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Indication: For the treatment of adult patients with relapsed or refractory grade 1, 2, or 3a follicular lymphoma after 2 or more lines of systemic therapy
CADTH recommends that Yescarta be reimbursed by public drug plans for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL) if certain conditions are met.
Yescarta should only be covered to treat adult patients who have grade 1, 2, or 3a FL and whose disease has returned following second-line treatment or later lines of treatments.
Yescarta should only be reimbursed for patients who have not already received a chimeric antigen receptor (CAR) T-cell therapy and are in relatively good health, and if the cost of Yescarta is reduced. Yescarta should be prescribed and administered by clinicians with expertise in blood cancers in a hospital setting with adequate resources to treat patients and manage side effects.
FL is a common type of non-Hodgkin lymphoma that develops when the body makes abnormal white blood cells (WBCs). In FL, the abnormal WBCs cluster together to form lumps in lymph nodes or other tissues. FL tends to progress slowly over many years; however, patients whose FL does not respond to treatment or whose FL returns after responding to previous treatments have a shortened life expectancy. It is estimated that 1 in 3,000 people have FL.
Patients with FL whose cancer does not respond to treatment or whose cancer returns after treatment have a poor prognosis and limited treatment options. Further, not all patients benefit from the limited treatments that are available. Therefore, there is a need for additional treatments that can prolong survival, cure the disease, and improve quality of life.
Treatment with Yescarta is expected to cost approximately $485,000 per infusion.
The CADTH pan-Canadian Oncology Drug Review Expert Review Committee (pERC) recommends that axicabtagene ciloleucel be reimbursed for the treatment of adult patients with relapsed or refractory (r/r) grade 1, 2, or 3a follicular lymphoma (FL) after 2 or more lines of systemic therapy only if the conditions listed in Table 1 are met.
One phase II, multicentre, single-arm, open-label trial (ZUMA-5; N = 127) demonstrated that treatment with axicabtagene ciloleucel resulted in benefits in the primary end point of response rates for adult patients with r/r FL after 2 or more lines of systemic therapy. The objective response rate (ORR) was 94% (95% confidence interval [CI], || || ||) and the complete response rate (CRR) was 79% (95% CI, || || ||). The observed response rates in the ZUMA-5 trial were deemed clinically meaningful by clinical experts compared with expected outcomes in adult patients with r/r grade 1, 2, or 3a FL. Axicabtagene ciloleucel was associated with potential benefits in survival outcomes; at the 36-month follow-up analysis, median overall survival (OS) was not reached, while the median progression-free survival (PFS) was 40.2 months (95% CI, 28.9 to not evaluable [NE]). The Kaplan-Meier (KM) survival probability at 36 months was 75.5% (95% CI, 66.9 to 82.2).
Patients identified a need for more effective treatments that extend survival and disease remission and improve quality of life. Furthermore, patients indicated that there is a need for easier access to new therapies such as chimeric antigen receptor (CAR) T-cell therapy. pERC considered that axicabtagene ciloleucel offers a subsequent therapy option for a heavily pretreated population in the form of a single treatment. Given the totality of the evidence, pERC concluded that axicabtagene ciloleucel may meet some of the needs identified by patients, since it appears to have durable responses, may prolong survival, and has a manageable toxicity profile.
The committee considered analyses conducted by CADTH, which evaluated the cost-effectiveness of axicabtagene ciloleucel relative to the current standard of care for the treatment of adult patients with r/r grade 1, 2, or 3a FL after 2 or more lines of systemic therapy. Given the magnitude of uncertainty surrounding OS for axicabtagene ciloleucel, its comparative efficacy against standard of care, and the durability of such a benefit, CADTH could not estimate a robust single base-case estimate of cost-effectiveness for axicabtagene ciloleucel. Using the sponsor’s submitted price for axicabtagene ciloleucel and publicly listed prices for all other drug costs, the incremental cost-effectiveness ratio (ICER) ranged from $243,879 to $544,875 per quality-adjusted life-year (QALY) gained, based on CADTH reanalyses exploring possible ranges of the extrapolated OS benefits for axicabtagene ciloleucel. In all reanalyses, a price reduction would be required for axicabtagene ciloleucel to achieve an ICER of $50,000 per QALY gained.
