CADTH Reimbursement Review

Cemiplimab (Libtayo)

Sponsor: Sanofi Genzyme, a division of Sanofi-Aventis Canada Inc.

Therapeutic area: Basal cell carcinoma

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Stakeholder Input

Clinical Review

Executive Summary

An overview of the submission details for cemiplimab is provided in Table 1.

Introduction

Non-melanoma skin cancer accounts for approximately 28% of new cancer diagnoses in Canada,¹ with basal cell carcinoma (BCC) accounting for 75% of all non-melanoma skin cancers.² BCC generally develops on sun-exposed skin. Other risk factors include male sex, light hair, northern European ancestry, and the inability to tan. Seventy percent of cases occur on the head, frequently on the face, whereas 25% occur on the trunk and limbs and 5% in the perineal region.³ Most BCCs are diagnosed and treated early; however, some BCCs become extensive and infiltrative, posing a greater risk to patients.⁴

The objective of this report was to perform a systematic review of the beneficial and harmful effects of cemiplimab (IV injection, 350 mg) for the treatment of patients with locally advanced BCC (laBCC) previously treated with a hedgehog pathway inhibitor (HHI).

Stakeholder Perspectives

The information in this section is a summary of input provided by the patient and clinician groups that responded to CADTH’s call for input and from the clinical experts consulted by CADTH for the purpose of this review.

Patient Input

Input was provided for this review by 2 patient groups, the Save Your Skin Foundation (SYSF) and the Melanoma Network of Canada (MNC). The SYSF gathered information from online surveys, virtual patient roundtables, and 1-on-one conversations from March 2021 to September 2021. All 23 patients consulted (20 of which were women) had been diagnosed with BCC; 5 patients had experience with cemiplimab. It was not reported whether patients had experience with HHI therapy before receiving cemiplimab. All but 4 patients were from Canada, with most of the Canadian responders being from Ontario. The MNC input was sourced from an online survey of 62 patients (44 of which were women) and 45 caregivers. All but 1 of the patients were from Canada, with 50% located in Ontario. Only 1 patient indicated they had experience with cemiplimab in metastatic disease and no patients had experience with HHI therapy.

In both surveys, patients highlighted the negative aspects of BCC and its treatment, including disfigurement, scaring, and the associated self-esteem difficulties. In both surveys, pain from the lesions and anxiety over finding recurrent disease were also mentioned by patients as key concerns. In the MNC survey, caregivers expressed that the disease caused much emotional stress from seeing their loved 1 in pain. Patients expressed a desire for less radiation and disfiguring surgery and greater access to treatments closer to their home and support network. Respondents from the SYSF submission with experience with cemiplimab indicated 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 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 difficulty with liver-related issues and flu-like symptoms.

Patients indicated there are no other options for treatment following progression on HHI therapy 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.

Clinician Input

Input From Clinical Experts Consulted by CADTH

Two clinical experts with expertise in the diagnosis and management of laBCC highlighted the lack of options available for patients with laBCC whose disease did not respond to HHI therapy, especially given the fact that response to HHI therapy is low and some patients cannot tolerate treatment side effects. As eligibility is based on whether the tumour is deemed unresectable or unsuitable for radiotherapy, this can be uncertain and, 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 health-related quality of life (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 an adequate duration of treatment (identified as 4 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.

Clinician Group Input

One clinician group, Ontario Health (Cancer Care Ontario), provided input for this review. No major views that were contrary to those provided by the clinical experts consulted by CADTH were presented. Ontario Health echoed the lack of options for patients with laBCC whose disease has not responded to HHI therapy, as well as the importance of HRQoL outcomes specifically relating to disfiguring lesions and surgical scarring.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may impact their ability to implement a recommendation. The drug plans identified implementation issues related to relevant comparators, consideration for initiation of therapy, consideration for prescribing of therapy, generalizability, care provision, system issues, and economic considerations. The clinical experts consulted by CADTH for this review weighed evidence from the included study and other clinical considerations to provide responses to the drug plans’ implementation questions. Refer to Table 4 for more details.

Clinical Evidence

Pivotal and Protocol Selected Studies

Description of Study

One phase II, single-arm, non-randomized, open-label multi-centre trial, Study 1620,^5,6 was included in the systematic review (Table 6). The primary objective of the study was to determine the efficacy of cemiplimab in achieving an objective tumour response in 2 cohorts: patients with laBCC and patients with metastatic basal cell carcinoma (mBCC).

The study enrolled patients with laBCC and mBCC who had previously received HHI therapy; however, the laBCC population (N = 84) was the focus of the CADTH review, since 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 (PD) or unacceptable toxicity. Tumour response was assessed using a composite of the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for lesions with radiologically measurable components, and modified WHO clinical criteria for lesions with externally visible components, and responses were designated by blinded independent central review (BICR).

Most patients in the study with laBCC were male (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%) occurring in the head or neck region. The mean age of patients with laBCC was 69.1 (standard deviation [SD] = 12.8). The primary outcome was objective response rate (ORR) by BICR, and secondary outcomes included ORR by investigator assessment, duration of response (DOR), progression-free survival (PFS), overall survival (OS), time-to-tumour response, disease control rate, and HRQoL.

As Study 1620 was a single-arm non-comparative trial, 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% and would be rejected if the lower bound of the 2-sided 95% confidence interval (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 though, notably, these trials were conducted in the first-line setting.^7,8 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 was ||||||||||||| and the mean duration of exposure was ||||||||||||.

Outcome Results

A summary of the results for key outcomes from Study 1620 is shown in Table 2.

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 (95% CI) of |||||||||||||||||||||||||||||||||||||||||||||. At the primary analysis, the median Kaplan–Meier estimation of DOR in the 24 patients who achieved either a complete response (CR) or partial response (PR) 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 European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and the Skindex-16. Changes over time in the global health status (HRQoL) score for the EORTC QLQ-C30 were smaller than the minimal important difference (MID) estimate of 5 to 10 points at both the primary and updated analyses. An analysis of the 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 cycles 7 and 9, though patient numbers were reduced at these time points. An improvement in excess of the MID of 10 points or greater 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.

At the time of the 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 was 19.3 months (95% CI, 8.6 to not evaluable). At the updated analysis, |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.

At the time of the primary analysis, deaths had occurred in 11.9% of patients and the median (95% CI) OS had not been reached. At the updated analysis, |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.

Harms Results

Treatment-emergent adverse events (TEAEs) occurred in almost all patients (97.6% and 98.8% at the primary and updated analyses, respectively). Serious adverse events (SAEs) occurred in 34.5% of patients and 36.9% at the primary and updated analyses, respectively, while TEAEs that led 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 increased, fatigue, and urinary tract infection, each occurring in 3.6% of patients. Deaths due to TEAEs occurred in 3.6% of patients and 4.8% at the primary and updated analyses, respectively; these included 1 occurrence each of cachexia, malignant brain neoplasm, and acute kidney injury.

Immune-related adverse events (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 greater 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. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

Critical Appraisal

The most notable limitation of Study 1620 relates to its 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%; 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%; 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 but were enrolled in the study despite this. According to the clinical experts consulted for this review, this would likely bias the results by increasing the ORR. Important protocol deviations occurred in 23.8% of the patients in the laBCC group of Study 1620, though 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 deviations in the inclusion (15.5%) and exclusion (3.6%) criteria. A relatively high number of patients discontinued the study for reasons other than PD or death (19.0% at the primary analysis data cut-off); these reasons included AEs, lost to follow-up, non-compliance with the protocol, withdrawal of consent, patient decision, and sponsor decision. Specifically, in the case of non-compliance with the protocol and sponsor decision, the CADTH review team indicated that these are not valid reasons to discontinue the study and are likely to bias the results in favour of cemiplimab.

According to the study protocol, for a patient to have achieved a CR or PR, the response must have been confirmed at least 4 weeks following the initial documented response. If a 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; this analysis includes initial responses from 2 patients that were unconfirmed at the time of the primary analysis. Both patients did ultimately have their responses confirmed; however, these results are based on an ad hoc redefinition of the primary outcome that differs from the study protocol. Since there was no adjustment for multiplicity in this analysis, there is an increased risk of type I error and, therefore, the results obtained should be interpreted with caution. The sponsor also provided the results of an unplanned updated analysis ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| the reported ORR (95% CI) at this data cut-off was |||||||||||||||||||||||. 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 PD or unacceptable toxicity up to 93 weeks. The protocol allowed for re-treatment of patients who had completed the full treatment course but experienced PD during the follow-up period. The sponsor confirmed that 1 patient had entered re-treatment with cemiplimab. The trial data may not be generalizable to treatment beyond the 93-week treatment course or within a re-treatment setting for patients who experience PD following discontinuation of cemiplimab, given the lack of data.

Indirect Comparisons

No indirect evidence was identified for this review.

Other Relevant Evidence

No other relevant evidence was identified for this review.

