CONFIDENTIAL UNTIL PUBLISHED

NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE

Appraisal consultation document

Lutetium-177 vipivotide tetraxetan for treating PSMA-positive hormone-relapsed metastatic prostate cancer after 2 or more treatments

The Department of Health and Social Care has asked the National Institute for Health and Care Excellence (NICE) to produce guidance on using lutetium (177Lu) vipivotide tetraxetan in the NHS in England. The appraisal committee has considered the evidence submitted by the company and the views of non-company consultees and commentators, clinical experts and patient experts.

This document has been prepared for consultation with the consultees. It summarises the evidence and views that have been considered, and sets out the recommendations made by the committee. NICE invites comments from the consultees and commentators for this appraisal and the public. This document should be read along with the evidence (see the committee papers).

The appraisal committee is interested in receiving comments on the following:

• Has all of the relevant evidence been taken into account?

• Are the summaries of clinical and cost effectiveness reasonable interpretations of the evidence?

• Are the recommendations sound and a suitable basis for guidance to the NHS?

• Are there any aspects of the recommendations that need particular consideration to ensure we avoid unlawful discrimination against any group of people on the grounds of race, sex, disability, religion or belief, sexual orientation, age, gender reassignment, pregnancy and maternity?

Appraisal consultation document – Lutetium-177 vipivotide tetraxetan for treating PSMA-positive hormonerelapsed metastatic prostate cancer after 2 or more treatments Page 1 of 28 Issue date: October 2022

CONFIDENTIAL UNTIL PUBLISHED

Note that this document is not NICE's final guidance on this technology. The recommendations in section 1 may change after consultation.

After consultation:

• The appraisal committee will meet again to consider the evidence, this appraisal consultation document and comments from the consultees.

• At that meeting, the committee will also consider comments made by people who are not consultees.

• After considering these comments, the committee will prepare the final appraisal document.

• Subject to any appeal by consultees, the final appraisal document may be used as the basis for NICE's guidance on using lutetium (177Lu) vipivotide tetraxetan in the NHS in England.

' For further details, see NICE s guide to the processes of technology appraisal.

The key dates for this appraisal are:

Closing date for comments: 2 November 2022

Second appraisal committee meeting: 12 January 2023

Details of membership of the appraisal committee are given in section 4

Appraisal consultation document – Lutetium-177 vipivotide tetraxetan for treating PSMA-positive hormonerelapsed metastatic prostate cancer after 2 or more treatments Page 2 of 28 Issue date: October 2022

CONFIDENTIAL UNTIL PUBLISHED

1 Recommendations

• 1.1 Lutetium-177 vipivotide tetraxetan is not recommended, within its marketing authorisation, for treating prostate-specific membrane antigen (PSMA) positive hormone-relapsed metastatic prostate cancer in adults:

  • after taxane-based chemotherapy and an anti-androgen or

  • when taxanes are medically unsuitable.

• 1.2 This recommendation is not intended to affect treatment with lutetium-177 vipivotide tetraxetan that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.

Why the committee made these recommendations

Treatments for hormone-relapsed metastatic prostate cancer that has progressed after taxane-based chemotherapy and an anti-androgen include best supportive care, radium-223 dichloride and retreatment with taxanes (for example, cabazitaxel).

Evidence from a clinical trial shows that lutetium-177 vipivotide tetraxetan increases the time before the cancer gets worse and how long people live compared with best supportive care. There is no evidence from a direct comparison with cabazitaxel. Indirect comparisons suggest that lutetium-177 vipivotide tetraxetan may be more effective than cabazitaxel. But they all have limitations, so the results are uncertain. Radium-223 dichloride may be a comparator for a few people. But no evidence was submitted for this comparison, so it could not be considered.

Lutetium-177 vipivotide tetraxetan meets NICE’s criteria for a life-extending treatment at the end of life compared with best supportive care. It is unclear whether this is the case when it is compared with cabazitaxel because of the uncertainty in the clinical evidence. But, for both comparisons, the most likely cost-effectiveness

Appraisal consultation document – Lutetium-177 vipivotide tetraxetan for treating PSMA-positive hormonerelapsed metastatic prostate cancer after 2 or more treatments Page 3 of 28 Issue date: October 2022

CONFIDENTIAL UNTIL PUBLISHED

estimates for lutetium-177 vipivotide tetraxetan are much higher than what NICE normally considers an acceptable use of NHS resources. So, it is not recommended.

2 Information about lutetium-177 vipivotide tetraxetan

Marketing authorisation indication

• 2.1 Lutetium-177 vipivotide tetraxetan (Pluvicto, Advanced Accelerator Applications) is indicated for ‘the treatment of adult patients with prostatespecific membrane antigen (PSMA)-positive metastatic castrationresistant prostate cancer (mCRPC) who have been treated with androgen receptor (AR) pathway inhibition and taxane-based chemotherapy or who are not medically suitable for taxanes’.

Dosage in the marketing authorisation

• 2.2 The dosage schedule is available in the summary of product characteristics for lutetium-177 vipivotide tetraxetan.

Price

• 2.3 The list price of lutetium-177 vipivotide tetraxetan is £20,000 per 7,400 MBq single dose vial per treatment cycle (excluding VAT; company submission). The company has a commercial arrangement, which would have applied if the technology had been recommended.

3 Committee discussion

The appraisal committee considered evidence submitted by Advanced Accelerator Applications, a review of this submission by the evidence review group (ERG) and responses from stakeholders. See the committee papers for full details of the evidence.

