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Beth benderfynodd Grŵp Asesu Meddyginiaethau Cymru’n Un?

Gellir rhoi trametinib i drin canser ofari serws gradd isel (a elwir yn LGSOC) - math prin, ymledol o ganser sy'n effeithio ar yr ofarïau. Dim ond i drin LGSOC nad yw wedi ymateb i o leiaf un driniaeth cemotherapi a oedd yn cynnwys meddyginiaeth seiliedig ar blatinwm y gellir defnyddio Trametinib, fel cisplatin, carboplatin neu oxaliplatin.

Bydd trametinib ar gael i gleifion cymwys sydd wedi cofrestru gyda phractis meddyg teulu yng Nghymru, hyd yn oed os oes angen iddynt dderbyn eu triniaeth y tu allan i Gymru.

Nid yw trametinib wedi'i drwyddedu i drin LGSOC, felly os caiff ei ddefnyddio i drin LGSOC fe’i gelwir yn ddefnydd “all-drwydded”. Pan gaiff meddyginiaeth ei defnyddio yn “all-drwydded”, rhaid i'ch meddyg esbonio'n glir i chi y risgiau a'r manteision o gymryd y feddyginiaeth. Dylai eich meddyg roi gwybodaeth glir i chi, siarad â chi am eich opsiynau a gwrando'n ofalus ar eich barn a'ch pryderon. Darllenwch ein taflen wybodaeth i gleifion am ddefnydd di-drwydded ac all-drwydded o feddyginiaethau.

Mae Grŵp Asesu Meddyginiaethau Cymru'n Un ac AWTTC yn adolygu'r penderfyniad hwn yn rheolaidd i weld a oes unrhyw dystiolaeth newydd a allai effeithio ar y penderfyniad hwn.

Am ragor o wybodaeth, ewch i: Ovarian Cancer Action and Target Ovarian Cancer (Saesneg yn unig)

 

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What did the One Wales Medicines Assessment Group decide?

Trametinib can be given to treat low-grade serous ovarian cancer (known as LGSOC) - a rare, invasive type of cancer affecting the ovaries. Trametinib can only be used to treat LGSOC that has not responded to at least one chemotherapy treatment that included a platinum-based medicine, such as cisplatin, carboplatin or oxaliplatin. 

Trametinib will be available to eligible patients who are registered with a GP practice in Wales, even if they need to receive their treatment outside Wales.

Trametinib is not licensed to treat LGSOC, so using it to treat LGSOC is called “off-label” use. When a medicine is used “off-label”, your doctor must clearly explain to you the risks and benefits of taking the medicine. Your doctor should give you clear information, talk with you about your options and listen carefully to your views and concerns. Read our patient information leaflet about unlicensed and off-label use of medicines.

The One Wales Medicines Assessment Group and AWTTC review this decision regularly to see if there is any new evidence that may affect this decision.

For more information about low grade serous ovarian cancer visit: Ovarian Cancer Action and Target Ovarian Cancer

Medicine: trametinib

Indication: Treatment of recurrent low grade serous ovarian carcinoma (LGSOC) which has progressed following at least 1 previous platinum-based regimen

Meeting date: 12 May 2025

Criterion: Clinical effectiveness and safety

OWMAG note that the clinical effectiveness evidence for the use of trametinib to treat recurrent LGSOC which has progressed following at least 1 previous platinum-based regimen is from the open-label, randomised GOG 281/LOGS phase II/III study. This study demonstrated clinical benefit of trametinib treatment in this population compared to patients receiving standard of care treatments (paclitaxel, pegylated liposomal doxorubicin, topotecan, tamoxifen, letrozole). Median progression-free survival in the trametinib group was 13·0 months compared with 7·2 months in the standard-of-care group. OWMAG note that three of the five standard-of-care treatments used in the study are treatments routinely used in Wales to treat LGSOC that has progressed after at least one previous platinum-containing regimen. OWMAG also note that the characteristics of patients treated in the study in terms of age, ECOG status and stage of disease is reflective of the population to be treated in Wales. OWMAG consider that the study results are likely to be generalisable to the patient population in Wales. OWMAG note that no new safety signals have been observed for the use of trametinib to treat LGSOC, although note that the majority of patients required dose reductions whilst receiving trametinib. OWMAG consider that the evidence provided demonstrates clinical effectiveness for using off-label trametinib to treat recurrent LGSOC which has progressed following at least 1 previous platinum-based regimen.

