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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
CADTH recommends that Lutathera should be reimbursed by public drug plans 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, if certain conditions are met.
Lutathera should only be covered to treat adult patients with unresectable or metastatic, well-differentiated, SSR-positive pNETs whose disease has progressed after treatment with a SSA, unless they could not receive an SSA.
Lutathera should only be reimbursed if it is prescribed by clinicians who are experts in radiopharmaceuticals, patients are treated in specialized centres with the infrastructure to safely use radiopharmaceuticals, and the cost of Lutathera is reduced.
pNETs are an uncommon type of cancer that start in hormone-producing cells of the pancreas. Less than 1 in 100,000 people develop pNETs each year.
pNETs are incurable, and patients with pNETs have a poor prognosis. There is a need for treatments that prolong patients’ lives and improve their quality of life.
Treatment with Lutathera is expected to cost approximately $23,333 per patient per month.
The CADTH pCODR Expert Review Committee (pERC) recommends that lutetium (177Lu) oxodotreotide be reimbursed 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, only if the conditions listed in Table 1 are met.
The efficacy or safety of lutetium (177Lu) oxodotreotide (henceforth shortened to “177Lu oxodotreotide”) in patients with pNETs has not been evaluated in randomized clinical trials; the best available evidence for this review was from 1 phase IV, non-interventional, non-comparative, post-authorization retrospective registry study (NETTER-R, N = 110) and 3 observational studies (Fröss-Baron et al. [2021], Marinova et al. [2018], and Zandee et al. [2019]). pERC noted that conducting a randomized controlled trial exclusively in this patient population would not be feasible considering the lack of clinical equipoise and rarity of the condition. The NETTER-R study suggested that treatment with 177Lu oxodotreotide resulted in clinical benefit for patients with SSR-positive pNETs who had unresectable or metastatic, progressive disease after SSA. Median progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumours Version 1.1 (RECIST 1.1) criteria was 24.8 months (95% confidence interval [CI], 17.5 to 34.5) and median overall survival (OS) was 41.4 months (95% CI, 28.6 to 50.2). Although there was no comparator group and there were other methodological limitations associated with the NETTER-R study design, these results represent a clinically meaningful improvement compared with patients with pNETs treated with other available regimens in Canada according to the clinical experts. Although results of the 3 observational studies were associated with uncertainty due to the study design, results were consistent with those of the NETTER-R study. Furthermore, indirect evidence provided by the sponsor suggested that 177Lu oxodotreotide compared favourably to everolimus and sunitinib in PFS.
There is a need for treatments for patients with pNETs that lead to extended survival and improved health-related quality of life (HRQoL). Patients reported that currently available treatments are associated with long recovery times, have debilitating side effects and complications, and these treatments do not cure or stop the progression of their disease. Given the totality of the evidence, pERC concluded that treatment with 177Lu oxodotreotide may meet some important needs identified by patients, such as controlling disease progression.
Using the sponsor submitted price for 177Lu oxodotreotide and publicly listed prices for all other drug costs, the incremental cost-effectiveness ratio (ICER) for 177Lu oxodotreotide was $120,931 per quality-adjusted life-year (QALY) compared with everolimus and $466,632 per QALY compared with sunitinib. At this ICER, 177Lu oxodotreotide is not cost-effective at a willingness-to-pay threshold of $50,000 per QALY gained for the treatment of unresectable or metastatic, well-differentiated, SSR-positive pNETs in adults with progressive disease. A price reduction is required for 177Lu oxodotreotide to be considered cost-effective at a $50,000 per QALY gained threshold.
Reimbursement Conditions and Reasons.
NETs are a heterogenous group of cancers that arise from the secretory cells of the diffuse neuroendocrine system. pNETs are a subset of GEP-NETs. SSRs are expressed in the majority (> 80%) of well-differentiated NETs. GEP-NETs represent the second most common type of digestive cancer in terms of prevalence. The annual incidence of pNETs is expected to be less than 1 per 100,000 persons. pNETs have a worse prognosis than NETs, and patients typically survive for less than 5 years. Due to the heterogenous nature of pNETs, different patients may not follow the same disease trajectory. Diagnosis of pNETs is typically done through biopsy. Staging of patients’ disease is usually conducted using CT imaging or MRI scans, although gallium PET scans are becoming a more standard form of imaging for this group of patients.
177Lu oxodotreotide (also known as 177Lu-dotatate) is considered a PRRT. 177Lu oxodotreotide is a radiolabelled SSA that binds to SSRs. 177Lu oxodotreotide has been approved by Health Canada for the treatment of unresectable or metastatic, well-differentiated, SSR-positive GEP-NETs in adults with progressive disease. The recommended dose is 7.4 GBq (200 mCi) as an IV infusion over 30 minutes every 8 weeks for a total of 4 doses. 177Lu oxodotreotide is administered together with octreotide long-acting release (LAR) which continues monthly for up to 18 months.
The original CADTH review of 177Lu oxodotreotide conducted in 2019 included a phase III, open-label, randomized controlled trial (NETTER-1) and a phase I/II non-randomized, single-arm study (ERASMUS). The original submission received a recommendation in favour of reimbursement for patients with SSR-positive midgut NETs whose disease had progressed on a SSA and was unresectable; however, the recommendation did not support reimbursement for patients with SSR-positive foregut and hindgut NETs whose disease had progressed and was unresectable. The previous CADTH review for 177Lu oxodotreotide did not support use among patients with pNETs because these patients were excluded from the pivotal NETTER-1 trial. The sponsor’s reimbursement request for this CADTH reassessment is for adult patients with unresectable or metastatic, well-differentiated, SSR-positive pNET tumours whose disease has progressed after treatment with an SSA, unless there is a contraindication or intolerance.
