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Indication: For the treatment of human leukocyte antigen (HLA)-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma
CADTH recommends that Kimmtrak be reimbursed by public drug plans for the treatment of unresectable or metastatic uveal melanoma (mUM) if certain conditions are met.
Kimmtrak should only be covered to treat adults with uveal melanoma whose cancer cannot be removed by surgery or has spread and who have tested positive for the HLA-A*02:01 gene. Patients receiving Kimmtrak should be in relatively good health (i.e., have a good performance status, as determined by a specialist). Cancer in central nervous system should either be controlled or that there be no spread of cancer to the brain at all.
Kimmtrak should only be reimbursed if prescribed by a specialist with expertise in managing uveal melanoma and cytokine release syndrome, and the cost of Kimmtrak is reduced.
Uveal melanoma is a rare form of cancer involving the pigment cells of the uvea in the eye. Unresectable means the cancer cannot be removed by surgery and metastatic means the cancer has spread to other parts of the body. Metastatic disease is associated with poor survival, with about 1 in 2 patients dying from the disease within 1 year of diagnosis despite first-line treatments. It is estimated that 3.75 new cases arose per million Canadians each year between 1992 and 2010, with an increase of 0.074 new cases per million individuals every year.
Metastatic uveal melanoma is an aggressive disease associated with poor survival and there are no current available therapies that predictably improve outcomes.
Treatment with Kimmtrak is expected to cost approximately $74,260 per 28-day cycle.
The CADTH pCODR Expert Review Committee (pERC) recommends that tebentafusp be reimbursed for the treatment of human leukocyte antigen (HLA)-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma (mUM) in the first-line setting only if the conditions listed in Table 1 are met.
One phase III, multi-centre, open-label, randomized controlled study (Study 202; N = 378) demonstrated that treatment with tebentafusp resulted in added clinical benefit for HLA-A*02:01-positive adult patients with mUM who had no prior systemic therapy in the advanced or metastatic setting. In the first overall survival (OS) interim analysis, Study 202 showed a statistically significant and clinically meaningful improvement in OS with tebentafusp compared to investigator’s choice of either dacarbazine, pembrolizumab, or ipilimumab (hazard ratio [HR] = 0.51; 95% confidence interval [CI], 0.37 to 0.71; P < 0.0001). Health-related quality of life (HRQoL) was assessed but not formally compared between the treatment groups in the trial; however, the available evidence suggested that there were no notable differences in HRQoL (measured using the EORTC QLQ-C30) observed between the tebentafusp and investigator’s choice arms in Study 202. Tebentafusp was associated with a risk of cytokine release syndrome and dermatological adverse events. pERC acknowledged that while not insignificant, these adverse events are transient and manageable with monitoring in an inpatient setting for initial doses, supportive care, and dose adjustment. Tebentafusp addresses an unmet therapeutic need for this rare condition given the poor prognosis and high morbidity, and lack of standard of care or effective alternatives.
Patients expressed a need for treatment that can preserve vision, provide a good quality of life, and improve survival. Given the totality of the evidence, pERC concluded that tebentafusp met the unmet need for a treatment that prolonged survival, as identified by patients.
Using the sponsor submitted price for tebentafusp and publicly listed prices for all other drug costs, the incremental cost-effectiveness ratio (ICER) for tebentafusp was $728,513 per quality-adjusted life-year (QALY) gained compared with investigator’s choice of therapy. At this ICER, tebentafusp is not cost-effective at a $50,000 per QALY gained willingness-to-pay (WTP) threshold for previously untreated adults with HLA-A*02:01-positive advanced (metastatic or unresectable) uveal melanoma. A price reduction is required for tebentafusp to be considered cost-effective at this threshold.
Reimbursement Conditions and Reasons.
