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Indication: Treatment of adults with prostate-specific membrane antigen-positive metastatic castration-resistant prostate cancer who have received at least one androgen receptor pathway inhibitor and taxane-based chemotherapy
CADTH recommends that Pluvicto should be reimbursed by public drug plans for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) if certain conditions are met.
Pluvicto should only be covered to treat patients with prostate-specific membrane antigen (PSMA)-positive mCRPC who have received previous treatment with at least 1 androgen receptor pathway inhibitor (ARPI) and at least 1 taxane-containing regimen (i.e., chemotherapy), and who are in relatively good health (i.e., have good performance status).
Pluvicto should not be reimbursed in combination with anticancer therapies other than androgen-deprivation therapy (ADT), usage should be limited to 6 cycles, and the cost of Pluvicto should be reduced.
mCRPC refers to prostate cancer that has spread to other parts of the body and that no longer responds to treatment that lowers testosterone levels. It is estimated that 24,600 people will be diagnosed with prostate cancer in 2022 and 4,600 men will die from prostate cancer in 2022.
There are currently limited effective treatments for patients with mCRPC whose disease has progressed following treatment with an ARPI and docetaxel.
Treatment with Pluvicto is expected to cost approximately $122,489 per patient.
The CADTH pCODR Expert Review Committee (pERC) recommends that lutetium [177Lu] vipivotide tetraxetan be reimbursed for the treatment of adults with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) who have received at least 1 ARPI and at least 1 taxane-based chemotherapy, only if the conditions listed in Table 1 are met.
One phase III randomized controlled trial (RCT) (VISION; N = 831) demonstrated that treatment with 177Lu vipivotide tetraxetan in combination with best supportive care (BSC) or best standard of care (BSoC) resulted in a clinically meaningful improvement in overall survival (OS) compared with BSC-BSoC alone in patients with progressive PSMA-positive mCRPC who had previously received at least 1 ARPI and at least 1 taxane regimen (hazard ratio [HR] = 0.62; 95% CI, 0.52 to 0.74; P < 0.001). The VISION trial excluded patients who were considered eligible to receive cabazitaxel as a second taxane regimen; however, 1 phase II study (TheraP; N = 200) enrolled patients for whom cabazitaxel was considered the appropriate treatment option. In the TheraP trial, 177Lu vipivotide tetraxetan was statistically superior to cabazitaxel for the primary end point of prostate-specific antigen (PSA) response, progression-free survival (PFS), radiographic progression-free survival (rPFS), objective response rate (ORR), and pain progression-free survival. TheraP was not designed or powered to evaluate potential differences in OS.
There are currently limited effective treatments for patients with mCRPC who have progressed following treatment with an ARPI and docetaxel and all stakeholders identified important patient unmet medical needs, particularly for patients who may be ineligible to receive cabazitaxel. pERC concluded that 177Lu vipivotide tetraxetan may help address identified patient needs for an additional effective treatment option that may prolong survival and delay the onset or worsening of symptoms for those living with mCRPC.
Based on the limitations with comparative evidence for 177Lu vipivotide tetraxetan and cabazitaxel, pERC could not derive conclusions regarding the relative effectiveness and cost-effectiveness of 177Lu vipivotide tetraxetan and cabazitaxel. Using the sponsor-submitted price for 177Lu vipivotide tetraxetan and publicly listed prices for all other drug costs, when compared with BSC-BSoC (i.e., excluding cabazitaxel from consideration), the incremental cost-effectiveness ratio (ICER) for 177Lu vipivotide tetraxetan was $451,407 per quality-adjusted life-year (QALY) gained. At this ICER, 177Lu vipivotide tetraxetan is not cost-effective at a $50,000 per QALY gained willingness-to-pay (WTP) threshold for patients with PSMA PET-scan positive mCRPC who have received ARPI and taxane-based chemotherapy.
Reimbursement Conditions and Reasons.
Prostate cancer is the most common cancer among men living in Canada (excluding nonmelanoma skin cancers), affecting 1 in 9 men throughout their lifetime. Prostate cancer represents approximately 20% of all new cancers diagnosed in men living in Canada and 10% of cancer deaths in men. An estimated 24,600 men in Canada will be diagnosed with prostate cancer in 2022, and 4,600 men will die from prostate cancer in 2022. Patients who die from prostate have typically progressed to the mCRPC stage, with a 5-year survival rate of approximately 30%. Castration-resistant prostate cancer is defined as disease progression despite castrate levels of testosterone, and that may present as a continuous rise in serum PSA levels, the progression of pre-existing disease, and/or the appearance of new metastases.
PSMA is a transmembrane glycoprotein that is highly expressed in prostate cancer cells. 177Lu vipivotide tetraxetan contains the radionuclide lutetium-177 linked to a targeting moiety that binds to PSMA, a transmembrane protein that is highly expressed in prostate cancer cells. Upon the binding of 177Lu vipivotide tetraxetan to PSMA-expressing cancer cells, the beta-minus emission from 177Lu delivers therapeutic radiation to the targeted cell, as well as to surrounding cells. It induces DNA damage, which can lead to cell death.
