Table 2, Responses to Questions From the Drug Programs - Lutetium (177Lu) Oxodotreotide (Lutathera)

Implementation issues	Response
Relevant comparators
NETTER-R is a phase IV, non-interventional, retrospective registry study of patients with pancreatic neuroendocrine tumours who have been treated with ¹⁷⁷Lu oxodotreotide. Relevant comparators for ¹⁷⁷Lu oxodotreotide may include sunitinib, everolimus, or combination temozolomide-capecitabine.	Comment from the drug programs to inform pERC deliberations.
Considerations for initiation of therapy
Can patients treated with octreotide LAR 60 mg be eligible for treatment with ¹⁷⁷Lu oxodotreotide? Can patients previously treated with lanreotide be eligible for treatment with ¹⁷⁷Lu oxodotreotide?	pERC and the clinical experts agreed that patients who were treated with octreotide LAR 60 mg or lanreotide would be eligible for treatment with ¹⁷⁷Lu oxodotreotide.
PAG noted that CADTH previously did not recommend ¹⁷⁷Lu oxodotreotide re-treatment for adult patients with SSR-positive midgut neuroendocrine tumours. Should ¹⁷⁷Lu oxodotreotide re-treatment be funded for patients with unresectable or metastatic SSR-positive pancreatic neuroendocrine tumours?	pERC could not comment on whether re-treatment with ¹⁷⁷Lu oxodotreotide should be funded for patients with unresectable or metastatic SSR-positive pancreatic neuroendocrine tumours because there is limited data to support re-treatment.
Considerations for discontinuation of therapy
The sponsor request is for ¹⁷⁷Lu oxodotreotide to be used after progression on a somatostatin analogue unless there is a contraindication or intolerance. Can pERC clarify what would constitute a contraindication or intolerance to a somatostatin analogue?	pERC and the clinical experts stated that contraindications to SSAs would include an anaphylactic reaction or consistent, reproducible, and severe diarrhea after an injection that takes time to resolve (i.e., greater than 1 week) or results in abdominal pain. In general, true contraindications are expected to be rare.
Considerations for prescribing of therapy
7.4 GBq (200 mCi) of ¹⁷⁷Lu oxodotreotide is infused intravenously over 30 minutes every 8 weeks for a maximum of 4 doses.	Comment from the drug programs to inform pERC deliberations.
Administration of ¹⁷⁷Lu oxodotreotide is restricted to specialized centres that have the infrastructure to handle, prepare, administer, and dispose of lutetium in a safe manner. Patients may have to travel long distances to access treatment. In some jurisdictions, patients may need to be referred out of the province.	Comment from the drug programs to inform pERC deliberations.
Funding algorithm (oncology only)
What is the optimal place in therapy for ¹⁷⁷Lu oxodotreotide? Under what clinical circumstances would ¹⁷⁷Lu oxodotreotide be preferred over everolimus, sunitinib, or temozolomide-capecitabine?	The NETTER-R study was retrospective and did not include a comparator group. The sponsor provided an ITC that compared ¹⁷⁷Lu oxodotreotide to everolimus and sunitinib. Although there were significant uncertainties with the results of the ITCs, the results suggested that ¹⁷⁷Lu oxodotreotide would be more efficacious over everolimus and sunitinib. The clinical experts agreed that ¹⁷⁷Lu oxodotreotide would be a preferred regimen over everolimus and sunitinib because ¹⁷⁷Lu oxodotreotide is better tolerated and, although there is no direct evidence, ¹⁷⁷Lu oxodotreotide may be more efficacious than other currently available treatment options. However, temozolomide-capecitabine may be preferred over ¹⁷⁷Lu oxodotreotide for patients with grade 3 well-differentiated pNETs. pERC agreed with the response provided by the clinical experts.
Care provision issues
¹⁷⁷Lu oxodotreotide has a shelf life of 72 hours, which may result in wastage if the patient is not able to receive a scheduled dose for whatever reason.	Comment from the drug programs to inform pERC deliberations.
Administration of an amino acid solution is required before, during, and after each ¹⁷⁷Lu oxodotreotide dose. The compounded solution is either prepared within the hospital or procured externally. An antiemetic is also given before the amino acid solution. Octreotide LAR 30 mg IM also needs to be administered between 4 and 24 hours after each ¹⁷⁷Lu oxodotreotide dose and then every 4 weeks after completing ¹⁷⁷Lu oxodotreotide until disease progression or for up to 18 months following treatment initiation. Is there evidence to support alternative SSA schedules relative to ¹⁷⁷Lu oxodotreotide?	pERC agreed with the clinical experts, who acknowledged that there can be variability in the schedule of administration of SSAs relative to ¹⁷⁷Lu oxodotreotide depending on the institution. The clinical experts agreed that scheduling SSA therapy after PRRT can be challenging in practice, and alternative administration schedules relative to ¹⁷⁷Lu oxodotreotide may be appropriate.
Access to functional imaging (e.g., ⁶⁸Ga-PET) is needed to confirm somatostatin receptor positivity. Does the patient require imaging after each ¹⁷⁷Lu oxodotreotide dose and when should imaging be done?	pERC agreed with the clinical experts, who commented that there may be some variation in imaging for patients. A ⁶⁸Ga-PET scan is required before starting treatment with ¹⁷⁷Lu oxodotreotide. ⁶⁸Ga-PET scans are not typically conducted after each cycle of treatment with ¹⁷⁷Lu. However, SPECT scans should be conducted after each cycle to confirm treatment uptake and to assess whether the patient’s disease has progressed. CT imaging is also used as another strategy for surveillance post-treatment. The clinical experts also commented that FDG PET scans may also be used to help identify when patients are progressing to higher grade disease, although this type of imaging may not be as common.
System and economic issues
The budget impact would be influenced by the actual place in therapy for ¹⁷⁷Lu oxodotreotide (use in earlier lines vs. later lines). There may be potential indication creep if ¹⁷⁷Lu oxodotreotide is preferred over a somatostatin analogue as ¹⁷⁷Lu oxodotreotide may be better tolerated.	Comment from the drug programs to inform pERC deliberations.
Additional resources and coordination between nuclear medicine, radiation oncology, and medical oncology teams are required for imaging, blood work monitoring, and management of adverse events. Inpatient administration may also be required.	Comment from the drug programs to inform pERC deliberations.
In most jurisdictions, oversight and funding of radiopharmaceuticals is through other areas of the Ministry, outside of the drug programs. Inpatient funding may also be covered through a different Ministry budget.	Comment from the drug programs to inform pERC deliberations.