Uveal melanoma (UM) is a rare subset of melanoma that arises from the uveal tract (choroid, ciliary, iris) in the eye. It is estimated that 3.75 new cases of UM arose per million Canadians each year between 1992 and 2010, with an increase of 0.074 new cases per million individuals annually. At diagnosis, most patients have localized disease and approximately 50% of patients are symptomatic (vision loss or disturbances). About 50% of patients will progress to metastatic disease, with metastasis most commonly in the liver (93%). The survival of metastatic uveal melanoma (mUM) is unfavourable, with an estimated 1-year survival rate of 43% to 52% with first-line treatments, and about 37% in second-or-later-line setting.
Systemic therapies are usually prescribed in patients with mUM who have a larger number of metastatic lesions and/or disease external to the liver. The most prescribed systemic therapies in a first-line setting are immunotherapies (off-label), given as monotherapies (i.e., nivolumab, or pembrolizumab alone), or in combination (i.e., ipilimumab plus nivolumab). Ipilimumab monotherapy is generally given in later-line settings in Canada. Systemic chemotherapies have a limited role in the treatment of mUM in Canada, due to toxicity and a low response rate. Given that there are poor survival benefits and tumour response to all available systemic treatments, the standard of care for mUM is enrollment in a clinical trial if available. Of note, funding for systemic therapies for mUM is usually assessed on a case-by-case basis by the jurisdictions.
Tebentafusp has been approved by Health Canada for the treatment of human leukocyte antigen (HLA)-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma. Tebentafusp is a gp100 peptide-HLA-A*02:01 directed T-cell receptor CD3 bispecific T-cell engager and is supplied as a solution (100 mcg/0.5 mL) for IV infusion. The recommended dosage of tebentafusp in the product monograph is 20 mcg on day 1, 30 mcg on day 8, 68 mcg on day 15, and 68 mcg once every week thereafter, administered by IV, until unacceptable toxicity or disease progression.
To make its recommendation, pERC considered the following information:
Two patient groups provided input for this reimbursement review - MC and SYSF. MC gathered information from patients with UM and caregivers (N = 19) via an online survey. SYSF collected responses from patients with ocular melanoma (N = 38) via patient interviews, patient roundtables and online surveys. Most of the SYSF respondents (n = 33) resided in Canada. The majority of respondents were diagnosed with early-stage or primary disease in both patient group input.
Respondents from MC mentioned that the diagnosis of UM affects their day-to-day life and quality of life, with most common issues being loss of vision, vision impairment, fear or anxiety, depression, and fatigue. In addition, respondents from SYSF mentioned that their balance is affected which causes huge physical and psychological deterioration.
There were 5 patients from MC and 10 patients from SYSF who indicated that they had experience with tebentafusp treatment through clinical trials or Health Canada compassionate access. According to the submissions by MC and SYSF, 3 patients (2 from MC and 1 from SYSF) who had access to tebentafusp indicated that the drug has shown effectiveness in slowing down the disease progression and another 2 patients could not comment on the effectiveness as it was too early for them to tell. The frequently reported side effects by patients from both groups were skin rash, fever, fatigue, cognitive impairment, gastro issues, nausea, muscle, joint pain, and headaches. Most patients described the side effects as short-term, tolerable, and manageable and that the benefits of the treatments outweighed the negative side effects based on their experience. Only 1 patient from SYSF said the side effects were not manageable. In addition, patients from both groups also reported that they had to travel long distances to access the drug and had financially difficulties.
Patients from both groups expressed their desire to have an effective treatment that can preserve vision, provide a good quality of life and longer survival. In addition, patients interview by MC indicated that they would like to have improvements in earlier diagnosis and detection of metastasis. Patient respondents highlighted their preference for HLA testing to be done as soon as possible following UM diagnosis.
The clinical expert highlighted that mUM is an aggressive disease associated with a poor survival and there are no current available therapies that predictably improve outcomes. The clinical expert expressed that a shift in current treatment paradigm is anticipated where tebentafusp is used in a first- or later-line setting, as supported by clinical trial and anecdotal evidence.