Reimbursement Conditions and Reasons.
Non-Hodgkin lymphoma (NHL) encompasses a heterogeneous group of more than 80 closely related cancers. It is characterized by the abnormal and uncontrolled proliferation of cells (i.e., T cells, B cells, and natural killer cells) of the lymphatic system. FL, a subtype of NHL, is an indolent B-cell lymphoma originating from the germinal centre of lymphoid tissues; characterized by slow growth and spread, it accounts for 20% to 30% of all NHL cases. The sponsor-calculated overall incidence rate of FL in Canada (based on NHL age-standardized incidence rates [25.7 per 100,000] and the proportion of FL among NHL cases [25%]) was 7.21 per 100,000. Although responsive to initial first-line or second- line therapies, FL is characterized by a relapsing and remitting disease course, especially in advanced disease stages. Patients will eventually require multiple treatments to manage or slow disease progression throughout their lifetime, as response to treatment declines upon repeated therapy. The clinical experts consulted by the sponsor reported that approximately 31% of patients with incident FL would progress to third-line therapy, of which 60% would proceed to receive active therapy. FL can be further classified into 3 grades (1, 2, and 3 [a and b]) based on cell structures under the microscope, specifically the number of large FL cells (centroblasts) observed. Grades 1, 2, and 3a diseases are generally considered low-grade or slow-growing compared to grade 3b, which grows quickly and is considered high-grade lymphoma. Statistics reported by the Canadian Cancer Care Society highlight that patients considered “low-risk” at diagnosis, according to the Follicular Lymphoma Internal Prognostic Index (FLIPI) score, have a 91% 5-year survival rate and 71% 10-year survival rate; intermediate-risk patients have a 78% 5-year survival rate and 51% 10-year survival rate; and high-risk patients have a 53% 5-year survival rate and 36% 10-year survival rate.
The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of axicabtagene ciloleucel, target of 2 × 106 CAR-positive T cells per kg of body weight with a maximum of 2 × 108 CAR-positive viable T cells, IV infusion, in the treatment of adult patients with r/r FL after 2 or more prior lines of systemic therapy.
Axicabtagene ciloleucel has been approved by Health Canada for the treatment of adult patients with r/r grade 1, 2, or 3a FL after 2 or more lines of systemic therapy. Axicabtagene ciloleucel is a CAR T-cell therapy, available as an IV drug. The dosage recommended in the product monograph is a target of 2 × 106 CAR-positive T cells per kg of body weight, with a maximum of 2 × 108 CAR-positive viable T cells.
To make its recommendation, the committee considered the following information:
One patient advocacy group, LC, provided input for this review. LC is a national Canadian registered charity whose mission is to empower patients and the lymphoma community through education, support, advocacy, and research. The LC patient group expressed the need for accessible treatment options for patients, highlighting that local access to treatments will significantly improve patients' experience by reducing fear and the risk of getting sick while travelling and patient quality of life.
