Belzutifan for treating tumours associated with von Hippel-Lindau disease

Von Hippel-Lindau disease (from now, VHL) is caused by a mutation in the VHL gene. This gene is responsible for producing a protein that controls cell growth. A mutation in the gene can cause cells to grow abnormally, leading to cysts or tumours developing in different parts of the body, such as the kidneys, brain and pancreas. This can lead to renal cell carcinoma (RCC), central nervous system haemangioblastomas (CNS Hbs) and pancreatic neuroendocrine tumours (pNETs). The patient experts explained that the experience of living with VHL varies from person to person. Some people with the condition might only develop 1 or a few tumours in their whole life, while others might have multiple tumours in different organs. There are also a wide variety of debilitating symptoms depending on tumour sites. These include constant pain, loss of balance and motor skills, loss of vision, breathlessness, coughing, headaches, confusion, severe nausea and fatigue. Scans before appointments can cause anxiety and people also worry about disability caused by surgery. The clinical experts stated that, with more effective treatment, there is potential for people with the condition to live longer and have a better quality of life. Also, the patient experts' statement highlighted that caring for a family with VHL is emotionally challenging and has a psychological effect. The patient experts explained that carers are often the family members of people with VHL. They worry that they are not able to help, and have to live with the constant worry that they also carry the gene for VHL and may pass it on to their children and grandchildren. The committee understood that people with VHL often have difficulty doing day-to-day tasks, and fear surgery. Also, the condition can have a negative effect on self-esteem and cause relationship difficulties. Survival with VHL has improved over time, and has become closer to that of siblings without VHL and the general population. Life expectancy for men with VHL is about 67 years and for women is about 60 years. The committee noted that living with the condition and caring for people with VHL is physically and emotionally challenging. It concluded that VHL is a highly heterogeneous condition, and has considerable physical and emotional effects from repeated surgeries and anxiety from scans.

Surgery and other localised procedures are the main treatment options for people with VHL, but sometimes they are not appropriate. The clinical and patient experts explained that there is an unmet need for effective new treatments for people with VHL when surgery is unsuitable. They explained that people often have repeated surgeries throughout their life, and this is the only way to remove VHL tumours. Because of this, people may lose their eyes, a part of or a whole kidney, or their pancreas. They may also develop neurological issues such as paralysis after spine or brain surgery or may need lifelong medical intervention such as dialysis. The patient experts explained that avoiding multiple surgeries could greatly improve physical and mental wellbeing, and improve quality of life for both people with VHL and their carers. The committee noted that there is an unmet need for treatments that could improve outcomes and quality of life for people with VHL. It concluded that the current unmet need could be addressed by belzutifan because it has the potential to preserve or delay the loss of organ function and the associated morbidity.

The patient and clinical experts explained that there is no treatment that addresses the underlying cause of VHL. It is a heterogeneous condition and clinical management usually is done by a multidisciplinary team. They explained that VHL management starts with diagnosis through genetic counselling or de novo testing. This is followed by regular surveillance by genetics services. Surveillance aims to detect tumours and monitor tumour growth. MRI or ultrasound examinations of the abdomen are done every 12 months for RCC tumours and pNETs. For CNS hemangioblastomas, MRI scans of the head are done every 12 to 36 months. If VHL-associated tumours need treatment, interventions are generally based on a specific threshold. The clinical experts explained that RCC tumours are kept under surveillance until they reach a diameter of 3 cm, and pNETs until they have a diameter of 2 cm. At this stage, the risk of metastasis exceeds the benefit of organ preservation and surgery can be recommended. Surgery for CNS Hb is normally needed when the tumours grow to a size that causes symptoms. The patient experts explained that standard care varies, and focuses on preventing tumour growth and metastasis while preserving organ function. The clinical experts explained that surgery is highly effective in most cases for all VHL tumours, with the most benefit for VHL-associated RCC. But surgery can result in organ loss after multiple surgeries or morbidity, depending upon the primary VHL-associated tumour. The clinical experts also explained that some people have VHL tumours that have grown to an extent that localised procedures are unsuitable or undesirable. This might be because of an increased risk of loss of organ function or risks from the procedures. These include people with:

