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Indication: For the treatment of adult patients with locally advanced or metastatic differentiated thyroid carcinoma that has progressed following prior VEGFR-targeted therapy and who are radioactive iodine-refractory or ineligible
CADTH recommends that Cabometyx should be reimbursed by public drug plans for the treatment of adult patients with locally advanced or metastatic differentiated thyroid carcinoma (DTC) if certain conditions are met.
Cabometyx should only be covered to treat patients who did not respond to prior radioactive iodine (RAI) therapy or are not eligible for RAI, those previously treated with 1 to 2 tyrosine kinase inhibitors (TKIs), and those who have good performance status (i.e., they are in relatively good health).
Cabometyx should only be reimbursed if it is prescribed by specialists with experience in the management of thyroid cancer and the cost of Cabometyx is reduced.
Evidence from a clinical trial demonstrated that patients with DTC treated with Cabometyx experienced benefits in survival without progression of disease. Patients in this trial had side effects that clinical experts considered manageable.
Cabometyx potentially meets important needs since there are currently no funded options available for patients with DTC who have failed to response to RAI and treatment with previous drugs.
Based on CADTH’s assessment of the health economic evidence, Cabometyx does not represent good value to the health care system at the public list price. A price reduction is therefore required.
Thyroid cancer is cancer that initiates in the thyroid gland. When these cancer cells resemble healthy cells to some degree it is called a differentiated cancer (or carcinoma). People with thyroid cancer whose cancer cells have spread to other parts of the body, such as the lung or bones, likely have advanced or metastatic cancer. In Canada, there are 2 to 3 new cases of DTC per 10,000 people every year (or about 8,600 new cases in total). About a third of these patients will have recurrence of the disease despite treatment, which limits survival and the overall prognosis.
Patients in Canada with advanced or metastatic DTC who do not respond to initial treatment have few treatment options available and not all patients respond to these treatments.
Treatment with Cabometyx is expected to cost approximately $8,436.24 per patient for a 28-day cycle.
The CADTH pCODR Expert Review Committee (pERC) recommends that cabozantinib be reimbursed for the treatment of adult patients with locally advanced or metastatic differentiated thyroid carcinoma (DTC) that has progressed following prior vascular endothelial growth factor receptor (VEGFR)-targeted therapy and who are radioactive iodine-refractory (RAI-R) or ineligible only if the conditions listed in Table 1 are met.
One ongoing phase III, randomized, double-blind, placebo-controlled trial (COSMIC-311) demonstrated that treatment with cabozantinib resulted in added progression-free survival (PFS) benefit for patients with advanced or metastatic DTC previously treated with a VEGFR tyrosine kinase inhibitor (TKI) and who are RAI-R. As of the most recent data cutoff date (February 8, 2021), median PFS was 11.1 months (96% confidence interval [CI], 7.4 to 13.8 months) in the cabozantinib group compared to 1.9 months (96% CI, 1.8 to 3.8 months) in the placebo group (P value < 0.0001). Clinical experts consulted by CADTH considered these PFS results to be meaningful for patients and clinicians. In addition, cabozantinib treatment was associated with serious but manageable adverse events (AEs). Overall, pERC recognized that cabozantinib addresses an unmet therapeutic need as there are currently no funded therapies available for patients with RAI-R DTC who have progressed on lenvatinib.
Using the sponsor submitted price for cabozantinib and publicly listed prices for all other drug costs, the incremental cost-effectiveness ratio (ICER) for cabozantinib plus best supportive care (BSC) was $664,742 per quality-adjusted life-year (QALY) compared with BSC alone. At this ICER, cabozantinib is not cost-effective at a $50,000 per QALY willingness-to-pay threshold for patients with locally advanced or metastatic DTC that have progressed following prior VEGFR-targeted therapy and who are RAI-R or ineligible. A price reduction is required for cabozantinib to be considered cost-effective at a $50,000 per QALY threshold.
Reimbursement Conditions and Reasons.
Thyroid cancer is considered to be the most common endocrine malignancy. In 2020, the incidence of thyroid cancer in Canada was estimated to be 23 per 100,000 patients, or about 8,600 new cases. Thyroid cancers arising from thyroid follicular cells include the differentiated thyroid cancer (DTC, which groups papillary thyroid cancer [PTC], follicular thyroid cancer [FTC], and Hurthle cell cancer), poorly differentiated thyroid cancer, and anaplastic thyroid cancer. Among all types of thyroid cancer, DTC is the most common, accounting for more than 95% of cases. In the Canadian population, this will represent approximately 2.7 cases per 10,000 per year.
