Indication: In combination with trastuzumab-capecitabine for the treatment of patients with locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer, including patients with brain metastases, who have received prior treatment with trastuzumab, pertuzumab, and trastuzumab emtansine (T-DM1), separately or in combination
Sponsor: Seagen Canada Inc.
Final recommendation: Reimburse with conditions
Summary
What Is the CADTH Reimbursement Recommendation for Tukysa?
CADTH recommends that Tukysa should be reimbursed by public drug plans for the treatment of patients with advanced human epidermal growth factor receptor 2 (HER2)-positive breast cancer that cannot be removed by surgery or is metastatic, including patients with brain metastases, if certain conditions are met.
What Are the Conditions for Reimbursement?
Tukysa should only be reimbursed if prescribed in combination with trastuzumab-capecitabine and the cost of Tukysa is reduced.
Which Patients Are Eligible for Coverage?
Tukysa should only be covered to treat patients who have been previously treated for HER2-positive breast cancer with trastuzumab, pertuzumab, and trastuzumab emtansine (T-DM1).
Why Did CADTH Make This Recommendation?
Evidence from a clinical trial demonstrated that Tukysa in combination with trastuzumab-capecitabine delayed disease progression and prolonged life compared with placebo plus trastuzumab-capecitabine.
Tukysa may meet some of the needs that are important to patients, including prolonging life.
Based on public list prices, Tukysa is not considered cost-effective at a willingness-to-pay threshold of $50,000 per quality-adjusted life-year (QALY) for patients included in the indication approved by Health Canada relative to other treatments that are already reimbursed by public drug plans in the second- or third-line setting. Economic evidence suggests that the price of Tukysa needs to be reduced by 48% for it to be cost-effective at a $50,000 per QALY threshold when used as a second-line treatment, and by 94% when used as a third-line treatment.
Based on public list prices, Tukysa is expected to cost the public drug plans $244 million over 3 years.
Additional Information
What Is HER2-Positive Breast Cancer?
HER2-positive breast cancers have higher than normal levels of HER2 protein and account for 15% to 20% of all breast cancers. Because HER2 can promote the growth of cancer cells, this type of breast cancer can be aggressive.
Unmet Needs in Advanced or Metastatic HER2-Positive Breast Cancer
There are no effective treatments available for patients with advanced or metastatic HER2-positive cancers who have failed on other treatment options, particularly patients with brain metastasis.
How Much Does Tukysa Cost?
Treatment with Tukysa in combination with trastuzumab-capecitabine is expected to cost approximately $12,216 for the first 21-day cycle and $11,710 for each subsequent 21-day cycle.
The CADTH pCODR Expert Review Committee (pERC) recommends that tucatinib in combination with trastuzumab and capecitabine be reimbursed for the treatment of patients with locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer, including patients with brain metastases, who have received prior treatment with trastuzumab, pertuzumab, and trastuzumab emtansine (T-DM1), separately or in combination, only if the conditions listed in Table 1 are met.
Evidence from 1 double-blind, phase II randomized controlled trial demonstrated that treatment with tucatinib in combination with trastuzumab-capecitabine resulted in added clinical benefit for adult patients with locally advanced unresectable or metastatic HER2-positive breast cancer, with or without brain metastases, who had received prior treatment with trastuzumab, pertuzumab, and T-DM1. The HER2CLIMB trial demonstrated that, when compared with placebo plus trastuzumab-capecitabine, treatment with tucatinib plus trastuzumab-capecitabine was associated with statistically significant and clinically meaningful improvements in progression-free survival (PFS) (stratified hazard ratio [HR] = 0.54; 95% confidence interval [CI], 0.42 to 0.71; P < 0.00001), PFS for patients with brain metastases (stratified HR = 0.48; 95% CI, 0.34 to 0.69, P < 0.00001), and overall survival (OS) (HR = 0.66; 95% CI, 0.50 to 0.88; P = 0.00480). Input from patient groups indicated that patients desire accessible and affordable treatment options that offer delayed disease progression, effective treatment for brain metastases, improved quality of life, and prolonged survival. Given the totality of the evidence, pERC concluded that tucatinib plus trastuzumab-capecitabine met some of the needs identified by patients because it provides an additional treatment option with improved PFS and OS and no deterioration in quality of life, and fulfills an unmet need for treatment of patients with brain metastases.
Using the sponsor-submitted price for tucatinib and publicly listed prices for all other drug costs, the incremental cost-effectiveness ratio (ICER) for tucatinib combination therapy is $512,403 per quality-adjusted life-year (QALY) compared to T-DM1 in the second-line setting and $381,429 per QALY compared to trastuzumab with capecitabine in the third-line setting. Tucatinib combination therapy is not cost-effective at a $50,000 per QALY willingness-to-pay (WTP) threshold for patients with locally advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received prior treatment with trastuzumab, pertuzumab, and T-DM1, separately or in combination. A reduction in price of at least 48% is required for tucatinib combination therapy to be considered cost-effective at a $50,000 per QALY threshold in the second-line setting, and a reduction in price of at least 94% is required for it to be considered cost-effective at a $50,000 per QALY threshold in the third-line setting.
Table 1: Reimbursement Conditions and Reasons
Reimbursement condition | Reason |
|---|---|
Initiation | |
1. Treatment with tucatinib plus trastuzumab-capecitabine should be initiated only in adults who have all of the following: 1.1. received at least 1 prior systemic treatment for HER2-positive locally advanced or metastatic breast cancer 1.2. received prior treatment with trastuzumab, pertuzumab, and T-DM1 1.3. HER2-positive status confirmed using ISH, FISH, or IHC methodology. | Evidence from the HER2CLIMB trial demonstrated that tucatinib plus trastuzumab-capecitabine resulted in significant improvements in PFS and OS in patients with locally advanced and HER2-positive breast cancer who had previously been treated with all of pertuzumab, trastuzumab, and T-DM1 treatments for breast cancer and had received at least 1 prior HER2-directed therapy in the advanced or metastatic setting. All patients in the HER2CLIMB trial had a confirmed HER2-positive status using IHC, ISH, or FISH testing methodologies. |
2. Patients must have an ECOG PS of 0 or 1. | The CADTH review identified no evidence to demonstrate a benefit of tucatinib in patients with ECOG PS > 1 at baseline because these patients were not enrolled in the HER2CLIMB trial. |
3. Patients must have adequate blood counts and organ function. | The CADTH review identified no evidence to demonstrate a benefit of tucatinib in patients with impaired hematologic parameters and organ function because the HER2CLIMB trial only enrolled patients with adequate hematologic parameters and organ function. |
Renewal | |
4. Assessment for renewal of tucatinib plus trastuzumab-capecitabine should be based on clinical and radiographic evaluation every 6 weeks to 9 weeks for the first 6 months after treatment initiation. | Efficacy assessments in the HER2CLIMB trial were performed every 6 weeks for the first 6 months and every 9 weeks thereafter. |
Discontinuation | |
5. Treatment with tucatinib should be discontinued upon the occurrence of any of the following: 5.1. In the event of documented disease progression (as per IWG response criteria), the combination of tucatinib, capecitabine, and trastuzumab should be discontinued. 5.2. In the event of unacceptable toxicity attributed to tucatinib, tucatinib alone may be discontinued and capecitabine and trastuzumab may be continued. | The CADTH review identified no evidence that continuing treatment with tucatinib in patients whose disease has progressed is effective. Patients who are unable to complete treatment with tucatinib due to unacceptable toxicity would likely not be able to receive further treatment with tucatinib. |
6. Treatment with tucatinib can continue if discontinuation is required for either capecitabine or trastuzumab due to toxicity. If trastuzumab and capecitabine are both discontinued, tucatinib must also be discontinued. | This condition reflects the treatment discontinuation criteria used in the HER2CLIMB trial. |
Prescribing | |
7. Tucatinib plus trastuzumab-capecitabine should only be prescribed by clinicians with expertise and experience in treating breast cancer in approved centres for trastuzumab infusion. | To ensure that the tucatinib plus trastuzumab-capecitabine combination is prescribed only for appropriate patients and adverse effects are managed in an optimized and timely manner. |
8. Tucatinib should only be prescribed in combination with trastuzumab-capecitabine for eligible patients. | There is no evidence to suggest an additional benefit of tucatinib as monotherapy or in combination with other treatments; tucatinib was administered in combination with trastuzumab-capecitabine in the HER2CLIMB trial. |
Pricing | |
9. A reduction in price. | The ICER for tucatinib combination therapy is $512,403 per QALY compared to T-DM1 in the second-line setting and $381,429 per QALY compared to trastuzumab with capecitabine in the third-line setting. A price reduction of 48% would be required for tucatinib combination therapy to be able to achieve an ICER of $50,000 per QALY compared to T-DM1 in the second-line setting. A price reduction of 94% would be required for tucatinib combination therapy to be able to achieve an ICER of $50,000 per QALY compared to trastuzumab with capecitabine in the third-line setting. |
FISH = fluorescence in situ hybridization; HER2 = human epidermal growth factor receptor 2; ICER = incremental cost-effectiveness ratio; IHC = immunohistochemistry; ISH = in situ hybridization; IWG = International Working Group; QALY = quality-adjusted life-year.