The clinical expert indicated that only patients with HLA-A*02:01-positive mUM are expected to benefit from tebentafusp owing to its unique mechanism of action. The clinical expert was unable to identify which HLA-A*02:01-positive patients are most likely to benefit from tebentafusp, noting that there is currently no good clinical or biological predictor of response to tebentafusp. The clinical expert indicated that patients with a poor performance status (i.e., Eastern Cooperative Oncology Group [ECOG] of 3 or above) are generally not eligible for treatment in clinical practice as they are less likely to benefit.
The clinical expert strongly suggested that patients be allowed to continue treatment as long as they continue to derive clinical benefits from tebentafusp, noting that there was some evidence from a post-hoc analysis of Study 202 that patients with radiographic progression on tebentafusp can continue to benefit from treatment beyond progression. The clinical expert highlighted that, given the complexity of the clinical considerations involved, treatment response and the decision to discontinue treatment should be left to the discretion of the attending oncologist based on assessments of history and physical examinations (every 3 to 4 weeks), laboratory tests (weekly) and imaging (every 12 to 16 weeks) findings. According to the clinical expert, treatment discontinuation is generally considered in clinical practice in the presence of intolerable toxicities, or clear evidence of significant progression, which is indicated by a decline in performance status, increased pain, rising lactate dehydrogenase (LDH) levels, and marked radiographic progression.
The clinical expert recommended that tebentafusp initially should only be prescribed by specialist physicians experienced in the use of tebentafusp and familiar with the management of cytokine release syndrome (CRS,) noting that the risk of CRS is the highest with the first 3 to 4 doses, and substantially lower with subsequent doses. The clinical expert noted that once a pattern of use is established and when the risk of CRS is absent, subsequent infusions can be performed in a community clinic setting.
CADTH received input from 1 clinician group, Ontario Health (Cancer Care Ontario) (OH-CCO) Skin Cancer Drug Advisory Committee, based on responses from 6 clinicians. OH-CCO’s Skin Cancer Drug Advisory Committees provide timely evidence-based clinical and health system guidance on drug-related issues in support of CCO’s mandate, including the Provincial Drug Reimbursement Programs and the Systemic Treatment Program. No major contrary views from those provided by the clinical expert consulted by CADTH for this review were presented.
The clinician group stated that UM is a disease that has a low tumour mutational burden and a low 1-year survival rate of 50% in the metastatic setting, which is distinct from cutaneous melanoma. None of the current systemic treatments for UM have been proven to have OS benefit, which represents a major unmet need in patients with mUM. The clinician group noted that tebentafusp has demonstrated an improvement in OS in clinical trials. The clinician group highlighted that the treatment goal is to improve OS and quality of life. The clinician group expressed that tebentafusp would be the first-line treatment of choice for HLA-A*0201 positive patients with mUM, although they did not comment on the use of tebentafusp in second- or later-line settings. The clinician group stated that HLA-A*0201 positive patients with mUM who do not meet the exclusion criteria of Study 202 would be suitable for tebentafusp. They noted that ongoing performance status, tumour size, and Response Evaluation Criteria in Solid Tumours (RECIST) progression requirements are the clinical outcomes used to determine whether a patient is responding. They indicated that treatment response is considered clinically meaningful in the presence of at least 20% reduction in tumour size and improved performance status, while noting that treatment may be continued in some patients with radiographic progression (new and/or increasing target lesions) if clinical benefits are observed. The clinician group highlighted that toxicity or symptomatic disease progression without clinical benefit would be considered when deciding to discontinue tebentafusp. The clinician group indicated that oncologists with experience in the inpatient management of side effects of tebentafusp are required due to the known toxicities that commonly occur following the first 3 doses.
Input was obtained from the drug programs that participate in the CADTH reimbursement review process. The following were identified as key factors that could potentially impact the implementation of a CADTH recommendation for tebentafusp:
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.
