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Indication: As a monotherapy for the adjuvant treatment of adult patients with urothelial carcinoma (UC) who are at high risk of recurrence after undergoing radical resection of UC
CADTH recommends that Opdivo should be reimbursed by public drug plans as a monotherapy for the adjuvant treatment of adult patients with urothelial carcinoma (UC) who are at high risk of recurrence after undergoing radical resection of UC.
Opdivo should only be covered in patients with UC that spreads into the muscle layer, was removed by surgery, and is at high risk of coming back. Patients should have either received cisplatin-based neoadjuvant chemotherapy or not have received neoadjuvant cisplatin-based chemotherapy and be ineligible or eligible for adjuvant cisplatin-based chemotherapy but decline to take it.
Opdivo should only be reimbursed if prescribed by qualified practitioners with expertise in treating UC, systemic therapy delivery, and management of immunotherapy-related side effects, and if the cost of Opdivo is reduced. Patients should be in relatively good health (i.e., have a good performance status, as determined by a specialist).
Urothelial cancer (UC) is a type of bladder cancer. It begins in the urothelial cells that line the urethra, bladder, ureter, and renal pelvis. Muscle-invasive UC has spread into the muscle layer, and about 40% to 50% of patients survive no longer than 5 years.
Patients with muscle-invasive UC that has been removed by surgery and that has a high risk to come back are in need of treatment options that prevent or delay the cancer from returning, prolong survival with an acceptable toxicity profile, and maintain quality of life.
Treatment with Opdivo is expected to cost approximately $9,387 per patient per 28 days.
The CADTH pCODR Expert Review Committee (pERC) recommends that nivolumab be reimbursed as a monotherapy for the adjuvant treatment of adult patients with urothelial carcinoma (UC) who are at high risk of recurrence after undergoing radical resection of UC, only if the conditions listed in Table 1 are met.
One multi-centre, randomized, double-blind, phase III trial (CheckMate-274, N = 709) demonstrated that treatment with adjuvant nivolumab resulted in added clinical benefit compared with placebo in patients with UC who are at high risk of recurrence after undergoing radical resection of muscle-invasive UC (MIUC). The CheckMate-274 trial showed a statistically significant and clinically meaningful improvement in disease-free survival (DFS) with nivolumab compared with placebo, with a hazard ratio (HR) of 0.70 (98.22% CI, 0.55 to 0.90; P = 0.0008). The secondary outcome, non-urothelial tract recurrence-free survival (NUTRS), was supportive of the observed DFS benefit with nivolumab. The adverse event (AE) results from the CheckMate-274 trial indicated that nivolumab was generally well tolerated and pERC considered the AEs to be manageable.
Patients expressed a need for treatments that can prevent recurrence, control disease progression, maintain quality of life, and have manageable side effects. pERC concluded that nivolumab met some of the needs identified by patients as it delays recurrence and controls disease progression compared with placebo, and has manageable side effects. Although patients expressed an unmet need for treatments that maintain quality of life, no definitive conclusion could be reached regarding the effects of nivolumab on health-related quality of life (HRQoL), due to a significant decline in the number of patients available to provide HRQoL assessments over time and a lack of statistical testing.
Using the sponsor-submitted price for nivolumab and publicly listed prices for all other drug costs, in patients who had received neoadjuvant chemotherapy or were not eligible to receive adjuvant chemotherapy, the incremental cost-effectiveness ratio (ICER) for nivolumab was $112,826 per quality-adjusted life-year (QALY) compared with observation. A price reduction is required for nivolumab to be considered cost-effective at a $50,000 per QALY threshold. In patients who had not received neoadjuvant chemotherapy and who were eligible to receive adjuvant chemotherapy, nivolumab does not represent a cost-effective treatment; as suggested by the sponsor, nivolumab is less effective and more costly. Given the high cost of treatment and uncertain clinical benefits in this population, even at a 100% price reduction, nivolumab is not a cost-effective treatment.