To make their recommendation, the committee considered the following information:
CADTH received 1 submission from CNETS for the review of 177Lu oxodotreotide for patients with GEP-NETs. The information used to inform the submission was based on an online questionnaire that was promoted to patients with neuroendocrine cancer on the CNETS website and across its social media platforms between February 25 to March 25, 2022. A total of 57 patients responded to the survey, including 21 (37%) patients with pNETs and 36 (63%) patients with GI-NETs; 33 (58%) patients reported having experience with 177Lu oxodotreotide.
Survey respondents reported that their NET cancer negatively impacted their quality of life with symptoms of fatigue and weakness, and diarrhea having an extremely high impact on quality of life. The most commonly used therapies for the management of NET cancer reported by respondents were SSA therapies, surgery, and PRRT. Respondents indicated that benefits of currently available treatments included temporarily slowing the progression of the disease and achieving symptom control, while the challenges were long recovery times, debilitating side effects, and complications. None of the respondents reported that current treatments cured or stopped the progression of their NET cancer. Respondents described current treatments as effective for symptom control (i.e., bloating, diarrhea, constipation, and energy levels), and as slightly or not effective for stopping disease progression, shrinking or stopping tumour growth, and preventing metastasis. According to respondents, common barriers to access included lack of private payer coverage, financial difficulties, and treatment was not accessible through their physician or was not funded for their specific type of NET cancer.
All 33 respondents with experience on 177Lu oxodotreotide agreed that its side effects were tolerable or manageable and the treatment experience was easier than the lengthy recovery from surgery or the debilitating side effects from chemotherapy. The most commonly reported benefits of 177Lu oxodotreotide included reduction in the progression of disease (69%), tumour shrinkage (59%), and decrease in disease symptoms (45%), while the most commonly reported side effects were increased fatigue (58%), followed by nausea and vomiting (27%).
The majority (98%) of respondents indicated disease progression is the most important outcome of NET cancer to control, followed by fatigue (36%), diarrhea (35%) and flushing (29%). Overall, patients reported a need for equitable access to 177Lu oxodotreotide for NET cancer to overcome challenges including the lack of funding for their type of NETs and travelling long distances to access treatment.
Input was gathered from 2 clinical specialists with expertise in the diagnosis and management of pNETs. The clinical experts highlighted an unmet need for treatments that extend patients’ lives and improve their quality of life because patients eventually become refractory to all currently available treatment options. The clinical experts stated that sequencing of 177Lu oxodotreotide would be individualized to each patient’s circumstances. In most instances, patients should have progressed on SSAs before receiving 177Lu oxodotreotide. The clinical experts stated that identifying patients eligible for 177Lu oxodotreotide will require gallium PET scans. They specified that there should be no strict criteria on Ki67 because there is too much variability in Ki67 among different specimens from the same patient. In addition, there is subjectivity in reading the specimens that results in variability in determining eligibility based on Ki67. Patient response to therapy was stated to be assessed through clinical assessment, radiographic information, and analysis of biomarkers (i.e., 5-hydroxyindoleacetic acid [5HIAA]). Clinical assessments were recommended to occur every few months initially, and before every cycle of PRRT. Radiographic assessments were recommended to occur every 3 to 6 months initially, depending on the clinical needs of the patients. Discontinuation of therapy was stated to be based on serious toxicities, including permanent renal toxicities and bone marrow toxicity (e.g., myelodysplastic syndrome [MDS]), and disease progression. Administration of 177Lu oxodotreotide was stated to require tertiary referral centre with dedicated nuclear medicine and/or radiation oncology.
Seven clinician groups provided input to CADTH for the review of 177Lu oxodotreotide: 2 clinicians from the Ontario Health Cancer Care Ontario (OH-CCO) Gastrointestinal Cancer Drug Advisory Committee, 1 clinician from the Canadian Association of Nuclear Medicine (CANM), 9 clinicians from the CNETS Scientific and Medical Advisory Board (SMAB), and 1 clinician from CHU de Québec – Université Laval Research Centre – Oncology Axis, Hôtel-Dieu de Québec – Nuclear Medicine Department, Fondation du CHU de Québec – Research Chair in Theranostics, and AMSMNQ.
The clinician groups identified the following unmet needs in patients with NETs including pNETs: currently available treatments are not effective for all patients, are not well tolerated, and can lead to the development of resistance or become refractory to current treatments. Further, the clinician groups expressed the need for treatments to slow the progression of the disease, control hormonal symptoms, and improve survival (i.e., PFS).
CANM, CNETS SMAB, CHU de Québec – Université Laval Research Centre – Oncology Axis, Hôtel-Dieu de Québec – Nuclear Medicine Department, Fondation du CHU de Québec – Research Chair in Theranostics and AMSMNQ indicated 177Lu oxodotreotide should be second line for patients with NETs, including pNETs, who have progressed on a somatostatin analogue. In contrast, OH-CCO indicated Lutathera should be a fourth-line treatment option following somatostatin analogues, everolimus, and sunitinib.
Input was obtained from the drug programs that participate in the CADTH reimbursement review process. The following were identified as key factors that could potentially impact the implementation of a CADTH recommendation for 177Lu oxodotreotide: considerations for initiation of therapy, considerations for discontinuation of therapy, considerations for prescribing of therapy, care provision issues, system and economic issues, and potential need for a provisional funding algorithm. The clinical experts consulted by CADTH provided advice on the potential implementation issues raised by the drug programs.