177Lu vipivotide tetraxetan injection is indicated for the treatment of adult patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) who have received at least 1 ARPI and taxane-based chemotherapy.
177Lu vipivotide tetraxetan is administered intravenously (IV), and the recommended dose is 7.4 GBq every 6 weeks (± 1 week) for a total of 6 doses. It is available as a 1,000 MBq/mL solution for injection in single-dose vials containing a total amount of radioactivity of 7.4 GBq ± 10% at the date and time of administration.
To make their recommendation, the pERC considered the following information:
Input provided by patient groups, clinician groups, and provincial drug programs, as well as direct engagement with clinical experts and relevant literature, were reviewed to identify ethical considerations relevant to the use of 177Lu vipivotide tetraxetan for the treatment of adults with mCRPC.
The information in this section is a summary of input provided by the patient groups who responded to CADTH’s call for patient input and from clinical expert(s) consulted by CADTH for this review.
Two patient groups, CCS and CCSN, provided input for the treatment of adult patients with PSMA-positive mCRPC who have been treated with AR-pathway inhibition and taxane-based chemotherapy or who are not medically suitable for taxanes. Patient input was gathered from surveys and interview responses among mCRPC patients and caregivers across Canada in August 2022. A total of 27 responses were gathered from the survey (19 from CCS and 8 from CCSN). A total of 7 patients (4 from CCS and 3 from CCSN) in the included submissions had experience with the treatment under review.
Patients noted that mCRPC has a substantial negative impact on their quality of life and ability to perform the activities of daily living, including the ability to engage in sexual activity, travel, and exercise, fulfill family obligations, maintain mental health, work, conduct household chores, concentrate, spend time with family and friends, fulfill practical needs (e.g., preparing meals, dressing, bathing). Patients can suffer from frequent urination, erectile dysfunction, bone or skeletal pain, hot flashes, weight gain, memory loss, and cognitive problems. Patient groups noted that they are seeking access to new treatment options that will prolong life, maintain quality of life (QoL), delay the onset of symptoms, and improve sexual function. They noted that existing treatment options can be associated with negative side effects, and there is a need for effective and more tolerable treatment options.
The clinical experts consulted by CADTH noted that there are limited effective treatments for patients with mCRPC who have progressed following treatment with an ARPI and docetaxel. OS is poor for those who have demonstrated disease refractory to multiple treatment options, and the symptoms of cancer progression pose a considerable burden for patients. Further standard of care treatments, such as cabazitaxel, are associated with significant toxicities for patients. The clinical experts noted that there is a need for therapies that improve OS and QoL compared to the current standard of care for this patient population and that are better tolerated and more convenient (e.g., less need for supportive medications, less frequent administration).
The clinical experts noted that 177Lu vipivotide tetraxetan could be considered for patients following disease progression on both an ARPI and docetaxel. The experts noted that there is uncertainty regarding the place in therapy relative to cabazitaxel for those patients who are considered appropriate candidates for treatment with a second chemotherapy regimen. The clinical experts consulted by CADTH also identified the requirement for suitable PSMA-PET expression as per the inclusion criteria of the pivotal trial (VISION) to be a candidate for therapy. The clinical experts noted that 177Lu vipivotide tetraxetan should be discontinued in patients with any of the following: disease progression defined as at least 2 of: sustained PSA rise, clinical progression (sustained, nonanalgesic responsive pain, performance status decline), radiographic progression; significant toxicity to the treatment; or worsening performance status (i.e., ECOG performance status ≥ 3).
Clinician group input was received from prostate-treating clinicians in Canada with a special interest in caring for those with metastatic prostate cancer (coordinated by the Canadian Cancer Society). The clinician group stated that there are unmet needs for mCRPC patients and a need for additional lines of therapy that can preserve QoL and provide meaningful survival benefits for those men with progressive metastatic prostate cancer. The clinician group mentioned that the treatment would be most suited for men with progressive (symptomatic, imaging, or biochemical) mCRPC, PSMA-expressing metastases based on a diagnostic PSMA targeted PET scan, and with adequate performance status (ECOG 0 to 2) and organ function (liver and bone marrow). The clinician group also pointed out that the most meaningful clinical response to treatment for this disease would be to avoid progression, reflected in stability or improvement in biochemical and imaging biomarkers such as serum PSA and bone scan and CT. The clinician group emphasized that appropriate facilities, certifications, and licensed personnel for delivering unsealed radiopharmaceutical treatments would be needed for the safe delivery of the treatment under review, in addition to the necessity of access to diagnostic PSMA targeted PET for proper patient selection.
Responses to Questions from the Drug Programs.