Reimbursement Conditions and Reasons.
Bladder cancer is the fifth most common cancer in Canada, resulting in an estimated 2,600 deaths in 2020; an estimated 12,500 new cases of bladder cancer were projected in Canada in 2021. The most common histological type of bladder cancer is UC, which typically arises in the bladder but may develop in any location lined with urothelium, including the renal pelvis, ureter, urethra, and prostatic urethra. Approximately 33% to 40% of patients with bladder cancer present with or progress to muscle-invasive disease.
Radical surgery (e.g., cystectomy) with regional lymphadenectomy along with cisplatin-based combination chemotherapy is considered the therapeutic gold standard for MIUC. The Canadian Urological Association guideline recommends that eligible patients with muscle-invasive bladder cancer (cT2-T4a N0 M0) should be considered to receive neoadjuvant cisplatin-based combination chemotherapy. There is a lack of high-quality evidence in patients with upper tract UC (UTUC) due to their small number. However, because both share similar etiology, findings for bladder cancer are generalized to patients with UTUC. The Canadian Urological Association guideline recommends that adjuvant cisplatin-based chemotherapy should be offered to patients with high risk of recurrence (pT3-T4 and/or N+) who are eligible for cisplatin-based chemotherapy and have not received neoadjuvant chemotherapy. The 5-year survival rate has been estimated to be 40% to 50% for patients with high-risk residual disease of pT3-pT4 pN- or any pT pN+ at radical cystectomy followed by cisplatin-based chemotherapy upon recurrence.
The clinical experts and clinician groups consulted by CADTH agreed that there is an unmet need for effective treatment options that improve OS and DFS in patients at high risk of disease recurrence at cystectomy. Specifically, the clinical experts felt that there was an unmet need in patients who have not received neoadjuvant chemotherapy and are ineligible for adjuvant cisplatin-based chemotherapy, and in patients who present with significant high-risk features at cystectomy after treatment with neoadjuvant cisplatin-based chemotherapy. These patients currently do not have any active adjuvant treatment options.
The reimbursement request submitted by the sponsor for review by CADTH, which is identical to the proposed Health Canada indication, is for nivolumab (240 mg every 2 weeks or 480 mg every 4 weeks, IV administration) as a monotherapy for the adjuvant treatment of patients with MIUC who are at high risk of recurrence after undergoing radical resection of MIUC. Nivolumab is available as IV infusion (sterile solution of injection 40 mg nivolumab/4mL and 100 mg nivolumab/10 mL). The recommended dosage is 240 mg every 2 weeks (30-minute IV infusion) or 480 mg every 4 weeks (60-minute IV infusion).
To make their recommendation, the committee considered the following information:
One patient advocacy group, Bladder Cancer Canada, provided input for adjuvant treatment of patients with MIUC who are at high risk of recurrence after undergoing radical resection. The group gathered information through online surveys and one-to-one telephone interviews and responses from a total of 7 patients (6 patients from Canada and 1 patient from the US) were included in the patient input. All patient respondents (N = 7) reported having been diagnosed with MIUC, and 2 patients reported receiving nivolumab (one patient indicated receiving nivolumab for the adjuvant treatment following radical resection and the other patient reported having received nivolumab in combination with ipilimumab).
When Bladder Cancer Canada asked respondents to indicate their experience with treatments they have undergone since diagnosis, most patient respondents (n = 6) reported having received radical cystectomy. Additional treatments received by patient respondents included cisplatin and gemcitabine (received by 3 patients each), transurethral resection (received by 2 patients), and methotrexate, vinblastine, doxorubicin, plus cisplatin and antibody drug conjugates (received by 1 patient each). Patients reported fatigue to be the most common as well as “the most-difficult-to-tolerate” side effect of these treatments, followed by nausea and constipation. Two respondents indicated that they had to be hospitalized due to side effects from treatment.