Responses to Questions From the Drug Programs.
The NETTER-R study was a non-interventional, non-comparative, post-authorization retrospective registry study to assess long-term efficacy and safety of treatment with 177Lu oxodotreotide in patients with SSR-positive pNETs who had unresectable or metastatic, progressive disease based on radiological, biochemical, or clinical assessment. The approximate number of patients to be enrolled was based on the number of potentially eligible patients included in the Compassionate Use Program (CUP) or receiving commercial 177Lu oxodotreotide at the selected study sites previously identified by investigators. Patients could have been treated with 177Lu oxodotreotide under the Advanced Accelerator Applications (AAA) Lutathera CUP approved in 10 European countries since 2011–2012 or with a commercial drug. The study included 110 patients from Spain, France, and the UK who met the pre-specified criteria for inclusion. Most patients with pNETs who received treatment in this study were part of the CUP in 1 of the European Neuroendocrine Tumor Society Centers participating in this program. The retrospective data collection from medical records began on October 31, 2018, at the first study site. Follow-up visits were tentatively collected every 3 months, depending on the standard of care for local practice and source document availability at the sites. The primary objective of the NETTER-R study was to determine the efficacy of 177Lu oxodotreotide in patients with pNET who met a set of pre-specified eligibility criteria. The secondary objective of the study was to determine the safety and tolerability of 177Lu oxodotreotide. All inclusion criteria and none of the exclusion criteria had to be met to be eligible for the NETTER-R study. Eligibility criteria included patients with SSR-positive, unresectable or metastatic, well-differentiated pNETs with progressive disease who had been treated with 177Lu oxodotreotide. Patients were not eligible if they were diagnosed with NETs of other origins.
Patients in the NETTER-R study had a mean age of 58 years (||||||||). Relatively equal proportions of males (53%) and females (47%) were enrolled. |||| of patients were White (|||). The primary sites of metastases before patients starting treatment with 177Lu oxodotreotide were the liver (96%), lymph nodes (43%), bone (29%), and lungs (4%). The liver tumour burden ranged from 10% to 25% or less (29%) and greater than 25% liver burden or more than 2 metastatic organs (36%). More than half of patients had non-functional tumours (57%), with 30% of patients with functional tumour status and the remaining without an assessment of tumour functionality (11%). Most patients had a Ki-67 index between 3% and 20% (66%) or 2% or less (24%), and a histopathological intermediate (grade 2; 65%) or low (grade 1; 27%) grade of disease. Many patients received an octreotide scan (|||) or a gallium PET scan (|||). For Eastern Cooperative Oncology Group Performance Status (ECOG PS), most patients who had it assessed had an ECOG PS of 0 (|||) or 1 (|||). Most patients received prior anticancer treatments (92%) and had received a mean 4.7 prior or concomitant therapies. Prior anticancer therapy for NET disease was received by 91% of patients; patients mostly received chemotherapy (|||), radiotherapy (|||), or other therapies (91%). Prior somatostatins and analogues were received by 70% of patients, mostly with lanreotide or octreotide (33% each). Prior tyrosine kinase inhibitors (TKIs) were received by 38% of patients, mostly with everolimus (33%) or sunitinib (20%). Approximately |||| of patients (|||) had received prior surgical and medical procedures; patients most commonly underwent pancreatic operations (|||), followed by liver operations (|||) and radiotherapy (|||).
A median follow-up time of 24.5 months was reported. There were 55 patients (50%) who experienced an OS event in the NETTER-R study. The median OS was 41.4 months (95% CI, 28.6 to 50.2). Half of the patients were censored for the analysis of OS.
Results for the primary end point of PFS were based on RECIST v 1.1. In the primary analysis of PFS, there were 41 PFS events (66%), of which most were disease progression (|||) with |||| deaths (|||). The median PFS was 24.8 months (95% CI, 17.5 to 34.5). PFS was also assessed using the RECIST v 1.1 criteria based on investigator opinion as a secondary end point. PFS based on investigator’s opinion 1 were based on tumour assessments and other radiological assessments. PFS based on investigator’s opinion 2 were based on other radiological, clinical, biomarker and metabolic assessments. The additional analyses of PFS were consistent with the primary analysis of PFS.
Objective response rate (ORR) based on the primary analysis was assessed in 62 patients. The ORR was 40.3% (95% CI, 28.1 to 53.6). None of the patients had a complete response using RECIST v 1.1 criteria. Partial response was reported in 40.3% of patients. Stable disease and progressive disease were reported for 35.5% and 21.0% of patients, respectively. Results for ORR based on investigators’ opinion 1 and 2 were consistent with the primary analysis of ORR, although the response was slightly better for ORR assessed by investigator’s opinion 2.
The median duration of response (DOR) was 60.7 months (95% CI, 13.1 to 62.1). At the time of the analysis, there were 8 PFS events observed. The DOR based on investigators’ opinion 1 and 2 were both shorter than the primary analysis of DOR. The median DOR based on investigator’s opinion 1 was 31.1 months (95% CI, 16.8 to 62.1) with |||| PFS events, while the DOR based on investigator’s opinion 2 was 28.3 months (95% CI, 16.8 to 60.7) with |||| PFS events.
There was a total of ||||||| time to progression (TTP) events with a median TTP of 29.5 months (95% CI, 21.4 to 67.6). As with PFS, TTP was assessed via investigators’ opinion 1 and 2, the results of which were both consistent with the primary analysis of TTP.