The evidence for the review of 177Lu vipivotide tetraxetan for the treatment of adults with PSMA-positive mCRPC who have received at least 1 ARPI and taxane-based chemotherapy was derived from a systematic literature review of pivotal and phase III studies supplemented with additional information to address important gaps in the RCT evidence. One RCT met the eligibility criteria for the systematic review. VISION (N = 831) was a phase III, open-label, RCT conducted to evaluate the efficacy and safety of 177Lu vipivotide tetraxetan administered in addition to BSC-BSoC as compared to BSC-BSoC only. VISION (N = 831) was a phase III, open-label, RCT conducted to evaluate the efficacy and safety of 177Lu vipivotide tetraxetan in patients with progressive PSMA-positive mCRPC, when administered in addition to BSC-BSoC as compared to BSC-BSoC only. Patients were randomized 2:1 either 177Lu vipivotide tetraxetan plus BSC-BSoC or BSC-BSoC only with allocation stratified by: lactase dehydrogenase (LDH) (≤ 260 IU/L versus > 260 IU/L); the presence of liver metastases (yes versus no); ECOG performance status (0 or 1 versus 2); inclusion of novel androgen axis drug in BSC-BSoC (yes versus no).
The VISION trial enrolled patients with PSMA-positive, progressive mCRPC (i.e., serum PSA progression, soft tissue progression, or progression of bone disease) who had received prior treatment with at least 1 ARPI and at least 1 taxane regimen. Patients who had received treatment with only 1 taxane regimen were required to be medically unsuitable to receive treatment with a second taxane regimen. The trial was limited to those with an ECOG performance status of 0 to 2. PSMA-positive patients were identified using 68Ga-PSMA-11 PET/CT scans that were evaluated centrally based on the following criteria:
Only patients with at least 1 PSMA-positive lesion identified on PSMA-PET (i.e., criterion 1) and no negative lesions (i.e., criteria 2 to 4) were to be enrolled in the study, provided all other inclusion/exclusion criteria were met. The sponsor reported that because the patient population in the VISION trial were heavily pretreated, distinguishing between healed, sclerotic bone metastases or active sclerotic bone disease on CT would have been difficult; therefore, the VISION enrolment criteria focused on aggressive/destructive bone disease with a soft tissue component for determining patient eligibility.
The VISION trial had considerable early withdrawal of consent and a disproportionate dropout in the BSC-BSoC group (patients typically cited disappointment that they would not receive 177Lu vipivotide tetraxetan). This was a major limitation of the study and required the sponsor to introduce protocol amendments that included: increasing the overall target sample size; introducing educational measures to try and bolster retaining patients in the comparator group; and, most importantly, from a critical appraisal perspective, defining a new analysis set that would be limited to those enrolled after the protocol amendments were introduced (i.e., the PFS-full-analysis set (FAS) set). This new analysis set was used for the primary evaluation of all end points except for OS (FAS) and ORR and disease control rate (DCR), which were evaluated using an even smaller subset of patients (i.e., those in the PFS-FAS who had RECIST evaluable disease).
The primary and secondary end points of the VISION trial were aligned with those recommended by PCWG3 (i.e., OS, rPFS, time to first symptomatic skeletal event (SSE), health-related QoL, PFS, and biochemical response (e.g., PSA). As noted above, only the analysis of OS was conducted using the FAS dataset.
OS: There was a statistically significant improvement in OS for patients in the 177Lu vipivotide tetraxetan plus BSC-BSoC group compared with those in the BSC-BSoC only group (HR = 0.62; 95% CI, 0.52 to 0.74; P < 0.001). The median OS was 15.3 months (95% CI, 14.2 to 16.9) in 177Lu vipivotide tetraxetan plus BSC-BSoC group compared with 11.3 months (95% CI, 9.8 to 13.5) in the BSC-BSoC only group. Subgroup analyses based on the number of prior taxane regimens favoured 177Lu vipivotide tetraxetan plus BSC-BSoC versus BSC-BSoC alone for both those with a single prior taxane (HR: 0.59; 95% CI, 0.46 to 0.75) and 2 or more prior taxane regimens (HR: 0.73; 95% CI, 0.53 to 0.99).
rPFS: There was a statistically significant improvement in rPFS for patients in the 177Lu vipivotide tetraxetan plus BSC-BSoC group compared with those in the BSC-BSoC only group (HR = 0.40; 99.2% CI, 0.29 to, 0.57; P < 0.001). Events of radiographic progression or death were reported for 66.0% of patients in the 177Lu vipivotide tetraxetan group (171 radiographic progression events and 83 deaths) and 47.4% of patients in the BSC-BSoC only group (59 radiographic progression events and 34 deaths). The median rPFS was 8.7 months (95% CI, 7.9 to 10.8) in the 177Lu vipivotide tetraxetan plus the BSC-BSoC group compared with 3.4 months (95% CI, 2.4 to 4.0) in the BSC-BSoC only group. The sponsor reported that the median follow-up time for rPFS was greater in the 177Lu vipivotide tetraxetan plus the BSC-BSoC group compared with the BSC-BSoC group (16.4 months and 3.9 months, respectively).
ORR: The ORR was statistically significantly greater in the 177Lu vipivotide tetraxetan plus BSC-BSoC group compared with the BSC-BSoC group (29.8% versus 1.7%) with an odds ratio of 24.99 (95% CI, 6.05 to 103.24).