Study 202 met the inclusion criteria for the CADTH systematic review. Study 202 was a phase III, open-label, randomized, active-controlled study that aimed to compare the efficacy and safety of tebentafusp and investigator’s choice (either pembrolizumab, ipilimumab, or dacarbazine) in HLA-A*02:01-positive adult patients with mUM who had no prior therapy in the metastatic setting (N = 378). Patients were randomized in a 2:1 ratio to receive either tebentafusp (20 mcg on day 1, 30 mcg on day 8, and 68 mcg on day 15 and weekly thereafter via IV infusion), or investigator’s choice of either: dacarbazine (1,000 mg/m2), ipilimumab (3 mg/kg), or pembrolizumab (2 mg/kg/dose - up to 200 mg/dose, or 200 mg flat dose), via IV infusion every 3 weeks. Treatments were continued until disease progression per RECIST v1.1, unacceptable toxicity, or completion of a maximum of 4 doses for ipilimumab. Patients receiving tebentafusp, pembrolizumab, and ipilimumab were permitted to continue treatment beyond initial disease progression if pre-specified criteria were met indicating clinical benefit and tolerance of the study drugs.
Study 202 aimed to establish the superiority of tebentafusp to investigator’s choice of therapy through the co-primary end points of OS in the Rash Analysis Set (RAS), which consisted of patients receiving tebentafusp who developed a rash within the first week of treatment and all patients in the investigator’s choice arm, and OS in the intention-to-treat (ITT) analysis set. The key secondary end points were progression-free survival (PFS) and best overall response (BOR) (evaluated statistically as objective response rate [ORR]). Other secondary outcomes included health-related quality of life (EuroQoL 5-Dimensions 5-Levels [EQ-5D-5L] and European Organization for Research and Treatment of Cancer Quality-of-life Questionnaire Core 30 [EORTC QLQ-C30]), disease control rate (DCR), duration of response (DOR), and safety, all of which were measured without control for multiplicity. The first interim OS analysis and the final PFS were performed based on the data cut-off date of October 13, 2020. An informal updated OS analysis and the primary ORR analysis were performed based on the data cut-off date of August 12, 2021 to fulfil the regulatory requirements in Europe.
The baseline patient characteristics were balanced between treatment arms. Overall, the mean age of patients was 62.1 (SD: 11.6) years. Approximately half of the patients were female. The majority of patients were white, had an ECOG performance status of 0, and had liver metastases. In most patients, there was no prior surgery for metastatic disease (91.3%). A small proportion of patients (3.7%) had prior antineoplastic systemic treatments (in any setting) and 40.2% of patients had prior local radiotherapy. In the investigator’s choice arm, the majority of patients were assigned pembrolizumab (81.7%), while others received ipilimumab (12.7%) and dacarbazine (5.6%).
In the first interim OS analysis (median duration of follow-up 14.1 months), the median OS in the RAS was 27.4 (95% confidence interval [CI], 20.2 to not reported [NR]) months in the tebentafusp arm, and 16.0 (95% CI, 9.7 to 18.4) months in the investigator’s choice arm, with a HR of 0.38 (95% CI, 0.25 to 0.56) and a P value of < 0.0001, in favour of tebentafusp. The median OS in the ITT analysis set was 21.7 (95% CI, 18.6 to 28.6) months in the tebentafusp arm, and 16.0 (95% CI, 9.7 to 18.4) months in the investigator’s choice arm, with a hazard ratio (HR) of 0.51 (95% CI, 0.37 to 0.71) and a P value of < 0.0001, in favour of tebentafusp. The results of the informal updated OS analysis were consistent with the first interim analysis.
In the final PFS analysis (median follow-up duration of 11.4 months), the median PFS in the ITT analysis set was 3.3 months (95% CI, 3.0 to 5.0) in the tebentafusp arm, and 2.9 months (95% CI, 2.8 to 3.0) in the investigator’s choice arm, with a HR of 0.73 (95% CI, 0.58 to 0.94) and a P value of 0.0139, in favour of tebentafusp.
