Table 2, Responses to Questions From the Drug Programs - Durvalumab (Imfinzi)

Drug program implementation questions	Response
Relevant comparators
The comparator arm of the TOPAZ-1 trial was gemcitabine plus cisplatin. This is a funded therapy and is considered standard of care for the first-line treatment of patients with locally advanced or metastatic BTC. If there are concerns about a patient’s renal function, carboplatin or oxaliplatin may be substituted for cisplatin. For patients with a poor performance status, gemcitabine monotherapy may be used as first-line treatment. If a patient is not able to tolerate cisplatin-based chemotherapy, is it reasonable to combine durvalumab with alternate chemotherapy?	In considering the current available evidence, Health Canada indication and clinical expert opinion, pERC concluded that reimbursement of durvalumab should only be with gemcitabine and platinum (cisplatin, carboplatin and oxaliplatin) based therapy.
Considerations for initiation of therapy
Is histologic diagnosis of BTC required to be eligible for durvalumab? Is a diagnosis of BTC ever made without histologic confirmation?	pERC noted that an attempt to histologically confirm diagnosis of BTC should be made. pERC acknowledged that the clinical experts noted that occasionally, diagnosis of BTC is made without histologic confirmation, and the current treatment paradigm of gemcitabine plus platinum-based chemotherapy would be given if no histological confirmation is possible.
Can durvalumab be restarted if treatment was stopped for reasons other than disease progression?	pERC agreed with the clinical experts that as long as durvalumab was not stopped for immune-related toxicities, then restarting durvalumab is reasonable.
Considerations for continuation or renewal of therapy
What is the recommended type and frequency of follow-up for patients on durvalumab maintenance?	pERC stated that initial clinical assessment and imaging should be conducted based on local standards.
Considerations for discontinuation of therapy
In the trial, treatment could be continued beyond disease progression at the discretion of the investigator if there was continued clinical benefit. What are the criteria for discontinuing durvalumab?	pERC agreed with the clinical experts that durvalumab should be discontinued when there is objective evidence of disease progression, or severe immune-related toxicity. Given the modest improvement in OS, the clinical experts stated that it is unlikely that clinical benefit would be observed in the presence of progression. The clinical experts also noted that if durvalumab was discontinued, they would also consider discontinuing treatment with gemcitabine and cisplatin (if during chemotherapy phase), unless toxicities were specific to individual treatments.
If there is progression during a drug holiday, can treatment be resumed? If retreatment with durvalumab is permitted in this scenario, would therapy consist of durvalumab monotherapy or durvalumab plus chemotherapy? Is there a minimum number of cycles of chemotherapy that must be given with durvalumab (e.g., what if the patient must discontinue the chemotherapy portion after 1 cycle)?	pERC agreed with the clinical experts that retreatment with durvalumab following progression during a drug holiday would be reasonable, however, would only be conducted when in combination with chemotherapy, and not given as monotherapy. It was also noted that this would only be considered in cases where patients had evidence of progression but were still well enough to receive treatment with chemotherapy. pERC acknowledged that some patients must discontinue the chemotherapy portion after 1 cycle, due to toxicity or intolerance, therefore pERC considered that a minimum of one cycle of chemotherapy to be reasonable.
Considerations for prescribing of therapy
In the trial, patients received durvalumab at a flat dose of 1,500 mg q.3.w. in combination with gemcitabine and cisplatin for up to 8 cycles, followed by 1,500 mg q.4.w. as a single drug until disease progression or unacceptable toxicity. If a patient’s weight fell to ≤ 30 kg they received a weight-based dose equivalent to 20 mg/kg of durvalumab q.3.w. in combination with chemotherapy, followed by 20 mg/kg q.4.w. as a single drug. Jurisdictions use weight-based dosing for IO therapies up to a cap. Can weight-based dosing up to a cap be used in place of flat-dosing for patients weighing more than 30 kg? If weight-based dosing up to a cap can be used, what mg/kg dose(s) of durvalumab should be used when given in combination with chemotherapy q.3.w. and then as a single drug q.4.w.? Should the weight-based dosing be 15 mg/kg up to 1,500 mg q.3.w. in combination with chemotherapy, followed by 20 mg/kg up to 1,500 mg q.4.w. as a single drug, vs. 20 mg/kg q.3.w. in combination with chemotherapy and then q.4.w. as a single drug?	There is no evidence to support weight-based dosing or to inform the appropriate dose cap of durvalumab in patients with locally advanced or metastatic BTC because this was not evaluated in the TOPAZ-1 trial. The clinical experts stated that flat-based dosing is preferred from a clinical standpoint and reflects how durvalumab was administered in the clinical trial. pERC and the clinical experts also noted that very few patients weigh less than 30 kg, and it is unlikely that they may be treated with chemotherapy at this weight.
Generalizability
Should durvalumab be considered in patients with ECOG PS 2 or greater, or in patients with AoV cancer, as these patients were excluded from the trial?	pERC and the clinical experts stated that patients with ECOG 2 or greater were not eligible for the TOPAZ-1 trial. pERC acknowledged that clinicians think it is reasonable to use durvalumab for patients with good ECOG performance status. pERC and the clinical experts noted that AoV cancers are treated differently than BTC, therefore should not be considered for treatment with durvalumab.
Should durvalumab be added to patients currently on, or who have just completed a first-line chemotherapy regimen?	In patients who are currently receiving first-line chemotherapy with no evidence of disease progression, pERC and the clinical experts felt that durvalumab may be initiated in these patients. However, if patients have already completed their first-line chemotherapy regimen, durvalumab should not be added.
System and economic issues
PAG has potential concerns regarding feasibility of adoption.	Comment from the drug programs to inform pERC deliberations.