Issues that may impact the drug plan’s ability to implement a recommendation as identified by pERC and the drug plans are summarized in Table 2.
Table 2: Implementation Guidance From pERC
Condition number | Implementation considerations and guidance |
|---|---|
1 | All patients in the HER2CLIMB trial were pretreated with trastuzumab, pertuzumab, and T-DM1. Input from public drug programs indicated that, in Canada, pertuzumab (in combination with trastuzumab) is only funded in the metastatic and relapsed setting. pERC recognized that the subgroup of patients who have not received pertuzumab as part of a previous treatment regimen, in the adjuvant treatment setting, have a specific clinical need for an effective treatment in a locally advanced or metastatic setting. Therefore, pERC agreed with the clinical experts that combination therapy with tucatinib plus trastuzumab-capecitabine fills a treatment gap in patients who cannot receive pertuzumab or T-DM1 due to contraindications or toxicity issues, relapse early on T-DM1 (as a first-line or second-line therapy), and relapse early on trastuzumab (as a second-line or third-line treatment). pERC noted that the public drug programs may need to consider addressing the variability in funding of pertuzumab across jurisdictions to help facilitate an equitable access to tucatinib plus trastuzumab-capecitabine. |
2 | Although patients enrolled in the HER2CLIMB trial were required to have an ECOG PS of 0 or 1, pERC agreed that clinicians may consider using tucatinib plus trastuzumab-capecitabine for patients with an ECOG PS of 2. The decision to use this treatment for patients with an ECOG PS of 2 should be based on the judgment of the treating physician. |
4 | In the HER2CLIMB trial, CT or MRI occurred every 6 weeks for 24 weeks, and every 9 weeks thereafter, to assess disease status using RECIST 1.1 criteria. Patients with brain metastases were required to be assessed using MRI. pERC agreed with the clinical experts that MRI is the preferred modality for brain imaging. However, for patients with brain metastases, CT may be considered when an MRI is not available. The clinical experts indicated that, in clinical practice, imaging assessments are typically performed every 3 months to 6 months, based on a clinical judgment. pERC agreed that follow-up intervals and imaging assessments may be prolonged at the discretion of the treating physician. |
7 | Tucatinib and capecitabine both have the potential for drug-drug interactions and dose adjustments in the event of toxicities; therefore, pERC noted that jurisdictions may need to provision adequate pharmacy resources to ensure accurate and safe administration of this regimen. |
8 | Input from public drug programs indicated that combination therapy with tucatinib plus trastuzumab-capecitabine, including both oral and IV agents, would need to be reimbursed through different drug programs in most jurisdictions. Some jurisdictions may have a co-pay for patients as part of funding for tucatinib and capecitabine. pERC noted that, upon implementation of the tucatinib reimbursement, jurisdictions would need to fund trastuzumab in the third-line setting for patients who are eligible to receive tucatinib in combination with trastuzumab-capecitabine. The public drug program expressed a concern about the complexity of administration of oral tucatinib and capecitabine due to differences in cyclical days of administration, twice-daily dosing, and multiple tablets required per drug per dose. pERC recognized that jurisdictions may need to establish detailed patient and caregiver education to address potential issues with outpatient dosing schedules and pill burden. |
9 | CADTH reanalyses estimated the incremental budget impact of reimbursing tucatinib combination therapy to be $64,395,873 in year 1, $80,786,751 in year 2, and $99,110,926 in year 3, for a 3-year expected total budget impact of $244,293,549. Therefore, the feasibility of reimbursing tucatinib combination therapy must be addressed. |
ECOG PS = Eastern Cooperative Oncology Group performance status; pERC = CADTH pCODR Expert Review Committee; RECIST 1.1 = Response Evaluation Criteria in Solid Tumours Version 1.1; T-DM1 = trastuzumab emtansine.
Based on input from clinical experts, pERC acknowledged that there is an unmet treatment need for patients with advanced or metastatic HER2-positive breast cancer in the third-line setting because no standard of care is currently available for these patients following disease progression on second-line therapy. The clinical experts noted that HER2-positive breast cancer patients with brain metastases do not have effective systemic treatment options and are often excluded from clinical trials, resulting in significant unmet need in this patient subgroup.
pERC discussed the results of a randomized phase II trial (HER2CLIMB) that demonstrated significant improvements in PFS and OS. The trial results showed greater improvement in PFS among a subgroup of patients with brain metastases, a group of patients with limited effective treatment options available. pERC agreed that the available evidence supports the comparative efficacy of tucatinib in combination with trastuzumab-capecitabine over trastuzumab plus capecitabine alone in the treatment of patients who are often difficult to treat using current treatment options in Canadian practice.
pERC acknowledged that there was a lack of direct evidence to show the comparative effectiveness of tucatinib plus trastuzumab-capecitabine versus other alternative therapies. One sponsor-submitted indirect treatment comparison (ITC) suggested that combination therapy with tucatinib plus trastuzumab-capecitabine may be more efficacious than capecitabine, neratinib, lapatinib plus capecitabine, and trastuzumab plus capecitabine. However, there were several significant limitations to the submitted ITC which introduced uncertainty about its overall results. Specifically, the sponsor’s ITC included studies that reported heterogeneity in trial and patient characteristics, lack of adjustment for relevant effect modifiers (e.g., prior exposure to treatments, line of therapy, and presence of brain metastases), and violation of the proportional hazard assumption, particularly for the analysis of PFS. Although these sources of bias introduced uncertainty about the magnitude of the estimates for between-treatment comparisons, pERC agreed with the CADTH review team that the overall direction of the ITC estimates could be considered reliable. However, the Committee acknowledged that many of the treatment options included in the ITC are not currently reimbursed by public drug plans for patients with locally advanced unresectable or metastatic HER2-positive breast cancer in Canada.
No differences in HRQoL (as measured using the EuroQol 5-Dimensions 5-Levels [EQ-5D-5L]) were observed in the HER2CLIMB trial between the tucatinib-combination and placebo-combination groups. Overall pERC agreed that tucatinib did not result in deterioration of patients’ quality of life. However, pERC noted that the patient-reported outcomes in the HER2CLIMB trial were exploratory in nature and only descriptive results were presented. Therefore, only limited interpretations could be made based on the available quality of life data.
