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Indication: For the treatment of patients with locally advanced basal cell carcinoma (BCC) previously treated with a hedgehog pathway inhibitor
CADTH recommends that Libtayo should be reimbursed by public drug plans for the treatment of adult patients with locally advanced basal cell carcinoma (laBCC) previously treated with a hedgehog pathway inhibitor (HHI) if certain conditions are met.
Libtayo should only be covered to treat adult patients who have laBCC that cannot be cured by surgery or radiation and are unlikely to benefit from further HHI therapy. Patients should have good performance status.
Libtayo should only be reimbursed if it is prescribed by a clinician with expertise in treating cancer and managing side effects. The price of Libtayo must be lowered to be cost-effective and affordable.
Evidence from a clinical trial demonstrated that patients with laBCC treated with Libtayo experienced tumour shrinkage or the tumour completely disappeared. The committee considered the significant psychosocial burden of visible skin lesions and lack of alternative treatment options for patients with laBCC.
Based on CADTH’s assessment of the health economic evidence, Libtayo does not represent good value to the health care system at the publicly listed price and requires at least a 97% price reduction. Based on public list prices, Libtayo is expected to cost the public drug plans an additional $40,205,838 over 3 years.
Basal cell carcinoma (BCC) is a type of skin cancer that starts in basal cells — cells found at the bottom of the top layer of skin, also known as the epidermis. Patients with BCC present with skin lesions that appear as open sores, red patches, scars, or growths that sometimes crust or bleed. BCC is considered locally advanced when the tumours grow deep into the skin or surrounding tissues, muscles, or nerves.
Patients with laBCC are treated with HHI therapy; however, there are no treatment options available for patients with tumours that cannot be cured by surgery or radiation and HHI therapy no longer works for them.
Treatment with Libtayo is expected to cost approximately $10,933 per 28 days.
The CADTH pan-Canadian Oncology Drug Review (pCODR) Expert Review Committee (pERC) recommends that cemiplimab be reimbursed for the treatment of patients with locally advanced basal cell carcinoma (laBCC) previously treated with a hedgehog pathway inhibitor (HHI) only if the conditions listed in Table 1 are met.
One single-arm, open-label, phase II trial (Study 1620) evaluated the efficacy and safety of cemiplimab in a cohort of patients with laBCC (N = 84) who had previously been treated with an HHI and were not candidates for curative surgery or curative radiation therapy. The trial demonstrated an objective response rate (ORR) of 28.6% (95% confidence interval [CI], 19.2% to 39.5%) at the primary analysis (median follow-up was 13.53 months) and an ORR of 32.1% (95% CI, 22.4% to 43.2%) at an updated analysis based on approximately |||||||||||| of additional follow-up (median follow-up ||||||||||||||||||||). The duration of response (DOR) among patients achieving complete response or partial response was not reached at either analysis data cut-off date, with DOR ranging from 2.1 months to greater than 21.4 months at the primary analysis. pERC considered these response outcomes clinically meaningful in a rare patient population with no active treatment options after progression on, or intolerance to, HHI therapy and who experience substantial morbidity from their disease. The duration of follow-up in Study 1620 was short. At the updated analysis, the median progression-free survival (PFS) time in the laBCC cohort was |||||||||||||||||||||||||||| months and median overall survival (OS) time was |||||||||||||||||||||||||| It is unlikely that mature survival data will be able to definitively confirm long-term benefit due to the single-arm trial design. Health-related quality of life (HRQoL) was identified as an outcome important to patients given the impact the disease has on physical appearance and psychosocial aspects of well-being. Although limitations were identified with the assessment of HRQoL in Study 1620, the available data suggested HRQoL was at least maintained in patients treated with cemiplimab; multiple measures of HRQoL either remained stable (i.e., function and symptom scales) or appeared improved (i.e., emotional scales). The safety data from Study 1620 did not identify any new safety signals associated with cemiplimab, and although more than half of patients experienced immune-related adverse events (AEs), pERC agreed these toxicities can be effectively managed in clinical practice through appropriate symptom management and supportive care. pERC considered patients with laBCC experience a high burden of disease symptoms and disfigurement, and that there is a significant unmet need for an active treatment option in patients who have progressed on, or are intolerant to, HHI therapy. Given the totality of the evidence, pERC concluded that cemiplimab met some of the needs identified by patients because it provides a second-line treatment option with manageable side effects and reasonable quality of life.
Owing to limitations with the sponsor’s modelling approach and the lack of comparative data, CADTH was unable to determine a base case estimate of cost-effectiveness for the Health Canada–approved indication. CADTH conducted an exploratory reanalysis based on more plausible assumptions; however, CADTH could not address modelling assumptions that overestimated the incremental benefit of cemiplimab because of the structure of the submitted model. In this analysis, the incremental cost-effectiveness ratio (ICER) for cemiplimab was $2,259,421 per quality-adjusted life-year (QALY) relative to best supportive care. In this analysis, a reduction in price of at least 97% is required for cemiplimab to be considered cost-effective at a $50,000 per QALY threshold. CADTH notes this exploratory analysis likely underestimates the true ICER.
