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Indication: In combination with bortezomib, cyclophosphamide, and dexamethasone for the treatment of adult patients with newly diagnosed light chain (AL) amyloidosis
What Is the CADTH Reimbursement Recommendation for Darzalex?
CADTH recommends that Darzalex (daratumumab) in combination with cyclophosphamide, bortezomib, and dexamethasone (DCyBorD) should be reimbursed by public drug plans for the treatment of adult patients with newly diagnosed light chain (AL) amyloidosis if certain conditions are met.
Which Patients Are Eligible for Coverage?
Darzalex should only be covered to treat adult patients with newly diagnosed AL amyloidosis who have good performance status. Patients eligible for reimbursement of Darzalex must not have had prior therapy for AL amyloidosis or multiple myeloma, a previous or current diagnosis of multiple myeloma, or be planning to have a stem cell transplant during the first 6 cycles of treatment with DCyBorD.
What Are the Conditions for Reimbursement?
Darzalex should only be reimbursed if prescribed in combination with cyclophosphamide, bortezomib, and dexamethasone for 6 months, followed by daratumumab alone until the disease progresses or for a maximum of 2 years (whichever comes first), and if the cost of Darzalex is reduced.
Why Did CADTH Make This Recommendation?
Additional Information
What Is AL Amyloidosis?
AL amyloidosis is a disease that occurs when an abnormal protein (amyloid) builds up in the organs, most commonly the heart and kidneys, and interferes with their normal function. AL amyloidosis is rare; in Canada, the annual incidence is 10 per million.
Unmet Needs in Darzalex
No treatments are currently publicly funded in Canada for patients with AL amyloidosis, and patients do not generally respond to those that are used. Therapies that can prevent, delay, or improve organ damage and are better tolerated by patients are needed.
How Much Does Darzalex Cost?
DCyBorD is given over a 28-day cycle. Treatment with DCyBorD is expected to cost public drug plans $31,892 per cycle in cycle 1 and cycle 2, $17,272 per cycle in cycle 3 to cycle 6, and $7,310 per cycle in subsequent cycles.
The CADTH pan-Canadian Oncology Drug Review (pCODR) Expert Review Committee (pERC) recommends that subcutaneous daratumumab in combination with cyclophosphamide, bortezomib, and dexamethasone (DCyBorD) be reimbursed for the treatment of adult patients with newly diagnosed light chain (AL) amyloidosis only if the conditions listed in Table 1 are met.
One open-label, phase III, randomized controlled trial demonstrated that treatment with DCyBorD resulted in clinically meaningful improvements in response outcomes for patients with newly diagnosed AL amyloidosis. The ANDROMEDA trial (N = 386) demonstrated that DCyBorD was associated with a higher hematologic complete response (CR) rate compared with cyclophosphamide, bortezomib, and dexamethasone (CyBorD) that was statistically significant (53.3% versus 18.1%; relative risk ratio = 2.9; 95% confidence interval [CI], 2.1 to 4.1, P < 0.001). The improvement in hematologic CR rate was consistent across patient subgroups of any cardiac stage and those with and without a t(11;14) translocation. The results for other response end points, including time to hematologic response and organ response (cardiac and renal), also favoured treatment with DCyBorD. The trial was powered to assess longer-term outcomes including major organ deterioration progression-free survival (MOD-PFS) — a composite end point comprising time to death, MOD, or hematologic progression — and overall survival (OS) but data on these end points were immature at the primary analysis. The assessment of health-related quality of life (HRQoL) was exploratory in the trial and had limitations that complicate interpretation of the data; however, the data suggested there was no detriment to patient HRQoL by adding daratumumab to CyBorD. The safety profile of DCyBorD was consistent with the known safety profile of daratumumab (i.e., neutropenia and infection) and the other individual components in the regimen, which were considered by pERC to be manageable.
AL amyloidosis is a rare and incurable disease that is associated with substantial morbidity and a poor prognosis. pERC agreed that there is a significant unmet need for effective publicly funded treatment options in this patient population. Patients identified a need for access to effective treatments that provide better quality of life without debilitating side effects so that they can carry out daily life activities. Given the totality of the evidence, pERC concluded that DCyBorD met some of these needs to a certain extent by providing an effective treatment that can prevent or delay side effects of the disease related to organ damage and maintain quality of life with manageable side effects.