Appraisal consultation document – Lutetium-177 vipivotide tetraxetan for treating PSMA-positive hormonerelapsed metastatic prostate cancer after 2 or more treatments Page 4 of 28 Issue date: October 2022

CONFIDENTIAL UNTIL PUBLISHED

The condition

There is an unmet need for new treatments for PSMA-positive hormonerelapsed metastatic prostate cancer

• 3.1 There are limited treatment options for prostate-specific membrane antigen (PSMA) positive, hormone-relapsed, metastatic prostate cancer after an anti-androgen and taxane-based chemotherapy or when taxanes are medically unsuitable. Also, people with advanced or metastatic prostate cancer have a poor prognosis. The patient experts explained that the condition affects all aspects of lives of people who have it and can affect the lives of their families and friends. They noted that there is no curative treatment and that there is a need for new treatments that improve both the quality of life and length of life. The clinical experts noted that the only available active treatment option for most people is taxanebased chemotherapy, which can have debilitating side effects. In contrast, a patient expert described leading an active and high-quality life with few side effects while having lutetium-177 vipivotide tetraxetan, from now referred to as lutetium-177. The clinical experts highlighted the importance of treatment sequencing and that lutetium-177 may be more effective earlier in the treatment pathway when the volume of cancer is likely to be lower. The committee was aware that it can only evaluate a treatment within its marketing authorisation, but understood the importance of patient choice in shared decision making with their clinicians. It concluded that there is an unmet need for effective treatment options for PSMApositive hormone-relapsed metastatic prostate cancer that improve quality of life and survival, and have few side effects.

Treatment pathway

Lutetium-177 is positioned appropriately in the treatment pathway

• 3.2 The treatment options for people with hormone-relapsed metastatic prostate cancer for which chemotherapy is not yet indicated, include:

Appraisal consultation document – Lutetium-177 vipivotide tetraxetan for treating PSMA-positive hormonerelapsed metastatic prostate cancer after 2 or more treatments Page 5 of 28 Issue date: October 2022

CONFIDENTIAL UNTIL PUBLISHED

• abiraterone or enzalutamide, if neither has been used before (see NICE’s technology appraisal guidance on enzalutamide and on abiraterone for treating metastatic hormone-relapsed prostate cancer before chemotherapy is indicated) or

• ‘watchful waiting’, then

• ’

• • docetaxel (see NICE s technology appraisal guidance on docetaxel for the treatment of hormone-refractory metastatic prostate cancer.

After docetaxel, abiraterone or enzalutamide can be used if neither has been used before, but a taxane can be used again (that is, cabazitaxel or docetaxel retreatment). The company highlighted that docetaxel retreatment is infrequent, which was confirmed by the clinical experts. Radium-223 dichloride is an option for people who have symptomatic ’ bone metastases (see NICE s technology appraisal guidance on radium- 223 dichloride for treating hormone relapsed prostate cancer with bone metastases). The clinical experts agreed with the positioning of lutetium177 in the treatment pathway, that is, for people who have had an antiandrogen and docetaxel, when docetaxel was suitable. The committee concluded that lutetium-177 was positioned appropriately in the treatment pathway.

Eligibility is determined by PSMA imaging, but access to this is limited and not standard practice across the NHS

• 3.3 PSMA is a transmembrane protein that can be found on prostate cancer cells. Its expression is usually increased in poorly differentiated, metastatic and hormone-relapsed prostate cancer. To have lutetium-177, a person needs to have their PSMA-positivity status confirmed. This can be done using PSMA positron-emission tomography CT (PET-CT) scans. This type of scan uses low-dose radiation to check the activity of cells in different parts of the body. PSMA-specific tests use radiolabelled PSMA to image the prostate cancer cells, and determine lymph node involvement and whether there are distant metastases. The clinical experts explained that PET-CT scans are used in salvage therapy options after radical

Appraisal consultation document – Lutetium-177 vipivotide tetraxetan for treating PSMA-positive hormonerelapsed metastatic prostate cancer after 2 or more treatments Page 6 of 28

CONFIDENTIAL UNTIL PUBLISHED

therapy. But they explained that, in the prostate-cancer setting, clinicians rely on conventional CT and bone scans for most people. They noted that evidence suggests about 80% to 85% of people with hormone-relapsed metastatic prostate cancer have a PSMA-positive status. This is because PSMA expression increases along the treatment pathway. The committee acknowledged that the summary of product characteristics for lutetium177 notes that determining eligibility for the treatment should be assessed using PSMA imaging. It noted that it had not seen any evidence on how well lutetium-177 works in people in whom PSMA expression has not been confirmed. It also reiterated that it can only appraise a technology within its marketing authorisation. The clinical experts explained there is a lack of consensus about using PSMA PET-CT scans in the treatment pathway. This is because of varied access and the limited treatment options available that need this specific test. They noted that, in some centres, people have a scan at diagnosis, about 5% to 10% of which are a PSMA PET-CT scan. They also noted that about 50% to 75% of people may have a PSMA PET-CT scan at some stage in the treatment pathway. The clinical experts agreed that a scan is more likely the more advanced the prostate cancer is, and with additional lines of treatment. They explained repeat scans may be needed even if the PSMA status had previously been determined earlier in the treatment pathway because changes in status are possible. The committee agreed that although some people already have PSMA PET-CT scans in the NHS, clinical practice varies, and it is not standard for everyone. The clinical experts explained that choline is typically used as a radio-isotope for PET-CT scans, but that fluorine and gallium are alternatives. Technetium-99m-labelled PSMA is used for single-photon emission computerised tomography (SPECT). It is an option that may become more widely available, with upscale particularly possible, because research has shown it to be an accurate but cheaper alternative than PET-CT scans. The clinical and patient experts agreed that there is variation across the UK in terms of access to PSMA imaging. But they expect its use to increase. The clinical lead for the

Appraisal consultation document – Lutetium-177 vipivotide tetraxetan for treating PSMA-positive hormonerelapsed metastatic prostate cancer after 2 or more treatments Page 7 of 28 Issue date: October 2022

CONFIDENTIAL UNTIL PUBLISHED

Cancer Drugs Fund agreed that access to PSMA imaging varies, and added that investment would be needed to ensuring access is timely and equitable. The committee concluded that PSMA imaging will be necessary to determine eligibility for treatment with lutetium-177.