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Adverse events (AEs) were reported in 79 patients (72%). The most common AEs included nausea (28%), fatigue (23%), abdominal pain (16%), vomiting (|||), upper abdominal pain (|||), anemia (|||), diarrhea, lymphopenia, and thrombocytopenia (|||||||). Grade 3 or 4 AEs were reported in 30 patients (27%). The incidence of grade 3 or 4 AEs was generally infrequent, with each event occurring in less than 5% of patients. The most common grade 3 or 4 AEs were lymphopenia (||), abdominal pain, ascites, hypercalcemia, and liver abscess (||||||).
Serious adverse events (SAEs) were reported in 29 patients (26%). SAEs were infrequently reported, with SAEs occurring in less than 3% of patients. The most common SAEs included liver abscess, ascites, and hypercalcemia (||||||||).
There were no treatment-emergent AEs which resulted in treatment discontinuation. Treatment-emergent AEs leading to dose modification were infrequent and occurred in 10 patients (9%). The most common treatment-emergent AEs that led to dose modifications included lymphopenia and nausea (||| each).
There was a total of |||| deaths (|||) due to AEs in the NETTER-R study. The causes of death were reported to be due to abdominal abscess, hepatorenal syndrome and metabolic encephalopathy, hepatic encephalopathy, ascites, and lower respiratory tract infection and pulmonary embolism.
Notable harms were detailed in the CADTH Systematic Review protocol and included myelotoxicity, renal toxicity, transformation to leukemia or MDS, nausea or vomiting, and fatigue.
Hematological toxicities were reported among |||||||||||||||. Hematological toxicities were mostly grade 1 or 2 (||||), with 5 patients with grade 3 events. Nausea and fatigue were the 2 most commonly reported AEs in the NETTER-R study, occurring in 31 patients (28%) and 25 patients (23%), respectively. Renal toxicity was infrequently reported among 6 patients (6%); of these, 3 patients had grade 1 or 2 events and 3 patients had grade 3 events. There were no reports of secondary hematological malignancies (acute leukemia or MDS) in any patient.
The NETTER-R study was a retrospective, non-comparative, registry-based, observational study. Without a comparison group, the safety and effectiveness of 177Lu oxodotreotide relative to currently available therapies is unknown. Moreover, due to lack of an adequate control group, the estimate of long-term efficacy was compromised. In particular, no causal inference could be made whether the treatment effect (e.g., changes on PFS or OS) could be completely attributable to 177Lu oxodotreotide or temporality changes in other factors, including concomitant therapies or natural course of disease. In retrospective observational cohort studies of drug effectiveness based on existing medical records, the lack of a sound study design to make an adjustment or control for potential bias has been recognized as a fatal limitation by various real-world evidence study guidance documents.
The CADTH team considered the retrospective design of the NETTER-R study could have allowed for a matched comparator group of patients who had received relevant therapies such as everolimus or sunitinib. The clinical experts consulted by CADTH for this review agreed that a retrospective study with a matched analysis incorporating a comparator group would have improved the strength of evidence for this funding request for pNETs. It was also acknowledged that a matched analysis would be dependent on whether such data were available.
There was a large amount of censoring for all efficacy analyses. For example, in the estimate of PFS, approximately one-third of patients were censored at the date of their last evaluable tumour assessment if they had not experienced disease progression or who had not died at the time of data collection in the context of time-to-event analyses. Similarly, in the assessment of OS, half of the patients were censored on their last date of contact if they were still alive or had an unknown status. The large amount of censoring (e.g., non-informative) for most efficacy outcomes (i.e., OS, PFS, DOR, TTP) would have resulted in biased estimates of the absolute changes overtime, as illustrated by the Kaplan-Meier curves, on those efficacy outcomes and further introduced uncertainty in the true effect of 177Lu oxodotreotide on OS and progression of patients with pNETs.
The median follow-up time of the NETTER-R study was 24.5 months. The clinical experts consulted by CADTH for this review commented that, although no control group was part of the study, efficacy results for PFS and OS showed benefit to patients treated with 177Lu oxodotreotide. However, longer-term data may have benefited the study by providing evidence of the impact of treatment with 177Lu oxodotreotide over a longer period of time.
The NETTER-R study was conducted in Europe with patients enrolled from the UK, France, and Spain. Consultation with clinical experts engaged by CADTH for this review suggested that eligibility criteria and baseline characteristics were generally representative of Canadian patients who might be treated in clinical practice, although European countries may have more experience administering PRRT than Canada. The clinical experts commented that although 1 patient received dactolisib as a prior therapy on the NETTER-R study, this treatment is not approved by Health Canada and not used among patients living in Canada; the effect of this is expected to be low because only 1 patient received this treatment. It was also noted that the eligibility criteria of the NETTER-R study specified that patients with unresectable or metastatic pNETs be included in the study. The clinical experts confirmed that inclusion of these patients would be unlikely to affect study outcomes; pNETs are a heterogenous group of tumours that result in aggressive disease and results of treatment with 177Lu oxodotreotide based on the NETTER-R study will likely apply to these patients as well.
Regarding prior therapies received by patients, it was noted that 70% of patients received prior treatment with SSAs, leaving 30% of patients who had not received prior treatment with SSAs. The funding request by the sponsor specifies that the patients’ disease must have progressed after prior treatment with an SSA unless they were contraindicated or intolerant. Further, the NETTER-R study did not specify that patients must have had prior treatment with SSAs; although this is not in exact alignment with the funding request, consultation by CADTH with clinical experts for this review confirmed that the results of the NETTER-R study would still be generalizable to most patients in Canadian clinical practice.