As of the data cut-off on October 13, 2020, the change in score from baseline in EORTC QLQ-C30 was generally stable and similar between treatment arms at most time points for almost all domains. With respect to the fatigue scale (higher scores indicate worse symptoms), the difference in least square mean change in score from baseline at end of treatment between tebentafusp versus investigator’s choice was −9.259. This analysis was not adjusted for multiplicity.
The baseline mean EQ visual analogue scale (higher scores indicate better HRQoL) was 81.0 (SD: 16.4) in the tebentafusp arm, and 80.4 (SD: 18.3) in the investigator’s choice arm. The mean change from baseline at end of treatment was −10.1 (SD: 22.53) in the tebentafusp arm, and −11.7 (SD: 21.40) in the investigator’s choice arm. The difference between arms was not tested statistically.
As of the data cut-off date of August 12, 2021, 26 (10.3%) patients receiving tebentafusp and 6 (4.76%) patients receiving investigator’s choice of therapy had complete or partial response. Among these patients, the median DOR was 9.9 months (95% CI, 5.6 to 22.1) in the tebentafusp arm, and 9.7 months (95% CI, 2.7 to NR) in the investigator’s choice arm. The difference between arms was not tested statistically.
In the primary ORR analysis (data cut-off on August 12, 2021), the ORR in the ITT analysis set was 10.3% (95% CI, 6.9% to 14.8%) in the tebentafusp arm, and 4.8% (95% CI, 1.8% to 10.1%) in the investigator’s choice arm, corresponding to an odds ratio of 2.26 (95% CI, 0.91 to 5.61) and a P value of 0.684. Due to imprecision, the results for ORR are inconclusive.
As of the data cut-off on August 12, 2021, the DCR in the ITT analysis set was 45.6% (95% CI, 39.4% to 52.0%) in the tebentafusp arm, and 27.0% (95% CI, 19.5% to 35.6%) in the investigator’s choice arm, corresponding to an odds ratio of 2.34 (95% CI, 1.45 to 3.76). This analysis was not adjusted for multiplicity.
As of data cut-off date of October 13, 2020, treatment-emergent adverse events (TEAE) were reported in all patients in the tebentafusp arm, and 94.6% of patients in the investigator’s choice arm. The most common TEAE were pyrexia (tebentafusp [76%] versus investigator’s choice [7.2%]), pruritus (69.0% versus 23.4%), rash (55.1% versus 16.2%), and fatigue (51.0% versus 35.1%). Serious TEAE were reported in 28.2% of patients in the tebentafusp and 23.1% of patients in the investigator’s choice arm. The most common serious TEAE in the tebentafusp arm was CRS (9.8% for tebentafusp; 0% in the investigator’s choice arm). The proportion of patients who discontinued treatment due to TEAE were 3.3% and 6.6% in the tebentafusp arm and the investigator’s choice arm, respectively. Eighty-four deaths (34.3%) and 57 deaths (51.4%) were reported in the tebentafusp arm and the investigator’s choice arm, respectively. The majority of deaths in both arms were attributed to disease progression.
The proportion of patients who reported CRS (or presentations related to CRS), and dermatological adverse events (AE) was notably higher in the tebentafusp arm than in the investigator’s choice arm. The most common notable harm of any grade (30% or greater) being pyrexia, pruritus, rash, fatigue, nausea, chills, hypotension, dry skin, headache, and maculopapular rash, all of which were mostly grade 1 or 2.