Reimbursement Conditions and Reasons.
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.
Implementation Guidance From pERC.
Cemiplimab has a Health Canada indication for the treatment of patients with laBCC previously treated with an HHI. The sponsor’s reimbursement request for cemiplimab is aligned with the Health Canada–approved indication. Cemiplimab is administered at a dose of 350 mg as an IV infusion over 30 minutes every 3 weeks and is continued until symptomatic disease progression or unacceptable toxicity.
Cemiplimab is a recombinant human IgG4 monoclonal antibody that binds to the programmed cell death 1 (PD-1) receptor, inhibiting interaction with the ligands PD-L1 and PD-L2. The inhibitory action of cemiplimab acting on PD-1 counteracts this inhibition of the immune response, including the antitumour immune response of T cells.
To make their recommendation, pERC considered the following information:
The information in this section is a summary of input provided by the patient and clinician groups who responded to CADTH’s call for input and from clinical experts consulted by CADTH for the purpose of this review.
Input was provided for this review by 2 patient groups: SYSF and the MNC. SYSF gathered information from online surveys, virtual patient roundtables, and one-on-one conversations over the previous 6 months. All 23 patients consulted (women: n = 20; men: n = 3) had been diagnosed with BCC and 5 had experience with cemiplimab. It was not reported whether patients had experience with HHI therapy before receiving cemiplimab. A total of 19 out 23 patient respondents were from Canada; most of the Canadian responders were from Ontario. The MNC input was sourced from an online survey of 62 patients (women: n = 44; men: n = 18) and 45 caregivers. All but 1 of the patients were from Canada, with 50% located within the province of Ontario. Only 1 patient indicated they had experience with cemiplimab in metastatic disease; no patients had experience with HHI therapy.
In both surveys, patients highlighted the negative aspects of BCC and its treatment, including disfigurement, scarring, and associated self-esteem difficulties. Other key concerns mentioned by patients in both surveys were pain from the lesions and anxiety over finding recurrent disease. In the MNC survey, caregivers expressed that the disease caused much emotional stress with seeing their loved one in pain. Patients expressed a desire for less radiation and disfiguring surgery and greater access to treatments closer to home and their support network. Respondents from the SYSF submission who had experience with cemiplimab indicated that the side effects were manageable, and the benefits would outweigh the side effects. Of the 5 patients with experience with cemiplimab, 2 had no side effects, 2 patients had fatigue, and 1 patient had skin rash. The 1 patient from the MNC submission who had experience with cemiplimab indicated that having the option for therapy was worth experiencing treatment side effects, which included liver issues and flu-like symptoms.
Patients indicated that there are no other options for treatment at this stage of disease and the ability to access new treatments to eliminate disease and prevent recurrence is needed. Earlier diagnosis, access to specialists, and less invasive procedures were highlighted as important to patients and caregivers in the MNC survey.
Two clinical experts with expertise in the diagnosis and management of laBCC highlighted the lack of options available for patients with laBCC who have failed HHI therapy, especially if response to HHI therapy is low and some patients cannot tolerate treatment side effects. Eligibility is based on whether the tumour is deemed unresectable or unsuitable for radiotherapy, which can be uncertain; therefore, the clinical experts suggested that tumour eligibility should be determined by a multidisciplinary tumour board. The main goals of therapy are to shrink the tumour and increase the HRQoL of patients with laBCC. The clinical experts highlighted the extreme importance of HRQoL in this patient population given the disfiguring nature of the disease. Treatment would usually be discontinued upon disease progression (increase in size or extension of lesions), severe or intolerable side effects, or a lack of response after adequate duration of treatment (identified as 4 months to 6 months of treatment). According to the clinical experts, treatment with cemiplimab would be initiated by a medical oncologist or associated team physician with expertise in cancer therapies and toxicity management.
One clinician group, Ontario Health (Cancer Care Ontario), provided input for this review. No major views contrary to those provided by the clinical experts consulted by CADTH were presented. Ontario Health echoed the lack of options for patients with laBCC who have failed HHI therapy and the importance of HRQoL outcomes, specifically relating to disfiguring lesions and surgical scarring.
The drug programs identified jurisdictional implementation issues related to relevant comparators, initiation and prescribing of therapy, generalizability, and care provision issues. pERC weighed evidence from the Study 1620 and other clinical considerations, including input from the clinical experts consulted by CADTH, to provide responses to the drug programs’ implementation questions, which are presented in Table 3.