Comparators

Cabazitaxel and best supportive care are relevant comparators for hormone-relapsed metastatic prostate cancer with metastases

• 3.4 The NICE scope for this appraisal lists docetaxel, cabazitaxel and radium-223 dichloride as comparators for lutetium-177. But the company submission only included cabazitaxel and best supportive care as comparators. The company and ERG agreed that, for the whole population, retreatment with docetaxel is infrequent, so it was excluded as a comparator. The committee concluded that cabazitaxel and best supportive care were relevant comparators for hormone-relapsed metastatic prostate cancer with metastases.

Radium-223 dichloride may be a relevant comparator for people with symptomatic bone metastases but more evidence is needed

• 3.5 The committee was aware that, with hormone-relapsed metastatic prostate cancer, metastases can occur in multiple locations, and that available treatment options can depend on these locations. Radium-223 dichloride was excluded as a comparator from the company’s decision problem because it considered that radium-223 dichloride is

  • recommended only when there are symptomatic bone metastases, and no visceral metastases. The clinical experts estimated that about 80% to 90% of people may have bone metastases alone when having first-line treatment. But they explained that the proportion of visceral metastases increases with progression and further lines of treatment. One expert estimated that about 30% of people who could have lutetium-177 may have bone metastases alone, but 10% to 15% would have isolated

  • symptomatic bone metastases (as needed for treatment with radium-233).

Appraisal consultation document – Lutetium-177 vipivotide tetraxetan for treating PSMA-positive hormonerelapsed metastatic prostate cancer after 2 or more treatments Page 8 of 28

CONFIDENTIAL UNTIL PUBLISHED

The clinical experts also explained that estimating what proportion of the eligible population has bone metastases alone is not straightforward. This is because the presence of metastases in lymph nodes may not be included in the proportion of people with visceral metastases. The clinical experts explained that radium-223 dichloride is not an option if there are metastases in the lymph nodes or peritoneal disease. So, the size of the relevant subgroup is uncertain but likely to be small. The company argued that radium-223 dichloride may be a relevant comparator for a small subgroup of people with symptomatic bone metastases alone. But it noted that radium-223 dichloride has a different mechanism of action from lutetium-177. It is used to alleviate bone pain whereas lutetium-177 would be used to improve survival. The clinical experts explained that ALSYMPCA (a trial that compared radium-223 dichloride plus best supportive care with placebo and best supportive care) found a survival benefit with radium-223 dichloride. They added that it looked at symptomatic bone metastases as a secondary outcome. But they agreed that, in clinical practice, radium-233 dichloride is used palliatively to treat symptomatic bone pain. The company also argued that there was not enough evidence for a population who had previously had an anti-

androgen and taxane chemotherapy to compare radium-223 dichloride to lutetium-177. The committee did not consider that a lack of evidence was a reason to exclude radium-223 dichloride as a comparator. It agreed that radium-223 dichloride may be a relevant comparator for some people but that there was limited information available about the size of the relevant population. It noted that it had not seen comparative evidence for this group. So, the committee concluded that it could not make any decision on the comparison of lutetium-177 with radium-223 dichloride for people with symptomatic bone metastases.

Appraisal consultation document – Lutetium-177 vipivotide tetraxetan for treating PSMA-positive hormonerelapsed metastatic prostate cancer after 2 or more treatments Page 9 of 28 Issue date: October 2022

CONFIDENTIAL UNTIL PUBLISHED

Subgroups

It is appropriate to include the whole marketing authorisation, but there is no evidence for when taxanes are medically unsuitable

• 3.6 There are 3 populations for whom lutetium-177’s marketing authorisation applies:

  • when further taxane treatment is possible

  • when further taxane treatment after docetaxel is not possible

  • when taxane treatment is medically unsuitable.

This matches the NICE scope for this appraisal but the company did not provide any clinical-effectiveness evidence for when taxanes are medically unsuitable. A clinical expert commented that, based on retrospective studies, the prognosis for this group is likely to be worse. The clinical experts noted that lutetium-177 appeared to be well tolerated in trials. They also noted that it is a targeted treatment with relatively few side effects compared with taxane chemotherapy. So, they thought it is likely to be suitable for more people, including when taxane chemotherapy is unsuitable. The clinical experts explained that taxanes may unsuitable because of:

• medical reasons such as a low red blood count or comorbidities

• social reasons such as living far away from a chemotherapy centre, which could affect access to treatment for potential sepsis associated with chemotherapy

• patient choice.

They added that it would be reasonable for people to decline further taxane treatment, given its side effects profile. The patient experts agreed that lutetium-177 would be preferred to taxane-based treatment when considering its favourable side effects profile. For example, they said it allowed them to lead an active lifestyle. The clinical experts estimated that lutetium-177 could be an option for about 30% of people for whom

Appraisal consultation document – Lutetium-177 vipivotide tetraxetan for treating PSMA-positive hormonerelapsed metastatic prostate cancer after 2 or more treatments Page 10 of 28 Issue date: October 2022

CONFIDENTIAL UNTIL PUBLISHED

taxanes are medically unsuitable. The committee noted that no clinical evidence had been provided for this subgroup. It concluded that it was appropriate to consider the whole population included in lutetium-177’s marketing authorisation, including when taxanes are medically unsuitable. This is because a proportion of people for whom taxanes are medically unsuitable would be able to have lutetium-177. But it acknowledged a likely worse prognosis in this subgroup. It agreed that scenario analyses using the same relative treatment effect as for the wider population but with a higher baseline risk, and so a worse overall survival would be useful.

Clinical evidence

The VISION trial is generalisable to clinical practice in the NHS

• 3.7 The clinical-effectiveness evidence for lutetium-177 compared with standard care was from the VISION trial. This was a phase 3, global, multicentre, prospective, open-label randomised controlled trial that compared lutetium-177 plus standard care with standard care alone. There were 831 adults enrolled in the full analysis set (intention to treat). The inclusion criteria involved at least 1 anti-androgen and 1 or 2 taxane treatment regimens. The trial stratified people according to:

  • baseline lactate dehydrogenase level

  • Eastern Cooperative Oncology Group (ECOG) performance score

  • whether there were liver metastases

  • whether anti-androgen treatment was part of standard care at baseline.