Conclusions

Study 1620 was a single-arm study of cemiplimab (350 mg every 3 weeks up to a maximum of 93 weeks) in patients with laBCC. The study did not meet the pre-specified threshold of a 20% ORR, which is considered clinically meaningful. At the updated analysis, the ORR ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. In the opinion of the clinical experts consulted by CADTH, despite the limitations of Study 1620, the observed ORR in patients with laBCC previously treated with an HHI was considered clinically meaningful and of value in a high-burden disease for which there is a high unmet need for treatment options. The descriptive assessment of HRQoL in the study was limited by the low number of respondents contributing to assessments at later time points, but these assessments suggested multiple measures of HRQoL were stable over the course of the study and a clinically meaningful improvement was observed for emotional functioning. Data on PFS and OS were immature, but longer-term data for these outcomes will be challenging to interpret due to the non-comparative trial design. The notable harms that were observed with cemiplimab, specifically immune-related AEs, were consistent with the known safety profile of the drug and were considered manageable, with appropriate supportive care, by both the clinical experts consulted by CADTH and by patients, according to the patient input. The major limitation of Study 1620 is its open-label, single-group study design, which introduces bias in favour of cemiplimab and precludes the ability to evaluate the efficacy and magnitude of the clinical benefit of cemiplimab in this treatment setting.

Introduction

Disease Background

Non-melanoma skin cancer accounts for approximately 28% of new cancer diagnoses in Canada,¹ with BCC accounting for 75% of all non-melanoma skin cancers.² BCC is a malignancy derived from the non-keratinizing cells that form the basal layer of the epidermis. Tumour size can be quite variable, from a few millimetres to several centimetres; BCC tends to invade locally and rarely metastasizes distantly. BCC is principally a disease of the elderly but has been increasingly detected among younger adults.⁹ BCC generally develops on sun-exposed areas of the skin, and other risk factors include male sex, light hair, northern European ancestry, and the inability to tan. Seventy percent of cases of BCC occur on the head and frequently on the face, whereas 25% occur on the trunk and limbs and 5% in the perineal region.³

Most BCCs are generally diagnosed and treated early; however, some BCCs become extensive and infiltrative, posing a greater risk to patients.⁴ Generally, BCC is a slow-growing tumour with a doubling rate of between 6 months to 1 year but, left untreated, it may invade into the subcutaneous tissue, muscle, and bone. Direct extension into the central nervous system can also occur. Perineural invasion is uncommon in BCC but does imply a more aggressive phenotype, which is associated with more extensive invasion and more frequent recurrences.¹⁰ In BCCs occurring in the periocular region, perineural progression can lead to invasion of the orbital structures and result in pain, paresthesias, eye muscle weakness, and blindness.¹¹ Metastasis of BCC is rare, with rates estimated to be less than 1%.^12,13 The most common sites of metastatic spread are the lymph nodes and lungs.¹⁴ In those rare cases, squamous differentiation may be present in the primary or metastatic sites and may contribute to the aggressive phenotype.

Standards of Therapy

The principal modality of therapy for BCC is surgery. Curettage and electric dissection are commonly employed, with cure rates of up to 98%.¹⁵ However, for larger BCCs, surgical excision offers the most potential for margin control and often provides optimal cosmetic results. To achieve local control, adequate surgical margins are required. Clear surgical margins may be difficult to achieve while still maintaining acceptable cosmesis and can be particularly challenging for eradicating extensive BCCs involving the face.¹⁶

Radiotherapy is also commonly used. It has the advantage of sparing normal tissue and may reduce the need for reconstructive surgery. However, in some sites, such as the nose, ear, and periocular regions, collateral damage of normal tissue may occur. Radiotherapy remains an option for poor surgical candidates, but higher failure rates may occur in large, recurrent, and aggressive subtypes of BCCs. Radiotherapy can also be used in the palliation and debulking of tumours that are otherwise inoperable. Adjuvant post-operative radiotherapy may also be considered in cases when the risk of recurrence is high.¹⁷

Although laBCC and mBCC are relatively rare disease states, they lead to significant morbidity in patients. In patients with locally advanced and recurrent disease, the primary goal of therapy is local control and not OS. With respect to lesions on the face and distal extremities, an additional therapeutic goal is to maintain or optimize organ function. In some cases of laBCC, extensive surgical resection may not be technically possible. Furthermore, resection may involve removing vital structures such as the orbits or cranial bones, which would result in significant deformity and functional impairment. Moreover, in cases where recurrent disease occurs, further radiotherapy may not possible and the goal of obtaining clear surgical margins may be impossible to achieve.

Canadian clinical practice guidelines for laBCC and mBCC report that treatment involves any combination of surgery, radiation, and chemotherapy, and that there is a lack of evidence to inform treatment recommendations for a standard therapy.¹⁸ These guidelines were published in 2015 and are therefore out of date. The most recent guidelines from the National Comprehensive Cancer Network state that systemic HHI therapy is to be considered in patients with laBCC and mBCC if surgery or radiotherapy are unlikely to be curative¹⁹ and, for patients previously treated with HHI therapy or for whom HHI therapy is not appropriate, treatment with cemiplimab can be considered.¹⁹

At least 90% of BCCs appear to have an acquired aberrant activation of the hedgehog pathway. Linkage analyses have identified a locus on chromosome 9 that is deleted in sporadic BCC.²⁰ The locus encodes for the patch 1 (PTCH1) gene, a transmembrane receptor that inhibits smoothened signalling and the downstream activation of cellular proliferation.²¹ Because abnormalities in the hedgehog signalling pathway are common in sporadic cases of BCC, routine testing to determine the precise nature of the signalling aberration is not recommended for clinical practice.

Currently, the only HHI therapy in Canada approved and publicly reimbursed for both laBCC and mBCC is vismodegib. The efficacy of vismodegib was evaluated in the multi-centre phase II ERIVANCE trial, which included 63 patients with laBCC and 33 patients with mBCC.⁸ Sekulic et al. reported a tumour response rate of 43% in patients with laBCC and 30% in patients with mBCC. AEs were common and generally mild and included muscle spasms, dysgeusia, weight loss, and fatigue. Sonidegib, another HHI, is also approved in Canada; however, CADTH did not recommend it for reimbursement when it was reviewed in 2021. The BOLT trial reported an ORR that ranged from 43% to 38% in patients with laBCC, depending on the dose of sonidegib received.⁷

Because there is currently no available therapy approved in Canada for patients who progress or become intolerant to HHI therapy, patients are treated according to best supportive care.

Drug

Cemiplimab is a recombinant human immunoglobulin G4 (IgG4) monoclonal antibody that binds to the programmed cell death 1 (PD-1) receptor, inhibiting the interaction with programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2). T-cells lose proliferation and function through increased expression of proteins like PD-1 and interaction with PD-L1 and PD-L2, down-modulating the antitumour response of T-cells.²² The inhibitory action of cemiplimab acting on PD-1 counteracts this inhibition of the immune response, including the antitumour immune response of T-cells.

On October 26, 2021, cemiplimab was issued market authorization without conditions 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 underwent review by Health Canada through a standard review pathway. Cemiplimab is also indicated for the treatment of patients with metastatic or locally advanced cutaneous squamous cell carcinoma and for first-line treatment of patients with non–small cell lung cancer expressing PD-L1, with no epidermal growth factor receptor, anaplastic lymphoma kinase, or ROS1 aberrations.²³ Cemiplimab received a positive recommendation with conditions from CADTH in 2020 for the cutaneous squamous cell carcinoma indication.²⁴

Cemiplimab was approved by the FDA for use in patients with laBCC previously treated with HHI therapy or for whom an HHI is inappropriate.²⁵ FDA approval in patients with mBCC was granted under the accelerated approval process and may be dependent on verification of clinical benefit.²⁵ The European Medicines Agency also approved cemiplimab in 2021 for the treatment of laBCC or mBCC following HHI therapy.²⁶

Cemiplimab is administered as an IV infusion over 30 minutes every 3 weeks at a dose of 350 mg and is continued until symptomatic disease progression or unacceptable toxicity. Key characteristics of cemiplimab are shown in Table 3.

Stakeholder Perspectives

Patient Group Input

This section was prepared by CADTH staff based on the input provided by patient groups.

Input was provided by 2 patient groups for this review, the SYSF and the MNC. The SYSF gathered information from online surveys, virtual patient roundtables, and 1-on-one conversations from March 2021 to September 2021. All 23 patients consulted (20 of whom were women) had been diagnosed with BCC, 5 of whom had experience with cemiplimab. It was not reported whether patients had experience with HHI therapy before receiving cemiplimab. All but 4 patients were from Canada, with most of the Canadian responders being from Ontario. The MNC input was sourced from an online survey of 62 patients (44 of which were women) and 45 caregivers. All but 1 of the patients were from Canada, with 50% located in Ontario. Only 1 patient indicated they had experience with cemiplimab in metastatic disease and no patients had experience with HHI therapy.

In both surveys, patients highlighted the negative aspects of BCC and its treatment, including disfigurement, scaring, and associated self-esteem difficulties. In both surveys, pain from the lesions and anxiety over finding recurrent disease were also mentioned by patients as key concerns. In the MNC survey, caregivers expressed that the disease caused much emotional stress due to seeing their loved 1 in pain. Patients expressed a desire for less radiation and disfiguring surgery and greater access to treatments closer to their home and support network. Respondents from the SYSF submission with 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 difficulty with liver-related issues and flu-like symptoms.

