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Indication: For the treatment of adult patients with diffuse large B-cell lymphoma or high-grade B-cell lymphoma that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy
CADTH recommends that Yescarta should be reimbursed by public drug plans for the treatment of adult patients with diffuse large B-cell lymphoma (DLBCL) or high-grade B-cell lymphoma (HGBL) that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy, who are eligible for autologous stem cell transplant (ASCT) if certain conditions are met.
Yescarta should only be covered to treat adults with DLBCL or HGBL that did not respond to or relapsed within 12 months of first-line therapy and are eligible for ASCT.
Yescarta should only be reimbursed for patients who have not yet been treated with chimeric antigen receptor (CAR) T-cell therapy, are in relatively good health, and if the cost of Yescarta is reduced. It should be prescribed and administered by clinicians with expertise in lymphomas and CAR T-cell therapy in a hospital setting with adequate resources.
BCLs, the most common types of non-Hodgkin lymphomas (NHLs), are closely related cancers formed from B lymphocytes, a type of white blood cell. An estimated 11,400 people living in Canada will be diagnosed with NHL each year and 3,000 will die.
Not all patients with BCL benefit from available treatments. Patients need additional treatment options that can prolong survival and remission and improve quality of life.
Treatment with Yescarta is expected to have a 1-time cost of $485,021 per patient. Additional costs associated with pre- and postinfusion management (i.e., leukapheresis, bridging therapy, conditioning chemotherapy) and administration will also apply.
The CADTH pCODR Expert Review Committee (pERC) recommends that axicabtagene ciloleucel be reimbursed for the treatment of adult patients with diffuse large B-cell lymphoma (DLBCL) or high-grade B-cell lymphoma (HGBL) that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy and who are eligible for autologous stem cell transplant (ASCT) only if the conditions listed in Table 1 are met.
One phase III, multicentre, randomized, open-label trial (ZUMA-7) demonstrated that treatment with axicabtagene ciloleucel resulted in added clinical benefit compared with standard of care (SOC) (salvage chemoimmunotherapy followed by high-dose therapy [HDT] and ASCT) as second-line treatment in ASCT-eligible patients with refractory or relapsed large B-cell lymphoma (LBCL) within 12 months of first-line therapy. The ZUMA-7 trial demonstrated that treatment with axicabtagene ciloleucel was associated with statistically significant and clinically meaningful improvements in event-free survival (EFS) compared with SOC. Median EFS based on blinded central assessment was 8.3 months (95% confidence interval [CI], 4.5 to 15.8) in the axicabtagene ciloleucel arm and 2.0 months (95% CI, 1.6 to 2.8) in the SOC arm; the stratified hazard ratio (HR) for event or death was 0.398 (95% CI, 0.308 to 0.514; P < 0.0001).
Patients indicated that there is a need for treatments that prolong survival and remission, improve quality of life, and have fewer side effects. Furthermore, patients indicated that treatment choice is important to them, and there is a need for more treatment options and improved access to chimeric antigen receptor (CAR) T-cell therapy. Given all the evidence, pERC concluded that axicabtagene ciloleucel met some of the needs identified by patients, such as prolonged EFS and an additional treatment option.
Using the sponsor-submitted price for axicabtagene ciloleucel and publicly listed prices for all other drug costs, the incremental cost-effectiveness ratio (ICER) for axicabtagene ciloleucel was $404,418 per quality-adjusted life-year (QALY) gained compared with SOC. At this ICER, axicabtagene ciloleucel is not cost-effective at a willingness-to-pay threshold of $50,000 per QALY for adult patients with refractory or relapsed LBCL who are candidates for ASCT. A price reduction is required for axicabtagene ciloleucel to be considered cost-effective at a $50,000 per QALY gained threshold.
Reimbursement Conditions and Reasons.
Non-Hodgkin lymphoma comprises a diverse group of closely related cancers of the lymphocytes. It is the most prevalent hematological malignancy and the fifth most common cancer diagnosed in Canada. LBCL is the most common subtype of non-Hodgkin lymphoma in Canada, constituting 30% to 40% of all cases. LBCL is an aggressive but potentially curable non-Hodgkin lymphoma that is typically diagnosed at an advanced stage (stage III or IV).