Thyroid tumours that are localized and well-differentiated usually are curable with total thyroidectomy or lobectomy, followed by postoperative treatment with radioactive iodine (RAI) therapy – for patients at high risk of persistent disease or disease recurrence after total thyroidectomy. Up to 30% of patients with DTC may have recurrence of disease and 60% of these recurrences occur within the first decade after initial therapy. In patients with primary or secondary radioiodine-refractory thyroid carcinoma, the prognosis becomes significantly poorer. Patients with distant metastases have an estimated median survival time of about 2.5 to 3.5 years. The overall mortality rates 5 and 10 years after diagnosis of distant metastases are 65% and 75%, respectively. Early diagnosis and early appropriate surgical treatment are considered to positively affect the prognosis of these patients. In Canada, 2 VEGFR-targeted TKIs, lenvatinib and sorafenib, are approved for progressive metastatic RAI-resistant cases, but only lenvatinib is currently reimbursed by public drug plans.
Cabozantinib has been approved by Health Canada for the treatment of adult patients with locally advanced or metastatic DTC that has progressed following prior VEGFR-targeted therapy and who are RAI-refractory or ineligible. Cabozantinib is a multi-targeted TKIs; it is available as oral tablets of 20 mg, 40 mg, and 60 mg. The recommended dosage in the product monograph is 60 mg administered orally once daily without food.
To make their recommendation, the Committee considered the following information:
Two patient groups submitted 1 joint input for this review. Canadian Cancer Society (CCS) is the only national charity that supports all Canadians living with all cancers across the country through research, advocacy, and compassionate support activities. Thyroid Cancer Canada (TCC) is a national organization of thyroid cancer survivors dedicated to providing emotional support and information to those affected by the disease. The submission was based on results from a survey distributed by the 2 groups. Two patients responded to the survey, of which 1 had experience with cabozantinib. The patient groups noted that this type of thyroid cancer is rare.
The 2 patients said their ability to work, travel, exercise, conduct household chores, fulfill family obligations, and maintain positive mental health were impacted to a moderate degree by symptoms associated with DTC. Also, both patients indicated there are financial barriers related to treatment (e.g., loss of income, transportation costs). No specific details with respect to outcomes that are important to patients was provided in the input. Of note, patients reported experiencing adverse effects from their treatments such as nausea, vomiting, diarrhea, and fatigue.
Clinical experts consulted by CADTH agreed that RAI-R DTC is a rare disease causing about 200 deaths per year in Canada. The clinical experts indicated that, as with most rare diseases, this raises issues about physician awareness and systemic barriers to access to therapy for patients. Although most patients respond to lenvatinib, all patients will eventually experience disease progression due to acquired drug resistance, per the clinical experts. The clinical experts reported that currently there are no funded and reliably effective treatments for these patients. The clinical experts indicated that treatment goals should be improving OS, PFS, and HRQoL by controlling symptoms, minimizing adverse effects of treatments, and increasing work-life productivity. There is an unmet need, on which both clinical experts agreed, that better treatments must be available for patients who do not respond or progress after first-line therapy, and for those patients who have to discontinue TKI treatment due to side effects or multi-kinase inhibitor resistance. The clinical experts noted that the ideal treatment should also have fewer harmful effects.
Clinical experts agreed that cabozantinib would provide a second-line treatment option for patients progressing despite lenvatinib therapy. Experts also agreed that cabozantinib should not be used as first-line treatment but could be an alternative for patients who are intolerant of lenvatinib. As per the clinical experts, cabozantinib treatment can be associated with significant AEs, so the main criteria for the timing and dosing of treatment would be based on clinical judgment considering patient factors such as tumour burden, age, comorbidities, and performance status. To monitor response, the clinical experts noted that patients should have baseline assessment and imaging and be assessed every 2 to 3 weeks to monitor for adverse effects and to modify drug dosing if necessary. Improved symptoms and a drop in serum thyroglobulin would be favourable signs of response early in treatment, per the clinical experts. The clinical experts indicated that in most patients, cabozantinib would be continued until there is unequivocal evidence of disease progression despite treatment or toxicity. The clinical experts suggested that patients should be under the care of a medical oncologist or endocrinologist experienced in TKI therapy for thyroid cancers. The clinical experts noted that, as RAI-R DTC is a rare condition; currently there is a small community of prescribers in Canada treating this disease. The clinical experts noted that indications for cabozantinib are growing, and a growing number of medical oncologists are becoming familiar with it.