Patients indicated there are no other options for treatment following progression on HHI therapy 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.

Clinician Input

Input From the Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise regarding the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). The following input was provided by 2 clinical specialists with expertise in the diagnosis and management of adults with laBCC previously treated with HHI therapy.

Unmet Needs

The clinical experts consulted by CADTH highlighted the immense patient burden due to physical disfigurement from the external lesions that commonly present on the face of the patient. There are currently no treatment options for patients with laBCC who have been treated previously with HHI therapy, especially given that response to HHI is low and some patients cannot tolerate the side effects of this therapy.

Place in Therapy

The clinical experts noted that cemiplimab is indicated for patients with laBCC following HHI therapy and, therefore, cemiplimab would be used as a second-line therapy. There is currently no available treatment option for patients following HHI failure and, therefore, cemiplimab would not be displacing any currently prescribed second-line treatment. The clinical experts noted that in the future, combination therapy with cemiplimab and an HHI in the first-line setting could be explored; however, the associated phase II trial is still in the recruitment phase.²⁷

Patient Population

According to the clinical experts, patients with laBCC and mBCC previously treated with HHI therapy would be best suited to receive cemiplimab. In the case of laBCC, lesions should be determined to be unresectable or unsuitable for radiation therapy by a multidisciplinary tumour board. As there were small numbers of patients in the pivotal trial, it is unclear if there are prognostic features that would determine response to treatment, and PD-L1 expression measurements do not appear to correlate with response in this setting. The patients most in need of intervention are those with laBCC that is disfiguring and invading vital structures.

Assessing Response to Treatment

Response to treatment is assessed by serial imaging demonstrating shrinking disease (objective responses) and clinical assessment, as well as more subjective measures such as maintained or improved HRQoL, cancer symptoms, and functional status. The outcomes used in clinical practice are the same as those used in clinical trials. Given the outward nature of locally advanced disease in these patients and the impact it has on HRQoL, patient-reported outcomes were identified by the clinical experts as extremely important in this setting. Increased survival is important if it comes with improvements in HRQoL, particularly in relation to disfigurement changes. Response to treatment should be assessed at each follow-up visit, with imaging performed as appropriate, typically every 3 months.

Discontinuing Treatment

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 an adequate duration of treatment (identified as 4 to 6 months of treatment).

Prescribing Conditions

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. Cemiplimab would be administered in cancer centres or centres supervised by cancer centre–approved physicians with the expertise and staff (chemotherapy nurses, oncology pharmacists) to administer systemic therapies and manage treatment-related toxicities.

Additional Considerations

It was reiterated by the clinical experts that individual or community-based physicians may not be aware of the specific indications or contraindications of surgery and radiation for patients with laBCC. Decisions on which lesions are unresectable or not fit for radiation are therefore best determined by a multidisciplinary tumour board.

Clinician Group Input

This section was prepared by CADTH staff based on the input provided by clinician groups.

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 whose disease did not respond to HHI therapy as well as the importance of HRQoL outcomes, specifically those related to disfiguring lesions and surgical scarring.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CADTH are summarized in Table 4.

Clinical Evidence

The clinical evidence included in the review of cemiplimab is presented in the systematic review, which includes the pivotal studies provided in the sponsor’s submission to CADTH and Health Canada as well as those studies that were selected according to an a priori protocol. No indirect evidence was provided by the sponsor or met the selection criteria specified in the review. No additional relevant studies were identified that were considered to address important gaps in the evidence included in the systematic review.

Systematic Review (Pivotal and Protocol Selected Studies)

Objectives

To perform a systematic review of the beneficial and harmful effects of cemiplimab for the treatment of laBCC in patients previously treated with an HHI.

Methods

The studies selected for inclusion in the systematic review included pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those meeting the selection criteria presented in Table 5. Outcomes included in the CADTH review protocol reflect outcomes considered to be important to patients, clinicians, and drug plans.

The literature search for clinical studies was performed by an information specialist using a peer-reviewed search strategy according to the PRESS Peer Review of Electronic Search Strategies checklist.²⁹

Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946–) through Ovid and Embase (1974–) through Ovid. All Ovid searches were run simultaneously as a multi-file search. Duplicates were removed using Ovid deduplication for multi-file searches followed by manual deduplication in Endnote. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were Libtayo (cemiplimab) and BCC. Clinical trials registries were searched: the US National Institutes of Health’s clinicaltrials.gov, the WHO International Clinical Trials Registry Platform search portal, Health Canada’s Clinical Trials Database, and the European Union Clinical Trials Register.

No filters were applied to limit the retrieval by study type. Retrieval was not limited by publication date or by language. Conference abstracts were excluded from the search results. See Appendix 1 for the detailed search strategies.

The initial search was completed on September 13, 2021. Regular alerts updated the search until the meeting of the CADTH pan-Canadian Oncology Drug Review Expert Committee (pERC) on January 12, 2022.

Grey literature (literature that is not commercially published) was identified by searching relevant websites from the Grey Matters: A Practical Tool for Searching Health-Related Grey Literature checklist.³⁰ Included in this search were the websites of regulatory agencies (FDA and European Medicines Agency). Google was used to search for additional internet-based materials. See Appendix 1 for more information on the grey literature search strategy.

Two CADTH clinical reviewers independently selected studies for inclusion in the review based on titles and abstracts, according to the predetermined protocol. Full-text articles of all citations considered potentially relevant by at least 1 reviewer were acquired. Reviewers independently made the final selection of studies to be included in the review, and differences were resolved through discussion.

Findings From the Literature

One study was identified from the literature for inclusion in the systematic review (Figure 1). The included study is summarized in Table 6. A list of excluded studies is presented in Appendix 2.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Description of Studies

Study 1620 (R2810-ONC-1620) is a phase II, single-arm, non-randomized, open-label study of cemiplimab in laBCC and patients with laBCC and mBCC following treatment with HHI therapy. The study was funded by Regeneron Pharmaceuticals and Sanofi. The primary objective of Study 1620 was to determine the efficacy of cemiplimab (350 mg every 3 weeks) in achieving an objective response in adult patients with laBCC or mBCC. The laBCC and mBCC populations were recruited and analyzed as 2 distinct groups and therefore the description of the study design includes references to the mBCC group. As the sponsor’s reimbursement request is limited to the laBCC population only, the results presented focus on the laBCC population. The results for the mBCC population are available in Appendix 3. Beginning on June 29, 2017, patients with laBCC or mBCC who had previously been treated with HHI therapy were enrolled in Study 1620 at 49 sites across North America (N = 3 patients in Canada) and Europe.

There were 4 amendments made to the trial protocol, 2 of which were made after patients had been enrolled. Notable amendments to mention include 1 made before the enrolment of patients where the protocol was amended to increase the dose from 250 mg to 350 mg every 3 weeks and to increase the length of the treatment period to 9 cycles. After patients had begun treatment, another protocol amendment was made to add an exclusion criterion for patients previously treatment with idelalisib. This amendment was made in response to safety findings from a separate trial of cemiplimab in patients with lymphoma where 2 patients previously treated with idelalisib experienced severe stomatitis and/or skin reactions, and a third patient experienced myositis and myasthenia gravis after treatment with cemiplimab. The second amendment was made after enrolment of patients began to extend the post-treatment follow-up for an additional year. How many patients had been enrolled before the implementation of these amendments was not reported.

Patients were screened for eligibility for up to 28 days before beginning study treatment. Patients were treated for up to 93 weeks or until progression, unacceptable toxicity, or confirmed response following a minimum of 48 weeks of treatment. Following the open-label treatment phase, patients entered the follow-up phase. This consisted of follow-up visits every 28 days for 7 visits and extended follow-up for 1 year with quarterly assessments. Patients who completed 9 cycles of treatment without progression but who progressed during the first 7 follow-up visits, without receiving any other systemic anti-cancer therapy, were permitted to enter re-treatment for an additional 48 weeks (maximum of 4 re-treatment cycles, 12 weeks per cycle).

The primary analysis was conducted based on a February 17, 2020, data cut-off date. An updated ||||||||||||||||||||||||||||||||||

Populations

Inclusion and Exclusion Criteria

The key inclusion and exclusion criteria for Study 1620 are summarized in Table 6. Adult patients (age ≥ 18 years) with a histologically confirmed diagnosis of laBCC or mBCC were eligible for inclusion if they were deemed unlikely to benefit from further HHI therapy due to prior progression on HHI therapy, intolerance to prior HHI therapy, or who achieved no better than stable disease after 9 months of HHI therapy. Eligible patients were required to have at least 1 measurable lesion with a longest diameter and a perpendicular diameter of 10 mm or greater if measured by digital medical photography (specifically for the laBCC group), and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Valid justification for unresectable disease included BCC that had recurred in the same location after 2 or more surgical resections, significant local invasion that precluded complete resection, as well as an anatomically difficult location for which surgery could result in severe disfigurement or disfunction. Similarly, patients were required to be deemed not fit for radiation therapy with acceptable justification being that a further dose would exceed the acceptable cumulative dose, the disease was unlikely to respond to therapy according to the judgment of the radiation oncologist, or an individualized risk-benefit assessment by a multidisciplinary team had deemed radiation to be contraindicated.

