Vorasidenib for treating astrocytoma or oligodendroglioma with IDH1 or IDH2 mutations after surgery in people 12 years and over

Gliomas are the most common type of brain tumour. They develop from the glial cells that support the nerve cells of the brain and spinal cord. Gliomas are classified by how quickly they grow. Most gliomas are grade 1 or 2 at diagnosis, referred to as low-grade glioma (LGG), and do not grow or only grow slowly. Grade 3 and 4 gliomas, referred to as high-grade glioma (HGG), grow quickly. Consequently, HGG is associated with worse outcomes than LGG. Up to 70% of LGGs may progress to high grade or become malignant within 10 years. The 3 main types of glioma in adults are astrocytoma, oligodendroglioma and ependymoma. Key genetic alterations in gliomas include mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes, which are involved in cell metabolism, and a chromosome alteration known as a 1p/19q codeletion. Gliomas with a 1p/19q codeletion or IDH mutation are thought to grow more slowly than gliomas without these alterations.

Symptoms of IDH-mutant astrocytoma and oligodendroglioma (from here, referred to as LGG) include headaches, seizures, difficulty thinking or remembering and changes in vision. Patient-organisation submissions highlighted the large impact on quality of life of living with LGG, which affects social life, education and work. The physical symptoms of the condition can be challenging, especially seizures, which can cause anxiety and affect independence by limiting the ability to drive. Living with an incurable and slowly progressing condition can also have a large mental impact on people with the condition, their families and carers. The patient expert at the meeting explained that the fear of inevitable progression of the disease can considerably affect quality of life. The committee noted that some people are diagnosed with LGG in their 20s, 30s, and 40s and so may have young families. This can increase the burden on carers who are often the sole financial provider. There are also practical challenges in providing support for people with LGG, which can lead to exhaustion for carers. The committee concluded that LGGs are slowly progressing conditions that significantly impact the lives of people affected, their families and carers.

The clinical experts explained that the aims of treatment for glioma include delaying progression and improving neurological function and quality of life. Section 1.2 of NICE's guideline on primary brain tumours and brain metastases in over 16s (NG99) recommends maximal safe surgical resection as first-line treatment for LGG. The clinical experts at the meeting explained that post-surgical outcomes determine the next treatment offered. People whose tumour is not considered at immediate risk of progression after surgery will usually have active surveillance. The clinical experts explained that people having active surveillance in the NHS have minimal residual disease volume after surgery. They said that these people are likely to have slow-growing disease that is appropriate to monitor using regular scans. They explained that the need for further treatment after surgery was based on a multidisciplinary team discussion instead of defined eligibility criteria. But they said that treatment was more likely to be offered to people whose tumour had a higher risk of progression because they:

• were older

• had post-surgical histology results that suggested transformation to HGG

• had a substantial amount of residual tumour after surgery

• had residual tumour volume around the areas of the brain responsible for motor, visual or speech control that was likely to cause a neurological defect

• had astrocytoma, which is generally more aggressive and progresses faster than oligodendroglioma

• preferred to have adjuvant treatment after discussion with their healthcare professional.
  
  Based on NG99, people whose tumours need immediate treatment after surgery or whose disease has progressed during active surveillance should have radiotherapy followed by a maximum of 6 cycles of procarbazine, lomustine (CCNU) and vincristine (PCV) chemotherapy. If the disease progresses further, additional treatments can be used. These could include another round of chemotherapy, more radiotherapy, surgery, or supportive care. The clinical experts at the meeting agreed that this pathway broadly represented the treatments used in the NHS but highlighted that treatment for LGG varies across centres. The patient expert explained that treatments for LGG have a large effect on quality of life. The psychological burden of active surveillance for a progressively enlarging tumour can lead to substantial anxiety. Chemotherapy and radiotherapy are also associated with debilitating side effects such as cognitive decline and fatigue. They can also negatively affect fertility and need regular hospital visits which can limit the ability to work. The patient expert highlighted that they would welcome a treatment that could be used after surgery to delay the need for chemotherapy or radiotherapy. This would also relieve the anxiety linked to having a progressing disease that is not being actively treated. The committee concluded that treatment for LGG includes chemotherapy or radiotherapy, active surveillance, surgery and best supportive care.