The SOC first-line treatment for patients with newly diagnosed LBCL is cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), often in combination with rituximab (R-CHOP). However, 30% to 50% of patients are refractory to or relapse after first-line therapy. OS in patients with primary refractory disease is very poor. Patients with partial response (PR) or complete response (CR) to first-line treatment also have poor survival at relapse. For patients who relapse or whose disease is refractory to first-line chemoimmunotherapy, second-line treatment comprises salvage chemotherapy; if responsive to salvage therapy, this is followed by HDT and ASCT. However, only about half of the patients with relapsed or refractory LBCL are fit enough for transplant (i.e., have adequate organ function with no major comorbidities), and only half of transplant-eligible patients respond to salvage chemotherapy and can proceed to ASCT. Treatment options for patients with relapsed or refractory LBCL who are ineligible for ASCT, do not respond to salvage chemotherapy, or relapse post-ASCT include palliative chemotherapy, radiotherapy, clinical trials, or third-line CAR T-cell therapy if the patient meets the eligibility criteria.
Axicabtagene ciloleucel is a CD19-directed, genetically modified autologous T-cell immunotherapy (i.e., CAR T-cell therapy). Axicabtagene ciloleucel has been approved by Health Canada for the treatment of adult patients with LBCL that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy. It is available as an IV infusion (target of 2 × 106 anti-CD19 CAR T cells per kg body weight).
In 2019, CADTH published an Optimal Use Report evaluating the beneficial and harmful effects of axicabtagene ciloleucel as third-line therapy for eligible types of relapsed or refractory B-cell lymphomas in adult patients. The original CADTH review of axicabtagene ciloleucel included the ZUMA-1 trial, which was a phase I/phase II, single-arm, multicentre, open-label clinical trial in patients with relapsed or refractory LBCL who had received at least 2 previous systemic therapies.
To make its recommendation, the committee considered the following information:
One patient group, Lymphoma Canada, submitted patient input for this review. This group gathered information from patients with DLBCL in Canada through 2 online surveys: 1 in 2018 and another in 2022. In both surveys, patients reported that fear of progression or relapse was the most common psychosocial impact (67%) affecting quality of life, followed by anxiety (37%), memory loss (37%), and concentration problems (36%). The majority of respondents (83%) were treated with CHOP with or without rituximab as their first-line of treatment since diagnosis. The respondents stated long-term treatment side effects (i.e., lasting longer than 2 years or that appeared at least 2 years after the end of treatment) included fatigue (52%) and “chemo brain” (42%). Patients from the 2018 survey reported their lymphoma treatment had the greatest negative impact on their work, travel, and other activities. Patients rated longer survival, longer remission, better quality of life, and fewer side effects as important outcomes expected from their treatment. More than half of the patients stated that they would choose a treatment with potentially serious side effects if their doctor recommended it to be the most effective option for DLBCL. Respondents also indicated treatment choice was an important factor, and 91% of patients felt a need for more therapy options for DLBCL patients.
Three patients reported receiving axicabtagene ciloleucel as third-line therapy. All were away from home for more than 3 months while receiving the treatment, and they highlighted the challenge of accessing CAR T-cell therapy currently. All 3 patients reported thrombocytopenia as a side effect of treatment with axicabtagene ciloleucel; fever, anemia, nausea/vomiting, neutropenia, diarrhea, joint or muscle pain, and fatigue were reported by 2 patients. Fear of progression or relapse and difficulty sleeping were reported by all 3 patients as psychosocial effects related to their CAR T-cell therapy.