Patients were considered ineligible for enrolment in Study 1620 if they had received prior treatment with a PD-1 or PD-L1 pathway inhibitor or they had an ongoing or recent autoimmune disease that required treatment with systemic immunosuppressive treatments. Other exclusion criteria included untreated brain metastasis, active infection requiring therapy, or prior treatment with idelalisib. Patients were excluded if they received any anti-cancer treatment other than radiation therapy, investigational or standard care, within 30 days of the initial administration of cemiplimab.

Baseline Characteristics

The baseline characteristics of the patients in Study 1620 are shown in Table 7. Two-thirds of the patients in both the laBCC and mBCC groups were male, with a mean age of 69.1 (SD = 12.8) and 63.6 (SD = 11.4) years in the laBCC and mBCC groups, respectively. Most patients were White (67.9% of the laBCC group and 85.4% of the mBCC group), though a large proportion of the laBCC group (32.1%) reported missing data for race.

The baseline disease characteristics of patients in Study 1620 are shown in Table 8. Most patients were classified as having an ECOG performance status of 0 at baseline in both the laBCC (60.7%) and mBCC (64.6%) groups. At baseline, the histological subtype as measured by central pathology review was mostly “other” (54.2%) or “unknown” (27.1%) in the mBCC group while, in the laBCC group, “other” accounted for 66.7% of participants’ histologic subtype. Of note, the classification of other could include morpheaform, metatypical, superficial, micronodular, mixed, basosquamous, keratotic, or desmoplastic subtypes. The proportion of tumours with infiltrative subtype was 8.3% in both the laBCC and mBCC groups. There were differences between laBCC and mBCC groups with regard to the primary site of tumour, with the majority of patients with laBCC with head and neck tumours (89.3%), while the mBCC group were more evenly distributed, with 41.7% head and neck tumours and 47.9% with trunk tumours. All patients had received prior HHI therapy. Vismodegib was the most common, received by 94.0% of patients in the laBCC group and 95.8% of patients in the mBCC group. Most patients (72.9% of patients with mBCC and 58.3% of patients with laBCC) received 1 prior HHI therapy, though some patients had received more than 1 prior HHI (27.1% of patients with mBCC and 41.7% of patients with laBCC). Progression of disease was reported as the most common reason for discontinuation of prior HHI therapy (71.4% of patients in the laBCC group and 81.3% of patients in the mBCC group), while 29.2% of patients with mBCC and 38.1% of patients with laBCC discontinued HHI therapy due to intolerance and only 8.3% and 12.5% of patients, respectively, indicated no better than stable disease for longer than 9 months as a reason for discontinuation. The proportion of patients with any number of prior cancer-related surgery was 83.3% in both the laBCC and mBCC groups, while prior radiotherapy was reported in 50.0% and 60.4%, respectively. For the laBCC population, the most common justification for surgical unresectability was an anatomically difficult location, with surgery likely to result in disfigurement or disfunction, which was cited for 40.5% of patients. The most common justification for further radiation being infeasible was that an individualized risk-benefit assessment by a multidisciplinary team deemed radiation to be contraindicated.

Interventions

All patients enrolled into Study 1620 were administered cemiplimab as an IV infusion every 3 weeks at a dose of 350 mg. The infusion was administered in an outpatient setting over approximately 30 minutes. As this was an open-label and single-arm trial, there was no blinding to treatment for patients or investigators.

Other than the study drug, all treatment administered from the time of signed consent to 30 days following the last administration of the study drug was considered concomitant medication. Focal palliative radiation was allowed for local control of a tumour if the patient had been on treatment for 24 weeks; the patient was considered to have experienced disease progression if radiation therapy was initiated. It was recommended that patients not receive systemic corticosteroids, except for a life-threatening emergency or to treat an immune-related AE. Physiologic replacement doses of systemic corticosteroids were permitted, along with any other medication considered in the investigator’s judgment to be necessary for the patient’s welfare and not expected to interfere with the study drug. Premedications for study treatments were permitted if deemed necessary by the investigator; however, no premedication was permitted for the first dose of the study drug.

Study rules for treatment-dose modifications and discontinuations are summarized in Table 9. Dose reductions of the first order reduced the dose to 120 mg every 3 weeks, and patients requiring a second dose reduction were reduced further to 60 mg every 3 weeks. Patients who experienced grade 3 or greater AEs were required to temporarily discontinue treatment with cemiplimab and could be considered for re-treatment when the toxicity resolved to grade 1 or baseline. Patients who required treatment to be discontinued for more than 84 consecutive days and patients with grade 3 or greater uveitis were permanently discontinued from cemiplimab. If a patient experienced an immune-related AE of grade 3 or greater, treatment was withheld and, if the corticosteroid (prednisone or equivalent) dose could not be brought down to less than 10 mg per day within 12 days of onset, treatment was discontinued.

Outcomes

A list of end points identified in the CADTH review protocol that were assessed in the study included in this review is provided in Table 10. A detailed discussion and critical appraisal of the outcome measures of HRQoL used in Study 1620, EORTC QLQ-C30 and Skindex-16, is provided in Appendix 4. The EORTC QLQ-C30 has been used extensively in oncology trials and has demonstrated reliability, validity, and responsiveness to change in cancer patients, including patients with non-melanoma skin cancer (NMSC). The consensus of several studies was that the MID on any of the instrument’s scales was approximately 5 to 10 points. The Skindex-16 has been used extensively in dermatologic diseases and has demonstrated reliability, validity, and responsiveness to change in patient populations, including those with NMSC. The consensus of several studies was that the MID on any of the instrument’s scales was approximately 10 points.

The primary outcome of ORR was assessed separately for the mBCC and laBCC groups. Tumour response was assessed every 9 weeks for cycles 1 through 5 and every 12 weeks for cycles 6 through 9. Patients with radiologically measurable lesions were assessed using RECIST 1.1, where CR was predefined as disappearance of all target lesions, PR represented at least a 30% reduction in the sum diameters of the target lesion, and PD represented at least a 20% increase in the sum of diameters of the target lesion, while stable disease was achieved when there was neither sufficient growth nor shrinkage to qualify for PD or PR, respectively.

Specifically for the laBCC population, patients with only externally visible lesions were assessed according to digital medical photography and clinical response was scored according to a modified bi-dimensional WHO criteria, where CR was achieved with the disappearance of all target and non-target lesions, PR was achieved with a decrease of 50% or more in the sum products of the perpendicular longest dimensions, PD was represented by an increase of 25% or more in the sum products of perpendicular longest dimensions, and stable disease was achieved if there was neither sufficient shrinkage nor growth to qualify for PR or PD. Patients with visible external lesions were also considered to have PD if there was a new lesion with a longest diameter and a perpendicular diameter of 10 mm or greater that was clearly documented as not having been present previously. Of note, PR and CR responses were required to be maintained and confirmed 4 weeks following initial documentation of response before the patient could be considered to have achieved a PR, while a CR also required a confirmatory biopsy result.

For patients with laBCC with lesions that were both visibly measurable with digital medical photography and radiologically measurable according to RECIST 1.1, composite scoring criteria were used. Methodology for the composite scoring is shown in Table 11. Additionally, any previously inoperable lesion that was deemed to become operable following study treatment was considered a PR.

All imaging data and response outcomes were reviewed by both the investigator and by BICR; however, these assessments were not completed in real time and, as such, clinical management decisions were made according to local investigator assessment. In the event of differing opinions between the investigator decision and the BICR, such that it would impact ongoing patient management, the situation would be discussed between the sponsor and the investigator.

HRQoL, as measured by the EORTC QLQ-C30 and Skindex-16 instruments, was measured on the first day of every cycle and at end of study, with the change in score from baseline measured from day 1 of the first treatment cycle. DOR was analyzed for patients who achieved a CR or PR from the time of meeting response criteria to the first date of recurrence, progression, or death due to any cause. Patients were censored at the last evaluable tumour assessment if they did not have documented tumour progression or death, or if they initiated new anti-cancer therapy without progression. PFS was analyzed from the start of treatment to the first date of recurrence, progression, or death due to any cause. Patients with no evaluable post-baseline tumour assessment were censored for PFS on the date of first study treatment. OS was measured from the start of treatment to death due to any cause; patients whose survival status was unknown were censored at the date at which they were last known to be alive. Time-to-tumour response was analyzed in patients with confirmed responses from the start of treatment to the date the response criteria were first met. All time-to-response variables were measured as date of event or censor minus the date of the first study treatment plus 1 day.

