a previous sponsor-initiated submission (project number PC0311-000) that was withdrawn.
To make its recommendation, the committee considered the following information:
a review of 1 phase III, open-label RCT (ECHELON-1) in adults (≥ 18 years of age) who were diagnosed with advanced stage (i.e., Ann Arbor stage III and IV) classical HL and had not received treatment and 1 phase III, open-label RCT in patients aged 2 years or older and younger than 22 years who were previously untreated for high-risk classical HL (i.e., Ann Arbor stage IIB with bulk tumour, stage IIIB, stage IVA, stage IVB)
patients’ perspectives gathered by 1 patient group, Lymphoma Canada
input from the public drug plans and cancer agencies that participate in the CADTH review process
3 clinical specialists with expertise diagnosing and treating patients with HL
input from 2 clinician groups, Ontario Health – Cancer Care Ontario (OH-CCO) Hematology Cancer Drug Advisory Committee and POGO
a review of the pharmacoeconomic model in adults only and report submitted by the manufacturer.
The information in this section is a summary of input provided by the patient and clinician groups that responded to the review team’s call for input and from the clinical experts consulted by the review team for the purpose of this review.
One patient group, Lymphoma Canada, provided input for BV for the treatment of patients with previously untreated advanced stage HL, in combination with AVD. Patient input was gathered from an online anonymous patient survey from March 14 to May 2, 2023. In total, 26 responses were gathered and 3 patients reported receiving BV + AVD treatment.
Patients were asked questions regarding the physical and psychosocial symptoms experienced at the time of diagnosis, current quality of life, and how these symptoms impacted their daily activities. At the time of their lymphoma diagnosis, most of the patients reported fatigue (79%) as the most impactful symptom (5 out of 5), followed by enlarged lymph nodes (58%), shortness of breath (63%), and weight loss (47%). In addition, 74% of patients reported experiencing anxiety or worry, 68% stressing about their diagnosis, 63% difficulty in sleeping, and 58% fearing progression of their lymphoma. Regarding physical symptoms that currently impact their quality of life, fatigue (29%) and headaches (14%) were identified as the most significant factors having a negative impact of quality of life (out of 7 responses). The most impactful psychosocial factors impacting the patients’ current quality of life were the stress of having cancer (71%), fear of progression (71%), anxiety or worry (71%), difficulty sleeping (43%), problems concentrating (43%), and inability to attend work or school (43%).
Among the surveyed patients, 3 patients indicated receiving ABVD in the frontline setting, 2 were treated with other forms of chemotherapy, and 1 was treated with AVEPC. While evaluating the importance of outcomes of new treatments, patients who completed the survey placed importance on the need for a novel lymphoma therapy to control disease symptoms, lengthen disease remission, provide a longer lifespan, and improve quality of life.
While describing the experience with the treatment under review, 1 of the 3 patients who had received BV + AVD indicated they have been in remission for 6 months up to a year, another in remission longer than a year, and the other patient is in post-treatment (not sure about remission status). Side effects from the BV + AVD treatment reported by patients were fatigue (n = 3), neutropenia (n = 2), constipation (n = 2), joint or muscle pain (n = 2), low platelet count (n = 1), decreased appetite (n = 1), and low blood pressure (n = 1). Moreover, 2 patients reported experiencing financial setbacks because of absence from work and 1 because of the cost of other medications. One of these patients mentioned having a poor experience with BV, and the other 2 rated their experience as very good.
The clinical experts consulted by the review team noted that improving the proportion of patients cured with first-line treatment is an important unmet need for patients with advanced stage HL. The clinical experts also highlighted the need to reduce treatment failure, prevent disease progression or relapse, and avoid late side effects (e.g., secondary malignancies, cardiac and pulmonary late effects) and further therapies that are toxic (e.g., autologous stem cell transplant [ASCT]), especially for patients diagnosed with advance stage HL at a younger age and for patients who are older and have poor tolerance to treatment.
The clinical experts noted that BV + AVD is considered frontline therapy for advanced HL. The clinical experts noted that, at the time of the review, BV + AVD had been approved for the treatment of patients with previously untreated stage IV HL only, and the use of BV + AVD in patients with stage III classical HL would cause a shift in the current treatment paradigm for those patients. The clinical experts indicated that in pediatric patients, BV would be used in combination with a different chemotherapy backbone, namely the 1 investigated in a phase III RCT in pediatric patients (AHOD133112) (i.e., BV + AVEPC). Trials of BV + AVD in pediatric patients have not been completed at the time of this review.13
The clinical experts noted that any adult patients with previously untreated stage III or IV classical HL who meet the eligibility criteria of the ECHELON-1 trial are best suited for BV + AVD. The clinical experts indicated that pediatric patients with advanced stage classical HL could also be eligible for BV in combination with chemotherapy, and the eligibility for therapy should be determined by the treating physician or using the eligibility criteria of the AHOD1331 trial.