The Medical Advisory Panel of TCC with administrative support provided by the Canadian Cancer Society provided input for this review. A total of 7 physicians (5 from Ontario, 1 from British Columbia, 1 from Alberta) were included and responded to the call for input.
In agreement with the clinical experts consulted by CADTH, the clinician group mentioned the lack of approved/funded options for patients with DTC who are radioactive iodine-refractory (or ineligible) and progress after VEGFR-targeted therapies. The clinician group believes that cabozantinib is expected to fill an urgent unmet need for patients who progress on prior therapy, since no other therapies are funded beyond lenvatinib as first-line treatment in Canada. The clinician group considers that the inclusion criteria for the COSMIC-311 trial define the patient population best suited for cabozantinib treatment. In addition to the criteria listed in the COSMIC-311 trial, patients with progressing non-measurable disease, such as bone metastases, should not be excluded in the real-world clinical setting; this was also in alignment with the input from the clinical experts. To assess response to treatment, clinical assessment, tumour markers, and radiological imaging, such as CT or MRI scans should generally be done every 3 to 4 months.
The group emphasized that RAI-R DTC is a rare disease with significant unmet need and cabozantinib should be reviewed in this regard.
Input was obtained from the drug programs that participate in the CADTH reimbursement review process. The clinical experts consulted by CADTH provided advice on the potential implementation issues raised by the drug programs.
pERC agreed with the responses provided by the clinical experts consulted by CADTH to each of the questions from the drug programs in Table 2.
Responses to Questions From the Drug Programs.
One phase III clinical study was included in the systematic review. The COSMIC-311 is a randomized, double-blind, placebo-controlled trial, conducted in several centres across Europe, Asia, Latin America, US, and Canada to evaluate the efficacy and safety of cabozantinib 60 mg once daily versus placebo. The randomization was stratified by age (< 65 or ≥ 65 years) and previous use of lenvatinib. The population included patients with advanced or metastatic DTC previously treated with a VEFGR-TKI and who are RAI-resistant. The key end points of objective response rate (ORR), PFS, OS, duration of response, and HRQoL were assessed in an initial cutoff date (August 19, 2020). There was a total of 187 randomized patients (the intention to treat [ITT] and safety population), from which the first 100 randomized patients were obtained and assessed as a specific ITT population for the primary end points of ORR and PFS (i.e., the OITT population). A second cutoff date (February 8, 2021) with a total of 187 patients in the primary analysis subset and 258 patients in the full ITT population, provided longer follow-up assessments, including safety. Crossover to cabozantinib was permitted throughout the study for eligible patients who experienced radiographic disease progression per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) by blinded independent radiology committee. Patients in the COSMIC-311 had advanced or metastatic DTC with Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1, with a slight predominance of female patients, and an average age of 65 years.
For OS at the data cutoff date of August 19, 2020, with a median follow-up time of 6.24 months, the median OS was not reached (95% CI, not estimable [NE] to NE) in either treatment group. The log-rank test for differences in the Kaplan–Meier (KM) curves for OS had a corresponding P value = 0.0879. For the cutoff date of February 8, 2021, with a median follow-up of 11.9 months, results of OS were overall consistent with the initial cutoff, with 34 deaths in the cabozantinib arm and 20 deaths in the placebo arm (27% vs. 32% respectively). Median OS was 19.4 (95% CI, 15.9 to NE) months in the cabozantinib group and was not reached (95% CI, NE to NE) in the placebo group. Of note, these results at a later data cutoff were assessed post-hoc, following the primary analysis, and so, are considered supplemental to the primary analysis results.
PFS was a co-primary end point and adjusted for multiplicity. At the data cutoff of August 19, 2020; a total of 74 events were reported. The median follow-up time was 6.24 months. The median PFS was not reached (96% CI, 5.7 to NE) in the cabozantinib arm compared with 1.9 months (1.8 to 3.6) in the placebo arm. The P value obtained from the log-rank stratified test was less than 0.0001. For the cutoff date of February 8, 2021, results of PFS were overall consistent. With a median follow-up time of 11.9 months in the primary analysis population (n = 187), the median PFS was reached at 11.1 months (96% CI, 7.4 to 13.8) in the cabozantinib arm vs. 1.9 months (1.8 to 3.8) in the placebo arm, with a P value obtained from the stratified log-rank test of less than 0.0001, below a critical P value used for testing of 0.00036.