Four clinical experts from across Canada contributed input to the CADTH review. The clinical experts consulted by CADTH noted that there is an unmet treatment need for patients who are refractory to or who relapsed after front-line therapy. Although HDT and ASCT has curative potential for the treatment of patients with relapsed or refractory LBCL, many patients are ineligible for ASCT or do not respond to salvage chemotherapy. The clinical experts indicated that axicabtagene ciloleucel would fit well earlier in the lines of treatment. The clinical experts suggested that axicabtagene ciloleucel could be used in second line and replace ASCT for most patients. The clinical experts noted that patient outcomes are expected to be better when they receive a potentially curative therapy earlier in the course of disease because some patients deteriorate rapidly and thus may be less likely to survive if definitive treatment is delayed.
The clinical experts noted that although the ZUMA-7 trial recruited only patients who were eligible for ASCT, in standard clinical practice there is no clinical rationale for restricting axicabtagene ciloleucel only to those who are candidates for ASCT and that any patient with adequate organ function and good performance status (Eastern Cooperative Oncology Group [ECOG] performance status ≤ 2) who, based on the clinician’s judgment can tolerate the known toxicities of CAR T-cell therapy (e.g., cytokine release syndrome [CRS]) would be suitable for axicabtagene ciloleucel treatment. The clinical experts noted that axicabtagene ciloleucel treatment can be provided by oncologists or hematologists in a hospital setting with adequate infrastructure for cell therapy with access to highly specialized multidisciplinary clinical care, including critical/intensive care and specialist care (e.g., neurology, nephrology) to manage toxicities as well as laboratory support to handle and process samples. The clinical experts also pointed out that the 13-day median manufacturing time reported in the ZUMA-7 study is rapid but may not be reproducible outside the clinical trial setting and longer delays may compromise patient outcomes.
Clinician group input was received from 3 groups: Lymphoma Canada, Ontario Health (Cancer Care Ontario) Hematology Cancer Drug Advisory Committee, and CTTC. The clinician groups agreed that there are unmet needs in the current second-line treatment for patients with relapsed or refractory LBCL. The clinician groups indicated that there may be limited eligibility or tolerability to further salvage chemotherapy for some patients (e.g., patients with primary refractory disease or early relapse, older patients). The clinician groups also noted that toxicities, such as febrile neutropenia, bacteremia and other infections, gastrointestinal toxicity, and mucositis, as well as the need for transfusion support and the secondary malignancies associated with ASCT treatment, have made it unsuitable for high-risk patients who are refractory to treatment or who relapse within 12 months of diagnosis.
The clinical experts consulted by CADTH provided advice on the potential implementation issues raised by the drug programs.
Responses to Questions From the Drug Programs.
A single sponsor-submitted pivotal study was included in this review. The ZUMA-7 study is a phase III, multicentre, randomized, open-label study evaluating the efficacy of axicabtagene ciloleucel compared with SOC (salvage chemoimmunotherapy followed by HDT and ASCT) as a second-line therapy in patients with relapsed or refractory LBCL after first-line rituximab- plus anthracycline-based chemotherapy. The trial was conducted in 14 countries; 20 patients from 8 centres were recruited in Canada. The first patient was enrolled (randomized) on January 25, 2018, and enrolment was completed on October 4, 2019; ZUMA-7 is currently ongoing. All patients had either primary refractory disease or relapse within 12 months of completing first-line therapy, were potentially eligible for ASCT, and had not yet received second-line treatment. The data cut-off date for the primary analysis was March 18, 2021. For patients in the axicabtagene ciloleucel arm (N = 180), treatment consisted of lymphodepleting chemotherapy followed by a single IV infusion of axicabtagene ciloleucel. Bridging therapy consisting of corticosteroids was allowed before lymphodepleting chemotherapy for patients with high disease burden at the discretion of the investigator. For patients in the SOC arm (N = 179), treatment consisted of a single protocol-defined, platinum-based salvage chemotherapy regimen for 2 to 3 cycles as selected by the treating investigator. Patients who responded to salvage chemotherapy were to proceed to HDT followed by ASCT. The mean age of patients was 57 years (standard deviation [SD] = 12 years); 30% of the patients were 65 years of age or older. Overall, 74% of the study population had primary refractory disease and 26% had early relapse. Approximately one-quarter of patients in both treatment arms had achieved a best response of CR to first-line treatment.