Input from patient groups indicated that patients desire accessible and affordable treatment options that offer delayed disease progression, effective treatment for brain metastases, improved quality of life, and prolonged survival. pERC concluded that tucatinib plus trastuzumab-capecitabine aligns with some of the patient needs because this combination offers meaningful improvements in PFS and OS with no deterioration in quality of life, and fulfills an unmet need in patients with brain metastases by providing them with an effective and tolerable systemic treatment option. However, different funding mechanisms for oral medications across Canada and the high cost of tucatinib may lead to administrative and financial barriers to access to this combination for many patients. In addition, the complexity of administration of oral tucatinib and capecitabine will require additional pharmacy resources to provide patient and caregiver education to ensure appropriate use and to understand how to monitor toxicities.
pERC discussed the safety profile of tucatinib and noted that, in the HER2CLIMB trial, grade 3 or higher adverse events (AEs) and serious adverse events (SAEs) were reported in similar proportion of patients in the tucatinib-combination and placebo-combination groups. pERC also noted that most AEs observed in the pivotal trial were grade 1 or grade 2 in severity, with the most commonly reported AEs in the tucatinib group being diarrhea, hand-foot syndrome, nausea, fatigue, and vomiting. Overall, pERC agreed that tucatinib was associated with a manageable toxicity profile.
Input submitted to CADTH by the provincial advisory group (PAG) indicated that, in Canada, pertuzumab (in combination with trastuzumab) is only funded in the relapsed or metastatic setting. PAG noted that patients with disease relapse during adjuvant trastuzumab therapy or within 6 months of completing adjuvant trastuzumab therapy are eligible to receive T-DM1 at disease relapse but are not eligible for funding for pertuzumab-trastuzumab in some jurisdictions. PAG identified that this subset of patients was not addressed in the HER2CLIMB population and sought guidance on the appropriateness of the tucatinib combination with patients who have not received prior treatment with pertuzumab if subsequent disease progression occurs after treatment with T-DM1. pERC acknowledged that no evidence was included in the review to show the efficacy and safety of the tucatinib combination therapy in the subgroup of patients who had not received pertuzumab as part of a previous treatment regimen. However, the Committee felt that variability in funding of pertuzumab across jurisdictions may not be equitable to all Canadian patients in terms of treatment options. pERC noted that patients who cannot receive pertuzumab or T-DM1 due to contraindications or toxicity issues and patients who relapse early on T-DM1 or trastuzumab in the adjuvant setting would benefit from the tucatinib combination. Therefore, pERC suggested that the variability in funding practices for pertuzumab should be further discussed by the public drug programs and addressed to help facilitate an equitable access to the tucatinib combination.
Tucatinib, in combination with trastuzumab-capecitabine, is approved by Health Canada for the treatment of patients with locally advanced or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received prior treatment with trastuzumab, pertuzumab, and T-DM1, separately or in combination. Tucatinib is a tyrosine kinase inhibitor (TKI) of the HER2 protein. It is available as 50 mg and 150 mg oral tablets; the Health Canada–approved dose is 300 mg orally twice daily combined with trastuzumab (6 mg/kg of body weight IV once every 21 days) and capecitabine (1,000 mg/m2 of body surface area orally twice daily on days 1 to 14 of each 21-day cycle).
To make their recommendation, the Committee considered the following information:
a review of 1 randomized controlled phase II trial in patients with locally advanced or metastatic HER2-positive breast cancer
patients’ perspectives gathered by 3 patient groups: the Canadian Breast Cancer Network (CBCN), Rethink Breast Cancer, and the CanCertainty Coalition
input from public drug plans and cancer agencies that participate in the CADTH review process
three clinical specialists with expertise diagnosing and treating patients with advanced HER2-positive breast cancer
input from 2 clinician groups, including Ottawa Hospital Cancer Centre’s (OHCC) Breast Disease Site Group and Ontario Health-Cancer Care Ontario (OH-CCO)’s Breast Disease Site Advisory Committee
a review of the pharmacoeconomic model and a report submitted by the sponsor.
Three patient groups provided input for the review of tucatinib: CBCN, Rethink Breast Cancer, and the CanCertainty Coalition. Information from CBCN was obtained via online surveys. Information from Rethink Breast Cancer was obtained using an online patient survey and patient interviews. Input from CanCertainty was based on published reports on statistics of breast cancer and patient drug coverage.
Patient groups stated that treatment options vary for patients depending on the line of therapy and patient characteristics. Trastuzumab and pertuzumab were reported to be the most commonly received treatments from patients, followed by T-DM1, capecitabine, paclitaxel, docetaxel, and trastuzumab-pertuzumab-T-DM1. Commonly reported side effects of treatment included fatigue, diarrhea, nausea, and insomnia, all of which had a notable impact on quality of life. The patient groups identified a lack of effective treatment options for patients with brain metastases, who are typically offered local therapies including surgery and radiation.
Eight patients were identified as having experience with tucatinib, including 6 patients with brain metastases. Commonly reported side effects due to treatment with tucatinib included diarrhea, decreased appetite, fatigue, nausea, hand-foot syndrome, and rash. In general, patients reported that side effects from tucatinib were manageable and did not negatively impact their quality of life. The patient groups highlighted the importance of delayed progression, improved quality of life, and survival as expectations for new treatments. Additional treatment options that are accessible and affordable were also acknowledged as an important need for patients.
The clinicians consulted by CADTH identified unmet treatment needs for patients with advanced or metastatic HER2-positive breast cancer because patients lack an effective standard of care following progression on second-line therapy. In particular, patients with brain metastases lack effective systemic treatment options and are often excluded from clinical trials, resulting in significant unmet need in this patient subgroup. Tucatinib in combination with trastuzumab-capecitabine was suggested to be administered as per the HER2CLIMB trial eligibility criteria and dosing schedule, and mainly in the third-line treatment setting. Tucatinib was suggested not to be used for patients with poor Eastern Cooperative Oncology Group Performance Status (ECOG PS), as in an ECOG PS of 2 to 4. However, patients with an ECOG PS of 2 may be considered for treatment with tucatinib based on the judgment of the treating physician. Because tucatinib is administered along with capecitabine and trastuzumab, tucatinib was stated to be administered in an outpatient clinical setting. Discontinuation of tucatinib should occur if there is evidence of disease progression or lack of benefit to patients with continued treatment, a patient has poor performance status, or if a patient experiences severe treatment toxicity.
Two group clinician inputs were received on behalf of OHCC Breast Disease Site Group and OH-CCO Breast Disease Site Advisory Committee. Both groups stated that, after first-line treatment with a combination of taxane chemotherapy, trastuzumab, and pertuzumab, and second-line treatment with T-DM1, no standard third-line options are available for HER2-positive metastatic breast cancer patients. Third-line treatment options may differ across jurisdictions and across countries. Both groups also acknowledged that there are limited treatment options for patients with brain metastases, aside from surgery and radiation. Both clinician group inputs suggested that tucatinib would be used in the third-line treatment setting. Both groups acknowledged that tucatinib combination therapy addresses patient needs because it demonstrated improved efficacy in patients with and without brain metastases.
Input from PAG identified factors pertaining to relevant comparators, generalizability, and considerations for initiation, renewal, and discontinuation of therapy. The clinical experts consulted by CADTH weighed evidence from the HER2CLIMB trial and other clinical considerations to provide responses which are presented in Table 3.