Harms outcomes included TEAEs, SAEs, and AEs requiring dose interruption or reduction; WDAEs; and AEs of special interest. AEs and SAEs were collected from the time of informed consent until 105 days following the last dose of the study drug, with AEs occurring before first dose recorded on the medical history page. AEs were coded to a preferred term and associated primary system organ class according to the Medical Dictionary for Regulatory Activities version 22.1. AEs of special interest for Study 1620 included grade 2 or greater infusion-related reactions, allergic or hypersensitivity reactions, grade 3 or greater immune-related toxicities, and any immune-related toxicity occurring in a patient previously treated with phosphoinositide 3-kinase inhibitors (PI3Ks). Laboratory safety variables, vital signs, electrocardiograms, and physical examination variables were also monitored.

Statistical Analysis

As Study 1620 was a single-arm non-comparative trial, the primary end point was based on rejecting the null hypothesis of an ORR equal to a chosen non-clinically meaningful response rate. For the laBCC group, the null hypothesis was an ORR equal to 20% and would be rejected if the lower bound of the 2-sided 95% CI excluded the value of 20%. For the mBCC group, the null hypothesis was an ORR equal to 15% and would be rejected if the lower bound of the 2-sided 95% CI excluded the value of 15%. These thresholds were chosen to be consistent with what was determined to be clinically meaningful for HHI therapy in advanced BCC.^7,8

In the laBCC group, it was determined that a sample size of 80 was required to provide 85% power to reject the null hypothesis if the true ORR was 30% or more. In the mBCC group, it was determined that a sample size of 50 was required to provide 85% power to reject the null hypothesis if the true ORR was 28% or more. Target sample sizes were further increased by 5% to 53 patients in the mBCC group and 84 patients in the laBCC group.

The primary outcome of ORR, as measured by BICR in both groups, was tested according to the previously described hypothesis; all other secondary outcomes were summarized descriptively. ORR as well as CR rate and disease control rate were summarized by group, with the exact binomial 95% CI reported according to the Clopper-Pearson method. DOR, PFS, and OS distributions were estimated using the Kaplan–Meier method along with their medians and 95% CI. Kaplan–Meier estimates were produced for specific time points. Time-to-tumour response was summarized descriptively for specific time periods of interest. Table 12 provides a summary of the statistical analysis for each end point in Study 1620. All statistical analyses were conducted separately for the mBCC and laBCC groups.

The data cut-off date for the primary analysis was chosen to allow the last patient enrolled to be followed for 27 weeks in order for an adequate time for response, plus an additional 30 weeks to allow for adequate follow-up for DOR, for a total of 57 weeks of follow-up. At the time of the primary analysis for the laBCC group, an interim analysis was conducted in the mBCC group for patients with sufficient follow-up. For tests where alpha spending was required, a 2-sided alpha of 0.0001 was applied to the interim analysis, with 0.0499 preserved for the final analysis. For the primary outcome of ORR in patients with mBCC at the interim analysis, both an adjusted 2-sided 99.99% CI and unadjusted 2-sided 95% CI were reported. The updated analysis |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

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Analysis Populations

The full analysis set included all patients who were enrolled in Study 1620 and deemed eligible for treatment by way of passing the screening criteria. All response and progression end points were analyzed in the full analysis set. The full analysis set for the interim analysis of the mBCC group included only patients with sufficient follow-up time, which was considered to be 6 months. The safety analysis set included all patients who received any study drug at the time of the data cut-off date.

Results

Patient Disposition

At the time of the primary analysis in the laBCC group, a total of 165 patients were screened, of which 132 were enrolled into Study 1620 and 33 were screening failures. The proportion of screen failures that comprised patients with laBCC or mBCC was not provided; therefore, Table 13 summarizes the reasons for screening failures for the 2 groups combined. Only the results for the laBCC group are presented in the following section, as these align with the reimbursement request; results for the mBCC group are presented in Appendix 3. The most common reason for screening failure was failure to meet the inclusion or exclusion criteria (72.7%), with the most commonly failed inclusion criteria being the requirement for a histologically confirmed diagnosis of invasive BCC and at least 1 measurable lesion, according to study criteria. Of the 33 total screening failures, 18.2% were classified as other.

Patient disposition in the laBCC group of Study 1620 is summarized in Table 14. Of the 84 patients enrolled, 15.5% of patients had completed treatment at the time of the primary analysis, while 61.9% of patients had discontinued treatment. The most common reason for discontinuing treatment was disease progression (34.5%) followed by AEs as the second most common reason (15.5%). At the time of the primary analysis, 33.3% of patients were ongoing in the study, and 7.1% of patients had completed 93 weeks of treatment plus follow-up periods. With regard to study discontinuation, PD was still the most common reason (33.3%); however, 19.0% of patients discontinued study for reasons other than PD or death. These reasons included lost to follow-up, non-compliance with protocol, patient decision, sponsor decision, withdrawal of consent, AEs, or other. Of the 2 patients who discontinued the study for reasons classified as “other,” 1 was due to a general worsening of clinical condition and the other was due to pulmonary inflammation and worsening dyspnea. The full analysis set included all patients who had received the study treatment and had sufficient follow-up; this set was therefore equal to the safety analysis set. At the time of the primary analysis, 21.4% of patients had entered the follow-up period. The mean follow-up duration was 13.53 (SD = 6.54) months.

At the time of the updated analysis, |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. The proportion of patients who had completed study treatment increased to ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. The full analysis and safety analysis sets ||||||||||||||||||||||||||||||||||||||||.

Protocol deviations are shown in Table 15. Of the 23.8% patients with an important protocol deviation, the most common deviations related to meeting exclusion criteria but being enrolled (3.6%), or failing to meet inclusion criteria but being enrolled (15.5%). Most notably, from the patients who did not meet the inclusion criteria, there were 2 patients with no measurable lesions who were enrolled in the study. Other more common inclusion criteria that were not met were tumour material not confirmed by central pathology review before enrolment, and creatine phosphokinase testing not performed at screening.

Exposure to Study Treatments

Treatment exposure in Study 1620 is shown in Table 16. At the time of the primary analysis, the mean duration of exposure for patients in the laBCC group was 52.80 (SD = 28.85) weeks, with a mean number of 16.7 (SD = 9.42) doses administered. Patients received a mean relative dose intensity of 0.95 (SD = 0.11), and 89.3% of patients had a treatment compliance rate of 80% or greater. At the updated analysis, ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.

A summary of dose delays and infusion interruptions is shown in Table 17. At the time of the primary analysis, 45.2% of patients had experienced at least 1 dose delay or an infusion interruption. More patients experienced at least 1 dose delay (40.5%) compared with infusion interruptions (4.8%). Of the 4 patients who experienced an infusion interruption, 3 were interrupted due to an AE, while the reason for the interruption in the other patient was reported as “other.” Details on TEAEs and infusion interruptions are summarized in the Harms section.

Concomitant medication use in Study 1620 is shown in Table 18. Overall, the use of any concomitant medication was high in patients with laBCC (97.6%). In the laBCC group, the most common categories of concomitant medications administered were analgesics (51.2%) and antibacterials for systemic use (52.4%).

Outcomes

Only those outcomes and analyses of subgroups identified in the review protocol are reported subsequently. See Appendix 3 for detailed results on other outcomes.

Objective Response Rate

ORR by BICR assessment was the primary end point in Study 1620 and the results are presented in Table 19. At the time of the primary analysis, the ORR in the laBCC group was 28.6% (95% CI, 19.2% to 39.5%), of which 6% achieved CR and 22.6% achieved PRs. The lower bound of the 95% CI did not exclude the pre-specified threshold of 20%.

Two pre-specified subgroup analyses of ORR were of interest to this review: reason for HHI discontinuation (progression or intolerance) and histologic subtype, as measured by central pathology review. In patients who discontinued HHI due to progression or lack of response (N = 63), the ORR was 28.6% (95% CI, 17.9% to 41.33%) and, in patients who discontinued due to intolerance (N = 21), the ORR was 28.6% (95% CI, 11.3% to 52.2%). The ORRs based on histologic subtypes were as follows: in patients with infiltrative histology (N = 7), the ORR was 42.9% (95% CI, 9.9% to 81.6%); in patients with nodular histology (N = 21), the ORR was 19.0% (95% CI, 5.4% to 41.9%); in patients with other histology (N = 56), the ORR was 30.4% (95% CI, 18.8% to 44.1%).

At the time of the primary analysis, it was noted that 2 patients with a PR were not included as responders in the analysis due to their responses not having been confirmed by BICR and, therefore, according to the protocol, were to be considered as having stable disease. These patients were included in a sensitivity analysis of the primary outcome because they ultimately were confirmed by BICR as having achieved a PR, albeit after the primary analysis data cut-off had passed. The results of this analysis show that the inclusion of these 2 patients pushes the lower bounds of the 95% CI above 20% (results not shown).

At the updated analysis, the ORR (95% CI) for the full analysis set was ||||||||||||||||||||||||||||||||||||||||||, of which |||||||| were CRs and |||||||| were PRs.