Implementation issues

Response

Relevant comparators

NETTER-R is a phase IV, non-interventional, retrospective registry study of patients with pancreatic neuroendocrine tumours who have been treated with ¹⁷⁷Lu oxodotreotide.

Relevant comparators for ¹⁷⁷Lu oxodotreotide may include sunitinib, everolimus, or combination temozolomide-capecitabine.

Comment from the drug programs to inform pERC deliberations.

Considerations for initiation of therapy

Can patients treated with octreotide LAR 60 mg be eligible for treatment with ¹⁷⁷Lu oxodotreotide?

Can patients previously treated with lanreotide be eligible for treatment with ¹⁷⁷Lu oxodotreotide?

pERC and the clinical experts agreed that patients who were treated with octreotide LAR 60 mg or lanreotide would be eligible for treatment with ¹⁷⁷Lu oxodotreotide.

PAG noted that CADTH previously did not recommend ¹⁷⁷Lu oxodotreotide re-treatment for adult patients with SSR-positive midgut neuroendocrine tumours. Should ¹⁷⁷Lu oxodotreotide re-treatment be funded for patients with unresectable or metastatic SSR-positive pancreatic neuroendocrine tumours?

pERC could not comment on whether re-treatment with ¹⁷⁷Lu oxodotreotide should be funded for patients with unresectable or metastatic SSR-positive pancreatic neuroendocrine tumours because there is limited data to support re-treatment.

Considerations for discontinuation of therapy

The sponsor request is for ¹⁷⁷Lu oxodotreotide to be used after progression on a somatostatin analogue unless there is a contraindication or intolerance.

Can pERC clarify what would constitute a contraindication or intolerance to a somatostatin analogue?

pERC and the clinical experts stated that contraindications to SSAs would include an anaphylactic reaction or consistent, reproducible, and severe diarrhea after an injection that takes time to resolve (i.e., greater than 1 week) or results in abdominal pain. In general, true contraindications are expected to be rare.

Considerations for prescribing of therapy

7.4 GBq (200 mCi) of ¹⁷⁷Lu oxodotreotide is infused intravenously over 30 minutes every 8 weeks for a maximum of 4 doses.

Comment from the drug programs to inform pERC deliberations.

Administration of ¹⁷⁷Lu oxodotreotide is restricted to specialized centres that have the infrastructure to handle, prepare, administer, and dispose of lutetium in a safe manner.

Patients may have to travel long distances to access treatment. In some jurisdictions, patients may need to be referred out of the province.

Comment from the drug programs to inform pERC deliberations.