According to the patient input received, respondents expected new treatments to improve the following key outcomes: preventing recurrence, controlling disease progression, reducing symptoms, maintaining quality of life, and managing side effects. Bladder Cancer Canada indicated that participants rated preventing recurrence as the most important outcome, and managing side effects as the least important outcome. According to Bladder Cancer Canada, the patients’ responses were indicative of a willingness to tolerate side effects if treatment was effective. Furthermore, when Bladder Cancer Canada asked specifically about their willingness to tolerate new side effects from treatment that could control disease progression or prevent recurrence, most patient respondents were supportive of tolerating side effects if the treatment showed benefit.
Patient respondents (n = 2) who had direct experience with nivolumab indicated that, overall, nivolumab was an effective treatment, controlling disease progression and preventing recurrence. One patient also reported having improved cancer symptoms, side effects, and quality of life, while the other patient indicated having slightly worse side effects and quality of life. One patient indicated having experienced the following side effects with nivolumab: itchy skin (pruritus) and fatigue. The other patient reported the following side effects from treatment with nivolumab: diarrhea, joint swelling, colitis, and pneumonitis. In addition, this patient experienced immune-checkpoint inhibitor (ICI)-related interstitial lung disease. However, this patient received both nivolumab and ipilimumab, and the patient reported that the treating respirologist did not indicate which drug caused the lung disease. Overall, 1 patient reported that the side effects of nivolumab were completely tolerable, while the other patient noted that they were somewhat challenging. Overall, both patient respondents noted that they would recommend nivolumab to other patients with MIUC.
The clinical experts consulted by CADTH agreed that there is an unmet need for effective treatment options that improve OS and DFS in patients at high risk of disease recurrence, who have not received neoadjuvant chemotherapy and are ineligible for adjuvant cisplatin-based chemotherapy for medical reasons; and in patients who present with residual disease at cystectomy after treatment with neoadjuvant cisplatin-based chemotherapy. The clinical experts noted that data on nivolumab compared to cisplatin-based chemotherapy in patients who have not received neoadjuvant chemotherapy, and are eligible to received cisplatin-based chemotherapy, were not available from the CheckMate-274 trial. Given the absence of robust comparative data between adjuvant nivolumab and adjuvant chemotherapy, the clinical experts consulted by CADTH were uncertain whether nivolumab addressed an unmet need in patients at high risk of recurrence who are eligible for adjuvant cisplatin-based chemotherapy. The clinical experts anticipated that adjuvant nivolumab would be the preferred treatment over adjuvant chemotherapy in select clinical circumstances only (e.g., gemcitabine allergy or strong patient preference against chemotherapy).
If publicly available, nivolumab could increase the number of patients who receive adjuvant systemic therapy, as some providers may underutilize perioperative systemic chemotherapy, or do not refer their patients for consideration of treatment. In the experts’ view, the benefits of perioperative cisplatin-based chemotherapy are well established from RCTs, and only patients who are not candidates for this treatment for specific medical reasons, or those at high risk of recurrence despite neoadjuvant chemotherapy, should be considered for nivolumab.
In the opinion of the clinical experts, an assessment of effectiveness of treatment should primarily be based on OS. DFS may be considered a reasonable surrogate in patients without other treatment options. However, for patients who are eligible for adjuvant chemotherapy, DFS on its own may not be an adequate outcome to guide treatment selection. Patients would be identified based on pathology results following surgery, and knowledge of prior systemic treatments for MIUC. The clinical experts also confirmed that nivolumab should be discontinued if there is disease recurrence or intractable severe adverse effects. As nivolumab is now commonly used and familiar to the oncological community, treatment and monitoring could be done by specialists in community settings.
The pivotal trial, CheckMate-274, also allowed entry of patients “who declined” adjuvant cisplatin-based chemotherapy. Nivolumab would usually have fewer adverse effects than chemotherapy. The clinical experts were of the opinion that an RCT comparing nivolumab to adjuvant chemotherapy (not placebo) should inform treatment of patients who are suitable for but “who declined” standard adjuvant cisplatin-based chemotherapy.