The overall study design of Study 202 was appropriate for the objectives of the study. There was no particular concern with the methods of randomization and allocation concealment. In consultation with the clinical expert, the open-label design was considered reasonable. However, there is potential for reporting bias on tumour response (ORR, DCR, BOR, DOR) and subjective harms outcomes since these outcomes were based on investigator’s assessment, although the extent and direction of bias are unclear. The statistical analyses were generally appropriate, with proper processes in place to preserve power in the interim and final OS analyses, and to account for multiplicity for the co-primary end points and key secondary end points using a hierarchal approach. DCR, DOR, and HRQoL outcomes however were not adjusted for multiplicity and were considered exploratory due to increased risk of type I error. It should be noted that the OS analyses were interim, and interim analyses are typically associated with a risk of over-estimating the treatment effects in favour of the experimental intervention (i.e., tebentafusp). Considering that the OS analyses were based on a relatively small number of events, the OS results are prone to imprecision. OS analysis in the RAS should also be interpreted with caution, due to the risk of confounding resulting from the absence of randomization in the comparison, although the direction of bias could not be determined. There is also uncertainty in the HRQoL outcomes, due to potential reporting and attrition bias, and also considering the instruments used (EORTC QLQ-C30 and EQ-5D-5L) had not been validated in patients with mUM.
In terms of generalizability, a limitation to note is that the studies included patients who had no prior therapies in the metastatic setting, therefore the applicability of trials results to patients who had prior therapies in the metastatic setting is unclear. The treatments included in the comparator arm accounts for a small proportion of systemic treatments prescribed for mUM in Canada which increases uncertainty in the generalizability of study results. The clinical expert consulted by CADTH commented that the impact on generalizability is likely to be small since the efficacy of immunotherapies is considered similar by clinicians. However, this opinion was formed based on a small retrospective cohort study and is associated with some uncertainties. The OS benefits of tebentafusp was considered clinically meaningful by the clinical expert, while PFS and tumour response outcomes were noted to have limited clinical relevance by the clinical expert since tumour response is poorly correlated with overall survival in patients with mUM receiving systemic therapy in general, according to the clinical expert. The clinical relevance of the HRQoL outcomes was also uncertain since the instruments used were not routinely administered in clinical practice, although they have captured some of the most common HRQoL concerns (e.g., anxiety, depression, fatigue) reported by patients. With respect to the safety, specifically CRS, the clinical expert expected the study findings to be generalizable to clinical practice provided that tebentafusp is administered in appropriate treatment settings as specified in the product monograph, noting that that in their clinical experience, CRS generally occurs following the first 3 to 4 infusions and is manageable if proper supportive care is provided.
One indirect treatment comparison (ITC) was submitted by the sponsor and included in this review. No additional ITCs were identified in the literature. The sponsor performed an unanchored match-adjusted indirect comparison (MAIC) to estimate the comparative OS and PFS of tebentafusp compared with ipilimumab plus nivolumab in patients with mUM who had no prior therapy in the metastatic setting, based on data from the GEM-1402 comparator trial, which was identified in a systematic literature review (SLR), and the index trial Study 202. Of note, the GEM-1402 trial enrolled patients with mUM regardless of HLA status and Study 202 enrolled HLA-A*02:01 positive patients with mUM. The sponsor submitted a supplementary analysis of the prognostic value of HLA-A*02:01 for OS to support the MAIC analyses.
The ITC included 237 patients in the tebentafusp arm from Study 202 and the effective sample size (ESS) of the ipilimumab plus nivolumab arm from the GEM-1402 trial was 115.9. The MAIC analysis between tebentafusp versus ipilimumab plus nivolumab showed results in favour of tebentafusp with respect to both OS (HR 0.507; 95% CI, 0.324 to 0.793), and PFS (HR 0.647; 95% CI, 0.445 to 0.941).
There were 80 patients included in the supplementary HLA status analysis (HLA-A*02:01-positive, N = 43; HLA-A*02:01-negative, N = 37). The median OS was 45.9 months (range = NR) in HLA-A*02:01-positive patients and 45.2 months (range = NR) in HLA-A*02:01-negative patients, with a HR of 0.82 (95% CI, 0.36 to 1.88).