Drug program implementation questions

Response

Relevant comparators

The comparator arm of the TOPAZ-1 trial was gemcitabine plus cisplatin. This is a funded therapy and is considered standard of care for the first-line treatment of patients with locally advanced or metastatic BTC. If there are concerns about a patient’s renal function, carboplatin or oxaliplatin may be substituted for cisplatin. For patients with a poor performance status, gemcitabine monotherapy may be used as first-line treatment.

If a patient is not able to tolerate cisplatin-based chemotherapy, is it reasonable to combine durvalumab with alternate chemotherapy?

In considering the current available evidence, Health Canada indication and clinical expert opinion, pERC concluded that reimbursement of durvalumab should only be with gemcitabine and platinum (cisplatin, carboplatin and oxaliplatin) based therapy.

Considerations for initiation of therapy

Is histologic diagnosis of BTC required to be eligible for durvalumab? Is a diagnosis of BTC ever made without histologic confirmation?

pERC noted that an attempt to histologically confirm diagnosis of BTC should be made. pERC acknowledged that the clinical experts noted that occasionally, diagnosis of BTC is made without histologic confirmation, and the current treatment paradigm of gemcitabine plus platinum-based chemotherapy would be given if no histological confirmation is possible.

Can durvalumab be restarted if treatment was stopped for reasons other than disease progression?

pERC agreed with the clinical experts that as long as durvalumab was not stopped for immune-related toxicities, then restarting durvalumab is reasonable.

Considerations for continuation or renewal of therapy

What is the recommended type and frequency of follow-up for patients on durvalumab maintenance?

pERC stated that initial clinical assessment and imaging should be conducted based on local standards.

Considerations for discontinuation of therapy

In the trial, treatment could be continued beyond disease progression at the discretion of the investigator if there was continued clinical benefit.

What are the criteria for discontinuing durvalumab?

pERC agreed with the clinical experts that durvalumab should be discontinued when there is objective evidence of disease progression, or severe immune-related toxicity. Given the modest improvement in OS, the clinical experts stated that it is unlikely that clinical benefit would be observed in the presence of progression. The clinical experts also noted that if durvalumab was discontinued, they would also consider discontinuing treatment with gemcitabine and cisplatin (if during chemotherapy phase), unless toxicities were specific to individual treatments.