The clinical experts agreed that the baseline characteristics were

generalisable to NHS clinical practice. The committee noted that only 1 anti-androgen is used in NHS practice but more than 2 could be used in VISION. In the full analysis set, about 54% of people having lutetium-177 had 1 anti-androgen and about 46% had best supportive care. In the trial, most people had an ECOG performance score of 0 or 1. The clinical

experts commented that people with an ECOG performance score of Appraisal consultation document – Lutetium-177 vipivotide tetraxetan for treating PSMA-positive hormonerelapsed metastatic prostate cancer after 2 or more treatments Page 11 of 28

CONFIDENTIAL UNTIL PUBLISHED

more than 1 may still have treatment if the score is because of symptoms related to the cancer rather than comorbidities. The committee concluded that, overall, VISION is generalisable to NHS clinical practice.

Lutetium-177 is clinically effective compared with standard care but a high withdrawal rate from VISION means the effect size is uncertain

• 3.8 The primary outcomes in VISION were overall survival and radiographic progression-free survival. These were presented in 2 analysis sets, the full analysis set and a progression-free survival full analysis set. In the progression-free survival set randomisation was after a US Food and Drug Administration approved education measure implemented to reduce withdrawals from the trial. Before this measure was implemented, 56% of people in the control arm withdrew from the trial before having the randomly assigned treatment compared with 16% after the education measure. In comparison, before it was implemented, 1% of people in the lutetium-177 arm withdrew compared with 4% after the education measure. The results for the full analysis set showed an increase in overall survival for lutetium-177 compared with standard care (hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.52 to 0.74). Results for radiographic progression-free survival were only available for the analysis set after education measures were implemented, meaning there was missing data for people who withdrew from the trial earlier. The results showed an increase in radiographic progression-free survival for lutetium177 compared with standard care (HR 0.40, 99.2% CI 0.29 to 0.57). The committee had concerns about the large proportion of withdrawals from the trial in the control group. The ERG explained that this was because people who withdrew from the trial were unlikely to have been a random selection. This would have introduced bias into the clinical estimates through informative censoring. The company confirmed that people were censored (removed from the analysis) but that it adjusted for this in exploratory survival analyses, which showed a small difference in the results. The committee agreed that the difference was small but

potentially important. The company adjustment included an inverse

Appraisal consultation document – Lutetium-177 vipivotide tetraxetan for treating PSMA-positive hormonerelapsed metastatic prostate cancer after 2 or more treatments Page 12 of 28

CONFIDENTIAL UNTIL PUBLISHED

probability of censoring weighting analysis. Also, the adjusted hazard ratios were greater than the unadjusted data. The committee agreed that accounting for any bias introduced in VISION and withdrawal rates was appropriate. It concluded that lutetium-177 appeared to be clinically effective compared with standard care. But it agreed that high levels of withdrawals from VISION from the standard-care arm meant the clinical outcomes were uncertain. It concluded that results from analyses adjusting for this were needed to estimate the relative treatment effect of lutetium-177.

Lutetium-177’s adverse events in the trial reflect the experiences of people having it in clinical practice

• 3.9 Clinical and patient expert feedback described lutetium-177 as well tolerated with relatively few side effects compared with taxane-based chemotherapy. The results from VISION showed that adverse events were more frequent with lutetium-177 than standard care. Higher rates of treatment-emergent adverse events of fatigue and myelosuppression, and more grades 1 or 2 levels of dry mouth, nausea, vomiting and hypersensitivity, were seen with lutetium-177 than standard care. A patient expert explained that although they experienced fatigue while having lutetium-177, it was only for 1 week, rather than the entire treatment cycle. The clinical experts explained that there are usually more side effects with chemotherapy, including neutropenia, fatigue and nausea. Also, evidence from the TheraP trial directly comparing lutetium177 with cabazitaxel showed fewer adverse events. It also showed a better quality of life with lutetium-177 in some domains of the European Organisation for Research and Treatment of Cancer core quality-of-life questionnaire. TheraP was a phase 2, multicentre, open-label randomised controlled trial in people with hormone-relapsed metastatic prostate cancer who had had docetaxel and an anti-androgen. Overall, the clinical experts agreed that they would expect a better quality of life with lutetium177 than cabazitaxel. The committee concluded that lutetium-177 may be

Appraisal consultation document – Lutetium-177 vipivotide tetraxetan for treating PSMA-positive hormonerelapsed metastatic prostate cancer after 2 or more treatments Page 13 of 28 Issue date: October 2022

CONFIDENTIAL UNTIL PUBLISHED

better tolerated than chemotherapy, and that the adverse events seen in the trials reflected people’s experience in clinical practice.

Indirect treatment comparison

The network meta-analysis is associated with high uncertainty, all included trials have limitations and there is heterogeneity between trials

• 3.10 The company’s network meta-analysis indirectly compared lutetium-177 with cabazitaxel even though there was direct evidence from TheraP. The company explained that TheraP was not suitable to use because it:

  • was a phase 2 trial

  • had differences compared with VISION in methodologies, the diagnostic process, intervention production and dose, and the stratification of people

  • was not powered for overall survival.

Instead, the company used TheraP as supportive evidence. The company’s network meta-analysis included 6 randomised controlled trials, and produced a network of:

• cabazitaxel compared with best supportive care, with no previous antiandrogen treatment (TROPIC)

• an anti-androgen compared with placebo, with no previous antiandrogen treatment (COU-AA-301; AFFIRM; Sun et al., 2016)

• cabazitaxel compared with an anti-androgen (CARD)

• lutetium-177 compared with standard care (VISION).