The clinical experts noted that PET scans, typically PET2 (after 2 cycles of chemotherapy) and a PET scan after all 6 cycles (end of treatment), are used for response assessment. In patients who have complete response, follow-up visits take place every 3 to 4 months for 2 years, then typically every 6 months for 3 more years. Patients with a partial response may undergo radiation therapy, and patients with refractory disease would undergo further investigations (e.g., biopsy) and treatment with a second-line regimen. The clinical expert specializing in pediatrics noted that outcomes used in clinical practice to assess treatment response are generally aligned with outcomes typically used in adults. The clinical experts noted that OS is the most clinically meaningful outcome to assess the efficacy of BV in combination with chemotherapy in patients with advanced stage HL, and PFS is an important outcome. In pediatric patients, EFS is also important.
The clinical experts agreed that overall, discontinuation of BV + AVD is uncommon because unacceptable toxicity or refractory HL is not common. The clinical experts highlighted several situations in which BV + AVD can be discontinued, including treatment is complete; there is clear progression of disease; or there is an unacceptable adverse event (AE).
The clinical experts noted that diagnosis of the disease in adults must be made by an experienced pathologist. Selection of patients for BV + AVD should be done by a hemato-oncologist who has experience treating HL. Treatment can be delivered in the specialty clinics of nonacademic centres. The clinical expert specializing in pediatrics noted that all pediatric oncology patients are cared for by pediatric oncology teams at a tertiary care centre. Some aspects of care may be provided at satellite centres after diagnostic and management decisions are made.
Clinician group input on the review of BV was received from the OH-CCO Hematology Cancer Drug Advisory Committee and POGO. A total of 6 clinicians provided input on behalf of OH-CCO. POGO is a collaboration of Ontario’s 5 specialized childhood cancer centres. The input collected from POGO was prepared in a consultative manner, where 1 clinician discussed the indication with other members of the submission panel and sought input from POGO’s Therapeutic and Technology Advisory Committee, based on which the final submission was prepared.
OH-CCO highlighted the need to improve outcomes with first-line therapy so that second-line therapy can be avoided. The group noted that patients with stage III and IV disease would be best suited for BV + AVD. The group indicated that typical lymphoma response measures, including PET scan, are used in clinical practice to assess patients’ response to treatment. They noted they would discontinue treatment with BV + AVD in cases of significant toxicities or disease progression.
POGO noted that while there are a variety of chemotherapy and radiation approaches as options for standard of care, these vary by region and between pediatric- and adult-focused practitioners in Canada. POGO reported that historically, the ABVD chemotherapy backbone used with BV in adults has not been used by pediatric oncologists to treat pediatric patients because of concerns of higher anthracycline (doxorubicin) and bleomycin exposure, and the known dose-dependent cardiac and pulmonary toxicities. POGO noted that BV has been studied and used in combination with another chemotherapy regimen (AVEPC) in patients aged 2 to 21 years with previously untreated high-risk HL.14 POGO indicated that this alternate chemotherapy backbone is more commonly used in the pediatric setting, and BV-AVEPC has become standard care for pediatric patients considered high risk in Ontario. Regarding treatment goals in pediatric patients with HL, POGO highlighted the need to avoid disease recurrence to minimize potential late effects from subsequent chemotherapies and ASCT received at relapse, and the associated impact on HRQoL. While describing the outcomes used to determine whether a pediatric patient is responding to treatment for HL, the POGO group emphasized the importance of OS and EFS, considering the higher chance of experiencing late effects of therapy after treatment among the younger patient population. Similar to OH-COO, POGO suggested treatment be discontinued at disease progression.
Input was obtained from the drug programs that participate in the CADTH reimbursement review process. The clinical experts consulted by CADTH provided advice on the potential implementation issues raised by the drug programs.