OS was a key secondary outcome in the ZUMA-7 study. The OS data remain immature at the time of this review. At the time of the data cut-off date (March 18, 2021), 72 patients (40%) had died in the axicabtagene ciloleucel arm and 81 patients (45%) had died in the SOC arm (153 OS events were observed in the full analysis set). The primary OS analysis will occur at approximately 210 deaths or 5 years after the first patient was enrolled. At the interim OS analysis, the HR for death was 0.730 (95% CI, 0.530 to 1.007; 1-sided stratified log-rank P = 0.0270).
An addendum to ZUMA-7 Clinical Study Report was made to provide data generated in response to a Health Authority request to obtain additional survival follow-up data, including from public records, for patients who discontinued from the ZUMA-7 trial. This was not available at the time of the interim OS analysis for completeness of the interim OS data. At the time of this analysis, there were an additional 4 deaths in the SOC arm identified for a total of 157 OS events (72 deaths in the axicabtagene ciloleucel arm and 85 deaths in the SOC arm). The stratified HR was 0.708 (95% CI, 0.515 to 0.972; P = 0.0159).
EFS based on blinded central assessment was the primary outcome of the ZUMA-7 study. At the time of the data cut-off, 252 EFS events based on blinded central assessment had occurred in 108 patients (60%) in the axicabtagene ciloleucel arm and 144 patients (80%) in the SOC arm. The median EFS was 8.3 months (95% CI, 4.5 to 15.8 months) in the axicabtagene ciloleucel arm and 2.0 months (95% CI, 1.6 to 2.8 months) in the SOC arm. The stratified HR for event or death was 0.398 (95% CI, 0.308 to 0.514; P < 0.0001).
HRQoL assessed by changes from screening in the global health status scale and the physical functioning domain of the EORTC QLQ-C30 and the EQ-5D-5L index and VAS scores were secondary outcomes. There was a clinically meaningful (based on the trial-specified threshold of ± 10 points) and statistically significant difference in mean change of scores from baseline to study day 100 for the EORTC QLQ-C30 global health status and physical functioning scores and EQ-5D-5L VAS scores with axicabtagene ciloleucel compared with SOC. However, the high attrition rate, which was imbalanced between groups, at all follow-up time points limits interpretation of these data.
For EORTC QLQ-C30 global health status there was a clinically meaningful difference in mean change of scores from screening at study day 100 (estimated difference = 18.1; 95% CI, 12.3 to 23.9; adjusted P < 0.0001) for patients treated with axicabtagene ciloleucel compared with SOC. At study day 150, the estimated difference was 9.8 (95% CI, 2.6 to 17.0; adjusted P = 0.0124).
For EORTC QLQ-C30 physical functioning, there was a clinically meaningful difference in mean change of scores from screening to study day 100 for patients treated with axicabtagene ciloleucel compared with SOC (estimated difference = 13.1; 95% CI, 8.0 to 18.2; adjusted P < 0.0001).
For EQ-5D-5L VAS, there was a clinically meaningful difference in mean change of scores for the EQ-5D-5L VAS from screening in the axicabtagene ciloleucel arm compared with SOC at study day 100 (estimated difference = 13.7; 95% CI, 8.5 to 18.8; adjusted P < 0.0001) and study day 150 (estimated difference = 11.3; 95% CI, 5.4 to 17.1; adjusted P = 0.0004).
Progression-free survival (PFS) was a secondary outcome. At the data cut-off date, the median duration of PFS based on investigator disease assessments was 14.9 months (95% CI, 7.2 months to not estimable [NE]) in the axicabtagene ciloleucel arm and 5.0 months (95% CI, 3.4 to 8.5 months) in the SOC arm, with a stratified HR of 0.562 (95% CI, 0.414 to 0.762).
Objective response rate (ORR) per blinded central assessment was a key secondary outcome in the ZUMA-7 trial. The ORR (CR or PR) per blinded central assessment was 83% in the axicabtagene ciloleucel arm and 50% in the SOC arm (difference in ORR = 33.1%; 95% CI, 23.2% to 42.1%; P < 0.0001).