The ERG preferred to include the direct evidence from TheraP. Also, it excluded the comparisons of anti-androgen treatment with placebo, and of cabazitaxel with best supportive care from the network. So, it limited its indirect comparison to 3 studies (CARD, TheraP, VISION). For the company’s and ERG’s analyses, the study populations all had hormone-

relapsed metastatic prostate cancer but there was heterogeneity between

the populations. The company, ERG, and clinical experts agreed that all

Appraisal consultation document – Lutetium-177 vipivotide tetraxetan for treating PSMA-positive hormonerelapsed metastatic prostate cancer after 2 or more treatments Page 14 of 28

CONFIDENTIAL UNTIL PUBLISHED

the trials were associated with limitations. Both the ERG and company’s network meta-analyses included CARD (an open-label randomised trial), but the clinical experts disagreed with its inclusion. This was because the trial population did not reflect UK clinical practice. They added that the trial had been used to show that using anti-androgen treatment was not effective if used more than once in the treatment pathway. People included in the trial had relapsed on an anti-androgen within the last 12 months, which likely affected treatment outcomes. The committee recalled that an anti-androgen would only be used once in the treatment pathway in the NHS. The ERG also explained that it included TheraP in its network meta-analysts because it is important to include direct evidence for an unbiased treatment effect estimate. But it did recognise that TheraP had limitations, including:

• differences in the population compared with VISION such as different doses of the intervention used

• that the bioequivalence of the study drug with lutetium-177 was not established

• consistency checking showed that there was a large overlap of direct and indirect evidence.

Including TheraP in the ERG’s network meta-analysis gave a smaller hazard ratio for lutetium-177 compared with cabazitaxel. The clinical experts agreed that TROPIC was also not reflective of clinical practice because only 1% or fewer people would have cabazitaxel without a previous anti-androgen. The committee noted that COU-AA-301, AFFIRM and Sun et al. would only be included in the network meta-analysis if TROPIC was included. The populations in these 4 studies had not had an anti-androgen. The committee recalled that treatments used earlier in the pathway were likely to be more effective (see section 3.1) and, in clinical practice, anti-androgens are used before chemotherapy. The ERG

suggested that treatment sequencing and anti-androgen sensitivity could be confounding factors. It commented that including TROPIC,

Appraisal consultation document – Lutetium-177 vipivotide tetraxetan for treating PSMA-positive hormonerelapsed metastatic prostate cancer after 2 or more treatments Page 15 of 28 Issue date: October 2022

CONFIDENTIAL UNTIL PUBLISHED

COU-AA-301, AFFIRM and Sun et al. affected the estimation of treatment effect of cabazitaxel compared with standard care, and so the comparison of lutetium-177 and cabazitaxel. The committee suggested adjusting for baseline risk in scenario analyses to account for some differences between the trials and increase confidence in the robustness of results. The ERG acknowledged this approach. But it added that there were challenges in comparing data when the entire population did not have an anti-androgen and another when the entire population did have one. The company added that no difference was seen when it attempted to control for some baseline characteristics. The committee concluded that both network meta-analyses were associated with high uncertainty because all the trials had limitations and because of the heterogeneity between trial populations. But it preferred inclusion of TheraP in the network metaanalysis as a source of direct evidence for lutetium-177 compared with cabazitaxel.

Using a fixed or random-effects network meta-analysis depends on the baseline risk-adjusted updated analysis

• 3.11 In its submission, the company used a fixed-effect network meta-analysis, which assumed no heterogeneity between studies. But the ERG preferred to use a random-effects model, with an informative prior, to account for the heterogeneity between studies. TheraP included 200 people and CARD included 250 people, which the committee considered to be relatively small compared with VISION. Using a random-effects model for the network meta-analysis would approximately give equal weighting to all 3 studies (see section 3.10) compared with a fixed-effect model, in which VISION would have more weight. The committee considered other approaches such as using additional trials to generate an informative prior or a multilevel network meta-regression using individual patient data from VISION. It acknowledged that an analysis of the size of effect of included studies would be possible with scenario analyses. The committee also noted that the adjusted estimates from VISION using the inverse

probability of censoring weighting analysis (see section 3.8) should have

Appraisal consultation document – Lutetium-177 vipivotide tetraxetan for treating PSMA-positive hormonerelapsed metastatic prostate cancer after 2 or more treatments Page 16 of 28

CONFIDENTIAL UNTIL PUBLISHED

been used in the network meta-analysis. It concluded that the company should explore using a baseline risk-adjusted network meta-analysis including all the studies. It also concluded that, if an adequately fitting model can be derived, this should be used in all subsequent analyses. This is because it may give the most robust estimate of treatment effect, given the data.

Cost effectiveness

The company’s model is appropriate for decision making

• 3.12 In its submission, the company presented a 3-state partitioned survival model to estimate the cost effectiveness of lutetium-177 compared with cabazitaxel and standard care. The 3 health states were progression-free, after progression and death. The model cycle was weekly, with no halfcycle correction, and a had 10-year time horizon. The ERG explained that the company had presented 1 cost-effectiveness analysis for the entire indicated population for lutetium-177. Only the comparator was different across subgroups (see section 3.6). The committee also noted that the quality-adjusted life years (QALYs) were accrued from people living longer, with a better quality of life while having lutetium-177. The committee acknowledged the uncertainties in the model, which included some model corrections by the ERG. It concluded the model was suitable for decision making.

Real-world evidence to estimate survival with cabazitaxel is appropriate but a network meta-analysis should inform relative treatment effect

• 3.13 The company acknowledged that its network meta-analysis had limitations in estimating the relative treatment effect for lutetium-177 compared with cabazitaxel. So, the company did a retrospective real-world evidence study. This combined data from 5 UK databases and aligned the population with a population with hormone-relapsed metastatic prostate cancer after an anti-androgen and a taxane. In its submission, the company estimated overall survival with cabazitaxel from its real-world

Appraisal consultation document – Lutetium-177 vipivotide tetraxetan for treating PSMA-positive hormonerelapsed metastatic prostate cancer after 2 or more treatments Page 17 of 28