Table 2: Responses to Questions From the Drug Programs
Implementation issues | Response |
|---|---|
Relevant comparators | |
The ECHELON-1 trial included ABVD as a comparator, which is the current standard frontline treatment for HL. An alternative regimen for patients considered young and healthy for whom the infertility implications are acceptable is BEACOPP, which can be given in fixed or escalated dosing. PET-CT scan guides treatment (i.e., number of cycles, change in therapy between ABVD and BEACOPP). In some provinces, CVPP can be given to patients with contraindications to anthracyclines and/or bleomycin. The ECHELON-1 trial compared BV + AVD to ABVD. PAG is also seeking comparison of BV with PET-adapted BEACOPP and ABVD. | For adults in Canada, the clinical experts consulted by CADTH noted that escalated BEACOPP and PET-adapted BEACOPP are only used in a few centres, and CVPP is not commonly used. For pediatric patients, relevant comparators to BV in combination with chemotherapy included ABVD, ABVE-PC or OEPA or COPDAC. pERC agreed that PET-adapted BEACOPP and PET-adapted ABVD are relevant comparators. However, pERC noted that only evidence comparing BV + AVD to ABVD from the ECHELON-1 trial and evidence comparing BV + AVEPC to ABVE-PC from the AHOD1331 trial was submitted for this review. Therefore, pERC could not comment on how BV + AVD compares to PET-adapted BEACOPP and PET-adapted ABVD. |
Considerations for initiation of therapy | |
Are there disease-specific features or prognostic features that would influence choice of therapy between PET-guided BEACOPP or ABVD and BV + AVD? | The clinical experts consulted by CADTH noted that the toxicity of BEACOPP and the improvement in OS with BV + AVD make BV + AVD a preferred treatment regimen in adults. Currently in clinical practice, the clinical experts favour BV + AVD over PET-guided ABVD or BEACOPP in adults with stage IV HL. The clinical experts also noted that if BV + AVD is approved for adults with stage III HL, BV + AVD will be preferred in this patient population as well. pERC discussed that there may be interprovincial and interclinician variability in choosing the optimal treatment. pERC did not identify any disease-specific features or prognostic features that would influence choice of therapy as this is a complex discussion between the treating clinician and individual patient based on multiple factors, including age, toxicity profile, and patient values. |
The indication requested for review is advanced stage HL. Is the advanced stage definition limited to stage III and IV? What staging system should be used (Lugano or Ann Arbor)? | The clinical experts consulted by CADTH noted that advanced stage HL in adults refers to stage III and IV HL according to the Ann Arbor staging system. The clinical expert specialized in pediatric oncology noted that in current clinical practice, pediatric patients with HL are usually classified into low-, intermediate-, and high-risk groups, and the high-risk group is generally considered equivalent to the advanced stage classical HL in adults. The clinical experts reported that the Children’s Oncology Group trial (AHOD133110) defined pediatric patients with high-risk or advanced stage HL as stage IIB with bulk tumour, stage III with B symptoms (stage IIIB), and stage IV with or without B symptoms (stage IVA and stage IVB) determined by Ann Arbor staging system. The clinical experts consulted by CADTH noted that Lugano criteria are criteria that allow one not only to stage the lymphoma but also to assess response. In the Lugano criteria, staging is performed using the Ann Arbor staging system. pERC agreed with defining advanced stage disease in alignment with the ECHELON-1 trial criteria for adults and the AHOD1331 trial criteria for the pediatric population. |
Per the current provisional funding algorithm, adults whose disease relapses would be eligible for BV re-treatment if relapse occurs more than 12 months after completion of prior BV therapy with at least 6 months of response. Is pERC in agreement with this guidance, which was informed by the pERC recommendation for BV + AVD in stage IV HL? | The clinical experts consulted by CADTH noted that in Ontario and Quebec, BV cannot be given unless a patient whose disease relapsed has had a transplant, in which case BV can be used as maintenance or if the patient has relapsed after the transplant. pERC agreed with the guidance informed by the 2020 pERC recommendation for BV + AVD in stage IV HL. |
Should BV + AVD be available to patients:
| The clinical experts consulted by CADTH noted that BV + AVD should be available to patients:
The clinical experts noted that CNS involvement is rare in patients with advanced HL. Reimbursement criteria regarding PS and disease stage are outlined in Table 1. pERC noted that patients with cerebral or meningeal disease (HL or any other etiology), including signs or symptoms of progressive multifocal leukoencephalopathy, were excluded from the ECHELON-1 trial. The clinical experts indicated that PML is a rare condition in these patients and fatal. They indicated they would not treat patients who had PML and HL for their lymphoma with BV + AVD. pERC agreed with the clinical experts. pERC agreed with the clinical experts that the trial results cannot be generalized to patients with nodular lymphocyte-predominant HL. Reed-Sternberg cells (that express CD30 antigens) are found only with classic HL. Nodular lymphocyte-predominant HL does not express CD30 and thus, it is not expected to respond to BV. |
Considerations for discontinuation of therapy | |