• RCC: expected surgery that would result in bilateral nephrectomy and the need for dialysis

• pNETs: expected surgery that would result in pancreatectomy (or pancreaticoduodenectomy, also known as the Whipple surgery) and that may lead to long-term morbidities such as diabetes

• CNS Hb: expected surgery with a high risk of complications (such as tumours at the craniospinal junction) that could result in neurological deficit or paralysis.

The company's trial population was at a different position in the treatment pathway than that in NICE's final scope on belzutifan for treating tumours associated with VHL disease and the marketing authorisation. The marketing authorisation population consists of adults with VHL who need treatment for VHL‑associated RCC, CNS Hb, or pNETs, and for whom localised procedures are unsuitable or undesirable. In contrast, the company's main clinical trial (MK‑6482‑004) included people who:

• had at least 1 more measurable VHL‑associated RCC only (could have other tumours), and

• did not need imminent surgery and may have had pNETs or CNS Hbs.

The clinical-effectiveness evidence for belzutifan came from MK‑6482‑004. This was a multicentre single-arm open-label phase 2 study. It included 61 people with VHL with at least 1 measurable RCC tumour. Fifty of them also had CNS Hbs and 22 also had pNETs. The primary outcome of MK‑6482‑004 was the objective response rate (complete response or partial response). The secondary outcomes were disease control rate, duration of response, time to response, progression-free survival and time to surgery. At the latest data cut (April 2022), the objective response rate was 63.9% for RCC (95% confidence interval [CI]: 50.6% to 75.8%), 44% for CNS Hbs (95% CI: 30.0% to 58.7%) and 90.9% for pNETs (95% CI:70.8% to 98.9%). This was assessed using the Response Evaluation Criteria in Solid Tumours 1.1 criteria. Disease control rate (complete response, partial response or stable disease) was 98.4% for RCC (95% CI: 91.2% to 100.0%), 90.0% for CNS Hbs (95% CI: 78.2% to 96.7%) and 100% for pNETs (95% CI: 84.6% to 100.0%). The median time to response for RCC was 11.1 months. Progression-free survival results are considered confidential by the company and cannot be reported here. The committee concluded that belzutifan was likely to be clinically effective in reducing tumour size and so the need for surgery. It noted that there was some uncertainty about how tumour size relates to symptom burden in CNS Hb. The committee also noted the time needed for the response was 11.1 months for RCC. It considered this in terms of the positioning of belzutifan and that assessing whether surgery is needed may be challenging to predict in clinical practice.

Because MK‑6482‑004 was a single-arm study, the company used data from a VHL natural history study to inform the comparative effectiveness of the standard care comparator. This study was a retrospective non-interventional study of existing medical records with supplemental electronic medical record data abstraction and review of abdominal imaging scans done during routine clinical care in a cohort of people in the US. It included people with at least 1 VHL‑associated RCC tumour measured during the study period. They also had to meet other VHL natural history study eligibility criteria that were identified and followed until the end of the assessment window (July 31 2004 to June 30 2020). The EAG noted that comparative effectiveness results derived from VHL natural study data did not:

• represent the population in the belzutifan's marketing authorisation

• collect the appropriate data to address the population of interest.

The company focused on collecting outcomes such as time to response, progression-free survival, time to surgery and overall survival. MK‑6482‑004 and the VHL natural history study were used to compare the outcomes of treatment with belzutifan with the outcomes in standard care to inform the model. The committee noted that these outcomes are not the same as those used in standard NICE cancer topic evaluations. The committee noted that time to surgery (a key model transition) represented a highly heterogeneous outcome that depended on several factors, such as:

• size and location of tumours

• symptom development

• the overall health of the person with VHL.