Using the sponsor-submitted price for daratumumab and publicly listed prices for all other drug costs, the incremental cost-effectiveness ratio (ICER) for DCyBorD was $67,484 per quality-adjusted life-year (QALY) compared with CyBorD. At this ICER, DCyBorD is not cost-effective at a $50,000 per QALY willingness-to-pay threshold for adults with AL amyloidosis. A price reduction of at least 21% is required for DCyBorD to be considered cost-effective at a $50,000 per QALY threshold.
Reimbursement Conditions and Reasons.
Issues that may impact the drug plan’s ability to implement a recommendation as identified by pERC and the drug plans are summarized in Table 2.
Implementation Guidance From pERC.
Daratumumab SC was approved by Health Canada in combination with CyBorD for the treatment of adult patients with newly diagnosed AL amyloidosis. Daratumumab is a human IgG1 kappa monoclonal antibody that binds CD38-expressing cells with high affinity. CD38 is a multifunctional glycoprotein ectoenzyme that is highly expressed on the cell surface of diverse hematologic malignancies including clonal plasma cells that produce the amyloidogenic immunoglobulin light chain. Daratumumab leads to the rapid and sustained elimination of highly immunosuppressive subsets of CD38+ cells. Daratumumab is supplied as an 1,800 mg/15 mL (120 mg/mL) solution for SC injection. The recommended dose is 1,800 mg administered subcutaneously over approximately 3 minutes to 5 minutes weekly (total of 8 doses) from week 1 to week 8, every 2 weeks (total of 8 doses) from week 9 to week 24, and every 4 weeks from week 25 onward until disease progression or 24 cycles up to a maximum of 2 years.
To make their recommendation, pERC considered the following information:
Myeloma Canada provided input for the review of daratumumab in combination with CyBorD for the treatment of AL amyloidosis. Myeloma Canada conducted a survey in their patient and caregiver community via email and social media. The survey was available from July 12 to July 25, 2021. The survey received 40 responses, 12 of which were deemed eligible (from 7 patients currently receiving CyBorD, 3 patients currently receiving DCyBorD, and 2 patients waiting to receive treatment). All patients surveyed rated access to effective treatments for AL amyloidosis as extremely important. The respondents who had treatment experience with CyBorD (n = 7) indicated that before taking CyBorD their expectations of a new treatment were “minimal side effects,” which was mentioned by most patients (n = 4), followed by “disease control” (n = 3) and “improved quality of life” (n = 1). All patients treated with CyBorD rated their experience with this treatment regimen as “somewhat tolerable,” “tolerable,” or “very tolerable.” Fatigue and neuropathy were cited as the least tolerable side effects of CyBorD. Patients who had been treated with combined daratumumab and CyBorD rated their overall side effects as “somewhat tolerable,” “tolerable,” or “very tolerable.” One patient found the side effects of bortezomib and cyclophosphamide intolerable; 1 patient was treated with daratumumab and dexamethasone only. In terms of what is important to patients when it comes to treating their AL amyloidosis, the majority of patient responses described a strong desire for effective treatments, a good or better quality of life, and being able to continue daily activities without debilitating side effects of treatment.
The clinical expert consulted by CADTH noted that no treatments other than DCyBorD are currently approved or generally funded for the treatment of AL amyloidosis in Canada. CyBorD is used off-label and may be accessed through the manufacturer’s special access program for a limited treatment duration and, in some provinces (e.g., Alberta), it is funded based on a special agreement with provincial groups. DCyBorD is amenable to use for most patients with newly diagnosed AL amyloidosis. In terms of response assessment, the clinical expert noted that improved hematologic response, PFS, OS, as well as organ response and HRQoL can be considered clinically meaningful responses to treatment. With respect to frequency of assessment of treatment response, the clinical expert indicated that monthly assessments are common in Canada but decisions on adequate hematologic and organ responses are made after 3 months and 6 months from initiation of treatment. The clinical expert indicated that daratumumab is a practice-changing regimen in a disease area where no approved or funded treatments exist.