The views of the clinician groups were consistent with the views of the clinical experts consulted by CADTH. Two clinician groups provided input: Bladder Cancer Canada (a registered national charity) surveyed 6 clinicians, and the Ontario Health (Cancer Care Ontario) GU Cancer Drug Advisory Committee included input from 3 clinicians. Clinicians from both groups commented that nivolumab would fill a gap in the standard of care for patients with a high risk of recurrence with or without neoadjuvant cisplatin-based chemotherapy, or for patients who are unfit or ineligible for adjuvant cisplatin-based chemotherapy. The clinicians from Bladder Cancer Canada highlighted that many patients recover poorly from surgery and are not fit for adjuvant chemotherapy. All UC patients categorized as ypT2 or higher, pT3 or higher, or node positive would be the target population, which constitutes about two-thirds of cystectomy/nephroureterectomy patients. These patients are often frail or have a solitary kidney and thus cannot receive the current standard of adjuvant chemotherapy. The clinicians from Bladder Cancer Canada noted the following important treatment goals in the adjuvant setting (in order of priority): increasing OS, preventing metastases, controlling disease progression, maintaining quality of life, minimizing adverse events, and reducing severity of symptoms. Clinicians from both inputs agreed that there is some debate on the effectiveness of adjuvant chemotherapy and currently poor use of it in clinical practice. Both groups mentioned that nivolumab would change how MIUC would be treated, and that it may become the main drug used in the adjuvant setting for patients.
Input was obtained from the drug programs that participate in the CADTH reimbursement review process.
Responses to Questions From the Drug Programs.
CheckMate-274 was a phase III, randomized, double-blind, placebo-controlled study (N = 709) funded by Bristol Myers Squibb. The primary objective was to compare the DFS for nivolumab versus placebo in all randomized patients and patients with tumours expressing PD-L1 (≥ 1% membranous staining in tumour cells). Secondary objectives included comparing the OS for nivolumab versus placebo in all randomized patients and in patients with tumours expressing PD-L1 (≥ 1% membranous staining in tumour cells) as well as evaluating non-urothelial tract recurrence fee-survival (NUTRFS) and disease-specific survival (DSS) in each study group in patients with tumours expressing PD-L1 (≥ 1% membranous staining in tumour cells) and all randomized patients.
After screening, eligible patients were randomized in a 1:1 ratio to the nivolumab or placebo treatment group and stratified by pathologic nodal status (N+ versus N0/x with < 10 nodes removed, versus N0 with ≥ 10 nodes removed), tumour cell programmed death-ligand 1 (PD-L1) expression (≥ 1%, < 1%, indeterminate), and use of cisplatin neoadjuvant chemotherapy (yes versus no). All patients were treated until recurrence of disease, unacceptable toxicity, or withdrawal of consent, with a maximum of 1 year of treatment. Tumour imaging assessments were to be performed every 12 weeks from the date of first dose to Week 96, then every 16 weeks from Week 96 to Week 160, then every 24 weeks until non-urothelial tract recurrence or treatment was discontinued (whichever occurred later) for a maximum of 5 years.
The mean ages of patients in the nivolumab and placebo arms were 65.3 years and 65.9 years, respectively, and the nivolumab group had a slightly larger proportion of patients older than 65 years of age (155 [43.9%] in nivolumab group and 136 [38.2%] in placebo group). Approximately 75% of patients in both groups were White males; almost ||||| were enrolled in Europe, and approximately ||||| in the US and |||||| in the rest of the world, including Canada. Approximately 79% of patients had a primary tumour in the urinary bladder, almost 74% had PT3 or PT4A at resection, and almost 59% had PD-L1 expression of < 1%. Regarding prior cancer therapy, almost 43% of patients had received prior neoadjuvant cisplatin therapy, and of those not treated with cisplatin, |||||||||| patients in the nivolumab group and |||||||||| patients in the placebo group declined to take cisplatin, while the rest were deemed ineligible. Baseline demographic and disease characteristics were generally well balanced between study arms.