The CR rates in the axicabtagene ciloleucel arm and the SOC arm were 65% (95% CI, 57.6% to 71.9%; n = 117) and 32% (95% CI, 25.6% to 39.8%; n = 58), respectively, and the PR rates were 18% (95% CI, 13.0% to 24.8%; n = 33) and 18% (95% CI, 12.6% to 24.3%; n = 32), respectively.
Duration of response was a secondary outcome. For the 150 patients in the axicabtagene ciloleucel arm and the 90 patients in the SOC arm who achieved an objective response of CR or PR by blinded central assessment, the Kaplan-Meier estimated median duration of response was 26.9 months (95% CI, 13.6 months to NE) in the axicabtagene ciloleucel arm compared with 8.9 months (95% CI, 5.7 months to NE) in the SOC arm (stratified HR = 0.736; 95% CI, 0.488 to 1.1085).
The Kaplan-Meier estimates of the percentage of patients who remained in response at 12 and 24 months from first objective response were 60.9% (95% CI, 52.4% to 68.4%) and 54.0% (95% CI, 45.1% to 62.0%), respectively, in the axicabtagene ciloleucel arm compared with 47.6% (95% CI, 35.2% to 58.9%) and 45.6% (95% CI, 33.2% to 57.1%), respectively, in the SOC arm.
Time to next treatment was an exploratory outcome. Time to next treatment events occurred for 99 patients (55%) in the axicabtagene ciloleucel arm and 135 patients (75%) in the SOC arm. The median time to next treatment was 14.7 months (95% CI, 6.5 months to NE) and 3.4 months (95% CI, 3.1 to 4.4 months), respectively (stratified HR = 0.430; 95% CI, 0.329 to 0.560).
A total of 42 patients (25%) in the axicabtagene ciloleucel arm and 9 patients (5%) in the SOC arm were admitted to the ICU. Median duration of ICU hospitalization was 5 days (range, 1 to 12 days) and 3 days (range, 2 to 17 days) in the axicabtagene ciloleucel and SOC arms, respectively. Median duration of hospitalization for axicabtagene ciloleucel infusion was 16 days (range, 5 to 103 days); median duration of inpatient hospitalization for stem cell transplant in the SOC arm was 21 days (range, 1 to 53 days).
All patients in the axicabtagene ciloleucel arm (n = 170; 100%) and the SOC arm (n = 168; 100%) had at least 1 treatment-emergent adverse event (TEAE), including 155 patients (91%) in the axicabtagene ciloleucel arm and 140 patients (83%) in the SOC arm who had a grade 3 or higher TEAE. The most frequently reported TEAEs of grade 3 or higher (reported in ≥ 20% of patients in both treatment arms) were neutropenia (n = 73; 43%), anemia (n = 51; 30%), decreased neutrophil count (n = 49; 29%), decreased and white blood cell count (n = 43; 25%) in the axicabtagene ciloleucel arm and anemia (n = 65; 39%), decreased platelet count (n = 60 patients; 36%), decreased neutrophil count (47 patients; 28%), febrile neutropenia (n = 46; 27%), and thrombocytopenia (n = 37; 22%) in the SOC arm.
A total of 85 patients (50%) in the axicabtagene ciloleucel arm and 77 patients (46%) in the SOC arm had at least 1 serious adverse event. The most frequently (in ≥ 5% of patients) reported serious adverse events of any grade were pyrexia (n = 27; 16%), encephalopathy (n = 17; 10%), hypotension (n = 15; 9%), aphasia (n = 9; 5%), and pneumonia (n = 8; 5%) in the axicabtagene ciloleucel arm and febrile neutropenia (n = 22; 13%), and acute kidney injury (n = 8; 5%), and pyrexia (n = 8; 5%) in the SOC arm.
No patient discontinued treatment due to TEAEs in the axicabtagene ciloleucel arm. Two patients in the SOC arm discontinued treatment due to TEAEs of grade 4 acute kidney injury and grade 1 blood stem cell harvest failure.