LC gathered information for this input via online surveys completed anonymously by patients between April 21, 2022, and April 3, 2023. Of the 143 responses submitted, 3 respondents reported having experience with axicabtagene ciloleucel. Respondents indicated that fatigue (50%), body aches and pain (33%), enlarged lymph nodes (33%), indigestion (32%), and bodily swelling (21%) were the most challenging symptoms that impacted their quality of life at the time of diagnosis. Respondents expressed that FL symptoms impacted their daily lives by presenting challenges to their ability to travel (46%), affecting time spent with family or friends (41%), impacting their ability to exercise (37%), impacting their ability to concentrate (36%), and impacting their ability to work or complete school or volunteer activities (35%). About half (49%) of the respondents reported that they went through a period of “watchful waiting” before commencing treatment. Most respondents (43%) had received 1 line of treatment. The most common treatments reported by respondents who had received 1 or 2 lines of therapy included chemotherapy, chemoimmunotherapy, rituximab with or without bendamustine, or radiation. The most significant symptoms that negatively impacted patients following treatment included treatment-related fatigue (28%), immediate side effects of treatment (26%), and low activity level (23%). Fatigue (69%), hair loss (41%), and constipation (38%) were the most common side effects reported by respondents. The most important outcomes highlighted by respondents included long life (84%), longer disease remission (82%), improved quality of life, ability to perform daily activities (69%), control of disease symptoms (63%), and the ability to normalize blood counts (58%). More than half of the respondents indicated that they were willing to tolerate nonsevere side effects in the short term as a trade-off for a novel treatment. Two respondents that had experience with axicabtagene ciloleucel reported having access to the drug via a clinical trial. Side effects reported were CRS, neutropenia, febrile neutropenia, thrombocytopenia, constipation, and swelling. Some of the challenges the patients highlighted associated with receiving axicabtagene ciloleucel included the frequent monitoring of side effects postinfusion, the inability to perform daily activities, and being away from family and friends. Both respondents expressed that they had a good or very good experience with axicabtagene ciloleucel and would recommend treatment to other patients with r/r FL.
A panel of 4 experts with experience treating r/r FL were consulted to determine the unmet need, place in therapy, patient populations most likely and least likely to benefit from treatment, when to start treatment, how best to assess response to treatment, and guidance for discontinuing treatment. The clinical experts indicated that the most important goals for treatment are to prolong life, and that the greatest unmet need exists in patients with cancer that progresses within 2 years after their initial therapy, patients who have already received autogenic stem cell transplant (auto-SCT) or are ineligible for auto-SCT, or those who have been double refractory to earlier-line treatments (implying limited treatment options available to them). The clinical panel suggested that axicabtagene ciloleucel be used as a third or later line of treatment for patients with r/r FL. These patients usually have a treatment response lasts less than 6 months from their last treatment (medication or stem cell transplant).
The clinical panel indicated that, in practice, CAR T-cell therapy is used in a broader patient population than in clinical trials, where a more selective population would be recruited. The panel indicated that, in clinical practice, patients are evaluated and followed in a similar manner to that described in the clinical trials of FL. Remission and survival are measured, and physical exams and imaging exams are routinely conducted to assess the patient’s response to CAR T-cell therapy. The panel suggested that meaningful responses to treatment with axicabtagene ciloleucel would include a high complete remission rate, in addition to durability of treatment response and long-term PFS and OS. The panel indicated that after infusion with axicabtagene ciloleucel, patients may participate in a clinical trial. In the absence of a clinical trial, they may try a different chemoimmunotherapy that they have not been exposed to, or undergo auto-SCT if they have not already. The panel emphasized the importance of an accredited multidisciplinary team involving hematologists, infectious disease specialists, neurologists, ICU team and all other specialists to diagnose, treat, and monitor the patients who would receive axicabtagene ciloleucel, and to ensure the safe and effective delivery of this treatment.
Input from 1 clinician group, the OH-CCO Hematology Cancer Drug Advisory Committee, was summarized for this review. The disease course of FL varies for every patient. Some patients may present with long remissions between therapies while others would have refractory disease. Current treatment goals for patients with FL, according to the clinician group include palliative care and, in some scenarios, treatment with curative intent using allogeneic stem cell transplant (allo-SCT). The most important goals outlined were to delay disease progression, improve patient health-related quality of life (HRQoL), and alleviate symptoms. The OH-CCO Hematology Cancer Drug Advisory Committee acknowledged that current treatment options do not meet the needs of patients with r/r FL. The clinicians in the group mentioned that patients who become refractory to chemotherapy have no other treatment options to delay the disease. In addition, the group highlighted that repeated administration of cytotoxic therapy may be associated with marrow damage (myelodysplastic syndrome), which further limits the ability to treat patients, and adversely affects quality of life. Hence, there is a need for treatment options that patients can tolerate. Treatment with CAR T-cell therapy, according to the clinician members, is not anticipated to cause long-term marrow damage issues. The clinicians expressed that a third-line therapy with CAR T-cell therapy would be appropriate, given that current therapy provides lower benefit to patients with relapse or refractory FL disease. Patients eligible to receive axicabtagene ciloleucel in clinical practice would reflect patients included in the clinical trial, according to the experts. However, patients with severe organ dysfunction, poor performance status, and uncontrolled infections would be excluded from receiving therapy. The clinicians pointed out that patients who had received prior CD19-directed therapy should be considered for treatment with CAR T-cell therapy and highlighted the need for flexibility around Eastern Cooperative Oncology (ECOG) performance status or Karnofsky Performance Status of patients. The group noted that some patients might become ineligible to receive CAR T-cell therapy during manufacturing, which might lead to discontinuation.