As of the final primary analysis August 27, 2020 data cut-off date, minimum follow-up time was 5.9 months, and median follow-up time among all randomized patients was 20.9 months and 19.5 months in the nivolumab and placebo groups, respectively. Median treatment durations were 8.77 months (range = 0 to 12.5) in the nivolumab group and 8.21 months (range = 0 to 12.6) in the placebo group. In all randomized patients with tumour cell PD-L1 expression greater than or equal to 1%, the minimum follow-up time was ||||| months, and the median follow-up was |||| months and |||| months in the nivolumab and placebo groups, respectively.
OS was a key secondary end point in the CheckMate-274 trial. OS data were immature and not available from the sponsor at the time of this review. Among all treated patients, there were ||||||||| deaths reported in the nivolumab group and |||||||||| deaths reported in the placebo group. The primary cause of death was ||||||||||||||||||||||||||| in the nivolumab group and ||||||||| in the placebo group.
At the data cut-off date of August 27, 2020, the efficacy analyses of DFS in all randomized patients showed that patients in the nivolumab group had longer DFS than those in the placebo arm. The observed median DFS was longer in the nivolumab group (20.8 months [95% CI, 16.5 to 27.6] versus 10.8 months [95% CI, 8.3 to 13.9]) compared with the placebo group, with HR = 0.70 (98.22% CI, 0.55 to 0.90); log-rank P = 0.0008. The observed median NUTRFS was 22.9 months (95% CI, 19.2 to 33.4) in the nivolumab group and 13.7 months (95% CI, 8.4 to 20.3) in the placebo group, with HR = 0.72 (95% CI, 0.59 to 0.89).||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Among exploratory outcomes, median distant metastasis-free survival (DMFS) was 40.5 months (95% CI, 22.4 to not reached) in the nivolumab group and 29.5 months (95% CI, 16.7 to not reached) in the placebo group with HR = 0.75 (95% CI, 0.59 to 0.94). Time to recurrence (TTR) was |||||||||||||||||||||||||||||||||| in the nivolumab group and ||||||||||||||||||||||||||||||||| in the placebo group with a |||||||||||||||||||||||||||||||||||. Recurrence rates were |||||| in the placebo group (|||||) than in the nivolumab group (|||||) at 6 months. ||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Results for patient reported outcomes (assessed by the European Organization for Research and Treatment of Care Core Quality of Life questionnaire [EORTC QLQ-C30] and EQ-5D-3L) suggested similar overall health status in both study groups.
A total of 347 (98.9%) of patients in the nivolumab group and 332 (95.4%) of patients in the placebo group experienced at least 1 AE, whereas a total of |||||||||| of patients in the nivolumab group and |||||||||| patients in the placebo group experienced a grade 3 or greater AE. A total of ||||||| of patients in the nivolumab group and ||||| of patients in the placebo group experienced an all-causality serious AE (SAE). The most common SAEs (≥ 2% in either of the arms) in nivolumab versus placebo arms were ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
All-causality adverse events leading to study drug discontinuation occurred in ||||| of patients in the nivolumab group versus |||| in the placebo arm. There were more deaths in the placebo group (||||||||||) than in the nivolumab group (|||||||||), most commonly due to |||||||||||||||||||||||| in the nivolumab group and ||||| in the placebo arm). There were 3 treatment-related deaths: 2 due to pneumonitis and 1 due to bowel perforation.