Criterion: Cost-effectiveness

OWMAG opinion OWMAG note one published analysis evaluating cost-effectiveness of trametinib vs standard-of-care from a US payer perspective based on results from the GOG 281/LOGS study. OWMAG consider that this has very limited generalisability to the UK based on differences in treatment and service costs and the assumptions used in the model. In addition, the absence of direct comparative efficacy between trametinib and comparative standard‑of‑care treatments used in NHS Wales means the actual cost-effectiveness of trametinib for this indication remains unknown. OWMAG note the results of a cost comparison assessment of trametinib versus the standard-of-care comparators used in NHS Wales undertaken by AWTTC. After taking into account the limitations of the cost comparison analysis, OWMAG consider that treatment with trametinib is likely to be both more effective and more costly than standard-of-care treatments. Based on the costs provided, OWMAG consider trametinib to be reasonable value for money for NHS Wales.

Criterion: Budget impact

OWMAG opinion OWMAG consider the clinical estimate of patient numbers reported to be reasonable although note that it is slightly higher than would be predicted using published incidence data which may cause the presented budget impact to be overestimated. The group note that additional monitoring, administration and adverse event costs have been included in the budget impact calculations although these may be subject to uncertainty. OWMAG note that the majority of patients receiving trametinib in the GOG 281/LOGS clinical trial required dose reduction. Therefore, the acquisition costs for trametinib may be lower than those presented. OWMAG consider that the base case provided in the report is a reasonable estimate of the associated cost to NHS Wales.

Criterion: Resource use

OWMAG opinion OWMAG agree that there is likely to be a reduction in use of NHS services as trametinib is an oral therapy taken at home unlike standard-of-care chemotherapy which require patients to attend a clinic or hospital to receive treatment by intravenous infusion. OWMAG acknowledge that some additional monitoring is required during treatment with trametinib.

Criterion: Other factors

OWMAG opinion OWMAG acknowledge the evidence provided by clinical experts at the meeting, who reported that there is no standard treatment pathway for recurrent LGSOC in Wales as it seldom responds to available standard-of-care treatments. Trametinib offers a potentially clinically-effective treatment option for this cohort of patients; it was also reported that the American Society of Clinical Oncology recently issued an alert recommending trametinib as standard-of-care for LGSOC, a recommendation which is increasingly becoming adopted worldwide. OWMAG note that the European Society of Clinical Oncology (ESMO) and US National Comprehensive Cancer Network (NCCN) both recommend using trametinib to treat recurrent LGSOC. Clinicians also highlighted that it is mainly younger women affected by LGSOC who are more likely to be of working age and have dependents in comparison to women with high-grade ovarian cancer which tends to occur in older populations. OWMAG note the patient perspectives as outlined in the submissions received from Ovarian Cancer Action and Target Ovarian Cancer, and how knowledge that recurrent LGSOC does not respond well to current standard-of-care treatments causes a sense of uncertainty and anxiety in patients that is difficult to live with. Knowing trametinib was available would reduce anxiety around recurrence for them, and their families and carers. OWMAG also note that trametinib, taken as an oral tablet at home, leads to less disruption of day-to-day life than some standard-of-care treatments currently offered in Wales which are delivered intravenously in a clinical setting. Patients also highlight that the improvements in progression-free survival that trametinib may give would help them to return to a more normal routine like work and spending time with friends and family. OWMAG note that trametinib is routinely commissioned by NHS England to treat recurrent LGSOC which has progressed following at least 1 previous platinum-based regimen and is also supported for use in NHS Scotland for this patient cohort. Clinicians and patients highlight this inequity of access for patients in Wales and the distress this may cause.

Final recommendation

OWMAG recommend the use of trametinib as an off-label treatment of recurrent low grade serous ovarian carcinoma (LGSOC) which has progressed following at least 1 previous platinum-based regimen. This recommendation is subject to the development of appropriate start/stop criteria.

Summary of rationale

There is clinical evidence to support the use of trametinib as an off-label treatment of recurrent low grade serous ovarian carcinoma (LGSOC) which has progressed following at least 1 previous platinum-based regimen. OWMAG is of the opinion that the use of trametinib treatment offers this patient cohort increased progression-free survival compared to current standard-of-care treatments and consider the associated cost to be a reasonable use of NHS resources. Real world data will be captured to assess the benefit of this treatment for this cohort of patients.

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Key findings

Licence status: Trametinib is not licensed for treatment of recurrent low-grade serous ovarian carcinoma (LGSOC) that has progressed after at least one previous platinum‑based regimen; its use for this indication is off-label.