There should be consistency with the discontinuation criteria associated with other drugs reviewed by CADTH in the same therapeutic space. Treatment with BV + AVD should continue until disease progression, unacceptable toxicity, or until a maximum of 6 cycles, whichever comes first. | pERC and the clinical experts consulted by CADTH agreed with the current discontinuation criteria for BV + AVD in adults. pERC noted that in the pediatric population, BV + AVEPC should continue until disease progression, unacceptable toxicity, or a maximum of 5 cycles, whichever comes first. |
Considerations for prescribing of therapy | |
For patients unable to receive doxorubicin, can etoposide be substituted (i.e., BV with etoposide, bleomycin, vinblastine, and dacarbazine)? | The clinical experts consulted by CADTH do not agree with the substitution. pERC also did not agree with the substitution. |
Consider alignment with prescribing criteria for BV + AVD in stage IV disease. | This is a comment from the drug plans to inform pERC deliberations. |
Generalizability | |
Should adults who recently initiated ABVD or BEACOPP be eligible to switch to BV + AVD? PAG noted that in the previous review for BV + AVD for stage IV disease, the CGP indicated it would be reasonable to switch patients initiated on ABVD to BV + AVD on a time-limited basis. The CGP noted that patients initiated on BEACOPP should not be offered BV + AVD on a time-limited basis. | The clinical experts who treat adults indicated there should be an option to switch on a time-limited basis. pERC agreed with the clinical experts. The clinical expert who treats pediatric patients noted that such situation would not likely occur when treating pediatric patients as the pediatric setting is different from the adult setting. pERC noted that it may be reasonable for pediatric patients to have the option to switch to BV + AVEPC on a time-limited basis as well. |
Funding algorithm | |
The existing algorithm will be updated to include use of BV + AVD for stage III disease if recommended for reimbursement. | This is a comment from the drug plans to inform pERC deliberations. |
Care provision issues | |
Primary prophylaxis with G-CSF is typically prescribed with BV + AVD and is associated with additional costs. | This is a comment from the drug plans to inform pERC deliberations. |
Is it appropriate for patients initiated on ABVD who experience treatment-related adverse effects to be switched to BV + AVD to complete a maximum of 6 cycles? | The clinical experts consulted by CADTH do not consider the switch appropriate. pERC agreed with the clinical experts. |
Can BV be combined with any other regimens other than AVD (i.e., substituting etoposide in patients unable to receive doxorubicin)? | pERC noted that the scope of this review is limited to BV + AVD for the treatment of patients with previously untreated advanced stage HL and BV + AVEPC in previously untreated high-risk HL in the pediatric population. Furthermore, only evidence comparing BV + AVD to ABVD in adults (ECHELON-1 trial) and evidence comparing BV + AVEPC to ABVE-PC in pediatric patients (AHOD1331 trial) was submitted. Therefore, pERC could not comment on combining BV with other regimens. |
ABVD = doxorubicin (Adriamycin), bleomycin, vinblastine, dacarbazine; ABVE-PC = adriamycin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide; BV = brentuximab vedotin; BV + AVEPC = brentuximab vedotin in combination with doxorubicin (Adriamycin), vincristine, etoposide, prednisone, and cyclophosphamide; BEACOPP = bleomycin, etoposide, doxorubicin (Adriamycin), cyclophosphamide, vincristine (Oncovin), procarbazine, and prednisone; BV + AVD = brentuximab vedotin in combination with doxorubicin (Adriamycin), vinblastine, dacarbazine; CGP = Clinical Guidance Panel; CNS = central nerve system; COPDAC = cyclophosphamide, vincristine (Oncovin), prednisone, and dacarbazine; CVPP = cyclophosphamide, vinblastine, procarbazine, and prednisone; ECOG = Eastern Cooperative Oncology Group; G-CSF = granulocyte colony-stimulating factor; HL = Hodgkin lymphoma; OPEA = vincristine (Oncovin), etoposide, prednisone, and doxorubicin (Adriamycin); OS = overall survival; PAG = Provincial Advisory Group; pERC = pCODR Expert Review Committee; PML = progressive multifocal leukoencephalopathy; PS = performance status.
One phase III, open-label, randomized, active-controlled, superiority trial (ECHELON-1, N = 1,334) was identified from a systematic literature review conducted by the manufacturer.15,16 The primary objective of the ECHELON-1 trial was to determine the efficacy of BV + AVD relative to ABVD measured by mPFS. The key secondary objective was to compare OS between BV + AVD and ABVD. The ECHELON-1 trial is ongoing. Data from the data cut-off date of April 20, 2017, and June 1, 2021, were assessed for this review. New data from a descriptive analysis of OS conducted in response to a request for supplementary information from the European Medicines Agency (EMA) with a data cut-off date of March 11, 2023, was also included in this report.
Participants eligible to be included in the ECHELON-1 trial were adults with previously untreated histologically confirmed advanced stage classical HL, consisting of patients with stage III and stage IV disease, determined by the Ann Arbor classification system. Patients with nodular lymphocyte-predominant HL and those with sensory or motor peripheral neuropathy were excluded. The median age of enrolled patients was 36 years (range, 18 to 83 years); most (66%) were younger than 45 years, and 14% were 60 years or older. Of the total number of patients enrolled, 58% were male and 84% were white. Notably, most patients had stage IV disease (64%), 2 or 3 (53%) International Prognostic Factor Project (IPFP) risk factors, Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 (57%), extranodal involvement at diagnosis (62%), and B symptoms (59%) at baseline.