Clinician input was received from the CMRG and the Ontario Health (Cancer Care Ontario) Hematology Cancer Drug Advisory Committee. The clinician group noted that the most important goals of any plasma cell–directed therapy is to achieve deep and rapid responses in terms of eliminating the clonal plasma cells and hence the monoclonal protein product it secretes. Based on the data from the ANDROMEDA trial’s control arm, the deep responses necessary for the organ improvement and prolonged disease control are not optimal with CyBorD alone. Given the toxic effect of the amyloid light chain, it is vital to achieve rapid and deep responses and to have access to therapies in the first line that produce deep and quick responses. The clinician group noted that DCyBorD is a major breakthrough in AL amyloidosis, which, if not treated quickly and with deep responses, can lead to irreversible organ damage. Based on encouraging results of the ANDROMEDA trial, fewer AL patients may require ASCT, with its attendant risk of morbidity and increased mortality in this disease, if DCyBorD is approved for this indication. The clinician group also noted that DCyBorD is well-tolerated with SC dosing of both daratumumab and bortezomib and produces minimal hematologic toxicity, therefore almost all newly diagnosed AL patients would be potential candidates. The rapid responses it can generate can be associated with rapid organ improvement. The clinician group also noted that an important consideration — and a particular concern for CMRG physicians — is the lack of access to daratumumab regimens for the current population of Canadian patients with AL amyloidosis who have already received first-line therapy and for whom daratumumab at relapse could be life-saving or life-extending. Although this is expected be a limited group of patients, the clinician group believes that these patients deserve the chance to receive daratumumab therapy at disease progression, because of the limited range of other options.
The drug programs identified jurisdictional implementation issues related to considerations for initiation and prescribing of therapy and generalizability. pERC weighed evidence from the ANDROMEDA trial and other clinical considerations, including input from the clinical experts consulted by CADTH, to provide responses to the drug programs’ implementation questions, which are presented in Table 3.
Responses to Questions From the Drug Programs.
The ANDROMEDA trial is an ongoing, randomized, open-label, active-controlled, phase III, multi-centre trial designed to compare the efficacy of DCyBorD to CyBorD alone in the treatment of patients with newly diagnosed AL amyloidosis. Patients were stratified by cardiac stage based on the Mayo Clinical Cardiac Staging System (stages I, II, and IIIa), ASCT availability in the country of residence, and renal function (creatinine clearance ≥ 60 mL/min or < 60 mL/min) and were randomly assigned in a 1:1 ratio to receive either DCyBorD or CyBorD. The primary end point was a hematological CR in the intention-to-treat population. The key secondary efficacy end points were MOD-PFS, organ response rate, OS, overall hematologic response (CR, very good partial response, or partial response), and time and duration of hematologic response. HRQoL and medical resource utilization were also evaluated as exploratory end points.
A total of 388 patients were randomized to treatment with either DCyBorD (n = 195) or CyBorD (n = 193). The median age in the study population was 64 years (62 years and 64 years in the DCyBorD and CyBorD treatment arms, respectively). The median number of organs involved at baseline was 2 (range = 1 to 6) and 65.5% of patients had 2 or more organs involved. Cardiac and renal involvement were most common, affecting 71.4% and 59.0% of patients in the DCyBorD and CyBorD treatment arms, respectively. Approximately one-third (36.6%) of patients were cardiac stage III at baseline. Of the 202 patients tested for t(11;14) at baseline, 106 had t(11;14) present (DCyBorD: 51patients; CyBorD: 55 patients).
At the primary analysis (data cut-off date: 14 February 2020; median follow-up of 11.4 months), 104 (53.3%) patients in the DCyBorD arm and 35 (18.1%) in the CyBorD arm had an independent review committee–assessed hematologic CR (relative risk ratio = 2.9; 95% CI, 2.1 to 4.1, P < 0.001).