The NETTER-R study did not include a comparator group. Consultation with clinical experts for this review suggested that a randomized trial may not have been possible because it would be unlikely for patients to have accepted assignment to a treatment group which did not include 177Lu oxodotreotide. In addition, treatment with PRRT has been accepted in Europe and in the US based on data from the NETTER-1 study, which was extrapolated to patients with pNETs.
The aim of the sponsor’s indirect treatment comparison (ITC) was to compare 177Lu oxodotreotide to relevant comparators. Due to the lack of published clinical trial data, the sponsor conducted MAICs comparing 177Lu oxodotreotide to everolimus and sunitinib. The RADIANT-3 trial, which compared everolimus to placebo, and NCT00428597, which compared sunitinib to placebo, were compared with the NETTER-R study through MAICs. Comparison of key eligibility across the trials suggested that characteristics across the trials were comparable. The median age was similar across all studies (between 56 and 58 years), with similar proportions of males and females. The majority of patients across all trials had an ECOG PS of 1 or 2, although the proportion of patients with an ECOG PS of 1 was greater in the RADIANT-3 and NCT00428597 (> 60%) than the NETTER-R study (33%). Similar proportions of patients in the NETTER-R and NCT00428597 study had a time between disease progression to randomization or receipt of study treatment between 3 and 12 months (26% and 28%, respectively). There were some differences noted across the populations of the included studies. Specifically, there were differences in the proportions of patients with organ involvement, time from disease progression to randomization or receipt of study treatment, and prior therapies. Classification of tumour functionality was not reported consistently across the trials.
The aim of the ITC by Khan et al. was to use MAICs to indirectly compare PFS in patients with GI-NETs or pNETs and OS in patients with pNETs after treatment with 177Lu oxodotreotide, everolimus, sunitinib, or best supportive care across different studies. Khan et al. compared 177Lu oxodotreotide to everolimus and sunitinib using data from the ERASMUS, RADIANT-3, and NCT00428597 studies. The authors concluded that there were no differences in key covariates between the ERASMUS, RADIANT-3, and NCT00428597 studies. Age, ECOG PS, previous chemotherapy, and previous radiotherapy were reported to be statistically significantly associated with PFS and OS in the ERASMUS study at the 20% level and were adjusted for in the MAICs.
PFS: The median PFS of 177Lu oxodotreotide before adjustment was ||||||||||||||||||||||||||||||||||. After adjustment, the median PFS of 177Lu oxodotreotide was |||||||||||||||||||||||||||||||, which was longer than the median PFS of everolimus at ||||||||||||||||||||||||||||||||||. The hazard ratio (HR) for PFS between 177Lu oxodotreotide and everolimus |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.
The median PFS of 177Lu oxodotreotide before adjustment was ||||||||||||||||||||||||||||||||||||. After adjustment, the median PFS of 177Lu oxodotreotide remained the same at |||||||||||||||||||||||||||||||||, which was longer than the median PFS of sunitinib at |||||||||||||||||||||||||||||||||||||||. The HR for PFS also favoured 177Lu oxodotreotide over sunitinib |||||||||||||||||||||||||||||||||||||.
OS: The median OS of 177Lu oxodotreotide before adjustment was |||||||||||||||||||||||||||||||||||||||||. After adjustment, the median PFS of 177Lu oxodotreotide was |||||||||||||||||||||||||||||||||||||||. The median OS of everolimus was |||||||||||||||||||||||||||||||||||||||. The 95% CI of HR for OS between 177Lu oxodotreotide and everolimus |||||||||||||||||||, even though the point estimate was in favour of 177Lu oxodotreotide over everolimus ||||||||||||||||||||||||||||||||||||||.
The median OS of 177Lu oxodotreotide before adjustment was |||||||||||||||||||||||||||||||||||||||||. After adjustment, the median OS of 177Lu oxodotreotide remained the same at |||||||||||||||||||||||||||||||||||||, which was longer than the median OS of sunitinib at |||||||||||||||||||||||||||||||||||||. The HR for OS failed to show a statistically significant difference in favour of 177Lu oxodotreotide over sunitinib ||||||||||||||||||||||||||||||||||||.
PFS: The MAIC suggested that PFS was longer in patients treated with 177Lu oxodotreotide compared with sunitinib (HR = 0.36; 95% CI, 0.18 to 0.70) and everolimus (HR = 0.46; 95% CI, 0.30 to 0.71). Results of the sensitivity analyses also supported improvement with 177Lu oxodotreotide over sunitinib and everolimus.
OS: The MAIC suggested that OS was longer in patients treated with 177Lu oxodotreotide compared with sunitinib (HR = 0.42; 95% CI, 0.25 to 0.72) and everolimus (HR = 0.53; 95% CI, 0.33 to 0.87). Results of the sensitivity analyses also supported improvement with 177Lu oxodotreotide over sunitinib and everolimus.
There were no analyses for harms conducted in either ITC.