If there is progression during a drug holiday, can treatment be resumed? If retreatment with durvalumab is permitted in this scenario, would therapy consist of durvalumab monotherapy or durvalumab plus chemotherapy?

Is there a minimum number of cycles of chemotherapy that must be given with durvalumab (e.g., what if the patient must discontinue the chemotherapy portion after 1 cycle)?

pERC agreed with the clinical experts that retreatment with durvalumab following progression during a drug holiday would be reasonable, however, would only be conducted when in combination with chemotherapy, and not given as monotherapy. It was also noted that this would only be considered in cases where patients had evidence of progression but were still well enough to receive treatment with chemotherapy.

pERC acknowledged that some patients must discontinue the chemotherapy portion after 1 cycle, due to toxicity or intolerance, therefore pERC considered that a minimum of one cycle of chemotherapy to be reasonable.

Considerations for prescribing of therapy

In the trial, patients received durvalumab at a flat dose of 1,500 mg q.3.w. in combination with gemcitabine and cisplatin for up to 8 cycles, followed by 1,500 mg q.4.w. as a single drug until disease progression or unacceptable toxicity. If a patient’s weight fell to ≤ 30 kg they received a weight-based dose equivalent to 20 mg/kg of durvalumab q.3.w. in combination with chemotherapy, followed by 20 mg/kg q.4.w. as a single drug.

Jurisdictions use weight-based dosing for IO therapies up to a cap. Can weight-based dosing up to a cap be used in place of flat-dosing for patients weighing more than 30 kg?

If weight-based dosing up to a cap can be used, what mg/kg dose(s) of durvalumab should be used when given in combination with chemotherapy q.3.w. and then as a single drug q.4.w.? Should the weight-based dosing be 15 mg/kg up to 1,500 mg q.3.w. in combination with chemotherapy, followed by 20 mg/kg up to 1,500 mg q.4.w. as a single drug, vs. 20 mg/kg q.3.w. in combination with chemotherapy and then q.4.w. as a single drug?

There is no evidence to support weight-based dosing or to inform the appropriate dose cap of durvalumab in patients with locally advanced or metastatic BTC because this was not evaluated in the TOPAZ-1 trial. The clinical experts stated that flat-based dosing is preferred from a clinical standpoint and reflects how durvalumab was administered in the clinical trial.

pERC and the clinical experts also noted that very few patients weigh less than 30 kg, and it is unlikely that they may be treated with chemotherapy at this weight.

Generalizability

Should durvalumab be considered in patients with ECOG PS 2 or greater, or in patients with AoV cancer, as these patients were excluded from the trial?

pERC and the clinical experts stated that patients with ECOG 2 or greater were not eligible for the TOPAZ-1 trial. pERC acknowledged that clinicians think it is reasonable to use durvalumab for patients with good ECOG performance status.

pERC and the clinical experts noted that AoV cancers are treated differently than BTC, therefore should not be considered for treatment with durvalumab.

Should durvalumab be added to patients currently on, or who have just completed a first-line chemotherapy regimen?

In patients who are currently receiving first-line chemotherapy with no evidence of disease progression, pERC and the clinical experts felt that durvalumab may be initiated in these patients. However, if patients have already completed their first-line chemotherapy regimen, durvalumab should not be added.

System and economic issues

PAG has potential concerns regarding feasibility of adoption.

Comment from the drug programs to inform pERC deliberations.

From: Durvalumab (Imfinzi)

Durvalumab (Imfinzi): CADTH Reimbursement Recommendation: Indication: In combination with gemcitabine-based chemotherapy, for the treatment of patients with locally advanced or metastatic biliary tract cancer [Internet].

Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2023 Feb.

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Table 2Responses to Questions From the Drug Programs