ORR was a co-primary end point in the COSMIC-311 trial and adjusted for multiplicity. In the OITT population, at the cutoff date of August 19, 2020, with a median follow-up time of 5.8 months, the ORR was 15% (99% CI, 5.8 to 29.3) in the cabozantinib group versus 0% (99% CI, 0 to 14.8) in the placebo group (P = 0.028, considered not significant at the prespecified critical value of 0.01). At the cutoff date of February 8, 2021, with a longer median follow-up time (11.9 months), the ORR was 15% (99% CI, 9.4 to 22.7) in the cabozantinib group versus 0% (99% CI, 0 to 5.8) in the placebo group (P = 0.0005).
HRQoL was assessed with the EQ index (a converted normalized measure of the EQ-5D-5L score for different countries) and EQ VAS. In both HRQoL measures, there was immaturity in the data and no evidence of different effects between the 2 arms of the study throughout the length of the study at the end of week 65.
AEs were more prevalent in the cabozantinib group as compared to placebo (166 [98%] vs. 75 [85%] respectively) at the cutoff of February 8, 2021, and included diarrhea (62% vs. 3.4% respectively), palmar plantar erythema syndrome (PPES) (47% vs. 1.1%), hypertension (32% vs. 3.4%), decreased appetite (31% vs. 13%), fatigue (29% vs. 8%), nausea (28% vs. 2.3%), increased liver enzymes (25% vs. 2.3%), hypocalcemia (25% vs. 3.4%), and decreased weight (22 vs. 2.3%).
SAEs at the cutoff date of February 8, 2021 were also more common in the cabozantinib arm (66 patients [39%]) when compared to placebo (24 patients [27%]), and included diarrhea, pleural effusion, pneumonia, pulmonary embolism, and dyspnea. AEs of special interest also occurred more frequently in the cabozantinib group than in the placebo group, including severe diarrhea (7.6% vs. 0% respectively), thromboembolism (10% vs. 1.1%), hypertension (34% vs. 3.4%), elevated liver enzymes (25% vs. 2.3%), PPES (47% vs. 1.1%), and hypocalcemia (25% vs. 3.4%). There were no treatment-related deaths.
Overall, the COSMIC-311 trial is at low risk of bias. It was a double-blind randomized trial with adequate randomization, concealment allocation, masking, and assessment of outcomes. Some concerns of internal validity remain, arising from the high number of patients who crossed over from the placebo to the intervention group, and the possibility of patients and researchers being aware of the intervention administered due to AEs more commonly observed in the cabozantinib arm (potential unblinding). Overall baseline characteristics were balanced. The authors performed an adequate adjustment for multiplicity in the evaluation of the 2 co-primary end points, ORR and PFS. Other outcomes, including HRQoL, were not adjusted for multiple comparisons. Concerns regarding external validity included the exclusion of patients who had brain metastases or previous radiation therapy for bone metastases. Furthermore, the study had a relatively short period of follow-up (median of 11.9 months at the cutoff date of February 8, 2021) denoting immaturity of the data for estimation of OS. Interpretation of the OS data is also limited by the sample size and crossover of patients from placebo to open-label cabozantinib. There is a gap in the overall body of evidence since no comparative efficacy or harms data were available for comparators of interest in the Canadian clinical context, such as selpercatinib or larotrectinib, which are used in the targeted mutation settings.
No indirect treatment comparisons were included in this report.
No other relevant evidence was included in this report.
Cost and Cost-Effectiveness.
CADTH identified the following key limitations with the sponsor’s budget impact analysis: the expected market share for cabozantinib was likely underestimated; and the number of patients who would be eligible for public funding of cabozantinib is expected to be higher than the sponsor’s estimates. The CADTH reanalysis updated the market share for cabozantinib to reflect an uptake of 55%, 65%, and 75% in year 1, year 2, and year 3, respectively. In the CADTH base-case analysis, the 3-year budget impact of reimbursing cabozantinib is $23,209,107 ($6,252,383 in year 1, $7,699,525 in year 2, and $9,257,199 in year 3). The estimated budget impact is highly sensitive to the proportion of patients with RAI-R DTC who would receive cabozantinib.
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: September 14, 2022.
Regrets: Three expert pERC members did not attend.
Conflicts of interest: None.
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Indication: For the treatment of adult patients with locally advanced or metastatic differentiated thyroid carcinoma that has progressed following prior VEGFR-targeted therapy and who are radioactive iodine-refractory or ineligible
Sponsor: Ipsen Biopharmaceuticals Canada Inc.
Final recommendation: Reimburse with conditions
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