Table 3: Responses to Questions From the Drug Programs
Implementation issues | Response |
|---|---|
Relevant comparators | |
The combination of trastuzumab plus capecitabine (comparator in HER2CLIMB) is not a funded therapy in most Canadian jurisdictions when used after pertuzumab, trastuzumab, and T-DM1. Funded therapies in this setting include capecitabine (monotherapy) and various other chemotherapy options. How does the combination of tucatinib-trastuzumab-capecitabine compare in efficacy and/or tolerability to chemotherapy alone? | No direct evidence comparing tucatinib plus trastuzumab-capecitabine to chemotherapy alone was identified in this CADTH review; therefore, the clinical experts consulted by CADTH noted that efficacy and safety comparisons to the available chemotherapy regimens cannot be known with certainty. However, based on the limited indirect evidence reviewed, the clinical experts suggested that combination therapy with tucatinib plus trastuzumab-capecitabine would likely be more efficacious than chemotherapy alone. The clinical experts acknowledged that there may be additional toxicities to consider with the tucatinib combination regimen compared with chemotherapy alone, including diarrhea, hand-foot syndrome, fatigue, nausea and/or emesis, elevated liver enzymes, and a small risk of cardiotoxicity. |
Some jurisdictions fund the combination of lapatinib plus capecitabine for patients with disease progression after trastuzumab-based therapy. Is lapatinib-capecitabine a relevant comparator to tucatinib-trastuzumab-capecitabine? If so, how do they compare with regards to efficacy and/or tolerability? | The clinical experts agreed that lapatinib plus capecitabine is a relevant comparator to the combination therapy with tucatinib plus trastuzumab-capecitabine. However, there is no direct evidence comparing tucatinib plus trastuzumab-capecitabine to lapatinib plus capecitabine directly. The clinical experts noted the choice of comparator (trastuzumab plus capecitabine) was made in the HER2CLIMB trial based on the CEREBREL trial, which compared combination therapy with lapatinib and capecitabine with trastuzumab plus capecitabine. The indirect comparisons between the HER2CLIMB and CEREBREL trials suggest that tucatinib plus trastuzumab-capecitabine may perform better than lapatinib plus capecitabine for PFS and OS. The clinical experts |
expected that there may be fewer or equal rates of diarrhea and nausea with the tucatinib combination therapy because lapatinib and capecitabine are associated with more of these toxicities than trastuzumab plus capecitabine. Overall, pERC agreed with the clinical experts consulted by CADTH that, without rigorous direct comparative evidence, the comparative efficacy and tolerability of each regimen remain uncertain. | |
Considerations for initiation of therapy | |
All patients in the HER2CLIMB trial were pretreated with trastuzumab, pertuzumab, and T-DM1. In Canada, pertuzumab (in combination with trastuzumab) is only funded in the metastatic or relapsed setting. Patients with disease relapse during adjuvant trastuzumab or within 6 months of completing adjuvant trastuzumab therapy are eligible to receive T-DM1 at disease relapse but are not eligible for funding for pertuzumab-trastuzumab in some jurisdictions. Therefore, this subset of patients was not addressed in the HER2CLIMB population. Should eligibility for tucatinib-trastuzumab-capecitabine be limited to patients with prior exposure to T-DM1, trastuzumab, and pertuzumab? | The clinical experts consulted by CADTH agreed that eligibility for treatment with tucatinib plus trastuzumab-capecitabine should be limited to patients with prior exposure to trastuzumab, pertuzumab, and T-DM1, as per the eligibility criteria of the HER2CLIMB trial. However, despite a lack of evidence to show the efficacy and safety of the tucatinib combination therapy in the subgroup of patients who have not received pertuzumab as part of a previous treatment regimen, pERC recognized that the subgroup of patients who have not received pertuzumab as part of a previous treatment regimen have a specific clinical need for an effective treatment in locally advanced or metastatic settings. Therefore, pERC agreed with the clinical experts that combination therapy with tucatinib plus trastuzumab-capecitabine would fill a treatment gap in patients who cannot receive pertuzumab or T-DM1 due to contraindications or toxicity issues and patients who relapse early on T-DM1 or trastuzumab in the adjuvant setting. pERC noted that public drug programs may need to consider addressing the variability in funding of pertuzumab across jurisdictions to help facilitate equitable access to tucatinib plus trastuzumab-capecitabine. |
HER2CLIMB excluded patients who received prior capecitabine or a HER2-targeted tyrosine kinase inhibitor (unless completed more than 12 months before trial). Are patients with previous treatment with lapatinib eligible to receive the tucatinib plus trastuzumab-capecitabine combination? | pERC agreed with the clinical experts consulted by CADTH that patients previously treated with capecitabine in the metastatic setting should not be treated with the tucatinib combination therapy. However, pERC agreed that upon the implementation of a funding recommendation for tucatinib plus trastuzumab-capecitabine, jurisdictions may consider addressing the time-limited need for this combination treatment in all otherwise eligible patients who are currently receiving single-agent capecitabine and who have not experienced disease progression. Prior treatment with lapatinib was permitted within the HER2CLIMB trial as long as patients had received lapatinib > 12 months before initiating HER2CLIMB trial regimens. Therefore, pERC agreed that patients may be eligible for treatment with tucatinib in combination with trastuzumab-capecitabine if they were previously treated with lapatinib, as long as they had completed (or stopped) treatment with lapatinib at least 12 months before initiating tucatinib combination therapy. |
HER2CLIMB included patients with brain metastases. For patients with brain metastases, how does efficacy and tolerability of the tucatinib-trastuzumab-capecitabine combination compare with currently funded comparators (e.g., chemotherapy)? | The clinical experts consulted by CADTH noted that there were no direct comparisons of the tucatinib combination to lapatinib plus capecitabine or chemotherapy alone. The clinical experts indicated that most chemotherapeutic agents currently used for patients with brain metastases have poor penetration to CNS. Hence, the clinical experts considered treatment with tucatinib plus trastuzumab-capecitabine would be a more a reasonable treatment than chemotherapy alone for patients with brain metastasis. The clinical experts noted that, in the HER2CLIMB trial, tucatinib plus trastuzumab-capecitabine demonstrated a statistically and clinically significant PFS benefit over trastuzumab plus capecitabine in patients with brain metastases and, in the CEREBEL trial, PFS in patients with brain metastases was not statistically different between the lapatinib plus capecitabine and trastuzumab plus capecitabine combination therapy groups. Given that lapatinib is known to have CNS activity, the clinical experts suggested that it was difficult to assume that the tucatinib combination would be superior to lapatinib plus capecitabine in the subgroup of patients with brain metastases. |
The combination of tucatinib-trastuzumab-capecitabine is proposed for use after pertuzumab, trastuzumab, and T-DM1. Is it appropriate to offer the tucatinib plus trastuzumab-capecitabine combination to patients, otherwise eligible for HER2CLIMB criteria, who are currently receiving systemic therapy (e.g., capecitabine) with no evidence of progressive disease or intolerance? | The clinical experts agreed that it would be appropriate to offer tucatinib plus trastuzumab-capecitabine to these patients. pERC agreed that upon the implementation of a funding recommendation for tucatinib plus trastuzumab-capecitabine, jurisdictions may consider addressing the time-limited need for this combination treatment in all otherwise eligible patients who are currently receiving systemic therapy (e.g., capecitabine) and who have not experienced disease progression. |
Considerations for continuation or renewal of therapy | |
In HER2CLIMB, CT or MRI occurred every 6 weeks for 24 weeks, and every 9 weeks thereafter, to assess disease status using RECIST 1.1 criteria. Patients with brain metastases were required to be assessed using MRI. In practice, which modality and frequency are most appropriate to assess disease status in patients receiving the tucatinib-trastuzumab-capecitabine combination? Do all patients with brain metastases require assessment by MRI and not CT? | To assess patient’s disease status, the clinical experts consulted by CADTH stated that patients can be assessed using CT scans, with or without bone scans, in addition to clinical assessments. pERC agreed with the clinical experts that MRI is the preferred modality for brain imaging. However, for patients with brain metastases, CT may be considered when an MRI is not available. The clinical experts indicated that, in clinical practice, imaging assessments are typically performed every 3 months to 6 months, based on clinical judgment. pERC agreed that follow-up intervals may be prolonged at the discretion of the treating physician. |
Considerations for discontinuation of therapy | |