Duration of Response

The results for DOR are summarized in Table 20. At the time of the primary analysis, the median Kaplan–Meier estimation of DOR in the 24 patients who achieved either a CR or PR 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. At the updated analysis, the Kaplan–Meier estimate of median DOR ||||||||||||||||||||. The observed DOR ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| of responders achieving a DOR greater than 6 months and |||||| of responders achieving a DOR greater than 12 months.

Health-Related Quality of Life

Results for HRQoL, measured using the global health status (HRQoL) scale of the EORTC QLQ-C30 at baseline and up to cycle 9, are shown in Table 21. Baseline completion of the questionnaire was 92.9% in patients with laBCC, with post-baseline completion rates greater than 80% through to cycle 7. Baseline global health status (on a scale of 0 to 100, with higher values signifying better HRQoL) was 64.30 (SD = 19.14) in the laBCC group. Changes in global health status (HRQoL) over time were smaller than the MID estimate of 5 to 10 points at |||||| the primary analysis ||||||||||||||||||||||. Analysis of the EORTC QLQ-C30 functional and symptom scales was consistent with the results for the global health status scale (Appendix 3). Symptom scales remained stable over time with the exception of fatigue, which showed worsening in excess of the MID for the fatigue scale at cycles 7 and 9, though patient numbers were reduced at these time points (Appendix 3).

The results for HRQoL, as measured by the Skindex-16 emotional, symptom, and functioning scales at baseline and up to cycle 9 (on a linear scale of 0 to 100, with 0 representing never bothered and 100 representing always bothered), are summarized in Table 22, Table 23, and Table 24, respectively. Patients with laBCC had baseline completion rates for the questionnaire of 94.0%, 96.4%, and 95.2% for the emotions, symptoms, and functioning domains, respectively. Post-baseline completion rates were greater than 80% through cycle 6. The baseline mean emotional scale score was 39.15 (SD = 39.15). By cycle 4, and through to the end of treatment, there was a change of 10 points or greater, exceeding the MID threshold for improvement in this scale. The Skindex-16 symptom and functioning scales remained stable across time. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.

Progression-Free Survival

The results for PFS by BICR assessment are shown in Table 25 and Figure 2. At the time of the 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 was 19.3 months (95% CI, 8.6 to not evaluable) with an estimate of event-free survival of 76.3% (95% CI, 65.1% to 84.4%) at 6 months, 56.5% (95% CI, 44.3% to 67.0%) at 12 months, and 35.3% (95% CI,19.1% to 52.0%) at 24 months. At the updated analysis, |||| of patients had experienced a PFS event, with |||||| of patients experiencing disease progression and ||||| experiencing death. The median (95% CI) PFS was ||||||||||||||||||||||||||||||||||, with an estimate of event-free survival (95% CI) at 6 months of ||||||||||||||||||||||||||||||||||||||||||||||||||||||||| at 12 months, and ||||||||||||||||||||||| at 24 months. A sensitivity analysis of PFS by BICR assessment was conducted to include patients starting anti-cancer therapy without documented progression as a PFS event. Results of this analysis were consistent with the primary analysis |||||||||||||||||||||||||||||||||||||||||||||| in the updated analysis (Appendix 3).

Figure 2: Kaplan–Meier of PFS by BICR Assessment in Study 1620

BICR = blinded independent central review; laBCC = locally advanced basal cell carcinoma; PFS = progression-free survival.

Source: Study 1620 Clinical Study Report.⁵

Overall Survival

The results for OS are summarized in Table 26 and Figure 3. At the time of the primary analysis, deaths had occurred in 11.9% of patients and the median OS had not been reached. The 6-month estimate of OS was 98.8% (95% CI, 91.8% to 99.8%) and, at 12 months, the estimate was 92.3% (95% CI, 83.6% to 96.5%). At 24 months, the estimate was 80.3% (95% CI, 62.6% to 90.3%). At the updated analysis, ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. The 6-month estimate of OS (95% CI) was |||||||||||||||||||||||||||||||||||||| and, at 12 months, the estimate was ||||||||||||||||||||||||||||||||||||||. At 24 months, the estimate was ||||||||||. ||||||||||||||||||||||. A sensitivity analysis was conducted censoring patients with subsequent therapy from the OS analysis. The results of this analysis were consistent with the primary analysis ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| the analysis (Appendix 3).

Figure 3: Kaplan–Meier of OS in Study 1620

laBCC = locally advanced basal cell carcinoma; OS = overall survival.

Source: Study 1620 Clinical Study Report.⁵

Time to Response

The time to response according to BICR assessment is summarized in Table 27. At the time of the primary analysis, the mean time to response in patients with laBCC with a CR or PR (N = 24) was 5.17 (SD = 2.60) months and ranged from 2.1 to 13.4 months, with 50% of those responses occurring from 4 to 6 months from the start of treatment. At the updated data cut-off, the mean (SD) time to response in patients with laBCC with CR or PR ||||||||||||||||||||||||||||||||||||||||| and ranged from ||||||||||||||||||||||, with ||||| of responses occurring from 4 to 6 months and ||||| of responses occurring greater than 6 months from the start of treatment.

Time to Progression

Results for time to progression were not assessed in Study 1620.

Harms

Only those harms identified in the review protocol are reported subsequently. Refer to Table 28 for detailed harms data.

Treatment-Emergent Adverse Events

At the time of the primary analysis, almost all patients (97.6%) treated with cemiplimab experienced at least 1 TEAE. The TEAEs (≥ 20%) that were common in patients receiving cemiplimab included fatigue (29.8%), diarrhea (23.8%), pruritis (21.4%), and asthenia (20.2%). At the updated analysis, 98.8% of patients reporting at least 1 TEAE, and the most frequently reported TEAEs ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| included fatigue |||||), diarrhea ||||||, pruritis ||||||, and asthenia |||||||.

Serious Adverse Events

At the time of the primary analysis, SAEs had occurred in 34.5% of patients, and the most commonly reported SAE was urinary tract infection (4.8% of patients). At the updated data cut-off, SAEs were reported in 36.9% of patients and |||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.

TEAEs Leading to Interruption, Dose Delay, or Dose Reduction

At the primary analysis, TEAEs that led to a dose delay occurred in 36.9% of patients. The most common TEAE that led to a dose delay was diarrhea (4.8% of patients), followed by blood creatinine increased, fatigue, and urinary tract infection, each occurring in 3.6% of patients. Less common were TEAEs that led to study drug interruption (3.6%); these included 1 occurrence each of palpitations, extravasation, and flank pain. One patient experienced a TEAE leading to dose reduction (1.2%), specifically, a cutaneous soft tissue infection of BCC. No additional AEs leading to study drug interruption, dose delay, or dose reduction were reported at the updated analysis.

Withdrawals Due to TEAEs

TEAEs that led to discontinuation of cemiplimab occurred in 16.7% of patients at the primary analysis and 17.9% of patients at the updated analysis. The most common TEAE leading to treatment discontinuation was colitis, occurring in 2.4% of patients.

Mortality

At the time of the primary analysis, TEAEs resulting in death occurred in 3.6% of patients. These included 1 occurrence each of cachexia, malignant brain neoplasm, and acute kidney injury. At the updated analysis, |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||.

Notable Harms

Notable harms specified in the CADTH review protocol included immune-related AEs and infusion-related reactions. At the time of the primary analysis, 56.0% of patients had experienced an immune-related AE, 11.9% had experienced an immune-related AE of grade 3 or greater, and 9.5% discontinued treatment with cemiplimab due to an immune-related AE. These | |||||||||||||||||||||||||||||||||||| at the updated data analysis ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||. Infusion-related reactions were less common, reported in ||||||||||||||||||| patients at |||| the primary analysis ||||||||||||||||||||||||||||||| |||||||||||||||||||.

Critical Appraisal

Internal Validity

Study 1620 was a phase II, single-arm, non-randomized, open-label, multi-centre study that evaluated cemiplimab in patients with laBCC and mBCC who had been previously treated with HHI therapy. Although non-comparative trial evidence is of lower quality, with an increased risk of bias compared with the preferred randomized controlled trial (RCT) design, it was acknowledged by the CADTH review team and the clinical experts consulted for this review that, due to the lack of a relevant active comparator and given the relative size of the patient population, conducting an RCT would be difficult. Nevertheless, it is impossible to draw conclusions of efficacy from a single-arm trial, as the causal relationship between outcomes and intervention cannot be ascertained without the inclusion of a comparator arm.

The outcomes assessed in Study 1620 (ORR, PFS, OS, HRQoL) are standard in oncology trials, and tumour responses were evaluated by BICR. As patients with laBCC had the potential for both external and internally measurable lesions, a composite scoring method was used that combined RECIST 1.1 and visual response criteria based on digital medical photography. The method of assessment was considered by the clinical experts consulted by CADTH to be valid for measuring response and consistent with previous trials conducted within the laBCC population.^7,8 For the analysis of PFS and DOR, patients receiving a new anti-cancer therapy before an event were censored, and this outcome was not treated as an event. As per FDA guidance, this is considered a biased censoring rule, and starting another treatment before a documented event should be considered as an event in the analysis.³¹ Using this censoring rule biases the results in favour of cemiplimab; however, its impact was small in Study 1620, since the results of the sensitivity analysis that considered starting a new anti-cancer therapy included only 1 additional patient with a progression event.