The relative treatment effects of belzutifan compared with standard care were derived from an indirect treatment comparison (ITC) using the propensity-score weighting-based MAIC methods. This used individual patient data from the VHL natural history study to match baseline characteristics with the MK-6482-004 trial. After matching, this made it easy to compare outcomes because the populations were likely to be more balanced. The company compared the results of MK‑6482‑004 and collected data for the standard care arm of the cost-effectiveness model. It did this by selecting a subgroup population from the VHL natural history study that matched MK‑6482‑004's inclusion and exclusion criteria. The committee noted that, for the comparison with standard care, the company did a series of adjustments, specifically:

• Kaplan–Meier curves were fitted to the VHL natural history study (standard care) and the MK‑6482‑004 trial data.

• The fitted Kaplan–Meier curves from the VHL natural history study data were then adjusted using MAIC to match the population in MK‑6482‑004 based on variables such as age, gender, previous surgeries and tumour size.

• Time to surgery, second surgery and metastasis in the VHL natural history study were adjusted to reflect a less active surveillance. This was because the company considered that the standard care seen in the VHL natural history study cohort may have been better than that routinely provided in UK clinical practice.

• An additional assumption that 90% of people with RCC or pNETs, and 50% of people with CNS Hbs, have immediate surgery was then applied.

The company used a Markov model structure to estimate the cost effectiveness of belzutifan compared with standard care. The model included 5 health states: presurgery, surgery, event-free after surgery, metastatic disease (pre progression and post progression) and death. The model had a lifetime horizon (59 years) and weekly cycle length. In the company's model, people started at age 41 years in the presurgery health state reflecting the treatment decision point. From there, they could transition to surgery, metastatic disease or death health states. The committee questioned the company for using a starting age of 41 years. This was because the marketing authorisation population was likely to have had many more surgeries and was much later in the treatment pathway. The EAG considered the company's model structure was appropriate for only the RCC cohort, but it noted a high level of uncertainty, specifically:

• There was an overlap in the data informing input parameters for the 3 cohorts.

• The rate of surgeries (moving from presurgery to surgery) was based on surgeries for the primary tumour. But it was not clear from the trial and the VHL natural history study whether the data used to specify these rates related to the treatment of primary tumour.

• Including people for whom surgery is not suitable but who would have it immediately as a 'last resort' in the standard care arm only was not appropriate.

The company assumed that people would stay on belzutifan until VHL progressed or until they had side effects. It used time on treatment data from MK‑6482‑004 to model time on treatment with belzutifan. The committee noted that almost half of the people who stopped belzutifan in the trial were reported to have done so through choice. A minority who were reported as stopping stated reasons of progression or side effects. The company explored different parametric fits to the patient level time on treatment data (exponential, Gompertz, log-logistic, log-normal, gamma generalised gamma and Weibull) using patient-level data from MK‑6482‑004. The company preferred using the Gompertz-based model that was based on statistical fit, visual inspection and clinical relevance in its base case. The company also explored the effect of using the second-best (Weibull) model in the scenario analysis. The EAG explained that there was uncertainty in the long-term extrapolations of this data. The committee noted that it was unclear why a high proportion of people stopped treatment for the stated reason of choice. It thought that this may not be generalisable to the population of interest in the company's model. This was because the alternative for people stopping treatment would be surgery resulting in organ loss, as assumed by the company in its model. So, the committee concluded it would have preferred to see the modelling using belzutifan continued until progression or until side effects because this would more closely match the target population.