Vorasidenib is licensed for people who do not need immediate chemotherapy or radiotherapy after surgery. The company explained that the marketing authorisation for vorasidenib included people with:

• a supramaximal resection (where all the tumour and some surrounding tissue is removed)

• a gross total or complete resection (where all visible tumour is removed)

• some residual disease not at immediate risk of progression.
  
  But, the clinical experts stated that they may not recommend adjuvant therapy after complete or supramaximal resection so as to reduce the treatment burden and avoid side effects. They also highlighted the lack of evidence to support the use of vorasidenib in this population (see section 3.6). But they said that using an IDH inhibitor may positively affect the biology of the condition, so there may be potential long-term benefits for these people (see section 3.10). They highlighted that the proportion of people who have a supramaximal resection is increasing because of improvements in surgical techniques. The committee agreed that vorasidenib may be used for people who have had a supramaximal or complete resection but that this would be determined on a case-by-case basis. It thought that all people who were not in need of immediate chemotherapy or radiotherapy after surgery would have active surveillance. So, the committee concluded that active surveillance was the relevant comparator but the exact population for which vorasidenib would be used in clinical practice was unclear.

The clinical-effectiveness evidence for vorasidenib came from INDIGO, an ongoing, multicentre, randomised, placebo-controlled trial, which included 4 sites in the UK. It included people with IDH-mutant grade 2 oligodendroglioma or astrocytoma who:

• were 12 years and over

• had measurable, non-enhancing LGG, defined by having at least 1 target lesion of 1 cm or over in both width and diameter, confirmed on MRI by blinded review

• had at least 1 surgery for glioma as their only treatment, the latest of which was within 1 to 5 years from screening

• had no high-risk features such as uncontrolled seizures, brain-stem involvement, or tumour-related functional or neurocognitive deficits.

At the most recent data cut (March 2023), 54 people (32%) in the vorasidenib arm and 104 people (64%) in the placebo arm had progressed disease. Median PFS was not reached (95% confidence interval [CI] 22.1 months to not estimable) in the vorasidenib arm and was 11.4 months (95% CI 11.1 months to 13.9 months) in the placebo arm. A benefit in PFS was seen across all prespecified subgroups for vorasidenib compared with placebo. The key results for the secondary endpoints as of the March 2023 data cut were as follows:

• The median time to next intervention was not evaluable in the vorasidenib arm and was 20.1 months (95% CI 17.5 months to 27.1 months) in the placebo arm. Twenty eight people in the vorasidenib arm and 78 people in the placebo arm had further treatment after their disease progressed. Of these, 70 people in the placebo arm crossed over to vorasidenib. This was 90% of the people who had subsequent treatment. The committee noted that this would not occur in NHS clinical practice because vorasidenib is not available.

• There were no significant improvements in neurological function or health-related quality of life between arms (see section 3.13).

The company developed a microsimulation model based on key treatment milestones to evaluate the cost effectiveness of vorasidenib. The base-case model included 8 health states:

• progression free, on treatment, where people having vorasidenib entered the model

• progression free, off treatment, where people having placebo entered the model

• progressed disease, off treatment

• first-line chemotherapy or radiotherapy, on treatment

• first-line chemotherapy or radiotherapy, off treatment

• second-line chemotherapy or radiotherapy onwards, on treatment

• best supportive care

• death.

The company used data from INDIGO to inform the clinical effectiveness for the following health states:

• The progression-free health states (both on and off treatment) were informed by the time to progression from INDIGO, extrapolated using a log-normal distribution. There were no deaths on treatment in INDIGO so the company assumed that PFS was a proxy for time to progression.