The statistical analysis was appropriate, given the single-arm study design. The statistical analysis plan provided by the sponsor specified 20% as the threshold for a clinically meaning primary end point of ORR. The clinical experts consulted by CADTH agreed that response rates that exceed this level would be clinically meaningful, and it was also noted that this threshold is consistent with the ORR thresholds used in previous single-arm trials in BCC patients.^7,8 Rejection of the null hypothesis (ORR = 20%) required the lower bound of the 95% CI to exclude 20%; however, this was not achieved at the time of primary analysis (ORR = 28.6; 95% CI, 19.2% to 39.5%).

According to the study protocol, for a patient to have achieved a CR or PR, 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; this includes the responses from 2 patients who had unconfirmed initial responses at the time of the primary analysis. Ultimately, both patients did have their responses confirmed; however, these results are based on an ad hoc redefinition of the primary outcome that differs from the study protocol. Since there was no adjustment for multiplicity in this analysis, there is an increased risk of type I error and, therefore, the results obtained should be interpreted with caution. The sponsor also provided the results of an ||||||||||||||||||||||| updated analysis ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||; the reported ORR (95% CI) at this data cut-off was ||||||||||||||||||||||||||||||||||||||. The same limitations regarding no adjustment for multiplicity and increased risk of type I error apply to the updated analysis and results.

Important protocol deviations occurred in a relatively high number of patients in the laBCC group (23.8%), though 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 deviations in inclusion (15.5%) and exclusion (3.6%) criteria. Notably, 2 patients did not meet the inclusion criterion that required enrolled patients to have at least 1 measurable lesion, which would likely bias the results in favour of cemiplimab. Neither patient was recorded as achieving either a PR or CR; 1 achieved a best overall response of stable disease and the status of the second was recorded as not evaluable at all visits. Therefore, it is unlikely that including these patients biased the primary end point in favour of cemiplimab, though it is likely that secondary end points such as HRQoL, PFS, and OS could have been biased in favour of cemiplimab. The impact of the high number of other important protocol deviations on the characteristics of the study population and the direction of bias was unclear.

The blinding of patients was not possible in the context of a non-comparative trial and, therefore, the open-label nature of the design may have contributed to the introduction of several potential biases, although their overall impact is unclear. There was a relatively high number of patients who discontinued the study for reasons other than PD or death (19.0% at the primary analysis data cut-off); the other reasons for discontinuation included AEs, lost to follow-up, non-compliance with the protocol, withdrawal of consent, patient decision, and sponsor decision. Specifically in the case of non-compliance with the protocol and sponsor decision, the CADTH review team indicated these are not valid reasons to discontinue the study and are likely to bias the results in favour of cemiplimab. The high overall number of study dropouts may have introduced potential bias into the results; however, their overall impact on patient characteristics and study outcomes as well as the direction of bias is unclear. The decision to discontinue patients from therapy was made by investigators based on unblinded review of local imaging results and/or clinical assessments. These decisions may have altered treatment exposure to cemiplimab and thus influenced results. Investigators were less likely to classify PD than BICR (6.0% versus 10.7% at the primary analysis), which suggests patients were exposed to cemiplimab for longer than would have been the case if treatment decisions were based on blinded review.

The secondary outcomes of DOR, PFS, OS, and HRQoL did not have any formal hypothesis testing conducted. HRQoL outcomes had good completion rates at baseline (89%) and up to cycle 6 (> 80%); however, as none of these end points were part of a formal testing hierarchy, these results should be viewed as exploratory. The subgroup analyses of interest to this review (outcome of prior HHI therapy and histologic subtype) were specified a priori; however, as these analyses were not part of a formal testing hierarchy, these results must also be considered exploratory.

External Validity

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 patients enrolled were required to have previously been treated with HHI therapy, 16.7% of whom were previously treated with sonidegib, an HHI that is Health Canada–approved but not publicly reimbursed in Canada. The clinical experts consulted by CADTH did not expect this to impact the generalizability of the study results to Canadian patients, who are unlikely to have received sonidegib. Similarly, 41.7% of patients received 2 or more lines of HHI therapy before receiving cemiplimab. As vismodegib is the only reimbursed HHI therapy in Canada, it is unlikely that the Canadian population would have received multiple lines of HHI therapy, suggesting a potential for better outcomes in Canadian patients.

The application of the inclusion and exclusion criteria to this patient population resulted in a relatively high proportion of screen failures (33 out of 165; 20%), though it was unclear what proportion of screen failures were in the laBCC group compared with the mBCC group. According to the clinical experts, the enrolment criteria, as in most oncology trials, likely selected for a healthier cross-section of the overall patient population who were better able to tolerate protocol therapy. The potential administration of cemiplimab outside of the Health Canada indication was identified as possible by the clinical experts consulted for this review. Study 1620 also included a small group of patients with mBCC who had previously received HHI therapy. The mBCC population was removed from the indication at the request of Health Canada, which cited the immaturity of the data at the time of the interim analysis for the mBCC group, with the ORR not reaching the pre-specified threshold for a clinically meaningful response, and uncertainty in the DOR due to limited follow-up and low patient numbers. Consequently, the generalizability of the trial data to the mBCC population is unclear. Study 1620 limited enrolment to patients with an ECOG performance status of 0 or 1 and, thus, the generalizability of the laBCC trial results to patients with a poorer ECOG performance status (score greater than 2) is unclear. According to the clinical experts, in clinical practice, the performance status of patients with mBCC or those with an ECOG performance status greater than 2 is expected to improve after initiating treatment with cemiplimab.

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 PD or unacceptable toxicity, up to 93 weeks. The protocol allowed for the re-treatment of patients who had completed the full treatment course but who experienced PD during the follow-up period. The sponsor confirmed that 1 patient in the study had entered re-treatment with cemiplimab.³² The trial data may not be generalizable to treatment beyond the 93-week treatment course or within a re-treatment setting for patients who experience PD following discontinuation of cemiplimab, given the lack of data. All outcomes evaluated in the trial and considered in this review (ORR, DOR, HRQoL, PFS, OS) were clinically relevant, important to patients, and are used in clinical practice. The duration of follow-up was sufficient for assessment of the primary outcome of ORR, DOR, and HRQoL; however, longer-term outcomes of PFS and OS are difficult to interpret, given the single-group trial design. Subgroup analyses were not powered to detect treatment effect in patients who progressed or who achieved only stable disease after 9 months on HHI therapy, patients intolerant to HHI therapy, and patients based on their histologic subtype. Nevertheless, the clinical experts consulted for this review felt that the results of the trial were generalizable across strata for all of these subgroups.

Since the administration of cemiplimab would occur in a hospital or specialty clinic setting, background care (oncologist visits, imaging frequency, bloodwork, and so forth) would be expected to be similar for Canadian patients compared with those participating in Study 1620.

Indirect Evidence

Objectives and Methods for the Summary of Indirect Evidence

No indirect evidence was submitted by the sponsor. A focused literature search for network meta-analyses dealing with BCC was run in MEDLINE All (1946–) on September 13, 2021. No limits were applied to the search. No indirect evidence was identified for this review.

Other Relevant Evidence

No other relevant evidence was identified for this review.

Discussion

Summary of Available Evidence

One phase II, single-arm, non-randomized, open-label multi-centre trial, Study 1620 (patients with laBCC; N = 84, primarily US and Europe)^5,6 comprised the evidence for this CADTH review. The study enrolled patients with laBCC and mBCC who had previously received HHI therapy; however, the laBCC population was the focus of this review, as the Health Canada indication and reimbursement request were focused on this subgroup of patients. Patients were treated with cemiplimab until PD or unacceptable toxicity for up to 93 weeks. Tumour response was assessed using a composite of RECIST 1.1 for lesions with radiologically measurable components and modified WHO clinical criteria for lesions with externally visible components, and responses were designated by BICR. The primary outcome was ORR, while secondary outcomes included DOR, PFS, OS, and HRQoL.

According to the clinical experts consulted by CADTH, the baseline characteristics of Study 1620 were representative of patients with laBCC in Canada who would be candidates for cemiplimab. Most patients in the laBCC subgroup were male (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%) occurring in the head or neck region. The mean age of the patients with laBCC was 69.1 (SD = 12.8) years. The limitations of the study included potential biases inherent to its single-arm, non-comparative design prohibiting the ability to draw causal conclusions between the intervention and outcomes.