CONFIDENTIAL UNTIL PUBLISHED

evidence study. The clinical experts thought that, because the data from the real-world evidence study reflected clinical practice, it was likely to better represent overall survival and be the best source of data. But results from this study gave a median overall survival with cabazitaxel that was less than that in the standard-care arm in VISION. The ERG thought that this lacked face validity. It added that treatment sequencing and previous response to anti-androgen may be associated with the treatment effect of cabazitaxel. The committee agreed that the real-world evidence study was a useful data source, and provided a measure of survival representative of NHS clinical practice. The company’s propensity score weighting analysis (that adjusted for baseline characteristics between VISION and the real-world evidence study) showed similar results to the unadjusted analysis. But the ERG had concerns that the prognostic covariates had not been selected appropriately, and highlighted the importance of the effects of differences in patient populations. It suggested using the real-world evidence study as a reference group. It also suggested applying a hazard ratio from its network meta-analysis to estimate overall and radiographic progression-free survival for cabazitaxel and lutetium-177 for people having cabazitaxel in clinical practice. In addition, the ERG suggested using the real-world evidence study to find out the lines of treatment of cabazitaxel used in clinical practice, and time to progression with an anti-androgen. The committee agreed that using a naive comparison between lutetium-177 and cabazitaxel increased uncertainty and potential bias into the estimates. It also agreed that there was uncertainty whether the company’s adjusted analysis effectively accounted for all possible confounding variables. So, it preferred using data from the real-world evidence study to estimate the absolute event estimates for cabazitaxel and applying a hazard ratio from the network meta-analysis to estimate the relative effect for survival for lutetium-177. The committee concluded that using the real-world evidence study was appropriate for estimating survival for people having cabazitaxel. But it thought that the relative treatment effect compared with lutetium-177

Appraisal consultation document – Lutetium-177 vipivotide tetraxetan for treating PSMA-positive hormonerelapsed metastatic prostate cancer after 2 or more treatments Page 18 of 28 Issue date: October 2022

CONFIDENTIAL UNTIL PUBLISHED

should come from the proposed re-analysed network meta-analysis, if appropriate (see section 3.11).

Health-related quality of life

The utility estimates are uncertain

• 3.14 In its model, the company preferred to use treatment-dependent utility values, before and after progression. This was to capture the tolerability and side effects of chemotherapy, and the psychological effects of having cabazitaxel. The company estimated values for lutetium-177 and standard care using a generalised linear mixed model fitted to EQ-5D-3L estimates mapped from EQ-5D-5L data collected in VISION. The model included terms for treatment assignment, progression status and the interaction between them. Because the interaction term was statistically significant, the company concluded it was appropriate to stratify quality of life according to treatment as well as progression status. For cabazitaxel, the company used the utility value from NICE’s technology appraisal guidance on cabazitaxel for hormone-relapsed metastatic prostate cancer treated with docetaxel for the postprogression state. But the company did not use the value from this technology appraisal for the preprogression health state with cabazitaxel, which was higher than it had estimated for lutetium177. Instead, it assumed that utility with cabazitaxel would be the same as with standard care until progression. The ERG preferred treatmentindependent utility values, before and after progression. This was because of:

  • a lack of face validity using treatment-dependent utilities

  • for consistency across treatments

  • to avoid introducing bias because of the high proportion of withdrawal rates in the VISION standard-care arm in which people had higher baseline health-related quality of life.

The ERG described that the utility values used by the company suggested

a lower health-related quality of life after progression when having Appraisal consultation document – Lutetium-177 vipivotide tetraxetan for treating PSMA-positive hormonerelapsed metastatic prostate cancer after 2 or more treatments Page 19 of 28 Issue date: October 2022

CONFIDENTIAL UNTIL PUBLISHED

cabazitaxel compared with best supportive care and lutetium-177. Also, the health-related quality of life with lutetium-177 after progression was greater than that with cabazitaxel before progression. Because this did not have face validity, the ERG provided an additional exploratory analysis. This used treatment-dependent utilities and assumed the utility value for cabazitaxel was the average between the lutetium-177 and cabazitaxel utilities. The ERG added that information from the UK Early Access Programme suggested that utilities may be stable for cabazitaxel after previously progressing on docetaxel, before and after progression. Also, the ERG suggested that, after considering adverse events, it was unlikely for cabazitaxel utility to be less than that for standard care. The clinical and patient experts explained that best supportive care and cabazitaxel can be associated with a high psychological burden. This is because of previous progression on a taxane or not having active treatment. The committee agreed that within-state differences were possible. It also agreed that lutetium-177 utility may be higher than that for cabazitaxel and standard care, even for people at the same stage of cancer progression. The ERG highlighted the potential for informative censoring when analysing the EQ-5D-5L data (see section 3.8). This was because people who withdrew from the control arm of VISION had greater baseline quality of life than people who continued. This meant that the quality-of-life estimates for standard care were likely underestimated. The committee considered whether it was possible to adjust for withdrawal in the healthrelated quality-of-life results. It considered that it may have been possible to apply inverse probability censoring weighting analyses to account for withdrawals. If there was still a meaningful difference in results between treatments, the uncertainty of using treatment-dependent utility values would be reduced. The committee concluded that all the utility values had uncertainty, although treatment-independent utilities had higher face validity across all treatments. It agreed that it preferred to see a scenario analysis to address the uncertainty.

Appraisal consultation document – Lutetium-177 vipivotide tetraxetan for treating PSMA-positive hormonerelapsed metastatic prostate cancer after 2 or more treatments Page 20 of 28 Issue date: October 2022

CONFIDENTIAL UNTIL PUBLISHED

Costs in the model

The costs of PSMA testing for the whole population need to be included in the cost-effectiveness estimates

• 3.15 The cost-effectiveness estimates did not include the cost of PSMA testing (see section 3.3). The committee noted that the cost should have accounted for PET-CT or SPECT scans and radiotracers. The number of people needing PSMA imaging is likely to be between 100% (if everyone needs a new scan to determine eligibility) and 25% (if 75% of people have a scan as part of standard care and no additional imaging is needed) . The committee recalled that the summary of product characteristics for lutetium-177 notes that the eligibility for treatment should be assessed using PSMA imaging. So, it concluded that the costs of PSMA testing should have been included, as per the NICE scope, in the base-case estimates for the entire population. It also thought that scenarios on the effect of up to 75% of people having either a PET-CT or SPECT scan should be explored. In addition, the cost should reflect the proportion of PSMA-positive cancer in the relevant population, to account for PSMAnegative cancer.