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.
The ZUMA-5 trial was a multicentre, international, open-label, single-arm phase II trial.18 The study objective was to determine the efficacy and safety of axicabtagene ciloleucel in patients with r/r FL or marginal zone lymphoma after 2 or more prior lines of systemic therapy. Between |||| |||| ||| |||| ||||, 127 patients with FL were enrolled at 15 sites in the US and 2 sites in France. No study sites were in Canada. Prior to receiving any treatments, patients underwent leukapheresis to obtain T cells as part of the manufacturing process for axicabtagene ciloleucel. Patients were then treated with cyclophosphamide and fludarabine lymphodepleting chemotherapy between 5 days and 3 days before axicabtagene ciloleucel infusion. After 2 days of rest, patients received axicabtagene ciloleucel through IV infusion, with a target dose of 2 × 106 anti-CD19 CAR T cells per kg of body weight. Analyses were conducted at 18 months, 24 months, and 36 months. The statistical analysis plan prespecified tests to be conducted on the inferential analysis set at 18 months, defined as the date when 80 patients had been followed for at least 18 months. Using all enrolled patients, analyses were conducted at 18 months, 24 months (not presented), and 36 months. The data cut-off date for the 18-month analysis set was September 14, 2020, while the data cut-off date for the 36-month analysis set was March 31, 2022.
The primary end point of the ZUMA-5 trial was ORR, defined as the incidence of a complete response (CR) or a partial response (PR), as determined by central read. These end points were defined by the Lugano classification criteria. Key secondary end points determined by central read included CR rate, defined as the incidence of CR as the best response to treatment, and the ORR and CR rate in patients who had 3 or more lines of prior therapy. Other secondary end points included best overall response (BOR), defined using CR, PR, stable disease, progressive disease, or “nonevaluable” as the best responses to treatment adjudicated by central read. Duration of response (DOR) was measured in patients who had an objective response and was defined as the time from the first objective response to disease progression or death. PFS was defined as the time from axicabtagene ciloleucel infusion date for the inferential or safety analysis sets (or date of leukapheresis for the full analysis set [FAS]) to the date of disease progression or death, while OS was defined as the time from axicabtagene ciloleucel infusion date for the inferential or safety analysis set (or date of leukapheresis for the FAS) to the date of death. Time to next treatment (TTNT) was defined as the time from axicabtagene ciloleucel infusion date to the start of new lymphoma therapy or death. Patient-reported outcomes were not reported in the ZUMA-5 trial.
At the 36-month time point for analysis, the median age (range) was || ||||| ||| || ||| and ||| || |||||||| ||| || |||| || || |. Of the enrolled patients, ||| had refractory disease, defined as progressing within 6 months of their most recent treatment. Most patients enrolled in the ZUMA-5 trial had received 2 prior therapies (||||| ||| had received 3 prior therapies, ||| had received 4 prior therapies, and ||| had received 5 or more prior therapies). The proportion of patients that had received prior auto-SCT was |||, while the proportion of patients with high-bulk tumour was |||. The proportion of patients who had progressed within 24 months of anti–CD20-chemotherapy combination therapy (i.e., progression of disease within 24 months [POD24]) was |||.
The proportion of patients that had died due to any cause was ||| after 36 months of follow-up. The median OS had not been reached. Clinical experts considered OS to be the ideal survival end point for decision-making, but they acknowledged that, due to the extended survival periods seen in r/r FL, immature OS results are common. The KM survival probability was 92.0% (95% confidence interval [CI], 85.7 to 95.6) at 18 months, 88.0% (95% CI, 81.0 to 92.6) at 24 months, and ||||| ||||| || ||||||at 36 months.