OS, PFS (per investigator), percentage of patients alive without HL, HRQoL measured with the (EORTC QLQ-C30), and EQ-5D-3L were obtained from the data with a cut-off date of June 1, 2021, while mPFS per independent review facility (IRF) was from the data with a cut-off date of April 20, 2017.
As of the data cut-off date June 1, 2021, the median follow-up was 73.3 months (95% CI, 72.61 to 74.05) in the BV + AVD group and 72.4 months (95% CI, 71.10 to 73.63) in the ABVD group. In the ITT population, the HR for OS was 0.59 (95% CI, 0.396 to 0.879; P = 0.009), favouring BV + AVD treatment. There was a 4% absolute difference in number of OS events between the BV + AVD (6%) and ABVD (10%) arms. Median OS was not reached for patients with advanced stage classical HL for either the BV + AVD group or the ABVD group. In subgroup analyses by disease stage, the HR for OS was 0.863 (95% CI, 0.452 to 1.648; P = 0.654) for patients with stage III classical HL and 0.478 (95% CI, 0.286 to 0.799; P = 0.004) for patients with stage IV classical HL.
As of the data cut-off date of March 11, 2023, the descriptive analysis for OS had a median follow-up of approximately 88 months for the ITT population. The median follow-up duration (months) was 89.7 (95% CI, 86.57 to 90.55) for the BV + AVD group and 86.3 (95% CI, 84.53 to 89.33) for the ABVD group. This analysis included 111 OS events (deaths): 44 deaths (7%) were reported in the BV+ AVD group and 67 deaths (10%) in the ABVD group. Median OS was not reached for either group. The HR for OS was 0.61 (95% CI, 0.414 to 0.892, descriptive P = 0.010). In the stage III subgroup, median OS was not reached for either treatment arm, and the HR for OS was 1.004 (95% CI, 0.540 to1.866) for patients in the BV + AVD group compared with those in the ABVD group. In the stage IV subgroup, median OS was not reached for either treatment arm, and the HR for OS was 0.48 (95% CI, 0.291 to 0.784; descriptive P = 0.003) for patients receiving BV + AVD compared with those receiving ABVD.
In the ITT population, the 3-year rates of being alive without HL were 96% (546 out of 567) in the BV + AVD group and 93% (503 out of 540) in the ABVD group. The 5-year rates of being alive without HL were about 94% (450 out of 480) in the BV + AVD group and 92% (408 out of 443) in the ABVD group. No subgroup analyses by disease stage were reported for this efficacy end point.
As of the data cut-off date June 1, 2021, the median follow-up was 73.2 months (95% CI, 72.48 to 74.05) in the BV + AVD group and 71.6 months (95% CI, 70.37 to 72.87) in the ABVD group. In the ITT population, the HR of PFS per investigator was 0.678 (95% CI, 0.532 to 0.863; P = 0.002), favouring treatment with BV + AVD. There was a 7% absolute difference in number of PFS events between the BV + AVD group (17%) and the ABVD group (24%). Median PFS per investigator was not reached for patients with advanced stage classical HL for either the BV + AVD group or the ABVD group. In subgroup analyses by disease stage, the HR for PFS per investigator was 0.603 (95% CI, 0.391 to 0.930; P = 0.021) for patients with stage III classical HL and 0.715 (95% CI, 0.534 to 0.959; P = 0.024) for patients with stage IV classical HL.
As of the data cut-off date April 20, 2017, median mPFS was not reached in either the BV + AVD group or the ABVD group. In the ITT population, the HR for mPFS per IRF was 0.770 (95% CI, 0.603 to 0.982; P = 0.035). There was a 4% absolute difference in number of mPFS events between the BV + AVD arm and the ABVD arm, favouring BV + AVD (18% versus 22%). In subgroup analyses by disease stage, the HR for mPFS per IRF was 0.923 (95% CI, 0.600 to 1.420; P = 0.716) for patients with stage III classical HL and 0.712 (95% CI, 0.530 to 0.957; P = 0.024) for patients with stage IV classical HL.
Deaths and secondary malignancies results were from the data cut-off date of June 1, 2021, while the remaining data were from the data cut-off of April 20, 2017.