Funding algorithm (oncology only)

What is the optimal place in therapy for ¹⁷⁷Lu oxodotreotide?

Under what clinical circumstances would ¹⁷⁷Lu oxodotreotide be preferred over everolimus, sunitinib, or temozolomide-capecitabine?

The NETTER-R study was retrospective and did not include a comparator group. The sponsor provided an ITC that compared ¹⁷⁷Lu oxodotreotide to everolimus and sunitinib. Although there were significant uncertainties with the results of the ITCs, the results suggested that ¹⁷⁷Lu oxodotreotide would be more efficacious over everolimus and sunitinib. The clinical experts agreed that ¹⁷⁷Lu oxodotreotide would be a preferred regimen over everolimus and sunitinib because ¹⁷⁷Lu oxodotreotide is better tolerated and, although there is no direct evidence, ¹⁷⁷Lu oxodotreotide may be more efficacious than other currently available treatment options. However, temozolomide-capecitabine may be preferred over ¹⁷⁷Lu oxodotreotide for patients with grade 3 well-differentiated pNETs. pERC agreed with the response provided by the clinical experts.

Care provision issues

¹⁷⁷Lu oxodotreotide has a shelf life of 72 hours, which may result in wastage if the patient is not able to receive a scheduled dose for whatever reason.

Comment from the drug programs to inform pERC deliberations.

Administration of an amino acid solution is required before, during, and after each ¹⁷⁷Lu oxodotreotide dose. The compounded solution is either prepared within the hospital or procured externally.

An antiemetic is also given before the amino acid solution.

Octreotide LAR 30 mg IM also needs to be administered between 4 and 24 hours after each ¹⁷⁷Lu oxodotreotide dose and then every 4 weeks after completing ¹⁷⁷Lu oxodotreotide until disease progression or for up to 18 months following treatment initiation. Is there evidence to support alternative SSA schedules relative to ¹⁷⁷Lu oxodotreotide?

pERC agreed with the clinical experts, who acknowledged that there can be variability in the schedule of administration of SSAs relative to ¹⁷⁷Lu oxodotreotide depending on the institution. The clinical experts agreed that scheduling SSA therapy after PRRT can be challenging in practice, and alternative administration schedules relative to ¹⁷⁷Lu oxodotreotide may be appropriate.

Access to functional imaging (e.g., ⁶⁸Ga-PET) is needed to confirm somatostatin receptor positivity.

Does the patient require imaging after each ¹⁷⁷Lu oxodotreotide dose and when should imaging be done?

pERC agreed with the clinical experts, who commented that there may be some variation in imaging for patients. A ⁶⁸Ga-PET scan is required before starting treatment with ¹⁷⁷Lu oxodotreotide. ⁶⁸Ga-PET scans are not typically conducted after each cycle of treatment with ¹⁷⁷Lu. However, SPECT scans should be conducted after each cycle to confirm treatment uptake and to assess whether the patient’s disease has progressed. CT imaging is also used as another strategy for surveillance post-treatment. The clinical experts also commented that FDG PET scans may also be used to help identify when patients are progressing to higher grade disease, although this type of imaging may not be as common.

System and economic issues

The budget impact would be influenced by the actual place in therapy for ¹⁷⁷Lu oxodotreotide (use in earlier lines vs. later lines). There may be potential indication creep if ¹⁷⁷Lu oxodotreotide is preferred over a somatostatin analogue as ¹⁷⁷Lu oxodotreotide may be better tolerated.

Comment from the drug programs to inform pERC deliberations.

Additional resources and coordination between nuclear medicine, radiation oncology, and medical oncology teams are required for imaging, blood work monitoring, and management of adverse events.

Inpatient administration may also be required.

Comment from the drug programs to inform pERC deliberations.

In most jurisdictions, oversight and funding of radiopharmaceuticals is through other areas of the Ministry, outside of the drug programs. Inpatient funding may also be covered through a different Ministry budget.

Comment from the drug programs to inform pERC deliberations.

From: Lutetium (¹⁷⁷Lu) Oxodotreotide (Lutathera)

Cover of Lutetium (177Lu) Oxodotreotide (Lutathera)

Lutetium (¹⁷⁷Lu) Oxodotreotide (Lutathera): CADTH Reimbursement Recommendation: Indication: For the treatment of unresectable or metastatic, well-differentiated, somatostatin receptor (SSR)–positive pancreatic neuroendocrine tumours (pNETs) in adults whose disease has progressed after treatment with a somatostatin analogue (SSA), unless there is a contraindication or intolerance [Internet].

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

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Table 2Responses to Questions From the Drug Programs