The proportion of patients who had experienced a progression event was ||| after 36 months of follow-up. The median PFS was 40.2 months (95% CI, 28.9 to NE). The Kaplan-Meier PFS probability (95% CI) at 18 months was ||||| ||||| || |||||, at ||||||||| ||| ||||| ||||| || |||||, and at 36 months was 54.4% (95% CI, 44.2 to 63.5).
At the 36-month time point for analysis, the estimated ORR as per investigator assessment was a clinically meaningful 94% (95% CI, || || ||) in the FAS, while the CRR was 79% (95% CI, || || ||). According to clinical experts, and within the context of the extended survival periods in r/r FL, ORR and CRR are considered acceptable and surrogate end points for more important survival end points.
The primary end point in the ZUMA-5 trial was ORR at the 18-month analysis in the inferential analysis set, with a prespecified threshold of 40% for ORR and 15% for CRR. The estimated ORR as per central review in the 18-month inferential analysis set was ||| ||| || ||||||||| |||||||; the CRR was ||| ||| || |||| |||| |||||||. Subgroup analyses conducted on prespecified baseline characteristics were consistent with the overall results.
At the 36-month time point for analysis, ||| of patients with a response had experienced a loss of response event. The estimated median DOR was 38.6 months (95% CI, 29.0 to NE), which was considered clinically meaningful by the clinical experts consulted by CADTH. The KM event-free estimated probability (95% CI) at 18 months was ||||| ||||| || ||||), at 24 months was ||||| ||||| || ||||), and at 36 months was ||||| ||||| || ||||).
At the 36-month time point for analysis, ||| of patients had experienced a TTNT event; the median TTNT was NE (95% CI, 37.8 months to NE). The KM-estimated event-free probability (95% CI) at 18 months was ||||| ||||| |||||||| at 24 months was ||||| ||||| || ||||), and at 36 months was ||||| ||||| || ||||).
At the 36-month time point for analysis, a total of ||| of patients in the safety analysis set experienced a treatment-emergent adverse event (TEAE), with pyrexia (||%), hypotension (|||), headache (|||), and fatigue (|||) being the most commonly reported TEAEs. A total of 49% of patients in the safety analysis set experienced a serious adverse event (SAE), with pyrexia (|||| and pneumonia (|%) being the most commonly reported SAEs. At the 36-month time point, ||| of patients in the safety analysis set had died. The most common reason was progressive disease (||), followed by AEs due to reasons other than progressive disease or subsequent therapy (||) and secondary malignancy (||).
Notable harms identified included CRS, neurologic events, cytopenias, infection, and hypogammaglobulinemia. At the 36-month analysis, ||| of patients in the safety analysis set had experienced CRS, with || experiencing grade 3 or higher CRS. Neurologic events were reported in ||| of patients with ||| reporting a grade 3 or higher neurologic event. Cytopenias were reported in ||| of patients, with ||| reporting a grade 3 or higher cytopenia. Infections were reported in ||| of patients, with ||| reporting a grade 3 or higher infection. Hypogammaglobulinemia was reported in ||| of patients, with | | reporting a grade 3 or higher hypogammaglobulinemia.
The ZUMA-5 trial, which was the only eligible study identified by the sponsor, was a phase II, single-arm, open-label clinical trial. The lack of comparative data is a key limitation to the interpretation of the results from the trial, as it is difficult to distinguish between the effect of the intervention, a placebo effect, or the effect of natural history. Due to the open-label design of the trial, the response outcomes measures (i.e., ORR, DOR, and PFS) and subjective harms are at risk of measurement or reporting bias, although the direction of this bias is unclear. It was noted that these limitations were partly addressed through the use of a prespecified threshold for ORR and CRR end points and the use of central review.