In the safety population, the proportions of patients experiencing treatment-emergent adverse events (TEAEs) up to 30 days after the last frontline dose were similar between patients treated with BV + AVD (99%) and patients treated with ABVD (98%). Higher percentages of patients in the BV + AVD group experienced treatment-emergent serious AEs up to 30 days after the last frontline dose compared to those in the ABVD group (43% versus 27%). Deaths were reported in 6% of the patients in the BV + AVD arm and 10% of the patients in the ABVD arm. Treatment discontinuation due to AEs occurred in 13% of the patients in the BV + AVD arm and 16% of the patients in the ABVD arm. In terms of notable harms, 67% of the patients in the BV + AVD group and 43% in the ABVD group experienced at least 1 peripheral neuropathy event. About 3% of the patients in the BV + ABVD group and 5% of the patients in the ABVD group developed secondary malignancies. The proportion of patients who experienced neutropenia as grade 3 or higher TEAEs was higher in the BV + ABVD group than in the ABVD group (54% versus 39%). Similarly, the proportion of patients who experienced febrile neutropenia as grade 3 or higher TEAEs was also higher in the BV + ABVD group than in the ABVD group (19% versus 8%). Fewer patients in the BV + AVD arm experienced AEs of pulmonary-related toxicity than those in the ABVD arm (13% versus 25%). The most common AE of pulmonary-related toxicity for either group was dyspnea (12% versus 24%).
Generally, no serious concerns were identified in the conduct of the ECHELON-1 trial. However, the validity of the primary outcome (mPFS) is a key consideration in evaluating the evidence for BV + AVD. mPFS was adopted in the ECHELON-1 trial with the aim of capturing all events that reflect a failure of frontline chemotherapy by counting a response that was less than complete at the end of the frontline therapy as an event. The ECHELON-1 trial defined the response of less than complete as “receipt of anticancer therapy or radiotherapy for HL after completion of frontline therapy for patients who were confirmed non-complete responders.” However, the clinical experts consulted by the review team noted that this definition is not consistent with practice in defining disease progression or first-line treatment failure in advanced HL, and receipt of radiotherapy does not necessarily indicate disease progression in clinical practice. Despite the end of treatment PET scans conducted by IRF, there is a concern that the results for mPFS would be biased given the administration of a new anticancer therapy was at the discretion of the treating physician. The clinical experts consulted by the review team noted that OS and PFS are more clinically relevant to assessing a patient’s benefit from treatment, and no evidence was included in the submission to the review team empirically validating mPFS as an outcome measure or that established a correlation with OS. High percentages in loss to follow-up and withdrawal by patients were noted in both OS and PFS analyses. Although the percentages of loss to follow-up and withdrawal by patients were balanced between treatment arms, reasons for loss to follow-up and withdrawal could be differential between groups, which consequently might lead to biased estimates of treatment effects. Moreover, sensitivity analyses assessing the potential impact of the loss to follow-up and withdrawal on OS and PFS results were not available. Subgroup analyses by HL stage signal that there might be a difference in treatment effects between patients with stage III disease and those with stage IV classical HL for mPFS and OS. However, the review team’s ability to make definitive conclusions on whether the difference between the disease stage subgroups is true was limited by several concerns, such as the balance of known and unknown factors between treatment groups achieved by randomization may not have been preserved in stage III or stage IV subgroups, as well as the trial was not specifically designed to test statistical inferences between BV + AVD and ABVD in stage III and stage IV subgroups.
All participants in the ECHELON-1 trial were required to be aged 18 years of age or older and diagnosed with classical HL. Therefore, the ECHELON-1 trial did not reflect results for pediatric patients or patients with nodular lymphocyte-predominant HL. The eligibility criteria of the ECHELON-1 trial in general were aligned with the selection criteria in the setting in Canada when identifying suitable candidates for BV + AVD, according to the clinical experts consulted by the review team. However, the clinical experts noted that in clinical practice, a small percentage of patients who were excluded from the ECHELON-1 trial might be eligible to receive BV + AVD, such as patients with HIV, as long as the disease is well managed, and patients with borderline left ventricular ejection fraction after consultation with a cardiologist. The clinical experts also noted that patients with higher ECOG PS scores (> 2) could be considered for treatment with BV + AVD on a case-by-case basis. The clinical experts noted that the doses of BV + AVD and ABVD used in the ECHELON-1 trial generally reflected the standard dose schedules used for adults in Canada. The clinical experts also confirmed that the direct comparator, ABVD up to 6 cycles (not adapted based on PET response), is a relevant therapy used in current standard of care, although it is not the only standard of care frontline therapy used in Canada and therefore there are other relevant comparators. In addition, the clinical experts noted that the percentages of patients who received transplant as subsequent treatment were lower in either group than they would expect in clinical practice. According to the clinical experts consulted by the review team, the study population characteristics generally reflected patients who would be eligible for BV + AVD in practice in Canada. However, the clinical experts noted that the percentage of patients with stage IV HL in the trial population and the percentage of white participants were higher than 1 would find in clinical practice.
No long-term extension studies were submitted by the manufacturer.
No indirect treatment comparisons were submitted by the manufacturer. The manufacturer provided a feasibility assessment that determined it would be infeasible to conduct indirect treatment comparisons of BV + AVD versus other frontline therapies examined in clinical studies for advanced HL.