In HER2CLIMB, patients with only brain disease progression were eligible to continue on study drugs after completion of local treatment (e.g., radiotherapy, surgery). In practice, which patients will be eligible to continue on the tucatinib plus trastuzumab-capecitabine combination despite documented disease progression? | pERC agreed with the clinical experts consulted by CADTH that patients with disease progression in an isolated brain lesion which is amenable to local therapies (i.e., radiation therapy or surgery) would be eligible to continue receiving tucatinib plus trastuzumab-capecitabine after the completion of the local treatment. |
In HER2CLIMB, patients who discontinued either capecitabine or trastuzumab (but not both) remained on tucatinib treatment. Patients who discontinued tucatinib or both of capecitabine and trastuzumab were not permitted to remain in the study. In practice, are treatment discontinuation parameters from HER2CLIMB reasonable? | The clinical experts consulted by CADTH considered the treatment discontinuation parameters in the HER2CLIMB trial to be reasonable, in general. However, in some clinical cases, patients may need to discontinue tucatinib due to treatment-related toxicity, and clinicians may consider keeping patients on treatment with trastuzumab plus capecitabine. The clinical experts stressed that continuing patients on treatment with trastuzumab plus capecitabine should be made at the treating physician’s discretion, considering the risks and benefits of discontinuing each treatment option. The clinical experts agreed that patients who experience disease progression would typically need to be considered for treatment with a different regimen. |
The combination of tucatinib plus trastuzumab-capecitabine is proposed for use after pertuzumab, trastuzumab, and T-DM1. Is it appropriate to offer the tucatinib plus trastuzumab-capecitabine combination to patients otherwise eligible by HER2CLIMB criteria who are currently receiving systemic therapy (e.g., capecitabine) with no evidence of progressive disease or intolerance? | The clinical experts consulted by CADTH agreed that it would be appropriate to offer tucatinib in combination with trastuzumab-capecitabine to patients who are currently receiving systematic therapy (e.g., capecitabine) who have no evidence of disease progression or intolerance if the patient is otherwise eligible to receive the tucatinib combination. |
Considerations for prescribing of therapy | |
The combination of tucatinib-trastuzumab-capecitabine will add trastuzumab doses for a patient population that currently does not receive funding for trastuzumab. This will increase health system resource use (chair time, sterile compounding). Self-administration of oral tucatinib and capecitabine is complex due to differing cyclical days of administration, twice-daily dosing, and multiple tablets required per drug per dose. | pERC noted that jurisdictions may need to establish detailed patient and caregiver education to address potential issues around outpatient dosing schedules and pill burden. |
The combination of tucatinib, trastuzumab, and capecitabine includes oral and IV drugs that would be reimbursed through different drug programs in most jurisdictions. Some jurisdictions may have a co-pay for patients as part of funding for tucatinib and capecitabine. | pERC noted that, upon implementation of the tucatinib reimbursement recommendation, jurisdictions would need to fund trastuzumab for patients who are eligible to receive tucatinib in combination with trastuzumab-capecitabine. |
Generalizability | |
Patients with an ECOG PS of > 1 were excluded from the HER2CLIMB trial. Which performance status is most appropriate for treatment with the tucatinib plus trastuzumab-capecitabine combination? | Patients with an ECOG PS of 0 or 1 were enrolled into the HER2CLIMB trial, and clinical experts agreed that these patients would be most appropriate for treatment with tucatinib in combination with trastuzumab-capecitabine. Although patients enrolled in the HER2CLIMB trial were required to have an ECOG PS of 0 or 1, pERC agreed that clinicians may consider using tucatinib plus trastuzumab-capecitabine for patients with an ECOG PS of 2. The decision to use this treatment for patients with an ECOG PS of 2 should be based on the judgment of the treating physician. |
Care provision issues | |
Tucatinib is supplied in 50 mg and 150 mg strengths in bottles of 60 tablets; the 150 mg tablet size is also available in a bottle of 120 tablets. The product monograph indicates that “A 2 g desiccant canister with silica gel is enclosed with the tablets in each bottle. Dispense only in original container. Do not discard desiccant. Replace cap securely each time after opening. Discard any unused tablets 3 months after opening the bottle.” As tucatinib must be dispensed in the original container:
| pERC noted that jurisdictions may need to provision adequate pharmacy resources to provide appropriate patient and caregiver education to ensure accurate and safe administration of this regimen. |
Determination of HER2 status is part of routine management of breast cancer in all Canadian jurisdictions. | pERC agreed that no companion diagnostic tests are required for the implementation of a funding recommendation for tucatinib plus tucatinib plus trastuzumab-capecitabine. |
System and economic issues | |
This combination has a high cost per cycle per patient and thus would have budget impact. In addition to new costs for tucatinib, this combination would introduce a new line of therapy for trastuzumab (which is currently not funded in this setting in most jurisdictions) and possible increased use and/or duration of capecitabine. Using the proposed list price, daily cost of tucatinib would be the same for a dose of 300 mg twice daily or 250 mg twice daily. | pERC noted that the feasibility and equity issues around reimbursing tucatinib combination therapy must be addressed by jurisdictions, upon implementation of a funding recommendation. |
CNS = central nervous system; ECOG PS = Eastern Cooperative Oncology Group Performance Status; OS = overall survival; pERC = CADTH pCODR Expert Review Committee; PFS = progression-free survival; RECIST 1.1 = Response Evaluation Criteria in Solid Tumours Version 1.1; T-DM1 = trastuzumab emtansine.
One multicentre, multinational, double-blind, randomized controlled phase II trial met the criteria for the CADTH systematic review protocol. The HER2CLIMB trial evaluated the efficacy and safety of tucatinib in combination with trastuzumab-capecitabine compared with placebo in combination with trastuzumab-capecitabine which, from here on, will be referred to as the tucatinib-combination group and the placebo-combination group, respectively. Eligible patients included adults with histologically confirmed HER2-positive advanced breast cancer, confirmed using immunohistochemistry, in situ hybridization, or fluorescence in situ hybridization testing. Patients must have had prior treatment with pertuzumab, trastuzumab, and T-DM1, measurable disease using RECIST 1.1 (Response Evaluation Criteria in Solid Tumours Version 1.1) criteria and an ECOG PS of 0 or 1. Patients with brain metastases were also eligible for enrolment. Presence of brain metastases was based on medical history and screening contrast brain MRI, as assessed by an investigator. This international trial was conducted in 15 countries across 155 sites, including a total of 38 patients from Canada. A total of 410 patients were randomized to the tucatinib-combination group and 202 patients were randomized to the placebo-combination group. Randomization was stratified according to the following: presence of brain metastases (yes versus no), ECOG PS (0 versus 1), and geographic region (US versus Canada versus rest of the world).
The doses of each treatment in the tucatinib-combination group were as follows:
Tucatinib (300 mg) was administered orally twice daily.
Capecitabine (1,000 mg/m2) was administered orally twice daily on days 1 to 14 of each 21-day cycle.
Trastuzumab was administered with an initial loading dose of 8 mg/kg IV, after which trastuzumab was administered at 6 mg/kg once every 21 days, except in specific circumstances when it was given weekly to compensate for modifications to the treatment schedule. Alternatively, trastuzumab could have been administered at a dose of 2 mg/kg IV every week (7 days), but only in circumstances when the trastuzumab infusion had been delayed, and weekly infusions were required to resynchronize the cycle length to 21 days, after discussion with a medical monitor.
Subcutaneous use of trastuzumab was permitted; in such instances when subcutaneous trastuzumab was administered, a fixed dose of 600 mg was provided without a loading dose. Subcutaneous trastuzumab was administered once every 3 weeks because there was no allowance for weekly dosing. Crossover from IV to subcutaneous trastuzumab was permitted within the trial.
If national regulatory authorities approved use of a trastuzumab biosimilar, either IV or subcutaneous, biosimilar trastuzumab could also be administered for patients if considered appropriate by the investigator.
The doses of treatments in the placebo-combination group were the same as the tucatinib-combination group, placebo tablets replacing tucatinib twice daily. Treatment for patients continued until unacceptable toxicity, disease progression, withdrawal of consent, or study closure.
The primary end point of the trial was PFS. Key secondary end points that were part of a hierarchical testing scheme included PFS among patients with brain metastases and OS. Other secondary and exploratory end points included objective response rate (ORR), PFS assessed by investigator, duration of response, and HRQoL assessed using the EQ-5D-5L.