Immune-mediated AEs (IMAEs) were identified as notable harms by the clinical experts and were more frequently reported in patients in the nivolumab group than in the placebo arm. They include |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
In spite of the trial’s blind design, it is possible that some AEs, such as IMAEs, allowed the possible detection of the intervention being received by some patients. If trial investigators or patients were aware of the intervention assignment, this may have affected behaviour (such as initiation of subsequent treatment given that DFS was investigator assessed or adherence to treatment), imaging assessments, or perceived HRQoL. Overall survival was considered an outcome of primary importance by the clinical experts consulted by CADTH in guiding treatment selection in clinical practice. The first interim analysis for OS was planned with the February 1, 2021 data cut-off date, at which point OS did not cross the prespecified boundary for declaring statistical significance. No OS data were submitted by the sponsor. ||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||. Updated results for DFS, NUTRFS, DMFS, and TTR from the February 1, 2021 data cut-off date were overall consistent with results from the final primary analysis. However, these updated results were only available in poster format (poster presentation at the Society of Urologic Oncology (SUO) congress in December 2021), and no Clinical Study Report was provided for this data cut-off, so the CADTH review team was unable to conduct a rigorous evaluation of the methods and reporting of these analyses. Maintaining quality of life was rated as an important outcome by patients, yet there was no formal statistical comparison and there were missing HRQoL data at later time points post-baseline. The interpretation of results for the HRQoL instruments (i.e., the ability to assess trends over time and to make comparisons across treatment groups) is limited by the significant decline in patients available to provide assessment over time.
According to the clinical experts consulted by CADTH for this review, the demographic and disease characteristics of the CheckMate-274 study population were reflective of the Canadian population with MIUC. The study protocol was amended based on findings from the CA209275 study (46% of study patients were PD-L1-positive) to cap PD-L1 negative patients included in the study at 54%. The clinical experts consulted by CADTH noted that the PD-L1 biomarker is currently not used in Canadian clinical practice to guide treatment selection in the target population. The experts noted that research on this biomarker’s definitions, methods of measurement, and cut-off values are currently still evolving. The trial capped the proportion of patients with upper tract UC (UTUC) at 20%, as supported by previous studies and confirmed by clinical experts consulted by CADTH. The experts felt that it was reasonable to generalize the CheckMate-274 results to patients with UTUC because of the similar etiology between UTUC and bladder cancer; patients with UTUC were included in the pivotal trial, and they are similarly treated as patients with bladder cancer in Canadian clinical practice. Almost 98% patients taking part in the study had an ECOG performance status (PS) of 0 or 1; however, the experts expected that, in clinical practice, a higher proportion of patients with an ECOG performance status of 2 may receive nivolumab because recurrence of the cancer is high and AEs are tolerable. Cisplatin ineligibility was defined using the Galsky criteria, which are commonly used in clinical trials and clinical practice. The clinical experts consulted by CADTH noted that experienced clinicians may apply some flexibility in terms of using adjuvant chemotherapy in patients with creatinine clearance greater than 50 mL/min and those with hearing loss, if patients choose to received adjuvant chemotherapy after a discussion of the clinical risks. The reimbursement request is for consideration of nivolumab 240 mg every 2 weeks or 480 mg every 4 weeks; however, the pivotal study only included a dosage of 240 mg every 2 weeks. The clinical experts felt that the results of the CheckMate-274 trial could be generalized to a dosage of 480 mg every 4 weeks, as this regimen has been previously approved for nivolumab as a monotherapy with other indications.