Patient demographic and disease characteristics across the 3 studies were mostly similar. However, there were some differences regarding organ involvement, time from initial diagnosis, time between disease progression and randomization, tumour functionality, and prior treatments. Residual confounding bias may exist as the matching adjustment was limited to a number of pre-identified covariates. As mentioned, the MAICs chosen for comparisons between 177Lu oxodotreotide and everolimus or sunitinib were designed based on the combination of covariates that resulted in the highest effective sample size (ESS). The ESS for the MAICs between 177Lu oxodotreotide versus everolimus and 177Lu oxodotreotide versus sunitinib were |||| and ||||, respectively. The reductions in ESS for these MAICs may indicate that there was not much overlap between the individual patient-level data of the NETTER-R study and the RADIANT-3 and NCT00428597 studies, with less overlap between the NETTER-R and RADIANT-3 study than NETTER-R and NCT00428597. Because there was not high overlap between patients across the studies, this may be an indicator of heterogeneity across patient characteristics. This may suggest the presence of additional unknown prognostic and predictive factors and introduce bias into the comparisons of efficacy between 177Lu oxodotreotide and everolimus or sunitinib.
The results of the MAICs suggested that 177Lu oxodotreotide was favoured over everolimus and sunitinib for PFS, but not for OS. It should be noted that the median OS was not reached in either the RADIANT-3 and NCT00428597 studies. Therefore, the efficacy analyses of the sponsor’s MAICs, particularly for OS, is of limited interpretability.
In general, the MAICs rely on statistical assumptions and a limited list of known predictive and prognostic covariates which are difficult to confirm. The MAIC has resulted in a significant reduction of sample size by excluding more than half of NETTER-R patients, which would have compromised the generalizability and reliability of the results.
Some differences in baseline characteristics were observed across the included studies. There were some noted differences in patients’ sex, tumour functionality, and previous treatments. These characteristics were not included in the matching between the ERASMUS and the NCT00428597 and RADIANT-3 studies. After matching, these characteristics were not well balanced. It is possible that these differences in patient characteristics may affect the validity of the comparisons between 177Lu oxodotreotide and everolimus and sunitinib.
The authors conducted matching with key covariates between the ERASMUS study and the comparator studies (NCT00428597 and RADIANT-3). The ESS after matching with the sunitinib comparator group in the NCT00428597 study was 77% of the initial sample. However, the ESS was much lower after matching with the everolimus group in the RADIANT-3 study, which was 35%. Characteristics of patients which were unadjusted for were not well balanced as illustrated through the differences in patients’ sex, previous surgery, and tumour functionality. Therefore, any unknown covariates are likely not balanced across studies. It is likely that there is little patient overlap between the ERASMUS and comparator studies, although more so with the RADIANT-3 study.
As mentioned previously, OS was not reached in either the RADIANT-3 and NCT00428597 studies. Therefore, the efficacy analyses for OS based on immature data may suffer from high uncertainty.
Three separate non-comparative observational studies by Fröss-Baron et al., Marinova et al., and Zandee et al. are briefly summarized here to provide additional efficacy and safety data on 177Lu oxodotreotide in patients with pNETs.
A retrospective study was conducted by Fröss-Baron et al. to determine the efficacy (PFS and OS) and safety of 177Lu oxodotreotide in 102 adult patients with metastatic and/or locally advanced pNETs who have been previously treated with chemotherapy. Patients treated with 177Lu oxodotreotide between 2005 and 2014 were identified using hospital records in Sweden, and medical and radiological reports were retrospectively examined. Patients received 7.4 GBq 177Lu oxodotreotide per cycle with an intended 6- to 8- week interval between each cycle.
A retrospective study was conducted by Marinova et al. to determine the change in HRQoL and symptom burden in 68 adult patients with pNETs following treatment with 177Lu oxodotreotide. Patients treated with 177Lu oxodotreotide between 2007 and 2015 at a hospital in Germany were identified, and data were retrospectively analyzed. Briefly, inclusion criteria for the study were unresectable metastatic pNETs confirmed with histopathology, an ECOG PS of 0 to 2, the intended number of cycles were administered, follow-up at 3 months after the last cycle was completed, and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) was completed before the first cycle and at least once after the last cycle. Patients received a mean activity of 7.6 GBq (SD = not reported [NR]) 177Lu oxodotreotide per cycle. Change in HRQoL and symptom status were evaluated according to the EORTC QLQ-C30. Higher scores on the Global Health Status and functional scales indicate better function and higher scores on the symptom scales and single items indicate significant symptomatology. Patients completed the EORTC QLQ-C30 at baseline and every 3 months following each treatment cycle for up to 12 months.
A retrospective study was conducted by Zandee et al. to determine the efficacy and safety of 177Lu oxodotreotide in 34 adult patients with functioning pNETs who were treated with 177Lu oxodotreotide between 2000 and 2017 at a centre in the Netherlands. Of these patients, 14 patients had insulinoma, 8 had glucagonoma, 7 had gastrinoma, and 5 had VIPoma. Patients received up to 4 cycles of 7.4 GBq 177Lu oxodotreotide per cycle with an intended interval of 6 to 10 weeks and an intended cumulative activity of 27.8 to 29.6 GBq. Patients were admitted for clinical observation or treatment of hormonal syndrome per protocol. The study aimed to evaluate symptomatic, biochemical, and radiological response and toxicity. Hematology, kidney, and liver function tests were completed after each cycle and at follow-up visits (6 weeks, 3 months, 6 months following the last cycle, and every 6 months thereafter). CT or MRI imaging was completed within 3 months of the first cycle and at each follow-up visit. Patients completed the EORTC QLQ-C30 at all visits.