Baseline characteristics of the HER2CLIMB trial were generally well balanced across both treatment groups in both the intention-to-treat (ITT) (N = 612) and ITT-PFS (N = 480) populations; baseline characteristics were also similar across both trial populations. In the ITT population, patients had a mean age of 54 years and most patients (> 80%) were younger than 65 years of age. Most patients were White (74%) and from the US (54%) or the rest of the world (40%). Relatively equal proportions of patients had an ECOG PS of 0 (48%) or 1 (51%). The majority of patients had metastatic disease (≥ 99%) and were positive for at least 1 hormone receptor (61%) or negative for both (38%). Non-CNS metastases were reported among 98% of patients; the most frequent metastasis sites were lung (49%), bone (55%), and liver (36%). Brain metastases were reported in 48% of patients. A mean of 4 lines of prior therapy were reported by all patients in both treatment groups, with a mean of 3 prior therapies, specifically in the metastatic setting. As per the eligibility criteria, all patients had received prior treatment with trastuzumab and T-DM1, and 99% of patients had also received prior therapy with pertuzumab.
Key efficacy results of the HER2CLIMB trial were reported based on a data cut-off date of September 4, 2019, and were considered to be the final analyses. Results of the primary outcome (PFS: stratified HR = 0.54; 95% CI, 0.42 to 0.71; stratified log-rank P < 0.00001) and key secondary end points (PFS for patients with brain metastases: stratified HR = 0.48; 95% CI, 0.34 to 0.69, stratified log-rank P < 0.00001; OS: HR = 0.66; 95% CI, 0.50 to 0.88; stratified log-rank P = 0.00480) indicated a statistically significant improvement in patients in the tucatinib-combination group over those in the placebo-combination group. ORR was considered as another secondary end point, and it also supported the results of the primary and key secondary analyses showing improved efficacy with the tucatinib-combination treatment versus the placebo-combination treatment. A post hoc analysis was conducted by the sponsor which provided an additional 15.6 months of follow-up time. The post hoc analysis provided updated data for OS and PFS, assessed among all randomized patients. Results of the post hoc analyses continued to support trastuzumab-combination therapy over the placebo-combination therapy. The assessments conducted as post hoc analyses were not formally tested; therefore, they should be considered descriptive. HRQoL data did not indicate any differences in EQ-5D-5L scores between patients in the tucatinib-combination and placebo-combination groups.
Safety data are reported based on a data cut-off data of September 4, 2019. In general, AEs were more commonly reported among patients in the tucatinib-combination group. The most common AEs of any grade in both the tucatinib-combination group and the placebo-combination group were diarrhea (80.9% versus 53.3%), hand-foot syndrome (63.4% versus 52.8%), nausea (58.4% versus 43.7%), fatigue (45.0% versus 43.1%), and vomiting (35.9% versus 25.4%); however, the proportion of patients experiencing these AEs was greater in the tucatinib-combination group. A total of 223 patients (55.2%) in the tucatinib-combination group experienced a AEs of grade 3 or higher compared with 96 patients (48.7%) in the placebo-combination group. In both the tucatinib-combination group and placebo-combination group, the most commonly reported AEs of grade 3 or higher were hand-foot syndrome (13.1% versus 9.1%) and diarrhea (12.9% versus 8.6%). A time-at-risk exposure-adjusted analysis of AEs of grade 3 or higher of hand-foot syndrome, diarrhea, and increased ALT and AST were performed to adjust for the longer exposure to treatment patients in the tucatinib-combination group experienced because these patients had a longer duration of treatment than patients in the placebo-combination group. After adjustment, the crude incidence of AEs of grade 3 or higher of hand-foot syndrome (13.1% versus 9.1%), diarrhea (12.9% versus 8.6%), ALT increase (5.4% versus 0.5%), and AST increase (4.5% versus 0.5%) were all higher in the tucatinib-combination group than the placebo-combination group, respectively; the time-at-risk exposure-adjusted incidence rates per 100 person-years were 21 versus 19, 21 versus 17, 8 versus 1, and 7 versus 1, respectively. SAEs of any grade were reported in similar proportions of patients in the tucatinib-combination and placebo-combination groups (25.7% and 26.9%, respectively). Grade 5 AEs were reported in 8 patients (2.0%) in the tucatinib-combination group and 6 patients (3.0% in the placebo-combination group).
The HER2CLIMB trial was an international, multicentre, double-blind, placebo-controlled phase II randomized controlled trial. The baseline demographic and clinical characteristics were balanced across the treatment groups, overall and across important analysis populations (i.e., ITT and ITT-PFS populations). Patients were randomized based on presence of brain metastases (yes versus no), ECOG PS (0 versus 1), and geographic region (US versus Canada versus rest of the world). This helped to ensure that the comparability between treatment arms in the subgroup analysis results according to each prespecified stratification factor. The sponsor also included specifications for a biased-coin assignment in the randomization scheme to prevent imbalances between treatment groups and any given hierarchical level (i.e., overall treatment group balance then treatment group balance within each stratification factor).
Results of the HER2CLIMB trial demonstrated statistically significantly improved OS and PFS among patients treated in the tucatinib-combination group compared with the placebo-combination group. In general, subgroup analyses favoured treatment with the tucatinib-combination group versus the placebo-combination group. However, it should be acknowledged that although subgroups for subgroup analyses were prespecified, they were not adjusted for multiplicity nor powered to detect differences, and may be indicative of imprecision due to wide confidence intervals. The lack of adjustment for subgroup analyses may increase the likelihood of type I error, resulting in an increased likelihood of detecting a treatment effect when one may not be present. The sponsor conducted a post hoc analysis that provided 15.6 months longer follow-up time (resulting in a total of 29.7 months of total follow-up time for the tucatinib-combination group and 29.4 months of total follow-up time for the placebo-combination group), and provided additional efficacy (OS, PFS) and safety data. After the primary analysis, the trial was unblinded and assessments for PFS were conducted by the investigator. The results of the post hoc analysis were consistent with results of the primary analysis, which remained blinded, and used the PFS results assessed by a blinded independent central review.
It is possible that choice of subsequent therapies could have affected efficacy assessments of OS because analyses for OS included patients who received subsequent therapies. A total of 202 patients (69.2%) in the tucatinib-combination group and 139 patients (79.4%) in the placebo-combination group received subsequent anti-cancer therapies. There were disproportional differences noted between treatment groups in types of subsequent anti-cancer therapies received because more patients in the placebo-combination group received antibody (57.1% versus 50.0%, respectively) and TKI (24.0% versus 16.8%) anti-HER2 regimens, and trastuzumab (12.2% versus 5.4%), while more patients in the tucatinib-combination group than in the placebo-combination group received trastuzumab plus chemotherapy (20.8% versus 15.8%, respectively). The differences in subsequent therapies are expected to introduce bias in the efficacy analyses of OS and other patient outcomes. However, the direction and extent of the biases are difficult to predict.
Standard first-line therapies for patients with MBC may include treatment with pertuzumab in combination with trastuzumab and taxane followed by pertuzumab plus trastuzumab. Second-line therapies for these patients may include T-DM1. Eligibility criteria in the HER2CLIMB trial specified that all patients must have had prior treatment with trastuzumab, pertuzumab, and T-DM1. Therefore, the patient population of patients in the HER2CLIMB trial is likely reflective of patients in the Canadian population and the treatment algorithms standard in Canadian clinical practice. Prior treatment with trastuzumab, T-DM1, and pertuzumab was not required to have specifically been in the metastatic setting; although, most patients did receive each agent in the metastatic setting, with some patients receiving it in both the neoadjuvant/adjuvant and metastatic settings, and few patients receiving prior therapy in the neoadjuvant/adjuvant setting only. The sponsor noted that the treatment landscape for HER2-positive breast cancer patients has changed drastically since completion of patient enrolment for the HER2CLIMB trial. During patient enrolment, T-DM1 was approved for and used only in the metastatic setting; however, since completion of patient enrolment, T-DM1 has been approved for use in the adjuvant setting. Almost all patients in the HER2CLIMB trial (> 98%) reported receiving prior therapy with T-DM1 in the metastatic setting only. It is expected that a greater proportion of patients in clinical practice will have received prior therapy with T-DM1 in other treatment settings as well.