Clinical evidence: The open-label GOG 281/LOGS study compared trametinib with the standard‑of‑care treatments (paclitaxel, pegylated liposomal doxorubicin, topotecan, tamoxifen, letrozole) in recurrent LGSOC. Median progression-free survival in the trametinib group was 13 months (95% CI 9.9 to 15.0), and 7.2 months (95% CI 5.6 to 9.9) in the standard-of-care group (hazard ratio 0.48 [95% CI 0.36 to 0.64]; p < 0.0001).

Safety: No new safety signals have been observed for the use of trametinib to treat LGSOC.

Patient factors: Trametinib is an oral treatment taken daily, that would be used in place of further chemotherapy treatments, such as paclitaxel and pegylated doxorubicin, which need to be given by intravenous infusion. This would mean less disruption of day‑to-day life for patients, and their families and carers.  

Cost effectiveness: One published cost-effectiveness analysis was conducted from the US payer perspective and has limited generalisability to the UK. Using data from the GOG 281/LOGS study, trametinib provided an additional 0.58 quality-adjusted life-years (1.14 life years). A cost comparison analysis conducted by AWTTC indicated that trametinib is a cost‑increasing intervention compared to NHS Wales standard­‑of‑care comparator treatments for patients with LGSOC after at least one prior platinum-based chemotherapy. Trametinib increased the cost of treatment by [commercial in confidence figure removed] per patient when using the confidential PAS price for trametinib and NHS contract prices for comparator treatments where applicable. Although the overall treatment costs increased, the medicine administration costs reduced by £3,328 per patient compared to NHS Wales standard‑of‑care. Considering the clinical evidence supporting the use of trametinib, it may offer clinical benefit compared to NHS Wales standard‑of‑care. However, in in the absence of direct comparative efficacy between trametinib and NHS Wales standard‑of‑care, it is difficult to quantify treatment benefits in relation to costs and the actual cost-effectiveness remains unknown.

Budget impact: The addition of trametinib is estimated to increase the spend associated with this patient group in Wales by [commercial in confidence figure removed] per year. This is based on an estimated uptake of 13 patients per year receiving 8 cycles of trametinib treatment, and takes into account full displacement of comparator standard-of-care therapies.

Impact on health and social care services: Likely to be beneficial. Reduced use of services as patients would not need to attend a clinic or hospital to receive treatment by intravenous infusion as trametinib is an oral treatment. Some additional monitoring is required (eye examinations as clinically indicated, left-ventricular ejection function at Month 1 and then every 3 months during treatment). 

Innovation and/or advantages: Recurrent LGSOC is usually resistant to standard chemotherapy. Being able to take an oral treatment at home is an advantage for patients, their families and carers, by not having to travel to a hospital for treatment.

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Background

Low-grade serous ovarian carcinoma (LGSOC) is a rare subtype of ovarian cancer that grows slowly and is more resistant to chemotherapy than other ovarian cancer types¹. 

Clinicians in Wales submitted trametinib (Mekinist^®) for consideration for assessment as a treatment option for LGSOC that has progressed after at least one platinum-based regimen. They consider there is an unmet need and have identified a cohort of patients who could benefit from this treatment. The Scrutiny Panel of the All Wales Medicines Strategy Group (AWMSG) considered that trametinib was suitable for assessment though the One Wales medicines process for off-label medicines.

Trametinib is an inhibitor of enzymes called protein kinases; it specifically inhibits the MEK-1 and MEK-2 kinases, which are part of the ERK/MAPK signally pathway².

Trametinib is not licensed to treat LGSOC. During the COVID-19 pandemic, trametinib was available in England and Wales as an oral alternative to intravenous (iv) chemotherapy for LGSOC, under NICE guideline NG161: COVID-19 rapid guideline: delivery of systemic anticancer treatments, which established an interim Systematic Anti-Cancer Therapy (SACT) treatment list³.

NICE guideline NG161 was withdrawn in September 2023 because current practice is to manage COVID-19 risk in line with risk of other respiratory infections³, and trametinib use is routinely commissioned in the NHS in England and in Scotland to treat LGSOC^1,2. However, in Wales the current route of access for treating LGSOC with trametinib is through the Individual Patient Funding Request (IPFR) process. [Confidential data removed].

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Target group

The indication being considered is the treatment of low-grade serous ovarian carcinoma (LGSOC) that has progressed after at least one platinum-based chemotherapy regimen.

Clinicians advised that trametinib is likely to be used instead of further chemotherapy or hormone therapy options including paclitaxel (alone or with carboplatin), letrozole or pegylated liposomal doxorubicin, all of which have limited efficacy in preventing further disease progression.