To address gaps in the pivotal RCT evidence related to the use of BV in pediatric patients with advanced HL, the review team reviewed evidence from an additional phase III RCT.
The AHOD1331 trial (N = 587) is a phase III, multicentre, open-label, randomized active-controlled trial comparing BV + AVEPC with ABVE-PC in patients aged 2 years or older and younger than aged 22 years with previously untreated high-risk classical HL, defined as Ann Arbor stage IIB with bulk tumour, stage IIIB, stage IVA and stage IVB. The primary objective of the AHOD1331 trial is to determine the efficacy of BV + AVEPC relative to ABVE-PC measured by EFS. OS and harms outcomes were also reported. The AHOD1331 trial is ongoing. The final analysis of EFS was based on the database lock date of December 31, 2021.
In the AHOD1331 trial, the median age of participants was 15.6 years (range, 3.4 to 21.99 years) and most patients (84.7%; 497 out of 587) were between 12 and 22 years. Of the total number of patients enrolled, 47% (276 out of 587) were female and 57.6% (338 out of 587) were non-Hispanic white. The proportions of patients by disease stage were 20.6% (121 out of 587) for stage IIB with bulk tumour, 19.3% (113 out of 587) for stage IIIB, 28.4% (167 out of 587) for stage IVA, and 31.7% (186 out of 587) for stage IVB. Most of the patients had nodular sclerosis classical HL (76.5%; 449 out of 587).
The median follow-up time was 42.1 months (range, 0.1 to 80.9). In terms of the 3-year OS in the ITT population, the proportion of patients who were censored was 99.3% (95% CI, 97.3 to 99.8) in the BV + AVEPC group and 98.5% (95% CI, 96.0 to 99.4) in the ABVE-PC group. The HR for 3-year OS was not provided.
In terms of the 3-year EFS in the ITT population, the proportion of patients who were censored was 92.1% (95% CI, 88.4 to 94.7) in the BV + AVEPC group and 82.5% (95% CI, 77.4 to 86.5) in the ABVE-PC group. The HR for 3-year EFS was 0.41 (95% CI, 0.25 to 0.67; P < 0.001), favouring the BV + AVEPC arm.
The incidence of any AEs of grade 3 or higher was 73.5% in patients treated with BV + AVEPC and 68.2% in patients treated with ABVE-PC. Peripheral neuropathy of grade 3 or higher occurred in 6.7% of the patients in the BV + AVEPC arm and 5.5% of the patients in the ABVE-PC arm. Febrile neutropenia occurred in 30.9% and 32.5% of patients in the BV + AVEPC arm and patients in the ABVE-PC arm, respectively. None of the patients in the BV + AVEPC group experienced pneumonitis compared to 1 patient in the ABVE-PC group.
Although details about the randomization process and allocation concealment were not reported in the research protocol or the main article, the risk of bias in the AHOD1331 trial is anticipated to be low given that the baseline characteristics between the treatment arms were generally similar for clinically important factors. The AHOD1331 trial was open-label but had blinded outcome assessors, the definition of EFS was aligned with accepted definitions from regulators, and treatment response was assessed via centralized review, thus helping to reduce the risk of detection bias related to the open-label design. Despite that patients were aware of the treatment allocation, which might result in performance bias, this risk is considered low because of reasons such as the 3-year PFS in the ABVE-PC group (82.5%) and the types of AEs were generally in line with what is expected by the clinical expert who specializes in pediatric oncology consulted by the review team. Those patients who remained PET positive after 2 cycles of chemotherapy received response-adapted involved-site radiation therapy guided by blinded central assessment of PET scans. This could bias EFS results if the radiation therapy could improve response, reduce the likelihood of relapse, and/or increase the risk of secondary malignancy. However, the risk of this potential bias was mitigated by the requirement that radiation therapy could not be administered until direction from the blinded assessment. Also, the percentages of patients who received involved-site radiation therapy were similar between the BV + AVEPC group and the ABVE-PC group (53.4% versus 56.8%). Concomitant anticancer medications were not allowed. Antibiotics and supportive medications (e.g., antiemetics) were permitted as needed. As well, patients received G-CSF support. None of the permitted medications would likely influence the results for either treatment group. However, after a progression event, the treating physician could treat the patient at their discretion, which may impact the longer-term OS results.