Duration of response (DOR): The median DOR in patients who demonstrated a response to treatment (i.e., CR or partial response) was 9.8 months (95% CI, 9.1 to 11.7) in the 177Lu vipivotide tetraxetan plus the BSC-BSoC group. Only 2 patients in the BSC-BSoC group demonstrated a response to treatment, and only 1 of those met the criteria for RECIST radiographic progression or death; therefore, the sponsor reported that the median DOR could not be reliably estimated for the BSC-BSoC group.
DCR: The DCR was statistically significantly greater in the 177Lu vipivotide tetraxetan plus BSC-BSoC group compared with the BSC-BSoC group (89.0% versus 66.7%) with an odds ratio of 5.79 (95% CI, 3.18 to 10.55; P < 0.001).
Time to first SSE: There were 256 events in the 177Lu vipivotide tetraxetan plus BSC-BSoC group (66.5%; 60 SSE events and 196 deaths) and 137 events (69.9% of patients; 34 SSE events and 103 deaths) in the BSC-BSoC only group. 177Lu vipivotide tetraxetan plus BSC-BSoC was associated with a statistically significant reduction in the risk of SSE (or death) as compared to BSC-BSoC alone (HR: 0.5; 95% CI, 0.40 to 0.62).
PFS: Progression events or death were reported for ||||| of patients in the 177Lu vipivotide tetraxetan plus BSC-BSoC group (||||| radiographic progression, ||||| clinical progression; ||||| PSA progression; |||| death) and ||||| of patients in the BSC-BSoC group (||||| radiographic progression, ||||| clinical progression; ||||| PSA progression; |||| death). 177Lu vipivotide tetraxetan plus BSC-BSoC was associated with a statistically significant reduction in the risk of radiographic disease progression, clinical progression, PSA progression or death as compared to BSC-BSoC alone (HR: ||||; 95% CI, ||||||||||; P < |||||). The median PFS was ||| months (95% CI, |||| |||) in the 177Lu vipivotide tetraxetan plus BSC-BSoC group and ||| months (95% CI, ||||||||) in the BSC-BSoC only group.
PSA levels: The sponsor reported a large disparity across the 2 treatment groups in the proportion of patients who could be evaluated for PSA doubling time (73.8% and 37.8%, respectively). For the subset of patients who could be evaluated, the mean PSA doubling time was 20.1 months (95% CI, 11.5 to 28.6) for 177Lu vipivotide tetraxetan and 12.4 months (95% CI, 7.9 to 16.9) for the BSC-BSoC group
Brief Pain Inventory – Short Form (BPI-SF): Worsening in pain intensity was defined as a ≥ 30% increase from baseline or ≥ 2-point increase from baseline in the BPI-SF scale at any time up through the end of treatment visit, clinical disease progression, or death. Time to worsening pain was delayed in the 177Lu vipivotide tetraxetan + BSC-BSoC group compared with the BSC-BSoC group (HR: 0.52; 95% CI, 0.43 to 0.63; P < 0.001). The median time to deterioration was 5.9 months (4.8, 6.9) in the 177Lu vipivotide tetraxetan + BSC-BSoC arm compared with 2.2 months (95% CI, 1.8 to 2.8) in the BSC-BSoC group.
FACT-P: Time to worsening in FACT-P scores was defined as time from randomization to the first occurrence of a at least a 10-point decrease in FACT-P total score compared to baseline, clinical disease progression, or death. The total events were similar between the 177Lu vipivotide tetraxetan and BSC-BSoC and the BSC-BSoC only groups (87.0% and 85.7%, respectively). Median time to worsening was reduced in those who received 177Lu vipivotide tetraxetan plus BSC-BSoC (5.7 months; 95% CI, 4.8 to 6.6) compared with the BSC-BSoC alone group (2.2 months; 95% CI, 1.8 to 2.8) (HR: 0.54; 95% CI, 0.45 to 0.66; P < 0.001).
FACT-G: Time to worsening in FACT-G scores was defined as the time from randomization to the first occurrence of at least a 10-point decrease in FACT-G total score compared to baseline, clinical disease progression, or death. Median time to worsening was reduced in those who received 177Lu vipivotide tetraxetan + BSC-BSoC (6.6 months; 95% CI, 5.5 to 7.3) compared with the BSC-BSoC alone group (2.4 months; 95% CI, 2.0 to 3.1) (HR: 0.53; 95% CI, 0.44 to 0.65; P < 0.001).
FAPSI-8: Time to worsening in FAPSI-8 scores was defined as the time from randomization to the first occurrence of a at least a 10-point decrease in total score compared to baseline, clinical disease progression, or death. The total events were nearly identical between the 177Lu vipivotide tetraxetan plus BSC-BSoC and BSC-BSoC only groups (86.0% and 86.2%, respectively). Median time to worsening in FAPSI-8 was reduced in those who received 177Lu vipivotide tetraxetan plus BSC-BSoC (5.9 months; 95% CI, 4.8 to 6.9) compared with the BSC-BSoC alone group (2.0 months; 95% CI, 1.7 to 2.6) (HR: 0.52; 95% CI, 0.43 to 0.64; P < 0.001).