The study included 3 groups of patients at high risk of disease recurrence: patients who received neoadjuvant cisplatin-based therapy and were therefore not eligible for adjuvant cisplatin-based therapy, patients who did not receive neoadjuvant cisplatin-based therapy and were either cisplatin-ineligible |||||||||||| or were cisplatin-eligible but refused adjuvant chemotherapy ||||||||||||| The clinical experts noted that data on adjuvant nivolumab compared to adjuvant cisplatin-based chemotherapy in patients who have not received neoadjuvant chemotherapy and are eligible to receive cisplatin-based chemotherapy were not available from the CheckMate-274 trial. Given the absence of robust comparative data between adjuvant nivolumab and adjuvant chemotherapy, the clinical experts consulted by CADTH were uncertain whether nivolumab addressed an unmet need in patients at high risk of recurrence who are eligible for adjuvant cisplatin-based chemotherapy. The clinical experts noted that more robust direct evidence from a randomized trial is required to address the comparative effectiveness and safety of nivolumab compared with cisplatin-based chemotherapy in the adjuvant setting. The clinical experts anticipated that adjuvant nivolumab would be the preferred treatment over adjuvant chemotherapy in select clinical circumstances only, for example gemcitabine allergy or strong patient preference against chemotherapy. The clinicians from the Ontario Health (Cancer Care Ontario) GU Cancer Drug Advisory Committee providing input for this submission concurred with the clinical experts consulted by CADTH, in that they noted that the comparative effectiveness between adjuvant nivolumab and chemotherapy is unknown at the moment, and it may be possible that patients eligible for cisplatin-based adjuvant chemotherapy may be better suited for chemotherapy than nivolumab. These clinicians noted that currently neither adjuvant nivolumab (long-term OS results are awaited from the CheckMate-274 trial) nor adjuvant chemotherapy have demonstrated an OS benefit versus surveillance. The CheckMate-274 trial was not designed to detect differences in treatment effects across subgroups of cisplatin-eligible versus cisplatin-ineligible patients, and the clinical experts noted that any assumption about the extent to which the subgroup of cisplatin-eligible patients may have influenced the results seen in the overall trial population is speculative.
A review of studies assessing the appropriateness of DFS as a surrogate outcome was conducted. At the individual level, there was a moderate to substantial agreement between DFS and OS. However, in the absence of the trial-level association between DFS and OS in the present target population, it cannot be firmly concluded to what extent the improvements in DFS observed in patients in the nivolumab group of the CheckMate-274 trial would translate into OS benefits. The clinical experts consulted by CADTH anticipated that, in the comparison of adjuvant nivolumab against an active comparator (e.g., adjuvant chemotherapy), primarily OS rather than DFS would guide treatment selection in the adjuvant setting.
Indirect evidence from 2 NMAs (1 sponsor-submitted NMA and 1 published NMA) evaluated the effectiveness of nivolumab compared to cisplatin-based chemotherapy in the treatment of UC. They address a gap in the pivotal clinical trial, which includes a subgroup of patients who are cisplatin-eligible but who decline to take it.
A total of ||| randomized trials comprising ||| patients were included in the sponsor-submitted ITC. The list of comparators included for the analysis included ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
The published NMA included 9 studies comprising 2,444 patients: 2 studies involved an assessment of investigator’s choice immunotherapy (nivolumab [n = 353] and atezolizumab [n = 406]) including the pivotal study of this review, 5 studies involved assessment of cisplatin-based chemotherapy (n = 468; regimens included: cisplatin; cisplatin and gemcitabine; cisplatin, vinblastine, and methotrexate; methotrexate, vinblastine, doxorubicin/epirubicin, and cisplatin; and cisplatin, doxorubicin, and cyclophosphamide) in bladder UC patients, and 2 studies involved assessment of cisplatin- or platin-based chemotherapy (gemcitabine with cisplatin or carboplatin) in UTUC patients. The authors conducted an NMA using random and fixed effect models with a Bayesian approach to compare treatments directly and indirectly with observation/placebo as the common comparator arm. Arm-based analyses were performed to estimate OR and 95% credible interval (Crl) to evaluate the disease progression rate in bladder UC and UTUC separately.
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In the published NMA, in patients with bladder UC, chemotherapy (OR = 0.50; 95% CrI, 0.19 to 1.06), atezolizumab (OR = 1.01; 95% CrI, 0.19 to 5.46), and nivolumab (OR = 0.59; 95% CrI, 0.11 to 3.34) did not lower the likelihood of disease progression compared to observation/placebo. In patients with UTUC, chemotherapy (OR = 0.36; 95% CrI, 0.13 to 0.92) was significantly associated with a lower likelihood of disease progression compared to observation/placebo. On the other hand, atezolizumab (OR = 1.39; 95% Crl, 0.28 to 7.25) and nivolumab (OR = 1.21; 95% CrI, 0.29 to 4.95) were not associated with a lower likelihood of disease progression compared to observation/placebo.