The AHOD1331 trial was appraised in this section to address an important gap with respect to the unmet needs of using BV + chemotherapy in pediatric patients with classical HL. However, there are several notable issues that need to be considered when generalizing results from the AHOD1331 trial. First, the chemotherapy backbone used in the AHOD1331 trial (i.e., AVEPC), although a preferred backbone for pediatric patients according to POGO and the clinical expert consulted by the review team, is different from the backbone used in adults (i.e., ABVD). Regarding the regulatory status of the pediatric regimen, the review team confirmed that BV is not approved for use in combination with the pediatric regimen and the manufacturer has confirmed they are not planning to file for Health Canada approval for BV + AVEPC. Second, the clinical experts consulted by the review team noted the definition of high-risk or advanced stage HL in pediatric patients is varying. While the AHOD1331 trial adopted the definition of advanced stage HL in pediatric patients as stage II with bulk tumour, stage IIIB, stage IVA, and stage IVB, some medical centres may define any stage III or IV as advanced stage disease in pediatric patients. Finally, the AHOD1331 trial involved both nonadults and young adults (up to 22 years old), while the pivotal ECHELON-1 trial enrolled patients 18 years and older. Therefore, there was an overlap in patient age between the pivotal ECHELON-1 trial and the AHOD1331 trial. The clinical expert consulted by the review team noted that the chemotherapy backbone AVEPC used in the AHOD1331 trial would not typically be used in patients aged 18 years or older in Canada, and the chemotherapy backbone ABVD investigated in the pivotal ECHELON-1 trial may be used in adolescents aged close to 18 years with HL.
Table 3: Summary of Economic Evaluation
Component | Description |
|---|---|
Type of economic evaluation | Cost-utility analysis Semi Markov model |
Target population | Previously untreated patients with advanced stage HL |
Treatment | BV + AVD |
Dose regimen | 1.2 mg/kg of body weight, given intravenously, on days 1 and 15 of each 28-day cycle for up to 6 cycles |
Submitted price | $4,840.00 per 50 mg vial |
Treatment cost | BV + AVD regimen = $21,584 over a 28-day cycle |
Comparator | ABVD |
Perspective | Canadian publicly funded health care payer |
Outcome | QALYs, LYs |
Time horizon | Lifetime (60 years) |
Key data source | ECHELON-1 trial, an open-label, multicentre, randomized phase III trial |
Key limitations |
|
CADTH reanalysis results |
|
ABVD = doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine; AE = adverse event; ASCT = autologous stem cell transplant; AVEPC = doxorubicin (Adriamycin), vincristine, etoposide, prednisone, and cyclophosphamide; BV = brentuximab vedotin; BV + AVD = brentuximab vedotin in combination with doxorubicin (Adriamycin), vinblastine, and dacarbazine; BEACOPP = bleomycin, etoposide, doxorubicin (Adriamycin), cyclophosphamide, vincristine (Oncovin), procarbazine, and prednisone; HL = Hodgkin lymphoma; LY = life-year; OS = overall survival; PFS = progression-free survival; QALY = quality-adjusted life-year; RDI = relative dose intensity; WTP = willingness to pay.
CADTH identified the following key limitations with the manufacturer’s analysis: relevant comparators were excluded, public coverage was inappropriate, and the market uptake for BV + AVD in stage III and IV HL was underestimated.
CADTH base-case revisions included increasing the public coverage rate, increasing the market uptake for patients with stage III and IV HL, and increasing the number of vials per cycle for specific drug therapies. CADTH reanalyses suggest the budget impact for funding BV + AVD for advanced stage HL (in both the adult and pediatric population) is expected to be $35,066,197 over 3 years (year 1: $10,658,052; year 2: $11,681,771; year 3: $12,726,344). Note that in CADTH’s base case, pediatric patients were included and it was assumed that the chemotherapy backbone and comparator treatment they will receive is identical to adults, which is contradictory to the feedback provided by the clinical experts for this review.
In a scenario that CADTH conducted in an adult-only population, CADTH estimated that there are approximately 13 pediatric patients per year in the pan-Canadian budget impact analysis (39 pediatric patients over 3 years). Based on the cost-comparison table, the 28-day cycle costs of treating pediatric patients with BV + AVEPC is $21,110, or $105,551 for 5 cycles of treatment. As such, the cost of treating pediatric patients with HL with BV + AVEPC would be approximately $1,372,165 per year (assuming 13 patients are treated per year).
Dr. Maureen Trudeau (Chair), Mr. Daryl Bell, Dr. Philip Blanchette, Dr. Kelvin Chan, Dr. Matthew Cheung; Dr. Michael Crump, Dr. Jennifer Fishman, Mr. Terry Hawrysh, Dr. Yoo-Joung Ko, Dr. Christian Kollmannsberger, Dr. Catherine Moltzan, Ms. Amy Peasgood, Dr. Anca Prica, Dr. Adam Raymakers, Dr. Patricia Tang, Dr. Marianne Taylor, and Dr. W. Dominika Wranik
Meeting date: July 10, 2024
Regrets: Two expert committee members did not attend.
Conflicts of interest: Two expert committee members did not participate because of considerations of conflict of interest.
ISSN: 2563-6596
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