The sponsor reported that the following events were reported more commonly with the 177Lu vipivotide tetraxetan plus BSC-BSoC group compared with the BSC-BSoC group (i.e., a difference of ≥ 10.0% between the groups): fatigue (43.1% versus 22.9%), dry mouth (38.8% versus 0.5%), nausea (35.3% versus 16.6%), anemia (31.8% versus 13.2%), diarrhea (18.9% versus 2.9%), vomiting (18.9% versus 6.3%), thrombocytopenia (17.2% versus 4.4%), lymphopenia (14.2% versus 3.9%), leucopenia (12.5% versus 2.0%), and urinary tract infection (11.0% versus 1.0%).
A greater proportion of patients in the 177Lu vipivotide tetraxetan plus BSC-BSoC group reported at least 1 grade, equal to or greater than 3 adverse event (AE) compared with the BSC-BSoC group (52.7% versus 38.0%). Grade of at least 3 events more commonly reported in the 177Lu vipivotide tetraxetan plus BSC-BSoC group included: anemia (12.9% versus 4.9%), thrombocytopenia (7.9% versus1.0%), lymphopenia (7.8% versus 0.5%) and fatigue (5.9% versus 1.5%). Spinal cord compression was reported more commonly in the BSC-BSoC treatment group compared with the 177Lu vipivotide tetraxetan plus BSC-BSoC (5.4% versus 1.3%). At least 1 SAE was reported for a greater proportion of patients in the lutetium vipivotide tetraxetan plus BSC-BSoC group compared with the BSC-BSoC group (36.3% versus 27.8%). As previously noted, spinal cord compression was reported more commonly in the BSC-BSoC treatment group compared with the 177Lu vipivotide tetraxetan plus BSC-BSoC.
Randomization was stratified by important prognostic factors, and the baseline and demographic characteristics were generally well balanced across the 177Lu vipivotide tetraxetan and BSC groups (including for prior systemic anticancer therapy). The sponsor reported that the open-label design was used because blinding would not be practical due to the specialized precautions required for the administration of a radiopharmaceutical, the toxicities related to exposure to a radiopharmaceutical, and it would not be appropriate to patients who did not receive a radiopharmaceutical to the post-treatment radiation protection protocols (e.g., maintaining physical distancing from family members). Radiographic images were evaluated using blinded independent central review, and those results were used in the primary evaluations for rPFS and ORR (local assessments were used for patient management and in sensitivity analyses).
The open-label study design contributed to the high rate of early withdrawal for those who were randomized to the BSC-BSoC alone group (i.e., patients were disappointed at not receiving 177Lu vipivotide tetraxetan, leading to a lack of willingness to comply with the study protocol and/or interest in receiving therapies that were prohibited in the study protocol). The sponsor established corrective actions through a protocol amendment that included site calls to discuss the management of control arm patients, investigator letters clarifying study aspects, and updates to prescreening to improve patient education about the trial. After implementing these measures, the sponsor noted that the withdrawal of consent decreased. However, withdrawal rates in the BSC-BSoC group were 56.0% and 16.3% before and after the protocol amendment (respectively), compared with 1.2% and 4.2% in the 177Lu vipivotide tetraxetan group (i.e., although the rate of discontinuation from the BSC-BSoC group improved after the protocol amendment, it remained considerably higher than the rate observed in 177Lu vipivotide tetraxetan group). As a result of the high dropout rate among the BSC-BSoC group, the sponsor also amended the protocol such that all end points, with the exception of OS, were analyzed using a newly established PFS-FAS dataset, that was composed of patients enrolled after the educational protocol amendments were introduced. The approach used is a method to handle the early withdrawals; however, the analyses based on the PFS-FAS would not likely have followed the intention-to-treat principle, which would impact many of the assumptions of the comparisons. This approach was acceptable to the FDA and Health Canada; however, both regulatory agencies stated that the interpretation of the magnitude of the rPFS effect was limited due to a high degree of censoring from early dropout in the control arm (neither the approved US label nor the product monograph in Canada included the effect size for rPFS from the VISION trial).
The high and disproportionate number of patients who withdrew from the control group could bias the study results in favour of 177Lu vipivotide tetraxetan, as those who remained in the study may have had a poorer prognosis in comparison with those who withdrew and subsequently received treatment with regimens that were not permitted in the VISION protocol. Similarly, those who remained in the trial may have had fewer therapeutic options (e.g., more advanced disease) and may have lacked resources to obtain access to alternative regimens outside of the clinical trial setting (e.g., due to socioeconomic factors).
The clinical experts consulted by CADTH noted that the baseline and demographic characteristics for the VISION trial are a reasonable reflection of the target patient population in Canada. The clinical experts consulted by CADTH noted that the duration of survival in the control group (i.e., 11.3 months) exceeds what would be anticipated for the target population in practice in Canada. The experts estimated that survival is typically in the range of 6 to 9 months for patients with progressive mCRPC who have demonstrated disease progression following prior treatment with both ARPI(s) and taxane regimen(s). It was noted that this is commonly observed in PC clinical trials where patients are often healthier with fewer comorbidities than the overall patient population encountered in routine clinical practice in Canada.
