Table 3, Responses to Questions From the Drug Programs - Cemiplimab (Libtayo)

Implementation issues	Response
Relevant comparators
There was no comparator in the pivotal trial submitted for consideration. The usual treatment in this setting is best supportive care. Chemotherapy with carboplatin and paclitaxel may occasionally be administered after disease progression with an HHI used for advanced (not amenable to local therapies) BCC.	pERC acknowledged the lack of a comparator as a limitation of Study 1620; however, currently there is no standard second-line treatment for patients with laBCC who have previously been treated with an HHI and have failed therapy or are intolerant to HHI.
Considerations for initiation of therapy
The treatment protocol includes re-treatment for an additional 4 cycles for patients who complete 9 cycles without disease progression. Should patients who completed 9 cycles but subsequently experience disease progression while off treatment be eligible for re-treatment?	In Study 1620, patients were permitted to receive re-treatment with cemiplimab after they experienced progression off treatment following the completion of the initial 93 weeks of treatment if recurrence occurred within the first 7 follow-up visits, which occurred every 28 days. Oncologic principles and experience with other immunotherapies have shown that patients with recurrence that occurs beyond 6 months of completing treatment also may benefit from re-treatment. Therefore, for patients who experience disease recurrence after the completion of the initial 93 weeks of treatment with cemiplimab, it would be reasonable to offer re-treatment with cemiplimab for an additional 48 weeks.
Patients are required to have previously been treated with a HHI such as vismodegib or sonidegib. Vismodegib is funded in most Canadian jurisdictions. Sonidegib is not funded in any Canadian jurisdiction because it was not recommended for reimbursement by CADTH pCODR.	pERC acknowledged that only vismodegib is funded in most jurisdictions in Canada, but patients may have had access to sonidegib through clinical trials or paid for it themselves. pERC agreed that patients previously treated with either HHI should be eligible for cemiplimab.
Considerations for prescribing of therapy
The usual starting dose of cemiplimab is 350 mg IV every 3 weeks. What is the maximum treatment duration? Should the maximum treatment duration be 93 weeks or until disease progression or unacceptable toxicity?	There are no data from Study 1620 for treating patients beyond the 93-week treatment schedule. In the absence of such data, pERC agreed that patients should be treated up to a maximum treatment duration of 93 weeks or until symptomatic disease progression or unacceptable toxicity, whichever occurs first.
Cemiplimab is administered as an IV infusion over 30 minutes through an IV line containing a sterile in-line or add-on filter (0.2 micron to 5 micron pore size). Sites will need to ensure they have appropriate supplies available to administer cemiplimab.	pERC acknowledged the administration requirements for cemiplimab.
Generalizability
Study 1620 included patients who had mBCC, those with no better than stable disease for 9 months following HHI therapy, and an ECOG Performance Status of 0 and 1. Should treatment with cemiplimab be extended to the following patients: mBCC patients patients with no better than stable disease after 9 months on HHI therapy patients who cannot tolerate or are ineligible for treatment with HHI therapy patients with ECOG Performance Status ≥ 2?	The sponsor’s reimbursement request aligns with the Health Canada indication, which only includes patients with laBCC. Patients with metastatic BCC were excluded from the Health Canada indication because of low patient numbers and immature interim results from Study 1620. Therefore, pERC’s recommendation is focused to the laBCC population. The results from this cohort in Study 1620 should not be generalized to patients with metastatic BCC. pERC agreed with the clinical experts that most clinicians would wait 3 months to 5 months for a response before exploring other treatment options for patients with laBCC; therefore, it would be reasonable to offer cemiplimab to patients without a response (stable disease) after 9 months on HHI. Many patients discontinue HHI therapy due to toxicity (e.g., taste disturbances, muscle spasms, alopecia, weight loss, and fatigue). pERC agreed with the clinical experts that the criteria used in Study 1620 (any grade 3 or grade 4 AE deemed related to HHI or grade 2 myalgia, dysgeusia, anorexia, nausea, or diarrhea in patients with at least 3 months exposure to HHI) would be reasonable criteria to use for establishing intolerance to an HHI. Study 1620 enrolled patients with an ECOG Performance Status of 0 or 1. It is recognized that performance status may be related to the underlying cancer; therefore, for some patients, an improvement in status would be expected after initiation of treatment with cemiplimab, whereas for others, increased comorbidities may contribute to a poorer Performance Status. As such, treatment of patients with an ECOG Performance Status ≥ 2 should be considered on a case-by-case basis by the treating clinician.
Care provision issues
Serious immune-mediated reactions can be severe to fatal and usually occur during the treatment course. Early diagnosis and appropriate management are essential to minimize life-threatening complications. Should cemiplimab be reimbursed, is a statement needed ensuring access to a treatment centre with expertise to manage these side effects, should they occur?	pERC agreed with the clinical experts that the oncology community is accustomed to the use of immunotherapies and their associated side effects and risks. Cemiplimab does not have any additional safety concerns beyond those that treatment centres (inpatient or outpatient) and prescribing clinicians are familiar with and are able to manage if they arise. Cemiplimab should be administered in cancer centres or centres supervised by physicians with expertise and with staffing (chemotherapy nurses, oncology pharmacists) to administer systemic therapies and manage treatment-related toxicities, particularly immune-mediated reactions, which can be severe or fatal and usually occur during the treatment course.
Preservative-free Intact vials are stored in the refrigerator and protected from light. Refrigerator space may be a concern for some pharmacies.	pERC acknowledged the refrigerator space requirement may be a challenge for some pharmacies.