The median follow-up period was 34 months (range = 4 to 160), and survival data for patients in Sweden (46.1%) were based on data from the National Health Registry until 2018. PFS was calculated using the Kaplan-Meier method and based on the first date of treatment to the date of radiologically confirmed progression per RECIST 1.1 or death from any cause. OS was calculated using the Kaplan-Meier method and based on the first day of treatment with 177Lu oxodotreotide to the day of death or the last day of follow-up. The median PFS was 24 months (95% CI, 17 to 28) and the median OS was 42 months (95% CI, 29 to 61). During follow-up, 63 (61.8%) patients died; tumour progression was reported as the cause of death in 60 patients. Tumour response was assessed with RECIST 1.1 criteria in 100 patients. Complete response was reported in 4 (4.0%) patients, partial response in 45 (45.0%) patients, stable disease in 44 (44.0%) patients, and progressive disease in 7 (7.0%) patients. Objective response, defined as complete or partial response, was reached by 49% of patients. The median time to best response was 14.8 months (range = 3 to 108). Disease control, which was defined as complete response, partial response, or stable disease, was reported in 91.0% of 92 patients with progressive disease at baseline.
The primary analysis using the EORTC QLQ-C30 scores was according to data collected at baseline and 3 months after the last cycle (follow-up). The mixed longitudinal (panel) model was used to evaluate the data and a non-parametric Skilling-Mack test was used to verify the unbalanced panel data; a value of less than 0.05 was considered to be statistically significant. An increase in the mean Global Health Status score was reported (P = 0.008); the mean score was 58.2 (95% CI, 53.1 to 63.2) at baseline and 69.3 (95% CI, 61.4 to 77.2) at follow-up. An increase in the mean social functioning score was reported (P = 0.049); the mean score was 63.9 (95% CI, 56.7 to 71.2) at baseline and 70.9 (95% CI, 61.1 to 80.7) at follow-up. A decrease in the mean fatigue symptom score was reported (P = 0.029); the mean score was 42.4 (95% CI, 36.3 to 48.4) at baseline and 32.0 (95% CI, 22.2 to 41.7) at follow-up. A decrease in the mean appetite loss symptom score was reported (P = 0.015); the mean score was 25.7 (95% CI, 19.5 to 31.9) at baseline and 11.6 (95% CI, 0.7 to 22.5) at follow-up. The difference in change from baseline in the mean scores on the remaining functional and symptom scales were not considered statistically significant. Further, the investigators reported a significantly greater improvement (magnitude of benefit was not reported) on the diarrhea and dyspnea symptom scale scores observed in patients with functioning versus non-functioning pNETs. The subanalysis of the EORTC QLQ-C30 results was based on data collected at baseline and 3 months after the first, second, and third cycle. Changes from baseline in the EORTC QLQ-C30 scores in the subanalysis were generally consistent with those observed in the primary analysis.
The median follow-up period was 39.3 months (range = NR). PFS was calculated using the Kaplan-Meier method and was based on the time from the first cycle of 177Lu oxodotreotide to objective disease progression, change to a new line of therapy, or death from any cause. The median PFS was 18.1 months (interquartile range = 3.3 to 35.7). A primary event was reported in 31 patients, of which 24 patients had progressive disease, 5 patients changed to a new line of therapy, and there were 2 deaths. Tumour response was evaluated with RECIST v1.1 criteria in 34 patients. Complete response was reported in 1 (2.9%) patient, partial response in 19 (55.9%) patients, stable disease in 8 (23.6%) patients, and progressive disease in 6 (17.6%) patients. Disease control, which was defined as patients with complete response, partial response, or stable disease, was reported in 18 of the 23 patients with progressive disease at baseline.
HRQoL was assessed in 22 patients using the EORTC QLQ-C30 by comparing the scores 3 months after the last cycle (follow-up) to baseline. For the comparison of continuous variables, a paired t-test and the Wilcoxon signed-rank test were used for normally distributed and non-normally distributed variables, respectively. An increase in the mean Global Health Score and Quality of Life was reported (P = 0.002); the mean score was 61.7 (95% CI, NR) at baseline and 79.5 (95% CI, NR) at follow-up. An increase in the mean physical functioning score was reported (P = 0.008); the mean score was 79.7 (95% CI, NR) at baseline and 90.0 (95% CI, NR) at follow-up. An increase in the mean role functioning score was reported (P = 0.006); the mean score was 62.7 (95% CI, NR) at baseline and 90.3 (95% CI, NR) at follow-up. An increase in the mean emotional functioning score was reported (P = 0.002); the mean score was 74.1 (95% CI, NR) at baseline and 84.5 (95% CI, NR) at follow-up. An increase in the mean social functioning score was reported (P = 0.047); the mean score was 77.3 (95% CI, NR) at baseline and 85.6 (95% CI, NR) at follow-up. A decrease in the mean fatigue symptom score was reported (P = 0.02); the mean score was 27.3 (95% CI, NR) at baseline and 17.2 (95% CI, NR) at follow-up. The difference in change from baseline in the mean scores on the remaining functional and symptom scales were not considered statistically significant.
Bone marrow, liver, and kidney toxicity were defined by the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Grade 3 or 4 bone marrow toxicity was reported in 11 (10.8%) patients. Grade 3 toxicity of white blood cells and/or granulocytes was reported in 5 (4.9%) patients, grade 3 or 4 toxicity of platelets was reported in 5 (4.9%) patients, and grade 3 toxicity of hemoglobin was reported in 2 (1.9%) patients. Grade 4 (lethal) thrombocytopenia and acute myeloid leukemia were reported in 1 (1.0%) patient each. Fatal liver toxicity was reported in 1 (1.0%) patient; the cause of death was also considered related to tumour progression. Grade 3 or 4 nephrotoxicity was not observed. Treatment discontinuations were due to the following: termination according to the dosimetry-guided protocol was applied to 51 (50.0%) patients, disease progression in 17 (16.7%) patients, bone marrow toxicity in 11 (10.8%) patients, the standard 4-cycle protocol was applied to 9 (8.8%) patients, reduced tumour load in 3 (2.9%) patients, deterioration in 2 (1.9%) patients, death was reported in 2 (1.9%) patients, and a combination of factors not specified in 7 (6.8%) patients.