Another important limitation of the ZUMA-5 trial is related to the insufficient follow-up time to draw strong conclusions on the long-term survival impacts of axicabtagene ciloleucel for patients with r/r FL. The clinical experts consulted by CADTH noted that r/r FL is a disease that can have very long periods of PFS and survival, suggesting that the follow-up duration was not long enough to fully capture the effects on OS and PFS. Additionally, subsequent treatments could confound the long-term survival results of the ZUMA-5 trial.
According to the clinical experts consulted by CADTH, the ZUMA-5 study population generally represents the patients in Canada with r/r FL who would be receiving axicabtagene ciloleucel. However, the clinical experts noted that patients seen in clinical practice would include those with poorer performance status (the ZUMA-5 trial only included patients with an ECOG performance status of 0 or 1, whereas clinical experts suggest that those with an ECOG performance status of 2 may be treated in the clinical setting), and patients who have more comorbidities. The clinical experts had differing opinions regarding patients who had received prior CD19-targeted therapy; some suggested that any prior CD19-targeted therapy would preclude the use of axicabtagene ciloleucel. Others suggested that only patients who are refractory to CD19-targeted therapy (who did not respond or relapsed within 6 months) would not be suitable for treatment with axicabtagene ciloleucel. According to the clinical experts consulted by CADTH, the efficacy outcomes used in this study are clinically relevant and important for the clinical trials in r/r FL, with the notable exception of HRQoL outcomes, which are important to patients but were excluded from the ZUMA-5 trial. As such, it is not possible to determine how the introduction of axicabtagene ciloleucel will impact the HRQoL of patients in Canada.
The sponsor aimed to provide an estimate of relative efficacy against standard-of-care therapies in patients with r/r FL who have received 2 or more prior lines of therapy.19
The relative efficacy of axicabtagene ciloleucel versus standard of care was estimated in the treated population in the ZUMA-5 trial using propensity scores with SMR weights. The SCHOLAR-5 study, which included the standard of care cohort, is a retrospective, observational, multicentre database study in patients with r/r FL (grades 1 to 3a) who have received 2 or more systemic therapies. Patient-level data for the ZUMA-5 and SCHOLAR-5 studies were used to inform the comparative analysis. Propensity scores were calculated for each patient in the pooled analysis set to account for differences in baseline characteristics across populations. Variable selection for the propensity score model was determined in a hierarchal manner and based on the advice of investigators and clinical experts, with the goal of minimizing the imbalance in prognostically important covariates.
The ORR in the ZUMA-5 population was 93.7%, compared to 54.0% in the propensity score–weighted SCHOLAR-5 population, with an odds ratio (OR) of 12.66 (95% CI, 5.24 to 30.57). The CRR in the ZUMA-5 population was 78.7%, compared to 34.9% in the propensity score–weighted SCHOLAR-5 population, with an OR of 6.90 (95% CI, 3.62 to 13.18). The median (95% CI) DOR in the ZUMA-5 population was ||||| |||||| |||||| || ||) compared to ||||| |||||| ||||| || |||||) in the propensity score–weighted SCHOLAR-5 population, with a hazard ratio (HR) (95% CI) of |||| ||||| || ||||).
The median PFS in the ZUMA-5 population was 40.21 months (95% CI, 28.94 to NE) compared to 12.97 months (95% CI, 7.75 to 15.47) in the propensity score–weighted SCHOLAR-5 population, with an HR of 0.27 (95% CI, 0.18 to 0.41). The median OS in the ZUMA-5 population was NE (95% CI, NE to NE) compared to NE (95% CI, 38.40 to NE) in the propensity score–weighted SCHOLAR-5 population, with an HR of 0.56 (95% CI, 0.33 to 0.95). The median TTNT in the ZUMA-5 population was NE (95% CI, 37.85 to NE) compared to 26.61 months (95% CI, 12.65 to NE) in the propensity score–weighted SCHOLAR-5 population, with an HR of 0.60 (95% CI, 0.39 to 0.93).
Safety end points were not included in the analysis.