The committed noted that, because of uncertainties in the modelled time on treatment, the company's model incorporated a treatment effect waning using 'off-treatment' health states. Transition probabilities from the 'off-treatment' health states were assumed to gradually converge to the respective values in the standard care arm based on data from the VHL natural history study. The company assumed treatment waning occurs gradually over 2.71 years (the amount of time until the largest RCC tumour reaches the baseline levels of growth) from the end of the maximum follow-up (3.84 years). It also assumed that tumour growth would return to baseline level at an average rate of 3.52 mm per year after stopping. The same assumption was used for CNS Hbs and pNETs. The EAG explained that the duration of assumed residual benefit over a period of 2.71 years might be appropriate for RCC but could be different for CNS Hbs and pNETs. The committee noted that treatment waning might be appropriate because of the tumour size reduction seen in MK‑6482‑004. But it reiterated that there were concerns around the generalisability of the data for the population of interest. The committee concluded that it would like to have seen extensive sensitivity analyses and testing alternative assumptions on the treatment waning of effect across the tumour types.

In MK‑6482‑004, no health-related quality-of-life data was collected. The committee noted that the company used health-state utility values in the economic model. These were derived from the VHL real-world quality-of-life disease burden study and a trial of pembrolizumab in the adjuvant treatment of RCC (KEYNOTE‑568). It considered the utility values to be mostly appropriate but noted that these were not measured in the population of interest. The company's model also applied disutilities from tumour-associated surgeries and surgical complications (including loss of organ function). The company used a variety of sources to derive disutility values for long-term and short-term complications, including the VHL real-world quality-of-life disease burden study and published literature. The committee noted that the company had used an additive approach to adjust disutility values in the model. It considered that the disutility values adopted by the company for long-term complications of surgery may have lacked face validity. The committee also noted that the multiplicative method is a preferred approach for combining disutilities, in line with NICE's health technology evaluations manual. It considered that the outputs of the effective utility loss for people after surgery were uncertain. The committee was aware that some of the utility decrements the company used to represent the long-term consequences of surgery were large. It noted that people having dialysis had a utility value of -0.527. This is much larger than the estimates seen in the literature and the values used in NICE's guidelines on renal replacement therapy and conservative management and chronic kidney disease. The committee understood that the company had derived the disutility values by deducting estimates of quality of life on dialysis from 1. The committee agreed that this approach was not appropriate because it effectively assumes that, if people were not on dialysis, they would be in perfect health. It noted that some of the health-related quality-of-life impact was double-counted, for example, separate disutilities for 'stroke' and 'neurological complications' were applied in the model. The committee considered that there was a more appropriate approach would be to calculate a relative utility impact. This would be done by comparing an absolute estimate of utility on dialysis with an age- and sex-matched expectation from the general population. The committee concluded that the total effective utility loss after surgery should have been calculated using a multiplicative method. It added that this should have been validated against literature for similar outcomes (such as end-stage renal disease, post pancreatectomy and neurological damage). It should also have taken account of any additional consideration for people with VHL.

The committee may apply a greater weight to quality-adjusted life years (QALYs; a severity modifier) if technologies are indicated for conditions with a high degree of severity. So, the committee considered the severity of VHL, that is, the future health lost by people living with the condition and having standard care in the NHS. The company provided absolute and proportional QALY shortfall estimates for all VHL cohorts in line with NICE's health technology evaluations manual. In its analyses, the proportional QALY shortfall was above 0.95 for RCC and CNS Hbs and below 0.95 for pNETs. So, a severity weight of 1.7 was applicable for RCC and CNS Hb and of 1.2 for pNETs. The company explained that in clinical practice or the real world, not all VHL cohorts are distinct from each other. People in MK‑6482‑004 had more than 1 tumour manifestation (see section 3.5), and pNET is associated with high mortality and morbidity because of pancreatic surgery. So, the company applied a QALY weighting of 1.7 to all 3 VHL cohorts. Based on the QALYs generated from the company's model, the company and EAG agreed that, for RCC and CNS Hbs, the QALY weighting 1.7 was applicable. But the EAG considered it inappropriate to apply the QALY weighting of 1.7 for pNETs. The committee acknowledged the substantial impact of VHL. The committee also noted that both the company's and the EAG's analyses were subject to a high degree of uncertainty because of the underlying assumptions adopted for modelling standard care. The committee concluded it was unable to apply an appropriate severity weight based on the calculations presented by the company because of uncertainty in its underlying assumptions.