Hematologic CR rates across cardiac stages were consistent with the results observed in the overall population of patients. The hematologic CR rate was higher in the DCyBorD arm compared with the CyBorD arm for all cardiac stages. The difference between hematologic CR rates in the 2 treatment arms increased by Mayo Cardiac Stage (DCyBorD versus CyBorD: 45% versus 28% for cardiac stage I; 54% versus 20% for stage II and 58% versus 10% for stage III, respectively). Similarly, the magnitude of hematologic CR rates in the t(11;14) translocation subgroup was similar to that observed in the overall population. Patients in the DCyBorD arm had equally high rates of hematologic CR regardless of t(11;14) translocation, whereas lower hematologic CR rates were observed for patients with the t(11;14) translocation treated with CyBorD.
Among the responders, the median time to hematologic CR was 60 (range = 8 to 299) days in the DCyBorD arm and 85 (range = 14 to 340) days in the CyBorD arm. At the time of the primary analysis, the median duration of hematological CR had not been reached in either treatment arm (range = 0.85 to 17.5 months for DCyBorD; 0.03 to 18.4 months for CyBorD). Of the 104 patients who achieved hematological CR in the DCyBorD arm, 4 patients died while in hematological CR and no patients relapsed following hematological CR. Of the 35 patients who achieved hematological CR in the CyBorD arm, 2 patients died while in hematological CR and 2 patients relapsed following hematological CR. The hazard ratio for MOD-PFS for DCyBorD versus CyBorD was 0.58 (95% CI, 0.36 to 0.93).
For patients who could be evaluated for cardiac response, 41.5% of patients in the DCyBorD arm and 22.2% of patients in the CyBorD arm had a cardiac response at 6 months. Among patients who could be evaluated for renal response, 53.0% of patients in the DCyBorD arm and 23.9% of patients in the CyBorD arm had a renal response at 6 months. In the updated analysis, the 12-month organ response rate for cardiac response in the DCyBorD arm and CyBorD arm was 57% and 28%, respectively; for renal response, it was 57% and 27%, respectively.
Median OS was not reached in either treatment arm.
The median time to improvement for global health status as measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) was 7.8 months in the DCyBorD arm and 16.7 months in the CyBorD arm (hazard ratio = 1.53, 95% CI, 1.10 to 2.13). EORTC QLQ-30 global health status showed continued improvement in the DCyBorD arm after 6 months when patients were receiving daratumumab monotherapy.
Medical resource utilization was reported for |||| and |||| of patients in the DCyBorD and CyBorD arms, respectively. Use | |||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. The most common indication for use of medical services was |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| arm.
Nearly all patients experienced at least 1 treatment-emergent AE (TEAE) (DCyBorD: 97.9%; CyBorD: 98.4%). In both treatment arms, TEAEs led to discontinuation of study treatment in approximately 4% of patients. A higher percentage of patients (43.0%) in the DCyBorD arm reported at least 1 serious TEAE compared with the CyBorD arm (36.2%). The most commonly reported (≥ 5% in either treatment arm) serious AEs were pneumonia (DCyBorD: 7.3%, CyBorD: 4.8%) and cardiac failure (DCyBorD: 6.2%, CyBorD: 4.8%). The incidence of was a minimum of 2% higher in the DCyBorD arm compared with the CyBorD arm for pneumonia (7.3% and 4.8%, respectively), sepsis (3.1% and 0%, respectively), and cardiac arrest (3.6% and 1.6%, respectively).
Across all cycles, the incidence of any grade of neutropenia (DCyBorD: 10.9%; CyBorD: 6.4%) and Grade 3 or 4 neutropenia (DCyBorD: 5.2%; CyBorD: 2.7%) was higher in the DCyBorD arm. The incidence of any grade of infection (DCyBorD: 65.8%; CyBorD: 53.7%), Grade 3 or 4 of infection (DCyBorD: 16.6%; CyBorD: 10.1%), and serious infection (DCyBorD:16.1%; CyBorD: 8.5%) was higher in the DCyBorD arm. The most commonly reported (> 10% in either treatment arm) infections (any grade) in the DCyBorD and CyBorD arms were upper respiratory tract infection (25.9% and 11.2%, respectively) and pneumonia (10.9% and 6.4%, respectively).