Due to differences in treatment allocation between the ZUMA-5 and SCHOLAR-5 cohorts, there is the possibility that the treatment effect estimate is confounded by imbalances in prognostic covariates across populations. The sponsor identified and adjusted for several important variables, resulting in a suitable balance of these characteristics across both populations; however, important characteristics, such as FLIPI score, could not be adjusted for due to missing data. Characteristics such as ECOG performance status, FL grade, and whether patients were double refractory were significantly different between populations after propensity score weighting. The clinical experts consulted by CADTH suggested that differences in ECOG performance status and the proportion of patients that are double refractory could have an impact on how patients would be expected to respond to treatment. The direction of this impact is uncertain, with some differences (e.g., double refractory status and FL grade) potentially favouring the SCHOLAR-5 comparator over axicabtagene ciloleucel and some differences (e.g., ECOG performance status) potentially favouring axicabtagene ciloleucel over the SCHOLAR-5 comparator.
There is additional uncertainty in the results due to the low effective sample sizes in both the ZUMA-5 trial and the SCHOLAR-5 study. The removal of the subset of patients from the SCHOLAR-5 cohort necessary to conduct the PFS analysis resulted in a statistically significant change in the mean (standard deviation [SD]) number of prior lines of therapy, |||| |||||| in the SCHOLAR-5 study compared to |||| |||||| in the ZUMA-5 trial. Differences in the number of prior lines of therapy between populations are particularly impactful in determining how patients would be expected to respond to treatment. The proportion of patients that were POD24 and the proportion of patients whose disease was refractory to their most recent treatment were also reduced with the exclusion of a subset of patients required to conduct the PFS analysis, indicating that the removal of these patients from the analysis resulted in a population with a lower-risk prognosis.
Cost and Cost-Effectiveness.
CADTH identified the following limitations in the sponsor’s base case: the projected market share of axicabtagene ciloleucel is underestimated, the proportion of patients who receive second-line therapy is underestimated, the proportion of patients who receive active therapy in the third line is underestimated, and CAR T-cell therapy pretreatment costs are underestimated. CADTH conducted reanalyses of the budget impact analysis by adjusting the projected share of axicabtagene ciloleucel and increasing the proportion of patients with FL who would relapse and continue with treatment in the second line. Based on the CADTH base case, the estimated budget impact associated with the reimbursement of axicabtagene ciloleucel for the treatment of r/r grade 1, 2, or 3a FL after 2 or more lines of systemic therapy is expected to be $36,353,386 in year 1, $74,624,909 in year 2, and $99,608,235 in year 3, with a 3-year total of $210,586,531, from the drug plan perspective. When considering a health care system perspective, the CADTH base case estimated a budgetary impact of $38,924,621 in year 1, $79,905,269 in year 2, and $106,624,743 in year 3, for a 3-year cumulative total of $225,454,632. Under the drug plan perspective, a scenario analysis based on the assumption that 80% of patients with r/r FL would receive active therapy in the third line resulted in an increase of axicabtagene ciloleucel’s estimated 3-year budget impact to $280,782,041. This indicates that the budget impact is highly sensitive to the estimation of the patient population that is likely to seek treatment.
Normative and empirical literature on CAR T-cell therapies, as well as past CADTH ethics reports, were reviewed to summarize ethical considerations relevant across CAR T-cell therapies in the treatment of hematological cancers described in the summary report Ethical Considerations in the Use of CAR-T Therapies for Hematological Cancers. Ethical considerations specific to the use of axicabtagene ciloleucel for the treatment of adult patients with r/r grade 1, 2, or 3a FL after 2 or more lines of systemic therapy have also been identified from a review of patient and clinician group and drug program input, as well as consultation with clinical experts engaged by CADTH for this review and CADTH clinical and economic reviewers:
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. Catherine Moltzan, Ms. Amy Peasgood, Dr. Anca Prica, Dr. Adam Raymakers, Dr. Patricia Tang, Dr. Marianne Taylor, and Dr. W. Dominika Wranik.
Meeting date: September 13, 2023
Regrets: One expert committee member did not attend.
Conflicts of interest: None
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Indication: For the treatment of adult patients with relapsed or refractory grade 1, 2, or 3a follicular lymphoma after 2 or more lines of systemic therapy.
Sponsor: Gilead Sciences Canada, Inc.
Final recommendation: Reimburse with conditions
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