Responses to Questions From the Drug Programs.
One phase II, single-arm, non-randomized, open-label multicentre study (Study 1620, laBCC: N = 84) was included in the systematic review. The primary objective of the study was to determine the efficacy of cemiplimab in achieving an objective tumour response in 2 cohorts of patients: those with laBCC and those with mBCC.
The study enrolled patients with either laBCC or mBCC who had previously received HHI therapy; however, the laBCC population was the focus of the CADTH review because the Health Canada indication and requested reimbursement request were restricted to this patient population.
In Study 1620, patients were treated with cemiplimab for up to 93 weeks or until progressive disease or unacceptable toxicity. Tumour response was assessed using a composite of Response Evaluation Criteria in Solid Tumours Version 1.1 (RECIST 1.1) for lesions with radiologically measurable components and modified WHO clinical criteria for lesions with externally visible components; responses were designated by blinded independent central review.
Most patients in the study with laBCC were men (66.7%) and White (67.9%). Infiltrative tumour histology accounted for 8.3% of laBCC lesions while the broad “other” category accounted for 66.7% of lesions with most (89.3%) located in the head or neck. The mean age of patients with laBCC was 69.1 (standard deviation [SD] = 12.8) years. The primary outcome was ORR by blinded independent central review; secondary outcomes included ORR by investigator assessment, DOR, PFS, OS, time to tumour response, disease control rate, and HRQoL.
Study 1620 was a single-arm, non-comparative trial; therefore, the primary outcome was based on rejecting the null hypothesis of an ORR equal to a chosen non-clinically meaningful response rate. In the laBCC group, the null hypothesis was an ORR equal to 20% that would be rejected if the lower bound of the 2-sided 95% CI excluded the value of 20%. This threshold was chosen to be consistent with what was determined to be clinically meaningful in previous trials for HHI therapy in advanced BCC, although these trials were conducted in the first-line setting. The assessment of secondary outcomes was descriptive.
The primary analysis of Study 1620 was conducted based on a data cut-off date of February 17, 2020, at which time the mean duration of patient follow-up was 13.53 months and the mean duration of treatment with cemiplimab was 52.80 weeks. An updated analysis was performed |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||, at which time the mean duration of follow-up |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||
The ORR at the time of the primary analysis was 28.6% (95% CI, 19.2% to 39.5%), which failed to meet the 20% pre-specified threshold based on the lower bound of the 95% CI. At the updated analysis, the pre-specified threshold was reached with an ORR of 32.1% (95% CI, 22.4% to 43.2%). At the primary analysis, the median Kaplan-Meier estimation of DOR in the 24 patients who achieved either a complete response or partial response had not been reached. The observed DORs ranged from 2.1 months to greater than 21.4 months with 79.2% of responders achieving a DOR greater than 6 months, and 45.8% of responders achieving a DOR greater than 12 months.
HRQoL was measured in Study 1620 using the EORTC QLQ-C30 and the Skindex-16. Changes over time in the global health status and HRQoL score of the EORTC QLQ-C30 were smaller than the MID estimate of 5 points to 10 points at both the primary and updated analysis. Analysis of EORTC QLQ-C30 functional and symptom scales showed scores consistent with the results for the global health status scale. Symptom scales remained stable over time with the exception of fatigue, which showed worsening in excess of the MID for the fatigue scale at cycle 7 and cycle 9, although patient numbers were reduced at these time points. An improvement in excess of the MID of 10 points or more was achieved in the emotion scale of the Skindex-16 at cycle 4 and maintained through the end of the study, while the symptom and functioning scales remained stable over time.
At the time of primary analysis, 45.2% of patients in the laBCC group had experienced a PFS event, with 39.3% of patients experiencing disease progression and 6.0% experiencing death. The median PFS time was 19.3 (95% CI, 8.6 to not estimable) months. At the updated analysis, |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
At the time of primary analysis, death had occurred in 11.9% of patients and the median OS had not been reached. At the updated analysis, ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Treatment emergent adverse events (TEAEs) occurred in almost all patients (97.6% and 98.8% at the primary and updated analyses, respectively). Serious AEs occurred in 34.5% and 36.9% of patients at the primary and updated analyses, respectively, while TEAEs leading to treatment discontinuation occurred in 16.7% and 17.9% of patients, respectively. The most common TEAE that led to a dose delay was diarrhea in 4.8% of patients, followed by blood creatinine increase, fatigue, and urinary tract infection, each occurring in 3.6% of patients. Deaths due to TEAEs occurred in 3.6% and 4.8% of patients at the primary and updated analyses, respectively, which included 1 occurrence of cachexia, malignant brain neoplasm, and acute kidney injury, respectively.