Among patients in the axicabtagene ciloleucel arm, 64 patients (38%) had died by the data cut-off date for reasons including progressive disease (n = 47; 28%), TEAEs (n = 6; 4%), other reasons (n = 10; 6%), and 1 patient (1%) died from an event reported by the investigator as a “secondary malignancy” (lung adenocarcinoma). In the SOC arm, 78 patients (46%) had died at the data cut-off date due to reasons including progressive disease (n = 64; 38%), TEAEs (n = 2; 1%), or other reasons (n = 12; 7%).
A total of 102 patients (60%) in the axicabtagene ciloleucel arm and 33 patients (20%) in the SOC arm had at least 1 treatment-emergent neurologic event; 36 patients (21%) and 1 patient (1%) in the axicabtagene ciloleucel and SOC arms, respectively, had a grade 3 or higher neurologic event. Of these, 10 patients (6%) in the axicabtagene ciloleucel arm had a grade 4 neurologic event, and no patients in either treatment arm had a grade 5 neurologic event. Serious treatment-emergent neurologic events of any grade were reported for 34 patients (20%) in the axicabtagene ciloleucel arm and 1 patient (1%) in the SOC arm, including 26 patients (15%) in the axicabtagene ciloleucel arm with a serious grade 3 or higher neurologic event and 1 patient (1%) in the SOC arm with a serious grade 2 neurologic event.
CRS of any grade was reported for 157 patients (92%), including 11 patients (6%) who had a grade 3 or higher CRS; no patient had grade 5 CRS.
The most common cytopenias of any grade reported in the axicabtagene ciloleucel arm were thrombocytopenia (50 patients; 29%), neutropenia (122 patients; 72%), and anemia (73 patients; 43%). The most common cytopenias of any grade reported in the SOC arm were thrombocytopenia (101 patients; 60%), neutropenia (92 patients; 55%), and anemia (92 patients; 55%).
Seventy patients (41%) in the axicabtagene ciloleucel arm and 51 patients (30%) in the SOC arm had at least 1 treatment-emergent infection, including 24 patients (14%) and 19 patients (11%), respectively, with a grade 3 or higher infections. Three patients (2%) in the axicabtagene ciloleucel arm and 6 patients (4%) in the SOC arm had a grade 4 infections. Five patients (3%) in the axicabtagene ciloleucel arm had a grade 5 TEAE of infection (2 patients with COVID-19, 1 patient with progressive multifocal leukoencephalopathy, 1 patient with hepatitis B reactivation, and 1 patient with sepsis). No patients in the SOC arm had a grade 5 TEAE of infection.
The ZUMA-7 trial was open label. Despite the open-label design, there is low risk of bias in the measurement of outcomes such as EFS, PFS, and ORR, which were assessed via independent blinded radiologic review of disease response, as well as OS which is an objective outcome. Although independent blinded radiologic review of disease response was performed as the primary analysis to minimize investigator bias, patient’s knowledge of their assigned treatment could affect HRQoL data and any subjective harm that is particularly susceptible to bias from a lack of blinding of patients to their treatment. The HRQoL data were also at high risk of attrition bias because there were large amounts of missing data for all follow-up time points and the amount of missing data was not balanced across treatment arms. The HRQoL tools were not validated in patients with LBCL. The primary and secondary efficacy end points of EFS, ORR, and OS are considered appropriate for the disease setting. The OS data were immature and there is a risk that the effect of axicabtagene ciloleucel compared with SOC on survival is overestimated because the results are based on an interim analysis. Although there is some evidence to suggest EFS is a robust surrogate end point for OS in hematological malignancies, it is unknown whether this could be extended to CAR T-cell therapies in the relapsed or refractory LBCL setting.