• The progressed disease, off-treatment health state (that is, the time between progression and the start of the next treatment) was informed by a conditional outcome calculated by the company, time to next intervention given progression (TTNI‑P). The progressed-disease, off-treatment health state (that is, the time between progression and the start of the next treatment) was informed by a conditional outcome calculated by the company, time to next intervention given progression (TTNI‑P). This was calculated using the difference between the PFS (as a proxy for time to progression) and TTNI in INDIGO, which was then extrapolated beyond the trial data (see section 3.10).

The company extrapolated the TTNI‑P data beyond the clinical trial follow up by fitting separate parametric curves to the Kaplan–Meier data from the vorasidenib and placebo arms of INDIGO. It chose the best-fitting curve, the generalised gamma, for its base case. The EAG was concerned about this approach because the data from the placebo arm was biased by the high levels of crossover to vorasidenib after progression. The committee recalled that this data was not appropriate for decision making (see section 3.7). The EAG was also concerned that the company's chosen parametric curves lacked face validity because:

• Twenty one per cent of people having vorasidenib and 9% having placebo had had no further treatment 20 years after their disease progressed, implying a cure, which they believed to be not plausible given the disease characteristics. The EAG queried whether the large difference in TTNI‑P was plausible, given that these benefits were modelled to apply in addition to the PFS benefit for vorasidenib seen in INDIGO.

• A small percentage of people in the vorasidenib arm stayed in the progressed-disease, off-treatment health state for the entire model lifetime. The EAG highlighted that these people never experienced the excess mortality from LGG because they never entered the best supportive care health state.

• People in the vorasidenib and placebo arms spent considerably more time with progressed disease off treatment than in the progression-free health state, which the EAG considered implausible.

There was no mature overall-survival data available from INDIGO, and no deaths reported before disease progression on vorasidenib and placebo. Because of this, the company model assumed in its base case that there was a benefit in overall survival for vorasidenib compared with placebo, driven by benefits in PFS and TTNI‑P. The company also only applied excess mortality for LGG to people having best supportive care. It used data from Ma et al. (2021) to extrapolate the long-term mortality rates. The clinical experts confirmed that this reflected clinical practice, where excess mortality generally occurs at the end of the treatment pathway. But the EAG was concerned that the surrogacy relationship between PFS, TTNI‑P and overall survival was uncertain and not supported by data. It noted that the company submitted data from Miller et al. (2019), a retrospective analysis of 275 people with IDH-mutant glioma who had treatment in the US between 1991 and 2007. This suggested that delaying the time to first and second progression improved overall survival. The clinical experts explained that it was difficult to directly translate improvements in PFS to overall survival without further evidence, but that this might be plausible. They noted that treatment options for LGG are limited, so a poorer overall survival would be expected in people whose disease progressed quickly through treatments. They noted that the transformation to HGG is associated with a known mortality risk and so would be a better surrogate marker for overall survival than those in the company's model.

The committee noted that there was no data to suggest a delayed transition to HGG or malignant glioma with vorasidenib compared with active surveillance. It was also concerned about the use of TTNI‑P as a surrogate marker for overall survival, because it was highly uncertain and was likely confounded by crossover (see section 3.7). It recalled that its preferred extrapolation did not have a TTNI‑P benefit for vorasidenib (see section 3.10). But it noted that in the company's base case, the more optimistic TTNI‑P curves and the substantial benefit for vorasidenib had a significant positive impact on overall survival. The company explained that an additional data cut from INDIGO was expected in May 2028. The EAG thought that this would reduce the uncertainty around PFS and TTNI for vorasidenib. But it thought that any overall-survival data would be difficult to interpret because of the high number of people who crossed over to vorasidenib in the placebo arm. It considered that the only alternative approach would be to model survival hazards based on progression events over time. But it acknowledged that collecting data to inform a progression-based model would be challenging given the rarity of LGG and the lack of published evidence on the condition. The committee agreed that any overall-survival benefit for vorasidenib was highly uncertain because of the uncertainty in the modelled inputs, especially the TTNI‑P from INDIGO. The committee noted that the company's overall-survival modelling method may be suitable for decision-making, although it was highly uncertain, but that it would evaluate any overall-survival outputs from updated analyses presented during consultation.