All of the patients included in the VISION trial had prior exposure to at least 1 taxane regimen. 41.2% of patients had received 2 taxane regimens and 1.0% had received more than 2 taxane regimens at the time of screening. 57.9% of the total study population had been treated with a single taxane at the time of enrolment in VISION and, therefore, should not have been medically suitable to receive another taxane regimen in accordance with the study protocol. The clinical experts consulted by CADTH noted that this number is greater than would be anticipated in practice in Canada for the target population where approximately 30% to 40% of patients would be considered not medically suitable to receive cabazitaxel. An important limitation with the external validity of the VISION trial was the large proportion of patients who received cabazitaxel in the poststudy treatment setting (i.e., as the VISION trial enrolment criteria stated that patients who had received a single taxane regimen must be medically unsuitable for an additional taxane regimen). The clinical experts consulted by CADTH noted that this would not be reflective of practice in Canada where a patient with mCRPC who is considered ineligible for a further taxane regimen is unlikely to become eligible at a later point in time, as this disease is progressive and improvements in functional status or physiological reserve are not anticipated. Other than these issues, the clinical experts noted that the subsequent therapies could be reflective of routine care for patients where there are no other therapies that have been shown to increase OS.
177Lu vipivotide tetraxetan was administered as an add-on therapy in the VISION trial, which included concomitant administration with other systemic cancer therapies. There are no clinical practice guidelines in Canada that address the use of 177Lu vipivotide tetraxetan and the clinical experts consulted by CADTH noted that it is unclear if combination usage of 177Lu vipivotide tetraxetan with other systemic anticancer therapies would be adopted in practice because of uncertainty regarding the additional clinical benefit and harms for patients.
Several potential comparators for 177Lu vipivotide tetraxetan were not permitted within the acceptable BSoC treatment regimes. These including cytotoxic chemotherapy (e.g., cabazitaxel), immunotherapies, and other systemic radio-isotopies (e.g., radium-223, or hemi-body radiotherapy). The rationale provided by the sponsor was that these therapies could confound the analysis of results and systemic anticancer options in the comparator group were limited to hormone therapies, including ARPIs (e.g., abiraterone and enzalutamide). All of the patients enrolled in the trial had prior exposure to novel ARPIs before enrolment. This approach may have biased the treatment effects in favour of 177Lu vipivotide tetraxetan, as the majority those in the BSC-BSoC group had already been treated with and demonstrated disease progression on the only systemic therapies that were permitted in the trial.
177Lu vipivotide tetraxetan could be administered for up to 6 cycles in the VISION trial which is consistent with recommendations in the product monograph in Canada. The VISION trial protocol also included an additional step where the patient was to be evaluated by the investigator after 4 cycles for evidence of treatment response (specified as either radiological response, PSA response, or clinical benefit in the opinion of the investigator); signs of residual disease on CT with contrast/MRI or bone scan; and good tolerance of the treatment. Patients meeting all those criteria could receive up to 2 additional cycles at the discretion of the treating physician. The clinical experts consulted by CADTH noted that evaluating response to treatment for the target patient population (i.e., those with progressive mCRPC) is multifactorial and would be based on clinical response, radiographic imaging, biochemical measures, and need for medications to manage pain. It was noted that a formal assessment of response after 4 cycles (as performed in the VISION trial) is unlikely to be standardized in clinical practice in Canada and could be challenging to implement if included as renewal criteria for 177Lu vipivotide tetraxetan. Overall, the clinical experts consulted by CADTH noted that the distribution of doses observed in the VISION is likely an accurate reflection of what would occur with patients in Canada, as the treatment is generally well tolerated with relatively few AEs leading to dose reductions, interruptions, and discontinuations.
The sponsor-submitted indirect comparison conducted a systematic review and used a Bayesian network meta-analysis (NMA) to evaluate the relative efficacy of 177Lu vipivotide tetraxetan to other comparators, including radium-223 plus BSC, cabazitaxel plus prednisone, olaparib, mitoxantrone-placebo plus prednisone, and ARPI for the treatment of patients with pretreated, progressive mCRPC. The NMA was based on a systematic review of the literature, and data from | studies were used to inform the analyses. The efficacy outcomes of interest were rPFS and OS.
The sponsor-submitted indirect comparison reported that the results for OS favoured 177Lu vipivotide tetraxetan versus radium-223 plus BSC (HR: ||||; 95% CrI, ||||||||||) and versus ARPI (HR: ||||; 95% CrI, ||||||||||). The sponsor-submitted indirect comparison reported that the results for rPFS favoured 177Lu vipivotide tetraxetan versus cabazitaxel + prednisone (HR: ||||; 95% CrI, ||||||||||), mitoxantrone-placebo plus prednisone (HR: ||||; 95% CrI, ||||||||||) and ARPI (HR: ||||; 95% CrI: ||||||||||). HRs for OS and rPFS were reported as a comparator versus 177Lu vipivotide tetraxetan.