In the Health Canada–approved product monograph, tucatinib in combination with trastuzumab-capecitabine is indicated for patients who have received at least 1 prior HER2-directed therapy in the metastatic setting. The treatment landscape for patients with MBC is complex and has changed to include new HER2-directed treatments, such as pertuzumab and T-DM1. Patients in the HER2CLIMB trial reported having received a mean of 3 prior therapies in the metastatic setting, and the sponsor confirmed that every patient in the HER2CLIMB trial received at least 1 prior therapy in the metastatic setting. Therefore, it was considered appropriate that, given the changes to the treatment landscape for this setting and the characteristics of patients in the HER2CLIMB trial, treatment with tucatinib in combination with trastuzumab-capecitabine be used for patients who received at least 1 HER2-targeted therapy in the metastatic setting.
The HER2CLIMB trial eligibility criteria required patients to have prior treatment with trastuzumab, pertuzumab, and T-DM1, either alone or in combination, and most patients (> 90%) reported having received each treatment. The median and mean number of therapies used among patients in the HER2CLIMB trial was 4, with most patients having received trastuzumab, pertuzumab, and T-DM1 in either the metastatic setting or in the metastatic and neoadjuvant/adjuvant setting. Therefore, patients would have received tucatinib combination therapy in the second-line or later setting. It may be unreasonable to suggest using tucatinib combination therapy as a first-line treatment option for patients with metastatic breast cancer because there is no evidence to support the use of this treatment in this context. Input received from the clinical expert consulted by CADTH and the Canadian clinician groups providing input on this submission suggest that tucatinib combination therapy would most likely be used as a third-line therapy.
The sponsor submitted an ITC that compared the efficacy of tucatinib in combination with trastuzumab-capecitabine to relevant comparators, including lapatinib plus capecitabine, margetuximab plus capecitabine, neratinib, neratinib plus capecitabine, pertuzumab plus trastuzumab-capecitabine, trastuzumab plus capecitabine, capecitabine, T-DM1, and T-DM1 plus capecitabine, for patients with HER2-positive metastatic breast cancer who had received at least 1 prior therapy. The ITC was conducted using a network metanalysis (NMA) that included 14 phase II and III trials identified by a systematic literature search.
Regarding PFS, the NMA results suggested that tucatinib combination treatment was favoured compared with capecitabine monotherapy (HR = 0.33; 95% credible interval [CrI], 0.23 to 0.47; P < 0.0001), neratinib (HR = 0.47; 95% CrI, 0.30 to 0.71; P = 0.0007), lapatinib plus capecitabine (HR = 0.55; 95% CrI, 0.40 to 0.76; P = 0.0003), trastuzumab plus capecitabine (HR = 0.53; 95% CrI, 0.42 to 0.68; P < 0.0001), and pertuzumab plus trastuzumab plus capecitabine (HR = 0.65; 95% CrI, 0.47 to 0.90; P = 0.0110). No differences were shown between the tucatinib combination and margetuximab plus capecitabine, neratinib plus capecitabine, T-DM1, and T-DM1 plus capecitabine.
Regarding OS, the NMA results suggested that the tucatinib combination treatment was favoured compared with capecitabine monotherapy (HR = 0.45; 95% CrI, 0.27 to 0.77; P < 0.0017), neratinib (HR = 0.47; 95% CrI, 0.27 to 0.80; P = 0.0073), lapatinib plus capecitabine (HR = 0.59; 95% CrI, 0.41 to 0.83; P = 0.0030), and trastuzumab plus capecitabine (HR = 0.66; 95% CrI, 0.50 to 0.88; P = 0.0040). No differences were shown between the tucatinib combination and margetuximab plus capecitabine, neratinib plus capecitabine, pertuzumab plus trastuzumab-capecitabine, and T-DM1.
Regarding ORR, the tucatinib combination therapy was favoured over capecitabine (HR = 0.90; 95% CrI, 0.48 to 1.31; P < 0.0001), neratinib (HR = 0.82; 95% CrI, 0.29 to 1.33; P = 0.0010), and trastuzumab plus capecitabine (HR = 0.39; 95% CrI, 0.18 to 0.60; P = 0.003). There were no differences between tucatinib combination therapy and lapatinib plus capecitabine, neratinib plus capecitabine, pertuzumab plus trastuzumab-capecitabine, T-DM1, and T-DM1 plus capecitabine.
No comparisons for harms or safety were incorporated in the sponsor’s ITC.
The sponsor’s ITC included both phase II and III trials. Some phase II trials were not powered to detect differences between treatment groups which may have affected the precision of treatment estimates obtained from those studies. Inclusion of such studies into the sponsor’s ITC may have introduced uncertainty into the comparisons made within the network. Treatment crossover reported in trials is likely to have introduced bias into the comparisons of the ITC because crossover is likely to have diluted treatment estimates of investigational therapies. In addition, differences in patient characteristics across the studies introduces uncertainty regarding the comparability of patients across trials. For example, patients receiving treatment in later lines of therapy are likely to have worse clinical outcomes because they have already progressed on more therapies than patients in earlier lines. Further, there were differences in patient ECOG PS, hormone receptor status, and presence of brain metastases. The sponsor’s ITC included trials published between 2008 and 2020. Due to changes in treatment paradigms for HER2-positive MBC, it is highly likely that patients across studies are not comparable due to the changing treatment landscapes that would have affected overall patient outcomes over time. There were some methodological limitations because some trials reported a violation of the proportional hazard assumption and there was a lack of available data to incorporate relevant effect modifiers.
Results of exploratory analyses of intracranial efficacy were reported in a subgroup of patients with brain metastases from the pivotal HER2CLIMB study. Patients with brain metastases were classified as follows:
treated and stable (prior local treatment and no evidence of progression at baseline brain MRI, including patients treated during the screening period)
treated and progressing (prior local treatment but evidence of progression of existing lesions, new lesions, or untreated lesions remaining after prior treatment at baseline brain MRI)
untreated (no prior local treatment).
A total of 198 patients randomized to the tucatinib-combination group and 93 patients randomized to the placebo-combination group had brain metastases. The interventions have been previously described for the HER2CLIMB study. Treatment with dexamethasone (up to 2 mg per day) was permitted to control symptoms of brain metastases. The majority of patients were older than 65 years (83.5%), 60.8% resided in North America, and 93.9% had non-CNS metastatic disease. Regarding ECOG PS, 44.7% of patients had a score of 0 and 55.3% had a score of 1, and 57.0% of patients were hormone receptor positive. The brain metastasis treatment status at baseline was treated and stable, treated and progressing, or untreated for 40.2%, 37.1%, and 22.7% of patients, respectively. Most patients (70.1%) had prior radiation therapy for brain metastases, 41.9% had whole brain radiation therapy, 42.6% had targeted radiation therapy, and 15.8% had surgery.
The treatment groups were well balanced by baseline characteristics with the exception of the proportion of patients that were hormone receptor positive (54.0% tucatinib-combination group versus 63.4% placebo-combination group), patients with an ECOG PS score of 1 (53.5% tucatinib-combination group versus 59.1% placebo-combination group), history of prior targeted radiation therapy (46.5% tucatinib-combination group versus 34.4% placebo-combination group).
For patients treated in the tucatinib-combination group, 40.2% (95% CI, 29.5% to 50.6%) of patients with brain metastases, 35.0% (95% CI, 23.2% to 47.0%) of patients with active brain metastases, and 53.3% (95% CI, 31.4% to 71.0%) of patients with stable brain metastases had PFS at 1 year. None of the patients with brain metastases receiving the placebo-combination had PFS at 1 year. An HR of 0.32 (95% CI, 0.22 to 0.48) was reported for the tucatinib-combination group compared with the placebo-combination group in all patients with brain metastases. Similar results were reported for patients with active brain metastases (HR = 0.36; 95% CI, 0.22 to 0.57) and patients with stable brain metastases (HR = 0.31; 95% CI, 0.14 to 0.67).