At the time of the primary analysis, 27 (14.0%) patients in the DCyBorD arm and 28 (14.9%) patients in the CyBorD arm died. One patient in the CyBorD arm died before receiving any treatment. A higher proportion of patients in the DCyBorD arm reported death due to an AE (11.9%) compared with the CyBorD arm (7.4%), and more patients in the CyBorD arm compared with the DCyBorD arm reported death due to progressive disease (1.0% and 4.8%, respectively) and “other” causes (1.0% and 2.7%, respectively). The most common (≥ 2% in either treatment arm) AEs leading to death in the DCyBorD and CyBorD arms were cardiac disorders: cardiac arrest (3.1%and 1.6%, respectively), sudden death (3.1% and 1.6%, respectively), and cardiac failure (2.6% and 0.5%, respectively). All patients who died due to cardiac disorders had cardiac involvement at baseline (DCyBorD: 14 of 14; CyBorD: 7 of 7).
The ANDROMEDA trial was an open-label study; patients and investigators were not blinded to study assignment, although patient blinding would not have been possible given the differences in the 2 study treatment regimens. Nonetheless, sources of bias that may result from lack of blinding of patients and investigators to assigned study treatments cannot be ruled out. For example, a patient’s knowledge of their assigned treatment may have affected some safety end points and particularly HRQoL, and different concomitant supportive care may have been offered to patients in the 2 treatment arms. The primary end point of hematologic CR and organ response were lab-based objective measures, which were unlikely to be affected by the open-label design. Longer duration of therapy in the DCyBorD arm and use of subsequent therapy in the trial is another possible source of bias. Only the primary outcome of hematologic CR is unaffected by this possible bias and can thus be considered valid. Use of subsequent therapy may impact other key secondary outcomes: very good partial response, partial response, and MOD-PFS. This issue is addressed in the primary analysis for MOD-PFS which employed the inverse probability of censoring weight method to adjust estimates of a treatment effect in the presence of subsequent non–cross-resistant, anti-plasma cell therapy, which still showed longer MOD-PFS in the DCyBorD arm. Missing data, including missing organ response assessments and patient attrition (26.6% in the DCyBorD and 35.2% in the CyBorD arm), although not unexpectedly high in the cancer trial setting, may also impact the internal validity of the evidence.
Although the ANDROMEDA trial included a heterogenous population of patients with AL amyloidosis and a wide range of clinical presentations were well-represented, some groups of patients, including those with an advanced cardiac stage, were excluded. Therefore, the evidence regarding efficacy and safety of DCyBorD compared with CyBorD in these groups of patients is limited based on trial evidence. The comparator of the trial (CyBorD) is not approved for treatment of patients with AL amyloidosis in Canada. However, CyBorD is an appropriate comparator because it is standard of care for newly diagnosed AL amyloidosis in Canada. This is a special instance in which the drug regimen under review (i.e., DCyBorD) is the only Health Canada–approved treatment. The primary and key secondary outcomes and the assessment schedule were also reflective of clinical practice. Based on input from the clinical expert consulted by CADTH and clinician groups, in clinical practice, patients are assessed every 3 to 6 months. Formal response criteria have been established previously and were included in the ANDROMEDA trial.
Cost and Cost-Effectiveness.
CADTH reanalysis fixed the derivation of the population size along with a small programming inconsistency. In the CADTH base case, the budget impact is expected to be $25,887,024 in year 1, $34,273,444 in year 2, and $34,756,670 in year 3, with a 3-year total of $94,917,168.
Dr. Maureen Trudeau (Chair), Mr. Daryl Bell, Dr. Jennifer Bell, Dr. Matthew Cheung; Dr. Winson Cheung, Dr. Michael Crump, Dr. Leela John, Dr. Christian Kollmannsberger, Mr. Cameron Lane, Dr. Christopher Longo, 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: December 1, 2021
Regrets: None
Conflicts of interest: None
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Indication: In combination with bortezomib, cyclophosphamide, and dexamethasone for the treatment of adult patients with newly diagnosed light chain (AL) amyloidosis
Sponsor: Janssen Inc.
Final recommendation: Reimburse with conditions
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