The ZUMA-7 trial included patients with relapsed or refractory LBCL with a wide range of clinical presentations, but patients with HIV and those with an ECOG PS of 2 or more were excluded. The clinical experts consulted by CADTH indicated that these patient groups should be eligible for CAR T-cell therapies including axicabtagene ciloleucel. Although the SOC treatment, including salvage chemotherapy regimens, used in the SOC arm of the ZUMA-7 trial are reflective of Canadian clinical practice, the clinical experts noted there are challenges in reproducing the same treatment processes for axicabtagene ciloleucel treatment in the real-world setting, notably because of the rapid manufacturing time (13 days in the ZUMA-7 trial). As per the clinical experts, delays in manufacturing and access times to axicabtagene ciloleucel treatment would potentially compromise patient outcomes because the probability of disease progression or other complications increase with longer axicabtagene ciloleucel manufacturing wait times. Data for all outcomes considered important to patients, clinicians, and drug plans as per the systematic review protocol were collected and reported; however, conclusions could not be drawn for effects of axicabtagene ciloleucel compared with SOC on HRQoL due to limitations in the data.
The sponsor provided long-term (≥ 4 year and ≥ 5 year) data from the ZUMA-1 trial, the pivotal multicentre, single-arm, registrational phase I and II study of axicabtagene ciloleucel in patients with relapsed or refractory LBCL.
In the 2-year analysis of the ZUMA-1 trial (n = 101; median follow-up from axicabtagene ciloleucel dosing to data cut-off: 27.1 months), the ORR was 83%; 58% of patients achieved a CR. The 2-year OS rate was 50.5% (95% CI not reported).
The most recently updated survival results from the phase II ZUMA-1 study, after 5 years of follow-up, showed a 5-year OS rate of 42.6% (95% CI, 32.8% to 51.9%) among patients treated with axicabtagene ciloleucel. The 5-year OS rate among complete responders was 64.4% (95% CI, 50.8% to 75.1%). The median survival time among complete responders was not reached (95% CI, 63.4% to NE). Of 59 patients who achieved CR, 37 patients (63%) were alive at the 5-year data cut-off. Since the 4-year data cut-off, 1 death at month 63 (CR) and 1 PD at month 54 (PR) were observed.
Supportive safety data comparing populations treated with axicabtagene ciloleucel in the ZUMA-7 and ZUMA-1 trials suggested comparable TEAEs between the 2 trials.
The ZUMA-1 trial was critically appraised in the 2019 CADTH Optimal Use Report. ZUMA-1 was a single-arm, phase I and II study of axicabtagene ciloleucel in patients with relapsed or refractory LBCL who had received at least 2 previous systemic therapies. The primary limitation of the ZUMA-1 study was the absence of a comparator group against which the treatment benefits and harms of axicabtagene ciloleucel could be compared. As such, causal effects cannot be inferred. In addition, patients in the ZUMA-1 study received axicabtagene ciloleucel as third- or later-line treatment. It is unknown whether results are generalizable to patients treated with axicabtagene ciloleucel as second-line treatment, which is the indication under review.
Cost and Cost-Effectiveness.
CADTH identified the following limitations in the sponsor’s budget impact analysis: axicabtagene ciloleucel use may be broader than the sponsor’s reimbursement request, the projected market share of axicabtagene ciloleucel was underestimated, the projected proportion of ASCT-eligible patients who would proceed to second-line treatment was underestimated, and the mix of subsequent therapies in the axicabtagene ciloleucel arm included investigational therapies. CADTH performed reanalyses, in line with clinician expert opinion, by revising the projected market share of axicabtagene ciloleucel, increasing the proportion of ASCT-eligible patients who would proceed to second-line treatment, and redistributing subsequent therapies in the axicabtagene ciloleucel arm. Based on the CADTH reanalyses, the budget impact from the introduction of axicabtagene ciloleucel for the treatment of r/r LBCL in adult patients who are candidates for ASCT is expected to be $103,063,855 in year 1, $117,507,525 in year 2, and $127,069,602 in year 3, with a 3-year total of $347,640,982.
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: November 8, 2022
Regrets: Two expert committee members did not attend
Conflicts of interest: Two expert committee members did not participate due to considerations of conflict of interest
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Indication: For the treatment of adult patients with diffuse large B-cell lymphoma or high-grade B-cell lymphoma that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy
Sponsor: Gilead Sciences Canada Inc.
Final recommendation: Reimburse with conditions
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