Clinical heterogeneity was present in the analysis due to the variation in patient characteristics across the included trials. In the absence of statistical adjustment, sensitivity analyses, or subgroup analyses, the potential impact of the between-study heterogeneity cannot be evaluated. The clinical experts consulted by CADTH noted that there was heterogeneity in clinically important patient characteristics (i.e., historical use of chemotherapy, disease severity, and treatment indication); therefore, the indirect comparison may be subject to bias. Of particular concern was that the patients included in the 177Lu vipivotide tetraxetan trial (i.e., VISION) had the more severe disease at baseline as indicated by a higher prior treatment count and at least 40% of patients having previously received cabazitaxel before enrolment. Inconsistency of the network was not reported, likely due to the limited ability to do so given the network only had 1 closed loop.
The sponsor-submitted indirect comparison had several limitations including the lack of reporting certain items that would better inform on the certainty of the indirect evidence. Despite the heterogeneity present for many patient and study characteristics, the indirect comparison did not adequately conduct sensitivity and subgroup analysis to investigate the root of heterogeneity or conduct a meta-regression that would adjust for effect modifiers that may influence the results. Consequentially, there is substantial uncertainty around the indirect comparison results and firm conclusions cannot be drawn the efficacy of 177Lu vipivotide tetraxetan versus relevant comparators.
The inclusion criteria VISION trial specified that patients who were previously treated with docetaxel and considered eligible to receive cabazitaxel were to be excluded from the study. As this population is included in the Health Canada–approved indication, CADTH considered this to be an important gap in the evidence and summarized the phase II TheraP which enrolled patients with prior exposure to docetaxel and for whom cabazitaxel was considered the appropriate treatment option.
TheraP was a multicenter, open-label, phase II RCT comparing the activity and safety of 177Lu vipivotide tetraxetan with cabazitaxel in patients with mCRPC. The study was conducted by the Australian and New Zealand Urogenital and Prostate Cancer Trials Group. Similar to the VISION trial, the study enrolled patients with PSMA-positive mCRPC, but the TheraP trial used a more rigorous 2-stage screening process for determining PSMA status:
Eligible patients were randomized (1:1) to receive either 177Lu vipivotide tetraxetan or cabazitaxel. Randomization was stratified by disease burden (> 20 sites versus ≤ 20 sites as assessed by PSMA PET-CT); previous treatment with enzalutamide or abiraterone; and study site.
Patients randomized to receive 177Lu vipivotide tetraxetan received IV infusions once every 6 weeks for a maximum of 6 cycles. The starting dose was 8.5 GBq and was decreased by 0.5 GBq each subsequent cycle (i.e., not administered at the dosages recommended in the product monograph in Canada, which is 7.4 GBq). Patients in the cabazitaxel group received IV infusions of 20 mg/m2 once every 3 weeks for a maximum of 10 cycles. Patients enrolled in TheraP continued to receive supportive cancer therapies (e.g., zoledronic acid or denosumab; palliative radiotherapy). An important difference with TheraP compared with VISION is that patients were prohibited from using other systemic anticancer therapy in the TheraP trial (i.e., the study investigated the use as monotherapy, which is more reflective of how 177Lu vipivotide tetraxetan would likely be administered in clinical practice in Canada). Patients could receive any treatment after completion or discontinuation of the study drugs at the discretion of the treating clinician(s).
A total of 291 patients were screened for eligibility, and 200 patients were randomized. Similar to the VISION trial, there was a greater proportion of patients in the comparator group (in this case, cabazitaxel) who withdrew before receiving any doses of the study medications (16 of 101 [15.8%] in the cabazitaxel group versus 1 of 99 [1.0%] in the 177Lu vipivotide tetraxetan group).
After 3 years of follow-up, there was no statistically significant difference between 177Lu vipivotide tetraxetan and cabazitaxel for OS (HR = 0.97; 95% CI, 0.70 to 1.4; P = 0.99). Treatment with 177Lu vipivotide tetraxetan was statistically superior to cabazitaxel for the primary end point of PSA response (i.e., reduction of ≥ 50% from baseline) (risk difference: 29%; 95% CI, 16 to 42); PFS (HR: 0.63; 95% CI, 0.46 to 0.86); rPFS (HR: 0.64; 95% CI, 0.46 to 0.88); ORR (relative risk: 2.12; 95% CI, 1.10 to 4.08); PSA PFS (HR: 0.60; 95% CI, 0.44 to 0.83); and pain PFS (HR: 0.72; 95% CI, 0.53 to 0.97).
Grade 1 or 2 AEs were more commonly reported in the 177Lu vipivotide tetraxetan group compared with the cabazitaxel group (54% versus 40%, respectively) and Grade 3 or 4 AEs were more commonly reported in the cabazitaxel group compared to the 177Lu vipivotide tetraxetan group (53% vs. 33%, respectively).
Randomization was stratified based by a different set of baseline parameters compared with the VISION trial (i.e., disease burden based on metastatic sites [> 20 sites versus ≤ 20 sites], whether or not the patient had received previous treatment with enzalutamide or abiraterone, and the study site). Overall, baseline and demographic characteristics were well balanced across the 177Lu vipivotide tetraxetan and cabazitaxel groups in TheraP. Similar to the VISION trial, the study drugs in TheraP were administered in an open-label manner (refer to the prior commentary on rationale for open-label administration). Radiographic images in TheraP were evaluated centrally, but not in a manner that was blinded to the evaluator.