Costs that reflect NHS clinical practice should be used in the modelling

• 3.16 The company and ERG had different views on the treatment duration of granulocyte-colony stimulating factor (G-CSF) used in the model. In its original submission, the company used the cost of 14 days of treatment per 21-day cycle of cabazitaxel. After technical engagement, it updated this to 9 days. The ERG preferred to use 5 days and provided an exploratory analysis using 7 days. The clinical lead for the Cancer Drugs Fund commented that the NHS commissions 5 to 7 days of G-CSF for different cancers across the NHS. But they noted that variation may occur. The clinical experts added that a minimum of 10 to 14 days should cover the 21-day cycle of cabazitaxel, and that American Society of Clinical Oncology guidelines recommend 14 days. This is because of a high risk

of neutropenia for people having chemotherapy. But they noted that there

Appraisal consultation document – Lutetium-177 vipivotide tetraxetan for treating PSMA-positive hormonerelapsed metastatic prostate cancer after 2 or more treatments Page 21 of 28

CONFIDENTIAL UNTIL PUBLISHED

is a difference between using filgrastim and pegylated filgrastim. The committee noted that 7 days of prophylactic G-CSF in the cabazitaxel arm was used in the NICE technology appraisal guidance on NICE’s technology appraisal guidance in development on olaparib for treating - previously treated, hormone relapsed, metastatic prostate cancer with homologous recombination repair gene mutations. It concluded that 7 days of G-CSF treatment should have been used because this is the maximum commissioned by the NHS and would account for variations in clinical practice.

Premedication and concomitant medication costs for cabazitaxel used by the ERG are preferred and better represent NHS practice

• 3.17 After technical engagement, there were some outstanding issues around premedication and concomitant medication costs for cabazitaxel identified by the ERG. These included:

  • premedication and concomitant treatment costs

  • administration costs for oral concomitant treatments as part of standard care

  • erythropoietin stimulating agents (ESAs) and G-CSF unit costs

  • the mean number of doses of lutetium-177 calculated from the mean duration of treatment rather than from data on the distribution of dose numbers in the clinical study report.

The company assumed that premedications (that is, antihistamines, H2-receptor antagonists and corticosteroids) were taken orally for the duration of cabazitaxel treatment. The ERG preferred that premedications were administered intravenously on the day of cabazitaxel treatment. It also included granisetron, metoclopramide, and prednisone or prednisolone as part of the treatment regimen. The company also applied Health State Resource Group costs for oral chemotherapy to lutetium177, standard care and cabazitaxel. The ERG determined that these costs were likely captured by outpatient visits because they are likely to be

Appraisal consultation document – Lutetium-177 vipivotide tetraxetan for treating PSMA-positive hormonerelapsed metastatic prostate cancer after 2 or more treatments Page 22 of 28 Issue date: October 2022

CONFIDENTIAL UNTIL PUBLISHED

prescribed as part of routine care. The clinical lead for the Cancer Drugs Fund agreed with the ERG that these costs are already applied. The company clarified that a one-time oral chemotherapy cost was applied to each treatment. This was to account for the costs of training people on concomitant medications, and to align with NICE’s technology appraisal guidance in development on olaparib for treating previously treated, hormone-relapsed, metastatic prostate cancer with homologous recombination repair gene mutations. The company and ERG applied different unit costs for ESAs and G-CSF based on the strength and pack size. The ERG’s costs included fewer administrations of ESAs and a lower cost for G-CSF. The clinical experts clarified that ESAs are not generally used for people having cabazitaxel unless needed. The committee concluded that the ERG’s costs included in the model should have better reflected NHS practice.

Cost-effectiveness estimate

Lutetium-177 is not a cost-effective option for hormone-relapsed

metastatic prostate cancer at the price chosen by the company

• 3.18 NICE’s guide to the methods of technology appraisal notes that, above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per QALY gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. Because of the confidential commercial arrangements for lutetium-177, cabazitaxel and other postprogression treatments, the costeffectiveness estimates cannot be reported here. The committee noted the high level of uncertainty in the cost-effectiveness estimates, specifically that:

  • the cost of PSMA testing was not included in the modelling

Appraisal consultation document – Lutetium-177 vipivotide tetraxetan for treating PSMA-positive hormonerelapsed metastatic prostate cancer after 2 or more treatments Page 23 of 28 Issue date: October 2022

CONFIDENTIAL UNTIL PUBLISHED

• there was no evidence comparing lutetium-177 with radium-223 dichloride for people with symptomatic bone metastases only

• there was no clinical evidence for when taxanes are medically unsuitable because this population was excluded from VISION

• the levels of withdrawal from VISION were high

• there was high uncertainty in the network meta-analyses

• there was uncertainty in modelling overall survival for cabazitaxel

• there was uncertainty in the utility estimates.

To address the committee’s preferred assumptions, several new analyses would be needed. These are:

• including the cost of PSMA testing, as per the NICE scope for this appraisal for 100% of people having treatment with lutetium-177, and scenarios of up to 75% of people having a PSMA PET-CT or SPECT scan (see section 3.3 and section 3.15)

• scenarios when taxanes are medically unsuitable in which a higher baseline risk, so a worse overall survival, is modelled but with the same relative treatment effect as for the wider population (see section 3.6)

• a subgroup analysis comparing lutetium-177 with radium-223 dichloride when there is symptomatic bone metastases only and no known visceral metastases (see section 3.5)

• inverse probability of censoring weighting-adjusted estimates from VISION used in the network meta-analyses (see section 3.8 and section 3.11)

• exploring the use of all studies in the network meta-analysis in a baseline risk-adjusted model and, if appropriate, using this for all subsequent analyses (see section 3.10 and section 3.11)

• using real-world evidence on survival with cabazitaxel as a reference group for the absolute event estimates, and applying a hazard ratio from the network meta-analysis to estimate survival for lutetium-177 for the relative estimates (see section 3.13)

Appraisal consultation document – Lutetium-177 vipivotide tetraxetan for treating PSMA-positive hormonerelapsed metastatic prostate cancer after 2 or more treatments Page 24 of 28 Issue date: October 2022

CONFIDENTIAL UNTIL PUBLISHED

• adjusting health-related quality-of-life results by applying an inverse probability of censoring weighting analysis to account for withdrawals (see section 3.14)

• using the ERG’s costs in the model because they are more

representative of NHS practice (see section 3.16 and section 3.17).