Implementation issues

Response

Relevant comparators

There was no comparator in the pivotal trial submitted for consideration. The usual treatment in this setting is best supportive care. Chemotherapy with carboplatin and paclitaxel may occasionally be administered after disease progression with an HHI used for advanced (not amenable to local therapies) BCC.

pERC acknowledged the lack of a comparator as a limitation of Study 1620; however, currently there is no standard second-line treatment for patients with laBCC who have previously been treated with an HHI and have failed therapy or are intolerant to HHI.

Considerations for initiation of therapy

The treatment protocol includes re-treatment for an additional 4 cycles for patients who complete 9 cycles without disease progression.

Should patients who completed 9 cycles but subsequently experience disease progression while off treatment be eligible for re-treatment?

In Study 1620, patients were permitted to receive re-treatment with cemiplimab after they experienced progression off treatment following the completion of the initial 93 weeks of treatment if recurrence occurred within the first 7 follow-up visits, which occurred every 28 days. Oncologic principles and experience with other immunotherapies have shown that patients with recurrence that occurs beyond 6 months of completing treatment also may benefit from re-treatment. Therefore, for patients who experience disease recurrence after the completion of the initial 93 weeks of treatment with cemiplimab, it would be reasonable to offer re-treatment with cemiplimab for an additional 48 weeks.

Patients are required to have previously been treated with a HHI such as vismodegib or sonidegib. Vismodegib is funded in most Canadian jurisdictions. Sonidegib is not funded in any Canadian jurisdiction because it was not recommended for reimbursement by CADTH pCODR.

pERC acknowledged that only vismodegib is funded in most jurisdictions in Canada, but patients may have had access to sonidegib through clinical trials or paid for it themselves. pERC agreed that patients previously treated with either HHI should be eligible for cemiplimab.

Considerations for prescribing of therapy

The usual starting dose of cemiplimab is 350 mg IV every 3 weeks.

What is the maximum treatment duration? Should the maximum treatment duration be 93 weeks or until disease progression or unacceptable toxicity?

There are no data from Study 1620 for treating patients beyond the 93-week treatment schedule. In the absence of such data, pERC agreed that patients should be treated up to a maximum treatment duration of 93 weeks or until symptomatic disease progression or unacceptable toxicity, whichever occurs first.

Cemiplimab is administered as an IV infusion over 30 minutes through an IV line containing a sterile in-line or add-on filter (0.2 micron to 5 micron pore size). Sites will need to ensure they have appropriate supplies available to administer cemiplimab.

pERC acknowledged the administration requirements for cemiplimab.

Generalizability

Study 1620 included patients who had mBCC, those with no better than stable disease for 9 months following HHI therapy, and an ECOG Performance Status of 0 and 1.

Should treatment with cemiplimab be extended to the following patients:

mBCC patients
patients with no better than stable disease after 9 months on HHI therapy
patients who cannot tolerate or are ineligible for treatment with HHI therapy
patients with ECOG Performance Status ≥ 2?

The sponsor’s reimbursement request aligns with the Health Canada indication, which only includes patients with laBCC. Patients with metastatic BCC were excluded from the Health Canada indication because of low patient numbers and immature interim results from Study 1620. Therefore, pERC’s recommendation is focused to the laBCC population. The results from this cohort in Study 1620 should not be generalized to patients with metastatic BCC.

pERC agreed with the clinical experts that most clinicians would wait 3 months to 5 months for a response before exploring other treatment options for patients with laBCC; therefore, it would be reasonable to offer cemiplimab to patients without a response (stable disease) after 9 months on HHI.

Many patients discontinue HHI therapy due to toxicity (e.g., taste disturbances, muscle spasms, alopecia, weight loss, and fatigue). pERC agreed with the clinical experts that the criteria used in Study 1620 (any grade 3 or grade 4 AE deemed related to HHI or grade 2 myalgia, dysgeusia, anorexia, nausea, or diarrhea in patients with at least 3 months exposure to HHI) would be reasonable criteria to use for establishing intolerance to an HHI.

Study 1620 enrolled patients with an ECOG Performance Status of 0 or 1. It is recognized that performance status may be related to the underlying cancer; therefore, for some patients, an improvement in status would be expected after initiation of treatment with cemiplimab, whereas for others, increased comorbidities may contribute to a poorer Performance Status. As such, treatment of patients with an ECOG Performance Status ≥ 2 should be considered on a case-by-case basis by the treating clinician.

Care provision issues

Serious immune-mediated reactions can be severe to fatal and usually occur during the treatment course. Early diagnosis and appropriate management are essential to minimize life-threatening complications.

Should cemiplimab be reimbursed, is a statement needed ensuring access to a treatment centre with expertise to manage these side effects, should they occur?

pERC agreed with the clinical experts that the oncology community is accustomed to the use of immunotherapies and their associated side effects and risks. Cemiplimab does not have any additional safety concerns beyond those that treatment centres (inpatient or outpatient) and prescribing clinicians are familiar with and are able to manage if they arise.

Cemiplimab should be administered in cancer centres or centres supervised by physicians with expertise and with staffing (chemotherapy nurses, oncology pharmacists) to administer systemic therapies and manage treatment-related toxicities, particularly immune-mediated reactions, which can be severe or fatal and usually occur during the treatment course.

Preservative-free Intact vials are stored in the refrigerator and protected from light. Refrigerator space may be a concern for some pharmacies.

pERC acknowledged the refrigerator space requirement may be a challenge for some pharmacies.

From: Cemiplimab (Libtayo)

Cemiplimab (Libtayo): CADTH Reimbursement Recommendation: Indication: For the treatment of patients with locally advanced basal cell carcinoma (BCC) previously treated with a hedgehog pathway inhibitor [Internet].

Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2022 Mar.

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Table 3Responses to Questions From the Drug Programs