No analyses for harms were conducted.
Nausea, vomiting, and pain were reported in 22 (17.6%), 6 (4.8%), and 10 (8.0%) of the 125 cycles administered in total, respectively. Toxicity was defined according to the CTCAE 4.03 criteria. Grade 3 anemia and grade 3 thrombocytopenia were reported in 1 (2.9%) patient each, and grade 3 leukopenia was reported in 3 (8.8%) patients. Hormonal crisis, which was defined as an acute complication of hormonal secretion following treatment with 177Lu oxodotreotide that required medical care, was reported in 3 (8.8%) patients, and late toxicity with myelodysplastic syndrome (MDS) was reported in 1 (2.9%) patient. Reasons for not having received the intended cumulative activity of 29.6 GBq 177Lu oxodotreotide included a reduced cumulative activity ranging from 18.5 to 25.9 GBq 177Lu oxodotreotide was administered in 5 (14.7%) patients due to hepatotoxicity; only 1 cycle was administered in 3 (8.8%) patients each due to noncompliance, unexplained progressive cognitive decline, and patient withdrawal; only 3 cycles were provided to 1 (2.9%) patient due to clinical progression; and the last patient case was not reported.
In the absence of an active comparator or placebo group, the interpretation of the efficacy and safety results from the 3 non-comparative observational studies is limited. The interpretation of treatment benefit is further limited by the retrospective non-randomized study design and relatively small sample size. This is compounded by the relatively large number of patients who were excluded from the analysis due to their incomplete questionnaires, as indicated in the study conducted by Marinova et al. However, the clinical experts consulted by CADTH indicated patients with NETs in general were rare, and Zandee et al. also indicated pNETs were rare. Although treatment with 177Lu oxodotreotide can be ascertained by the use of hospital records, data were sourced from 1 hospital in either Sweden, Germany, or the Netherlands and were retrospectively analyzed. The use of a single source for the recruitment of patients may introduce the risk of selection bias because patients under the care of 1 team may share common characteristics, including treatment history, disease severity, and level of supportive care, which can bias the estimation of treatment effect and limit the external validity of the results. Notably, the place of 177Lu oxodotreotide in the treatment sequence varied within the cohort and was preceded by various therapies, which the clinical experts suggested can bias the median OS. It should also be noted that Marinova et al. indicated the validated German version of EORTC QLQ-C30 was used in the study but did not identify a clinically meaningful difference; Zandee et al. also did not identify a clinically meaningful difference. Although it was indicated that patients did not undergo further therapies after treatment with 177Lu oxodotreotide and follow-up, it was unclear if patients received any concomitant therapy that could bias the reporting on the HRQoL questionnaire.
A number of baseline characteristics of the cohorts in the studies, specifically the mean age, proportion of patients with liver metastases, and the proportion of patients with an ECOG PS of 0, were similar to the NETTER-R study, which the clinical experts consulted by CADTH suggested were representative of patients seen in clinical practice in Canada (refer to the Systematic Review section for a detailed description of the patient population in NETTER-R). The retrospective studies included patients with experience with various treatment histories, thereby placing 177Lu oxodotreotide at various lines in the treatment sequence and preceded by different therapies. Only 56.9%, 36.8%, and 64.7% of patients received a somatostatin analogue before treatment with 177Lu oxodotreotide in the study conducted by Fröss-Baron et al., Marinova et al., and Zandee et al., respectively, and thus would match the reimbursement request for this review. Further, the number of cycles administered and the intervals between the cycles varied between studies, such as the application of the dosimetry-guided protocol and the use of 3-month intervals. Finally, Zandee et al. included patients with functioning pNETs, specifically patients with insulinoma, glucagonoma, gastrinoma, and VIPoma, but did not include patients with non-functioning pNETs.
Cost and Cost-Effectiveness.
CADTH identified a key limitation with the sponsor’s analysis. The use of relative dose intensity to estimate actual drug costs was not appropriate. In CADTH reanalysis, a dose intensity of 100% was assumed for 177Lu oxodotreotide and comparators, which decreased the 3-year total budget impact of reimbursing 177Lu oxodotreotide to $7,934,115 ($1,420,013 in year 1, $2,875,197 in year 2, and $3,638,906 in year 3).
Dr. Maureen Trudeau (Chair), Mr. Daryl Bell, Dr. Jennifer Bell, Dr. Matthew Cheung; Dr. Winson Cheung, Dr. Michael Crump, Dr. Leela John, Dr. Christian Kollmannsberger, Mr. Cameron Lane, Dr. Christopher Longo, Dr. Catherine Moltzan, Ms. Amy Peasgood, Dr. Anca Prica, Dr. Adam Raymakers, Dr. Patricia Tang, Dr. Marianne Taylor, and Dr. W. Dominika Wranik
Meeting date: August 10, 2022
Regrets: 3 expert committee members did not attend
Conflicts of interest: None
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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
Sponsor: Advanced Accelerator Applications
Final recommendation: Reimburse with conditions
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