The committee noted that the company had not provided data on the effectiveness of belzutifan for the marketing authorisation population (see section 3.5). The committee recalled that there were issues with the ITC and the company's model, which needed resolving before it could be considered suitable for decision making. The committee was aware that the EAG was unable to define its base case because of uncertainties in the evidence and assumptions made in the model. In particular, the committee noted the high level of uncertainty in the following areas, in which it would like to see further analyses and exploration by the company:

• the evidence for the generalisability of the MK‑6482‑004 population to the marketing authorisation population (see section 3.5)

• the ITC approach and using the propensity-score weighting method, which were highly uncertain, with alternative methods explored (see section 3.9)

• the uncertainty in the model input parameters and assumptions and uncertainties in the model outputs (see section 3.10)

• modelled time on treatment for belzutifan until progression or until side effects (see section 3.11)

• extensive sensitivity analyses and testing alternative assumptions on the treatment waning effect across the tumour types (see section 3.12)

• the uncertainty in the company's approach to surgery-associated disutility values, with an exploration of the multiplicative approach and use of validated disutility values against literature for similar outcomes (see section 3.13).

Having concluded that belzutifan could not be recommended for routine use in the NHS, the committee then considered whether it could be recommended within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund technology appraisal process and methods guide (addendum). The committee recognised that people with VHL have a high unmet need, and the availability of new treatment for VHL is very important. The committee was aware that the company had expressed an interest in being considered for funding through the Cancer Drugs Fund in its submission. This was because of acknowledged uncertainties and lack of data directly relevant to the decision problem. The committee recognised that belzutifan is innovative and its use in clinical practice would help address unmet needs. But it also noted that it had not been presented with sufficient evidence of the plausible potential for belzutifan to be considered a cost-effective use of NHS resources. This was because of considerable uncertainties relating to relative treatment effectiveness and assumptions used in the model. The committee also noted that the Cancer Drugs Fund may provide the opportunity to collect additional data to address some uncertainties about belzutifan's efficacy in clinical practice. But it thought that whether this would provide data to address the issues of its comparative effectiveness compared with standard care was uncertain. So, the committee concluded that belzutifan did not meet the criteria to be considered for inclusion in the Cancer Drugs Fund.

The committee noted that, because VHL is a genetic condition, some families are disproportionately affected. The condition can affect people when they are very young. It also noted that people from deprived areas, with language, learning or cultural barriers, or those with disabilities may be at a disadvantage. The committee agreed that, if belzutifan were recommended, the recommendation would not restrict access for some people over others. No other equality or social value judgment issues were identified.

The company considered belzutifan to be innovative for treating VHL in people with a very high unmet need. The company explained that belzutifan got regulatory approval through the Medicines and Healthcare Products Regulatory Agency Innovative Licensing and Access Pathway, which is reserved for innovative medicines. The clinical experts also considered belzutifan a step change for VHL treatment because it can stop or even turn back the growth of tumours. They also explained that belzutifan helps avoid surgeries, lowers the risk of metastasis and reduces the need for dialysis. The committee acknowledged the benefits offered by belzutifan. It considered that it was uncertain whether these had been fully captured in the model, given the uncertainties in the evidence and use of several assumptions in the model. The committee concluded that belzutifan could offer some additional benefits, including reduced anxiety associated with scans and fear of disability for people with VHL and their caregivers. But it noted that it had not been presented with evidence of any additional benefits specific to belzutifan that were not captured in the measurement of the QALY.

The committee's concerns about the clinical evidence and cost-effectiveness model meant that it was not confident about the results presented. It concluded that it would like the uncertainties to be addressed and that belzutifan could not be recommended.