The ITC did not assess safety outcomes.
A key limitation of the ITC was that the selection criteria for the SLR were not determined a priori, increasing the risk of selection bias for comparator trial included in the MAIC analysis. In addition, patient population heterogeneity, specifically with respect to HLA-A*02:01 status, could be a potential source of confounding given that the comparator trial included patients regardless of HLA-A*02:01 status. Based on the sponsor-submitted supplementary HLA analysis, the CADTH review team was unable to rule out the possible confounding effect of HLA status on OS given the study was based on a small observational cohort and results are subject to imprecision (wide 95% CI for HR with respect to OS). Further, time since primary diagnosis, a covariate identified in the multivariate analysis, was excluded from adjustment since it was not reported in the comparator trial, which may contribute to the uncertainty of the results. There is also concern with a loss of precision in the results given a significant reduction in the ESS. Overall, the direction of bias of the limitations noted could not be determined and the results of the MAIC should be interpreted with caution due to the potential biases. There is also an evidence gap in that HRQoL and harms outcomes, as well as the efficacy of tebentafusp in treatment-experienced patients were not addressed in this analysis.
This section includes 2 additional studies from the sponsor’s submission to CADTH that were considered to address important gaps in the evidence included in the systematic review. The first study was a phase I-II, multi-centre, open-label study (Study 102), which analyzed the efficacy and safety of tebentafusp in HLA-A*02:01 positive patients with mUM who had 1 or 2 prior lines of therapy in the metastatic or advanced setting. The second study was an observational study that compared patients receiving tebentafusp from Study 202 versus patients receiving ipilimumab plus nivolumab from the GEM-1402 trial in a first-line mUM setting following propensity score weighting. The analysis was based on the same studies that informed the sponsor-submitted MAIC and was submitted to CADTH after the sponsor had obtained individual patient data (IPD) from the GEM-1402 trial. The study aimed to address the limitations of the MAIC analysis due to the use of aggregate data from the GEM-1402 trial.
The Study 102 was a phase I-II study, which analyzed the efficacy and safety of tebentafusp in HLA-A*02:01-positive patients with mUM who had 1 or 2 prior lines of therapy in the advanced or metastatic setting. The primary end point for phase I was the incidence (number) of dose limiting toxicities i; whereas, ORR was the primary end point for the phase II single-arm dose expansion. The secondary end points for phase II were OS, PFS, DOR, DCR, and BOR.
In the phase II expansion cohort (N = 127) (data cut-off date of March 20, 2020), the ORR was 4.7% (95% CI, 1.8% to 10.0%) based on 6 of 127 patients receiving tebentafusp who achieved a partial response (PR); no patients achieved a complete response (CR). After a median duration of follow-up of 19.6 months (95% CI, 16.0 to 22.2 months), the median overall survival was 16.8 months (95% CI, 12.9 to 21.3 months). The median PFS was 2.8 months (95% CI, 2.0 to 3.7 months) as per the assessed by RECIST v1.1 by independent central review. The median DOR (CR or PR) by RECIST v1.1 assessed by independent central review was 8.7 months (95% CI, 5.6 to 24.5 months). The DCR (CR, PR, or stable disease [SD]) was 22.8% (95% CI, 15.7% to 31.2%) of at least 24 weeks. The most frequently observed BOR was disease progression (47.2%), followed by SD (44.9%), and PR (4.7%).