In the company's model, the chemotherapy regimens and the proportion having radiotherapy differed by treatment line. The distribution of chemotherapy treatments was based on a French periodic synthesis report for ivosidenib. This included people with IDH1-mutant LGG who could not have surgery. The percentage of people having radiotherapy with chemotherapy at first line was based on the rates in the INDIGO trial, and the company assumed a 50% reduction in radiotherapy use at each successive line. The EAG's clinical advisers suggested there were differences in the use of subsequent treatments between Europe and the NHS. Specifically, subsequent treatments in the NHS:

• include higher use of PCV at first line than in the company's model

• do not include bevacizumab, which was included as a third- and fifth-line chemotherapy in the French review.
  
  At the meeting, the company highlighted that some people in England and Wales self-fund bevacizumab because is not funded by the NHS. But the clinical experts agreed that any use of bevacizumab would be negligible because it is not the preferred treatment for LGG. The EAG's clinical advisers also considered that the proportion of people having radiotherapy in the NHS was likely to be higher at first line and lower at subsequent lines than was modelled by the company. Based on clinical-expert advice and NG99, the EAG's base case assumed that:

• 100% of people had PCV with radiotherapy as the first subsequent treatment

• 100% of people had temozolomide and 50% of people had radiotherapy as their second subsequent treatment

• 33% of people each had PCV, temozolomide and lomustine (CCNU) as their third subsequent treatment; no one had radiotherapy.
  
  The clinical experts supported the EAG's modelling of subsequent treatments. The committee also noted that use of temozolomide was limited by NICE's technology appraisal guidance on temozolomide for treating recurrent malignant glioma (TA23) and so PCV may be more accessible in the NHS. The committee acknowledged the uncertainty in the modelling of subsequent treatments. But it concluded that it preferred the EAG's base-case distributions because they better reflected NHS practice.

The company derived health-state utility values for the progression-free and progressed-disease health states from EQ-5D-5L data collected in the INDIGO trial. It mapped the EQ-5D-5L data to the EQ-5D-3L value set, using the average utility across arms. The company did a vignette study to inform utility values for people who had subsequent treatments in the model. This was because INDIGO did not collect this data and the company had not identified any appropriate utility values in the literature. The vignette study asked members of the public to estimate health-related quality of life based on descriptions of the hypothetical health states using EQ-5D and time trade-off approaches. The utility values derived from the vignette study were higher for people who had stopped chemotherapy or radiotherapy than for people who were having this treatment. The company thought this implausible, so applied the average utility value between on and off treatment for each subsequent treatment line in the model using the EQ-5D values in its base case.

The EAG had several concerns about the company's utilities. It noted that the progression-free utility values from INDIGO were relatively high, supporting that the trial cohort was stable compared with the wider LGG population (see section 3.6). Also, moving from progression free to progressed disease resulted in a small utility decrease (0.009), which the EAG thought was an implausibly small drop. It was also concerned about the utility values derived from the vignette study. It highlighted that a vignette study is the lowest quality of evidence for utility values according to NICE's health technology evaluations manual. It also said that the description of health states in the vignette did not differentiate by glioma type or grade. Firstly, the EAG thought it inappropriate to average the on- and off-treatment utility values from the vignette study. This was based on clinical-expert advice that quality of life would likely increase after chemotherapy and radiotherapy because the side effects of these treatments would stop. So, the EAG used the unadjusted EQ-5D vignette utilities in its base case. The clinical experts supported this. They reiterated that chemotherapy and radiotherapy cause major, short-term side effects that disrupt daily life and work. Though quality of life is likely to improve after treatment, the experts stressed that long-term side effects like cognitive decline and fatigue can still emerge years down the line. The EAG explained that the description used in the vignette study for the off-treatment health states assumed no adverse events from treatment. So, the committee thought that the unadjusted vignette utilities may not have captured the long-term impacts of chemotherapy or radiotherapy.