Interpretation of Results

Outcomes

Administration of cemiplimab in Study 1620 resulted in an ORR of 28.6% (95% CI, 19.2% to 39.5%) at the primary analysis, and this increased to 32.1% (95% CI, 22.4% to 43.2%) at the updated analysis. At the primary analysis, the primary end point of ORR did not meet the pre-specified threshold (lower bound of the 95% CI, excluding the value of 20%) to reject the null hypothesis. The sponsor noted that with the inclusion of the 2 patients with unconfirmed initial responses (a deviation from the study protocol), the requirement for the rejection of the null hypothesis was met. The DOR at the primary analysis ranged from 2.1 months to 21.4 months, with 79.2% of responders achieving a DOR of greater than 6 months and 45.8% of responders achieving a DOR of greater than 12 months. The clinical experts consulted by CADTH considered the results to be clinically meaningful in this population, which had been previously treated with HHI therapy and had no alternative treatment options. Responses from the clinician and patient groups also specifically highlighted the lack of treatment options in this patient population. However, there are significant issues with analyzing the primary outcome in a manner that deviates from the study protocol to include additional responders.

As laBCC is a very disfiguring malignancy, there is a very large impact on the HRQoL of the patient, including reduced self-esteem due to their physical appearance, constant anxiety about finding new lesions, and pain. As such, HRQoL was identified in the patient group input as being very important to patients and was measured in Study 1620 using the EORTC QLQ-C30 and Skindex-16. The global health status or HRQoL score remained stable throughout the study, with no increase or decrease from baseline that met the MID estimate of 5 to 10 points. Functional and symptom scales were similarly stable throughout the study. An improvement in excess of the MID was achieved in the emotion scale of the Skindex-16 at cycle 4 and maintained through to the end of the study, while the symptom and functioning scales remained stable. The clinical experts consulted were hopeful, given the signal of improvement in some scales and the lack of deterioration in others, and commended the sponsor for using dermatology-specific HRQoL measures along with an oncology-specific instrument. However, the analyses of HRQoL outcomes were descriptive and potentially impacted by the low number of patients participating in later cycles of the study; there is also the potential for bias in favour of cemiplimab due to the open-label design of the study. At the primary analysis, the median PFS was 19.3 (95% CI, 8.6 to not evaluable) months, and the median OS was not reached. Given the low number of PFS and OS events in the study and the non-comparative study design, the effect of cemiplimab on long-term outcomes is unknown. The subgroup analyses were consistent with the primary analysis; however, as they were not part of a formal testing hierarchy, these results must be considered exploratory.

Harms

The safety profile of cemiplimab in Study 1620, which did not identify any new safety signals, was as expected, based on prior experience with the drug. Immune-related AEs occurred in more than half of patients and should be monitored, as is common practice with immunotherapies. The clinical experts consulted for this review felt the safety profile of cemiplimab in patients with laBCC is acceptable and can be managed with appropriate supportive care, and this aligned with the perspectives of patients gathered from patient groups indicating the side effects of cemiplimab were manageable and worth the potential benefit.

Other Considerations

No other considerations were identified for this review.

Conclusions

Study 1620 was a single-arm study of cemiplimab (350 mg every 3 weeks up to a maximum of 93 weeks) in patients with laBCC. The study did not meet the pre-specified threshold of a 20% ORR, which is considered clinically meaningful. At the updated analysis, ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. In the opinion of the clinical experts consulted by CADTH, despite the limitations of Study 1620, the observed ORR in patients with laBCC previously treated with an HHI was considered clinically meaningful and of value in a high-burden disease for which there is a high unmet need for treatment options. The descriptive assessment of HRQoL in the study was limited by the low number of respondents contributing to assessments at later time points, but suggested multiple measures of HRQoL were stable over the course of the study and a clinically meaningful improvement was observed for emotional functioning. Data on PFS and OS were immature, but longer-term data for these outcomes will be challenging to interpret due to the non-comparative study design. The notable harms that were observed with cemiplimab, specifically immune-related AEs, were consistent with the known safety profile of the drug and were considered by the clinical experts consulted by CADTH as well as by patients to be manageable with appropriate supportive care. The major limitation of Study 1620 is its open-label, single-group trial design, which introduces bias in favour of cemiplimab and precludes the ability to evaluate the efficacy and magnitude of the clinical benefit of cemiplimab in this treatment setting.

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Appendix 1: Literature Search Strategy

Note that this appendix has not been copy-edited.

Clinical Literature Search

Overview

Interface: Ovid

Databases

• MEDLINE All (1946–present)

• Embase (1974–present)

• Note: Subject headings and search fields have been customized for each database. Duplicates between databases were removed in Ovid.

Date of search: September 13, 2021

Alerts: Bi-weekly search updates until project completion

Search filters applied: No filters were applied to limit the retrieval by study type.

Limits

• Conference abstracts: excluded

Table 29: Syntax Guide

Multi-Database Strategy

1. (Cemiplimab* or Libtayo* or regn2810 or regn 2810 or sar 439684 or sar439684 or 6QVL057INT).ti,ab,ot,kf,,hw,nm,rn.

2. 1 use medall

3. *cemiplimab/

4. (Cemiplimab* or Libtayo* or regn2810 or regn 2810 or sar 439684 or sar439684).ti,ab,kw,dq.

5. 3 or 4

6. 5 use oemezd

7. (conference abstract or conference review).pt.

8. 6 not 7

9. 2 or 8

10. remove duplicates from 9

Clinical Trials Registries

ClinicalTrials.gov

Produced by the US National Library of Medicine. Targeted search used to capture registered clinical trials.

Search — Studies with results: Libtayo (cemiplimab) AND basal cell carcinoma (BCC)

WHO International Clinical Trials Registry Platform

International Clinical Trials Registry Platform, produced by the World Health Organization. Targeted search used to capture registered clinical trials.

Search terms: Libtayo (cemiplimab) AND basal cell carcinoma (BCC)

Health Canada’s Clinical Trials Database

Produced by Health Canada. Targeted search used to capture registered clinical trials.

Search terms: Libtayo (cemiplimab) AND basal cell carcinoma (BCC)

EU Clinical Trials Register

European Union Clinical Trials Register, produced by the European Union. Targeted search used to capture registered clinical trials.

Search terms: Libtayo (cemiplimab) AND basal cell carcinoma (BCC)

Grey Literature

Search dates: September 7, 2021 September 10, 2021

Keywords: Search terms: (Libtayo OR cemiplimab OR REGN-2810 ) AND basal cell carcinoma

Limits: No limits

Updated: Search updated prior to the completion of stakeholder feedback period

Relevant websites from the following sections of the CADTH grey literature checklist Grey Matters: A Practical Tool for Searching Health-Related Grey Literature were searched:

• Health Technology Assessment Agencies

• Health Economics

• Clinical Practice Guidelines

• Drug and Device Regulatory Approvals

• Advisories and Warnings

• Drug Class Reviews

• Clinical Trials Registries

• Databases (free)

• Health Statistics

• Internet Search

• Open Access Journals.

Appendix 2: Excluded Studies

No publications beyond the included pivotal trial were ordered for full-text review, therefore there are no excluded studies to report in this appendix.

Appendix 3: Detailed Outcome Data

Note that this appendix has not been copy-edited.

Detailed Outcome Data in the laBCC Population

Main Outcome Analysis by Investigator Assessment

Table 30: ORR by Investigator Assessment in Study 1620

CI = confidence interval; CR = complete response; CRR = complete response rate; DCR = disease control rate; laBCC = locally advanced basal cell carcinoma; NE = not evaluable; ORR = objective response rate; PD = progressive disease; PR = partial response.

^a CR/PR must be confirmed by repeated assessments no less than 4 weeks apart.

^b Clopper-Person exact CI.

^c CR+PR+Stable disease.

^d Stable disease criteria must be met at least once after a minimum duration of 39 days after first dose date.

^e Not evaluable response includes the missing and unknown tumour response.

Source: Study 1620 Clinical Study Report.⁵

Table 31: DOR by Investigator Assessment in Study 1620

CI = confidence interval; CR = complete response; DOR = duration of response; KM = Kaplan-Meier; laBCC = locally advanced basal cell carcinoma; NA = not applicable; NE = not evaluable; NR = not reached; PR = partial response.

^a Events include progressive disease or deaths. Percentages are based on number of patients with confirmed CR or PR.

^b Percentages are based on number of patients with confirmed CR or PR. The numerator includes the number of patients whose observed DOR reached at least the specified time. Patients who did not have the opportunity to reach the specified time point were included in the denominator only. Because responses for some patients are ongoing, the percentages at the specified time points may increase as data mature.

Source: Study 1620 Clinical Study Report.⁵

Table 32: PFS by Investigator Assessment in Study 1620

CI = confidence interval; KM = Kaplan-Meier; laBCC = locally advanced basal cell carcinoma; NA = not applicable; PD = progressive disease; PFS = progression-free survival.

Source: Study 1620 Clinical Study Report.⁵

Figure 4: Kaplan-Meier of PFS by Investigator Assessment in Study 1620

Source: Study 1620 Clinical Study Report.⁵

Table 33: Summary of Time to Response by Investigator Assessment in Study 1620

CR = complete response; laBCC = locally advanced basal cell carcinoma; PR = partial response; SD = standard deviation.

^a Percentages are based on number of patients with confirmed CR or PR.

Source: Study 1620 Clinical Study Report.⁵

ORR Subgroup Analysis by Outcome of Prior HHI

Table 34: ORR by BICR in Patients Who Progressed/Lack of Response on HHI Therapy in Study 1620