As with the VISION trial, the internal validity of the TheraP trial was limited by the high and disproportionate early dropout in the comparator group (15.8% in the cabazitaxel group versus 1.0% in the 177Lu vipivotide tetraxetan group withdrew before receiving any doses of the study medications). The rationale provided was similar to VISION (i.e., patient disappointment at not having access to 177Lu vipivotide tetraxetan). As with VISION, the high and disproportionate number of patients who withdrew from the control group could bias the study results in favour 177Lu vipivotide tetraxetan as those who remained in the study may have had a poorer prognosis in comparison with those who withdrew (though the direction and magnitude of any potential bias are uncertain).
TheraP was a phase II study that was not designed or powered to evaluate differences between177Lu vipivotide tetraxetan and cabazitaxel for the primary end points that are recommended by PCWG3 (e.g., OS). The investigators reported an OS analysis after 3 years of follow-up which noted no statistically significant difference across the 2 treatment groups; however, this analysis may be confounded by crossover and other potential differences in the subsequent therapy settings.
Unlike the VISION trial, 177Lu vipivotide tetraxetan was administered as monotherapy (as no other systemic anticancer drugs were permitted as part of the study protocol in TheraP). This is likely more generalizable to the setting in Canada as the clinical experts consulted by CADTH noted that 177Lu vipivotide tetraxetan is likely to be used as monotherapy, noting the lack of evidence to evaluate the potential benefits of combination usage; potential for increased drug-related AEs; and the likelihood that reimbursement status would likely be limited to monotherapy.
The comparator in TheraP (cabazitaxel) was highly relevant to the context in Canada for patients who have previously been treated with docetaxel and an ARPI. Unlike the VISION trial, the TheraP study did not include an eligibility criterion that patients must be considered medically unsuitable to receive further treatment with taxane regimen. The maximum number of cycles used in the TheraP trial (i.e., 6 cycles) was consistent with VISION and the product monograph in Canada; however, the dosage strength was not consistent with recommendations in the product monograph. Patients in TheraP received an initial dose of 8.5 GBq, which was decreased by 0.5 GBq each subsequent cycle which is not reflective of the standardized dose of 7.4 GBq that is recommended in the product monograph.
PSMA status in the TheraP trial was determined using a 2-stage screening process where patients were initially screened using 68Ga-PSMA PET-CT and then subsequently evaluated using FDG PET-CT. Those who demonstrated discordant imaging between 68GA-PSMA PET-CT and FDG PET-CT (e.g., FDG intensity levels greater than those observed using the 68Ga-PSMA PET-CT) were excluded from the trial. The clinical experts consulted by CADTH noted that the more rigorous criteria applied in the TheraP could help identify patients who may be most likely to respond to 177Lu vipivotide tetraxetan; however, the need for 2 diagnostic PET-CT scans to determine PSMA status would likely pose implementation challenges in clinical practice for clinicians and the health system.
Summary of Economic Evaluation.
CADTH identified the following key limitations with the sponsor’s analysis: the BIA and economic evaluation excluded relevant comparators; the sponsor underestimated the market share of the comparators but including inflated clinical trial market capture; the cost of testing was not considered within the sponsor’s BIA; and concomitant treatments in standard care arm, as well as add-on treatments in the comparator arms, were not representative of the treatments used in clinical practice.
CADTH reanalysis included updating relevant treatment costs and dosages, altering market shares of standard care and cabazitaxel, and updating the standard care regimen to include treatments used in clinical practice. Based on these changes, CADTH reanalysis reported that the reimbursement of 177Lu vipivotide tetraxetan for the treatment of PSMA-positive mCRPC would be associated with a budgetary increase of be $13,670,690 in year 1, $23,120,229 in year 2, and $32,793,211 in year 3, with a 3-year total incremental cost of $69,584,130.
Exploratory analyses were undertaken to estimate the budget impact of 177Lu vipivotide tetraxetan in the cabazitaxel-eligible and ineligible populations; and scenarios in which testing costs are considered. In the exploratory analyses relating to the patient population, based on an assumption that 65% of the population that is eligible for cabazitaxel, 177Lu vipivotide tetraxetan was associated with a budget impact of approximately $45,229,685. In patients ineligible for cabazitaxel, 177Lu vipivotide tetraxetan was associated with a budget impact of approximately $24,354,446. When testing costs are included, the incremental budget impact of reimbursing 177Lu vipivotide tetraxetan may increase to as much as $142,924,498.
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: January 11, 2023
Regrets: Of the expert committee members, 2 did not attend
Conflicts of interest: None
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Indication: Treatment of adults with prostate-specific membrane antigen-positive metastatic castration-resistant prostate cancer who have received at least one androgen receptor pathway inhibitor and taxane-based chemotherapy.
Sponsor: Advanced Accelerator Applications Canada, Inc.
Final recommendation: Reimburse with conditions
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