The EAG was also concerned that when people moved from progressed disease, off treatment to first-line chemotherapy or radiotherapy (that is, from the utility values derived from the INDIGO study to the values derived from the vignette study), there was a very large drop in health-related quality of life (0.328). The company explained that the quality-of-life data in INDIGO was collected relatively close to disease progression and was based on very small numbers. So, by the time people started chemotherapy or radiotherapy they would be expected to have a poorer quality of life than was recorded in the trial. The committee recalled that, in the company's base case, people spent a long time in the progressed-disease, off-treatment health state. The company explained that during this time, people got older and there would likely be some progressive deterioration in their LGG. The committee also recalled that people having active surveillance spent considerably less time off treatment with progressed disease (that is, less time in the health states with higher quality of life) than people having vorasidenib. So, the committee agreed with the EAG that the large drop between the INDIGO and vignette utility values may not be plausible and noted it was amplifying the impact of the TTNI‑P difference between arms. The EAG thought that using different sources resulted in utilities that lacked face validity. It also noted a big difference between the off-treatment health states before and after having first-line chemotherapy or radiotherapy. It noted that the vignette study had not included descriptions of progression-free and progressed-disease health states that could be used to anchor them to the vignette and INDIGO utilities.

The committee thought both the company's and the EAG's preferred utility values were highly uncertain because they used 2 different unanchored sources. It noted that the company's literature search had identified a utility value of 0.60 that was used for glioma recurrence in TA23. It thought that using the utility value of 0.60 for first-line chemotherapy and radiotherapy in the model, and applying the relative difference between health-state utilities in the unadjusted EQ-5D vignette applied for later health states, would result in a more plausible set of utility values. This was because it would capture the burden of treatment from subsequent treatments but remove the implausible drop in utility when moving to subsequent treatments. The committee also requested further analysis to consider the quality-of-life decrement of moving from progression-free to progressed-disease health states, because of the uncertainty around time spent in the progressed-disease state without treatment (see section 3.10). The committee agreed that these analyses, including the approach outlined, should be provided at consultation. It concluded that the utility values from the vignette study were highly uncertain, and that further analyses should be presented at consultation.

The company base case included monitoring costs for 3-monthly MRI and CT scans for people having vorasidenib and placebo. Based on clinical-expert advice, the EAG only included an imaging cost for monitoring with MRIs in its base case. This was supported by the clinical experts who stated that CT scans are rarely used to monitor LGG. The committee concluded that the cost of CT scans should be excluded from the modelling in line with clinical practice.

NICE's health technology evaluations manual states alternative analyses using rates of 1.5% for both costs and health effects may be presented alongside the reference-case analysis. This may be considered by committee when it is highly likely that, on the basis of the evidence presented, the treatment is likely to restore people to full or near-full health when they would otherwise die or have a very severely impaired life, and when this is sustained over a very long period. Rather than present the reference case discount rate (3.5%) in its base case, the company used a discount rate of 1.5% for health benefits and costs. The EAG used a 3.5% discount rate, stating that the criteria for applying a lower discount rate were not met. The committee thought that:

• Although people with LGG have severely impaired quality of life as the disease progresses, the population having vorasidenib in clinical practice would have stable disease not in immediate need of further systemic treatment. This was evidenced by the relevant comparator being active surveillance (see section 3.3). The EAG also highlighted that there was also only a small decrease in quality of life between the public and people in INDIGO whose glioma was progression free after surgery. The committee noted that the company's base-case analyses predicted an overall survival for people having active surveillance of around 20 years after entering the model. So, the committee agreed that people would not have a severely impaired quality of life or otherwise die at the point in the treatment pathway where vorasidenib would be used.