Similar to in Study 202, all patients in Study 102 experienced any grade AEs. In addition, Study 102 phase II expansion and Study 202 had comparable rates of at least grade 3 treatment-emergent adverse events (TEAEs) (59.1% versus 54.3%). In Study 102 phase II expansion, 9 patients (7.1%) experienced TEAEs leading to tebentafusp discontinuation, and the proportion was comparable to that of Study 202 (6.6%). The most frequently reported any grade TEAEs were pyrexia (81.1%), pruritus (68.5%), nausea (67.7%), chills (66.1%) and hypotension (41.7%). These TEAEs were also observed in the tebentafusp arm in Study 202. A total of 86 serious TEAEs were reported in 42 (33.1%) patients. The proportion was comparable to that of Study 202 (28.2%). The serious TEAEs were cytokine release syndrome in 4 (3.1%) patients; and sepsis, alanine transaminase increased, rash maculo-papular, and hypotension in 3 (2.4%) patients each. No deaths related to TEAEs or caused by the study drug were observed.
The non-comparative design of Study 102, with no statistical testing, is the key limitation. The lack of direct comparative data means there is uncertainty regarding the magnitude of effects obtained for the efficacy outcomes. Although the clinician expert consulted highlighted that the efficacy outcomes of tebentafusp in Study 102 were clinically meaningful and demonstrated the activity of the drug and were compatible to the phase III Study 202, CADTH review team notes that in the absence of a comparative arm, the findings obtained from the efficacy and safety analysis are uncertain as the single-arm design does not allow for drawing conclusions about the comparative efficacy for tebentafusp and differentiating of the symptoms of underlying mUM disease from treatment-related adverse events.
The sponsor-submitted observational study compared patients in the tebentafusp arm from Study 202 with patients receiving ipilimumab plus nivolumab from the GEM-1402 trial in a first-line metastatic setting. The study was not randomized, and propensity score weighting using the IPTW approach was used in an attempt to adjust for confounding.
The ESS of the GEM-1402 trial was 34.4 after weighting, compared to a sample size of 45 before weighting. The patient characteristics were generally balanced between the tebentafusp and ipilimumab plus nivolumab cohorts after weighting.
In the primary analysis, the median OS of the tebentafusp cohort was 21.7 months (SD = not reported [NR]), and the weighted median OS of the ipilimumab plus nivolumab cohort was 12.6 months (SD = NR). The HR between tebentafusp and ipilimumab plus nivolumab with respect to OS was 0.430 (95% CI, 0.287 to 0.643), in favour of tebentafusp.
The study did not assess safety outcomes.
The IPTW approach improved upon the MAIC by leveraging IPD from the GEM-1402 trial; however, many of the limitations of the MAIC analysis also apply to the current analysis. Specifically, the lack of a priori selection criteria for the SLR is a potential source of selection bias for comparator studies. It is also unclear if all known or unknown confounding factors have been adequately adjusted for. Heterogeneity in HLA status was noted in the comparator groups and considering the supplementary analysis submitted by the sponsor that assessed the impact of HLA status on OS, the CADTH review was unable to confidently rule out confounding effects by the difference in HLA status between the cohorts. Lastly, outcomes that are of interest to stakeholders such as HRQoL and harms, and the efficacy of tebentafusp in patients with prior systemic therapy in the metastatic setting were not addressed in this analysis.
Cost and Cost-Effectiveness.
CADTH identified the following key limitations with the sponsor’s analysis. The budget impact estimated on the sponsor’s assumptions regarding compassionate access of tebentafusp does not represent likely use of tebentafusp. The drug acquisition costs are underestimated because drug wastage was not included. The market share of tebentafusp was underestimated and treatment duration was uncertain.
CADTH reanalysis included: excluding the sponsor’s assumption on compassionate access, including drug wastage and increasing the market share of tebentafusp. Based on the CADTH reanalysis, the 3-year budget impact to the public health care payer of introducing tebentafusp was $54,017,379 (year 1: $20,229,773; year 2: $17,499,596; year 3: $16,288,010). The estimated budget impact was sensitive to treatment duration of tebentafusp.
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 9, 2022
Regrets: Of the expert committee members, 2 did not attend
Conflicts of interest: None
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Indication: For the treatment of human leukocyte antigen (HLA)-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma
Sponsor: Medison Pharma Canada Inc.
Final recommendation: Reimburse with conditions
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