Immune-related AEs occurred in 56% and 58.3% of patients at the primary and updated analyses, respectively. This included 11.9% of patients who experienced grade 3 or higher TEAEs, 9.5% who experienced serious immune-related AEs, and 9.5% who experienced an immune-related AE leading to treatment discontinuation. Infusion reactions occurred at a much lower rate, with only 1.2% of patients experiencing any infusion-related reaction. The incidence of notable harms was unchanged at the updated analysis.
The most notable limitations of Study 1620 relate to the single-arm, open-label design. Due to this, it is impossible to draw any conclusions about efficacy with any level of certainty. The clinical experts consulted by CADTH agreed with the clinically meaningful ORR threshold of 20%, and it was also noted that this threshold is consistent with what was used in previous single-arm trials in patients with laBCC. Rejection of the null hypothesis (ORR = 20%) required the lower bound of the 95% CI to exclude 20%, and this was not achieved at the time of the primary analysis (ORR = 28.6%; 95% CI, 19.2% to 39.5%). Additionally, 2 patients did not meet the inclusion criterion requiring enrolled patients to have at least 1 measurable lesion. They were enrolled in the study despite this which, according to clinical experts consulted for this review, would likely bias the results by increasing the ORR. Important protocol deviations occurred in 23.8% of all patients in the laBCC group of Study 1620, although the observed protocol deviations were considered acceptable for a second-line oncology clinical trial. The most common important protocol deviations were related to enrolling patients despite inclusion criteria (15.5%) and exclusion criteria (3.6%) deviations. There was a relatively high number of patients that discontinued the study for reasons other than progressive disease or death (19.0% at the primary analysis data cut). These reasons included AEs, loss to follow-up, noncompliance with the protocol, withdrawal of consent, patient decision, and sponsor decision. In the case of noncompliance with the protocol and sponsor decision, the CADTH review team did not believe that these were valid reasons to discontinue the study and this was likely to bias the results in favour of cemiplimab.
According to the study protocol, for a patient to have achieved complete response or partial response, a response must have been confirmed at least 4 weeks following the initial documented response. If the response was not confirmed, the patient was reported as having stable disease. The sponsor presented an unplanned sensitivity analysis in which the pre-specified threshold to reject the null hypothesis was reached, which included the responses from 2 patients who had unconfirmed initial responses at the time of primary analysis. Both patients ultimately had their responses confirmed; however, these results were based on an ad hoc redefinition of the primary outcome that differs from the study protocol. There is an increased risk of type I error because there was no adjustment for multiplicity in this analysis; therefore, the obtained results should be interpreted with caution. The sponsor also provided the results of an unplanned updated analysis |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| the reported ORR at this data cut was 32.1% (95% CI, 22.4% to 43.2%). The same limitations regarding no adjustment for multiplicity and increased risk of type I error apply to the updated analysis and results.
According to the clinical experts consulted by CADTH, the demographic and disease characteristics of the Study 1620 population were reflective of the Canadian population with laBCC. The dosage of cemiplimab in Study 1620 was aligned with the Health Canada–approved dosing and with clinical practice. In the study, treatment with cemiplimab was administered until progressive disease, unacceptable toxicity, or up to 93 weeks duration. The protocol allowed for re-treatment of patients who had completed the full treatment course but experienced progressive disease during the follow-up period. The sponsor confirmed that 1 patient had entered re-treatment with cemiplimab. Given the lack of data, data from this trial may not be generalizable to treatment beyond the 93-week treatment course or within a re-treatment setting for patients who experience progressive disease following discontinuation of cemiplimab.
No indirect evidence was identified for this review.
No other relevant evidence was identified for this review.
Cost and Cost-Effectiveness.
CADTH reanalysis increased the market shares for cemiplimab and applied the mean treatment duration to calculate costs. In the CADTH base case, the budget impact is expected to be $6,481,980 in year 1, $13,433,342 in year 2, and $20,290,516 in year 3, with a 3-year total budget impact of $40,205,838. CADTH found the budget impact of cemiplimab to be sensitive to market shares and medical eligibility. This budget impact also assumes there is no re-treatment.
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. Catherine Moltzan, Dr. Christopher Longo, Ms. Amy Peasgood, Dr. Anca Prica, Dr. Adam Raymakers, Dr. Patricia Tang, Dr. Marianne Taylor, and Dr. W. Dominika Wranik.
Meeting date: January 12, 2022
Regrets: None
Conflicts of interest: None
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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.
Indication: For the treatment of patients with locally advanced basal cell carcinoma (BCC) previously treated with a hedgehog pathway inhibitor
Sponsor: Sanofi Genzyme, a division of Sanofi-Aventis Canada Inc.
Final recommendation: Reimburse with conditions
Except where otherwise noted, this work is distributed under the terms of a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence (CC BY-NC-ND), a copy of which is available at http://creativecommons.org/licenses/by-nc-nd/4.0/
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