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Both NMAs included a limited number of studies with heterogeneity across these studies. In the sponsor-submitted ITC, there was heterogeneity in the tumour staging of patients, definition of end points, treatment doses and regimens, and median follow-up times. Moreover, ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| In the published NMA, there was heterogeneity in the components of the chemotherapy regimen and the median follow-up time. Four trials were older chemotherapy trials with smaller sample sizes and inconsistent reporting of outcomes, which may have led to confounding of the results. In both ITCs, the methodological concerns identified and the observed heterogeneity across study designs and populations precluded drawing definitive conclusions about the comparative effectiveness of adjuvant nivolumab versus adjuvant chemotherapy.
One sponsor-submitted, ongoing, phase III, multinational, double-blind, randomized placebo-controlled trial provided evidence regarding the efficacy and safety of nivolumab compared with placebo in patients at high risk of recurrence after radical resection of MIUC (with primary site either in the bladder or upper urinary tract). Compared to placebo, adjuvant treatment with nivolumab (240 mg every 2 weeks IV infusion until disease recurrence or unacceptable toxicity, for a total treatment duration of 1 year) showed a statistically significant DFS benefit in the treatment of patients (≥ 18 years old) with completely resected MIUC. The absolute difference in median DFS between treatment groups (approximately 10 months) was considered clinically meaningful by the clinical experts consulted by CADTH in patients at high risk of recurrence who are ineligible to receive adjuvant cisplatin-based chemotherapy. Results for OS were not available at the time of this review. While some evidence suggests individual-level associations between DFS and OS, trial-level associations between DFS and OS have not been assessed in the target population. Therefore, it cannot be firmly concluded to what extent the improvements in DFS observed in patients in the nivolumab group of the CheckMate-274 trial would translate into OS benefits. HRQoL analyses were descriptive only and limited by high rates of missing data; thus, changes over time could not be interpreted. Data on adjuvant nivolumab compared to adjuvant cisplatin-based chemotherapy in patients at high-risk of recurrence who are eligible to receive cisplatin-based chemotherapy were not available from the CheckMate-274 trial. Indirect treatment comparisons of nivolumab with cisplatin-based chemotherapy ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||| Given the lack of robust comparative data between adjuvant nivolumab and adjuvant chemotherapy, the clinical experts consulted by CADTH were unsure if adjuvant nivolumab addressed an unmet need in patients who are at high risk of recurrence and eligible for adjuvant chemotherapy.
The safety profile of nivolumab in this study was consistent with the known safety profile of nivolumab, and no additional safety signals were identified with adjuvant nivolumab therapy in this study.
Cost and Cost-Effectiveness.
CADTH identified key limitations with the sponsor’s analysis. Some treatment costs were based on outdated prices. Further, the number of eligible patients and market share of nivolumab were underestimated. In reanalysis, CADTH updated the number of bladder cancer cases, the proportion of high-risk bladder cancer patients, the proportion of UTUC patients eligible for adjuvant therapy, and the market share of nivolumab. Based on the CADTH reanalysis, the 3-year budget impact to the public drug plans of introducing nivolumab is expected to be $180,672,898 (Year 1: $51,773,325; Year 2: $60,173,636; Year 3: $68,725,937). The budget impact model has limited feasibility to estimate the budget impact in subgroups of MIUC population that may or may not be eligible for adjuvant chemotherapy. As such, the estimated budget impact for either subgroup is highly uncertain.
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: August 9, 2022
Regrets: 2 expert committee members did not attend
Conflicts of interest: None
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Indication: As a monotherapy for the adjuvant treatment of adult patients with urothelial carcinoma (UC) who are at high risk of recurrence after undergoing radical resection of UC
Sponsor: Bristol Myers Squibb Canada
Final recommendation: Reimburse with conditions
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