• The committee next considered whether vorasidenib restored people to full or near-full health. They noted that it aims to delay time to progression and next treatment but was not a cure for the condition. There was also better health-related quality of life in the placebo arm in INDIGO after progression than the vorasidenib arm. A patient expert explained that vorasidenib helped greatly lower the anxiety of living with an inevitably progressive disease, but did not eliminate this completely. So, the committee agreed that vorasidenib does not restore people to full or near-full health.

• The long-term benefits for vorasidenib including overall survival are unknown because of the high level of uncertainty about the benefit in TTNI‑P and overall survival for vorasidenib in the model (see sections 3.10 and 3.11). Because of this, the committee agreed that it could not be confident that there was a plausible case for the maintenance of benefits over time.
  
  The committee concluded that a 3.5% discount rate should be used for health benefits and costs in the model.

The committee noted that some potential benefits of vorasidenib may not have been included in company's model:

• The committee recalled the psychological impact of LGG (see section 3.1). A patient expert at the meeting explained that, since starting vorasidenib, their mental health had improved considerably, to the point where they could live a close-to-normal life and had returned to work and social events. The committee thought that the full impact of vorasidenib on mental health may not be captured in the model.

• The committee recalled that the seizures associated with LGG stop people from driving, which can limit their independence (see section 3.1). The clinical experts explained that people needed to have not had a seizure for 12 months to restore driving eligibility. It noted that the INDIGO trial reported a reduction in the number of seizures compared with placebo, and that this reduction had been included in the model (see section 3.5). But, given the median PFS of 22.1 months in the vorasidenib arm, it considered it unlikely that many people having vorasidenib would be seizure-free for an entire year to allow them to return to driving. It concluded that it was uncertain whether the full quality-of-life benefit from reducing seizures had been captured in the model.

• The committee recalled the large physical and psychological impact on carers and family members of people with LGG (see section 3.1). The patient expert explained that family members often have to take time off work to provide physical and emotional care, and transport to regular hospital visits. They explained that, since taking vorasidenib, the level of care needed had reduced considerably because of improvements in their mental health. The committee considered that the impact on carers may not be captured in the economic modelling.

• The patient experts highlighted the socioeconomic benefits of increasing the time before people have chemotherapy and radiotherapy for people with LGG. Postponing the associated debilitating side effects extends the time people can function at their best, both professionally and personally. The committee recalled that people who would have vorasidenib are often in the middle of their careers and have young families to support (see section 3.1). It agreed that the socioeconomic benefits of vorasidenib may not be captured in the modelling.
  
  The committee considered the uncaptured benefits of vorasidenib in its decision making by accepting a higher level of uncertainty (see section 3.18).

NICE's manual on health technology evaluations 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. But it will also take into account other aspects including uncaptured health benefits. The committee noted the high level of uncertainty, specifically the:

• time off treatment with progressed disease

• overall-survival benefit for vorasidenib compared with active surveillance

• utility values for health states and subsequent treatments.
  
  It considered whether other factors should be included in its decision making. It recalled that astrocytoma and oligodendroglioma are rare conditions, which may present specific challenges in data collection. But it felt that it had already applied flexibility for rarity by accepting the generalisability of the INDIGO population to that in the NHS (see section 3.6). It also noted the uncaptured benefits for vorasidenib including the impact on carers and the wider socioeconomic benefits (see section 3.17). Because of this, the committee agreed that it was appropriate to accept some of the extra uncertainty in the economic modelling, as it considered the uncertainties in key issues such as overall survival, time to next intervention given progression and utility values, were higher than in many other evaluations. But it determined that based on the evidence presented, the level of uncertainty surrounding the data was significant enough that any potential uncaptured benefits did not justify a higher threshold. So, the committee concluded that an acceptable ICER would be around £20,000 per QALY.