End of life

Lutetium-177 meets the end of life criteria compared with standard care but comparison with cabazitaxel is uncertain

• 3.19 The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE’s guide to the methods of technology appraisal. The company proposed that lutetium-177 does meet the end of life criteria based on:

  • it being indicated for people with a short life expectancy (that is, less than 24 months)

  • there being sufficient evidence that it can offer an extension to life (that is, a mean value of at least 3 months).

In VISION, the median overall survival was 15.3 months for lutetium-177 compared with 11.3 months for standard care. The comparison of lutetium-177 with cabazitaxel also showed an increase in overall survival, but the results are confidential and cannot be reported here. The ERG agreed that the short life-expectancy criterion was met for people with hormone-relapsed metastatic prostate cancer after an anti-androgen and taxane-based chemotherapy. But it thought that the extension to life criterion was only met for the comparison of lutetium-177 with best supportive care. The committee agreed that the end of life criteria were likely met for the comparison with best supportive care. But it did not see the preferred estimates of lutetium-177 compared with cabazitaxel. It also did not see any evidence on the comparison of lutetium-177 with

radium-223 dichloride. So, it could not assess whether the end of life

Appraisal consultation document – Lutetium-177 vipivotide tetraxetan for treating PSMA-positive hormonerelapsed metastatic prostate cancer after 2 or more treatments Page 25 of 28 Issue date: October 2022

CONFIDENTIAL UNTIL PUBLISHED

criteria were met for this. It concluded that an updated model and survival estimates are needed for it to be able to assess whether lutetium-177 meets end of life criteria compared with all comparators.

The cost-effectiveness estimates for lutetium-177 are uncertain but suggest that it is not cost effective

• 3.20 The committee recalled high uncertainty in the results from the company’s cost-effectiveness modelling and estimates using the end of life criteria. It noted modelling for cabazitaxel was particularly uncertain as there was no direct treatment comparison. It concluded that the most likely cost effectiveness of lutetium-177 compared with standard care and cabazitaxel were considerably above the level that NICE normally considers an acceptable use of NHS resources. This was even if the end of life criteria were applicable.

Cancer Drugs Fund

Lutetium-177 is not suitable for use in the Cancer Drugs Fund

• 3.21 The committee considered whether lutetium-177 could be recommended for use within the Cancer Drugs Fund. It discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, ’

• noting NICE s Cancer Drugs Fund methods guide (addendum). The company indicated that it may explore a managed access route for the subgroup for whom taxanes are not medically suitable. But the costeffectiveness estimates for lutetium-177 were above that considered an effective use of NHS resources. So, the committee concluded that it could not be considered for use in the Cancer Drugs Fund.

Other factors

There are no equality issues to address in this technology appraisal

• 3.22 The marketing authorisation for lutetium-177 includes people for whom taxanes are medically unsuitable. The committee noted that on average

Appraisal consultation document – Lutetium-177 vipivotide tetraxetan for treating PSMA-positive hormonerelapsed metastatic prostate cancer after 2 or more treatments Page 26 of 28 Issue date: October 2022

CONFIDENTIAL UNTIL PUBLISHED

this group may be older than people who can have a taxane. The committee recalled that it would look at all relevant subgroups within the marketing authorisation (see section 3.6), so its recommendation for lutetium-177 was not affected by this. It concluded that its recommendation for lutetium-177 would not have a different effect on people protected by the equality legislation than on the wider population.

Lutetium-177 is not innovative beyond what is captured in the cost-

effectiveness estimates

• 3.23 The company describe lutetium-177 as innovative because it:

  • offers a targeted approach to treating hormone-relapsed metastatic prostate cancer

  • has a different mechanism of action (as a radioligand) than other treatments for prostate cancer

  • addresses an unmet need.

The committee acknowledged the innovative aspects of lutetium-177. But it concluded that there were no additional benefits associated with it that had not been captured in the cost-effectiveness estimates.

Conclusion

Lutetium-177 is not recommended

• 3.24 The committee did not see cost-effectiveness estimates using its preferred modelling assumptions or within the range considered an acceptable use of NHS resources. So, it concluded that it could not recommend lutetium-177 for treating PSMA-positive hormone-relapsed metastatic prostate cancer.

Appraisal consultation document – Lutetium-177 vipivotide tetraxetan for treating PSMA-positive hormonerelapsed metastatic prostate cancer after 2 or more treatments Page 27 of 28 Issue date: October 2022

CONFIDENTIAL UNTIL PUBLISHED

4 Appraisal committee members and NICE project team

Appraisal committee members

The 4 technology appraisal committees are standing advisory committees of NICE. This topic was considered by committee B.

Committee members are asked to declare any interests in the technology to be

appraised. If it is considered there is a conflict of interest, the member is excluded from participating further in that appraisal.

The minutes of each appraisal committee meeting, which include the names of the members who attended and their declarations of interests, are posted on the NICE website.

Chair

Baljit Singh

Chair, appraisal committee

NICE project team

Each technology appraisal is assigned to a team consisting of 1 or more health technology analysts (who act as technical leads for the appraisal), a technical adviser and a project manager.

Summaya Mohammad

Technical lead

Lorna Dunning

Technical adviser

Thomas Feist

Project manager

ISBN: [to be added at publication]

Appraisal consultation document – Lutetium-177 vipivotide tetraxetan for treating PSMA-positive hormonerelapsed metastatic prostate cancer after 2 or more treatments Page 28 of 28 Issue date: October 2022