Among all patients with brain metastases, 1-year OS was reported for 70.1% (95% CI, 62.1% to 76.7%) of patients in the tucatinib combination treatment group and 46.7% (95% CI, 33.9% to 58.4%) of patients in the placebo-combination treatment group. For patients with active brain metastases, 1-year OS was reported for 71.7% (95% CI, 61.4% to 79.7%) and 41.1% (95% CI, 25.5% to 56.1%) of patients randomized to the tucatinib-combination and placebo-combination groups, respectively. For patients with stable brain metastases, 1-year OS was reported for 67.6% (95% CI, 53.8% to 78.0%) and 55.6% (95% CI, 34.1% to 72.6%) of patients randomized to the tucatinib-combination and placebo-combination groups, respectively. This data for 1-year OS corresponded to an HR of 0.58 (95% CI, 0.40 to 0.85) for all patients with brain metastases, 0.49 (95% CI, 0.30 to 0.80) for patients with active brain metastases, and 0.88 (95% CI, 0.45 to 1.70) for patients with stable brain metastases.
Intracranial response was also reported for patients with active brain metastases and measurable intracranial lesions at baseline.
Safety outcomes were not reported for the subgroup of patients with brain metastases.
Information about reasons for or timing of discontinuation from treatment was not available in the intracranial efficacy subgroup analyses report. The proportion of patients who were hormone receptor positive and that had a history of prior targeted radiation therapy was greater in the tucatinib treatment group, which may bias the results for PFS and OS against tucatinib. Additionally, a greater proportion of patients had received prior targeted radiation therapy in the tucatinib treatment group, which may also indicate bias against tucatinib. The analyses were exploratory, and the statistical tests could not be interpreted as statistically significant. Finally, CNS target lesions were assessed by the investigator and not externally validated. Issues of generalizability for the overall HER2CLIMB study also apply to the exploratory analyses described here. This study or exploratory analysis was specific to patients with brain lesions, which were identified using MRI and is consistent with Canadian clinical practice. Trastuzumab was available for administration intravenously or subcutaneously; however, the available evidence (published article) did not provide this level of detail for patients in the post hoc analyses.
Table 4: Cost and Cost-Effectiveness
Component | Description |
|---|---|
Type of economic evaluation | Cost-utility analysis Partitioned survival model |
Target population | Adults with locally advanced unresectable or metastatic HER2-positive breast cancer who have received prior treatment with trastuzumab, pertuzumab, and T-DM1, separately or in combination |
Treatment | Tucatinib in combination with trastuzumab-capecitabine (tucatinib combination therapy) |
Submitted price | Tucatinib, 50 mg: $60.17 per tablet Tucatinib, 150 mg: $119.50 per tablet |
Treatment price | First 21-day cycle: $10,038 for tucatinib, $12,216 in combination Subsequent 21-day cycles: $10,038 for tucatinib, $11,710 in combination |
Comparators |
|
Perspective | Canadian publicly funded health care payer |
Outcomes | QALYs, LYs |
Time horizon | Lifetime (10 years) |
Key data source | HER2CLIMB trial and network meta-analysis |
Submitted results |
|
Key limitations |
|
CADTH reanalysis results |
|
HER2 = human epidermal growth factor receptor 2; ICER = incremental cost-effectiveness ratio; ITC = indirect treatment comparison; LY = life-year; OS = overall survival; PFS = progression-free survival; PSM = partitioned survival model; QALY = quality-adjusted life-year; RDI = relative dose intensity; T-DM1 = trastuzumab emtansine; WTP = willingness to pay.
CADTH identified the following key limitations with the sponsor’s analysis: uncertainty associated with the exclusion of relevant comparators, the inclusion of comparators that may not be funded in most jurisdictions, uncertain estimates for the derivation of the eligible patient population, and an underestimate of market share estimates for tucatinib in the third-line treatment setting.
CADTH revised the mean treatment durations assumed for tucatinib combination therapy and trastuzumab with capecitabine to align with the pharmacoeconomic evaluation, increased the percentage of patients assumed to have HER2-positive breast cancer, and increased the market share assumptions for tucatinib for years 1 to 3. In the CADTH reanalysis, the estimated budget impact for tucatinib combination therapy was $64,395,873 in year 1, $80,786,751 in year 2, and $99,110,926 in year 3, for a 3-year expected total budget impact of $244,293,549.
The majority of the budget impact (98% to 99%) in the CADTH base case and across all scenario analyses is driven by the use of tucatinib in the third-line setting. The price of tucatinib, market share estimates, and percentage of patients eligible for tucatinib are key drivers of the results. Changes to the eligible population size, including assumptions related to public coverage, may make the budget impact even larger.
Dr. Maureen Trudeau (Chair), Dr. Catherine Moltzan (Vice-Chair), Mr. Daryl Bell, Dr. Jennifer Bell, Dr. Kelvin Chan, Dr. Matthew Cheung; Dr. Winson Cheung, Dr. Michael Crump, Dr. Leela John, Dr. Christine Kennedy, Dr. Christian Kollmannsberger, Mr. Cameron Lane, Dr. Christopher Longo, Ms. Valerie McDonald, Dr. Marianne Taylor, and Dr. W. Dominika Wranik.
Meeting date: September 8, 2021
Regrets: None
Conflicts of interest: None
ISSN: 2563-6596
Disclaimer: The information in this document is intended to help Canadian health care decision-makers, health care professionals, health systems leaders, and policy-makers make well-informed decisions and thereby improve the quality of health care services. While patients and others may access this document, the document is made available for informational purposes only and no representations or warranties are made with respect to its fitness for any particular purpose. The information in this document should not be used as a substitute for professional medical advice or as a substitute for the application of clinical judgment in respect of the care of a particular patient or other professional judgment in any decision-making process. The Canadian Agency for Drugs and Technologies in Health (CADTH) does not endorse any information, drugs, therapies, treatments, products, processes, or services.
While care has been taken to ensure that the information prepared by CADTH in this document is accurate, complete, and up-to-date as at the applicable date the material was first published by CADTH, CADTH does not make any guarantees to that effect. CADTH does not guarantee and is not responsible for the quality, currency, propriety, accuracy, or reasonableness of any statements, information, or conclusions contained in any third-party materials used in preparing this document. The views and opinions of third parties published in this document do not necessarily state or reflect those of CADTH.
CADTH is not responsible for any errors, omissions, injury, loss, or damage arising from or relating to the use (or misuse) of any information, statements, or conclusions contained in or implied by the contents of this document or any of the source materials.
This document may contain links to third-party websites. CADTH does not have control over the content of such sites. Use of third-party sites is governed by the third-party website owners’ own terms and conditions set out for such sites. CADTH does not make any guarantee with respect to any information contained on such third-party sites and CADTH is not responsible for any injury, loss, or damage suffered as a result of using such third-party sites. CADTH has no responsibility for the collection, use, and disclosure of personal information by third-party sites.
Subject to the aforementioned limitations, the views expressed herein are those of CADTH and do not necessarily represent the views of Canada’s federal, provincial, or territorial governments or any third-party supplier of information.
This document is prepared and intended for use in the context of the Canadian health care system. The use of this document outside of Canada is done so at the user’s own risk.
This disclaimer and any questions or matters of any nature arising from or relating to the content or use (or misuse) of this document will be governed by and interpreted in accordance with the laws of the Province of Ontario and the laws of Canada applicable therein, and all proceedings shall be subject to the exclusive jurisdiction of the courts of the Province of Ontario, Canada.
The copyright and other intellectual property rights in this document are owned by CADTH and its licensors. These rights are protected by the Canadian Copyright Act and other national and international laws and agreements. Users are permitted to make copies of this document for non-commercial purposes only, provided it is not modified when reproduced and appropriate credit is given to CADTH and its licensors.
Redactions: Confidential information in this document may be redacted at the request of the sponsor in accordance with the CADTH Drug Reimbursement Review Confidentiality Guidelines.
About CADTH: CADTH is an independent, not-for-profit organization responsible for providing Canada’s health care decision-makers with objective evidence to help make informed decisions about the optimal use of drugs, medical devices, diagnostics, and procedures in our health care system.
Funding: CADTH receives funding from Canada’s federal, provincial, and territorial governments, with the exception of Quebec.