Because of confidential commercial arrangements for vorasidenib and other treatments in the model, the exact cost-effectiveness estimates are confidential and cannot be reported here. The company's base-case ICER for vorasidenib compared with active surveillance was just above the committee's acceptable ICER (see section 3.18). The EAG's base-case ICER for vorasidenib compared with active surveillance was considerably above this range. The committee noted that using its preferred 3.5% discount rate (see section 3.15) increased the company's base-case ICER considerably, as did using pooled data from INDIGO to inform the TTNI‑P curve (see section 3.10). The committee concluded that, when using its preferred discount rate, both the company's and EAG's base-case ICERs were considerably above the range normally considered a cost-effective use of NHS resources.

For the model assumptions, the committee preferred to:

• use the baseline characteristics for the population from INDIGO (see section 3.6)

• use the PFS data from INDIGO for vorasidenib and placebo, using a log-normal distribution (see section 3.9)

• use the vorasidenib TTNI‑P data to model the time off treatment with progression for both vorasidenib and placebo but exploring alternative approaches (see section 3.10)

• use the company's modelling of overall survival while noting the uncertainty in this approach, but would assess outputs from updated analyses (see section 3.11)

• use the EAG's preferred distribution of subsequent treatments, informed by clinical experts and NG99 (see section 3.12)

• exclude the cost for using bevacizumab as a subsequent treatment (see section 3.12)

• exclude the cost of using CT scans for monitoring for vorasidenib and placebo (see section 3.14)

• use a discount rate of 3.5% for health benefits and costs (see section 3.15)

• add a severity weight of 1.2 to the QALYs (see section 3.16).
  
  The committee could not establish a plausible ICER because of the modelling of relative effectiveness and utilities. It noted that all of the scenarios provided by the EAG that included a 3.5% discount rate were above the threshold considered a cost-effective use of NHS resources. So, vorasidenib was unlikely to be cost effective using its preferred assumptions. It agreed that it could not recommend vorasidenib for treating LGG with IDH1 or IDH2 mutations after surgery in people 12 years and over.

The committee noted that there was considerable uncertainty surrounding the cost effectiveness of vorasidenib for LGG. It agreed that the company's model after consultation should:

• explore alternative ways to model TTNI‑P, including but not limited to:

  • providing full parametric distributions for TTNI‑P, applying data from the INDIGO vorasidenib arm to both vorasidenib and active surveillance in the model

  • exploring alternative ways to plausibly model a benefit in TTNI‑P for vorasidenib without using data from the placebo arm of INDIGO as a scenario (see section 3.10)

• model the quality-of-life burden for subsequent treatments by applying the relative difference between health-state utilities in the unadjusted EQ-5D vignette study to the value for glioma recurrence from TA23, and consider alternative quality-of-life decrements moving from progression-free disease to progressed disease (see section 3.13).

The committee noted that many people with LGG with IDH1 or IDH2 mutations may be young. A patient-organisation submission also highlighted that vorasidenib is not licensed for use in pregnancy and treatment is expected to continue until progression which affects the ability to have children. Age and pregnancy are protected under the Equality Act 2010. But because its recommendation does not restrict access to treatment for some people over others, the committee agreed these were not potential equalities issues that could be addressed by this evaluation. A patient organisation also highlighted that treatment cost related to vorasidenib including travel or time away from work could disproportionately affect poeple from lower-income backgrounds if additional monitoring was needed for vorasidenib. But a patient expert explained that there was no significant additional monitoring compared with active surveillance because vorasidenib was an oral treatment that could be taken at home. The committee concluded that there were no equality issues relevant to the recommendations.

The committee noted the important uncertainties in the cost-effectiveness evidence. This meant it was not possible to reliably estimate the cost effectiveness of vorasidenib. So, it should not be used. The committee concluded that the company should provide additional information for consideration at the next evaluation committee meeting.