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Marketing authorisation date

Not applicable for this indication, off-label. 

Trametinib is licensed in the UK for use as monotherapy, or in combination with dabrafenib, to treat unresectable or metastatic melanoma with a BRAF V600 mutation⁴. It is also licensed for use in combination with dabrafenib to treat advanced non-small cell lung cancer (NSCLC) with a BRAF V600 mutation, and as adjuvant treatment after complete resection of stage III melanoma with a BRAF V600 mutation⁴. [Commercial in confidence text removed].

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Dosing information

Trametinib should be used as monotherapy at a maximum dose of 2 mg orally once daily, as part of a 28-day cycle¹. Treatment is continued until disease progression occurs or toxicity stops treatment. Dose reduction due to adverse events may be required down to either 1.5 mg orally once daily or 1 mg orally once daily¹.

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Clinical background

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Incidence/prevalence

In 2021, 330 cases of ovarian cancer were diagnosed in Wales⁸. If 90% of those are epithelial ovarian cancer, and 5% of those are LGSOC, then we would expect around 15 cases of LGSOC to be diagnosed in Wales per year. Assuming that 70% of patients would have a recurrence of LGSOC, 11 patients per year would be eligible for treatment with trametinib. This is slightly lower than the estimate provided by clinicians in Wales of 13 patients per year.

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Current treatment options and relevant guidance

Standard treatment for LGSOC is surgery to achieve a complete or optimal cytoreduction⁵. After surgery, platinum-based chemotherapy and paclitaxel can be offered, though their benefit is uncertain. Further surgery may be considered for people who have recurrent LGSOC with operable disease. If surgery is not possible, a platinum‑based chemotherapy and paclitaxel will be given as first‑line treatment¹. Paclitaxel plus cisplatin is the standard systemic chemotherapy used in LGSOC⁵.

After chemotherapy or surgery, maintenance hormonal therapy can be given: often letrozole and tamoxifen. These are usually continued until disease progression or unacceptable toxicity^1,5. For most people, LGSOC does not respond to platinum‑based chemotherapy, and they will have disease progression or recurrence¹.

After disease progression or recurrence, the treatment options offered can include hormonal therapy (if not previously given) or further chemotherapy (options include paclitaxel alone or pegylated liposomal doxorubicin hydrochloride)⁹. However, these treatments show limited effectiveness in preventing further disease progression⁵. Once recurrence occurs, patients will require support from palliative care specialists and community teams. The most frequent complications of recurrent LGSOC include bowel obstruction, hydronephrosis, fistulation and general organ failure.

The European Society for Medical Oncology (ESMO) Clinical Practice Guideline for diagnosis, treatment and follow-up of newly diagnosed and relapsed epithelial ovarian cancer, recommends that trametinib should be considered for treating recurrent LGSOC after prior platinum-based chemotherapy and hormone therapy⁵.

Based on results from a phase II/III open-label randomised clinical trial (study GOG 281/LOGS), the US National Comprehensive Cancer Network (NCCN) recommends the use of trametinib as a category 2A option (defined as: based on lower level evidence) to treat recurrent LGSOC¹⁰. There is uniform NCCN consensus that the intervention is appropriate¹⁰.

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Summary of evidence on clinical effectiveness

A literature search was conducted by the All Wales Therapeutics and Toxicology Centre (AWTTC) in March 2025 to identify evidence about the use of trametinib to treat LGSOC. Searches were performed using MEDLINE, EMBASE and the Cochrane Library. The search terms used were trametinib, ‘low grade serous ovarian cancer’, and LGSOC. The primary outcomes intended were overall survival, progression-free survival (PFS), adverse events, health-related quality of life, resource use, response rates and/or symptom control. Conference abstracts, reviews, non-systematic reviews, letters and editorials were excluded. See the PRISMA diagram in Appendix 1 (opens image in new tab).

A total of 71 clinical papers were retrieved during the literature search, from which 24 duplicates were removed. 44 clinical papers were excluded by inspecting titles and abstracts, and the full texts of 3 papers were reviewed for suitability in this report.

The literature search identified one clinical study of a randomised, open-label multicentre phase 2/3 trial of trametinib in LGSOC (study GOG 281/LOGS), one case report of LGSOC treated with trametinib, and a cost-effectiveness analysis of trametinib in LGSOC. Only the phase 2/3 trial and cost-effectiveness analysis were reviewed for this report.

Efficacy

Safety

Discussion

The main evidence is the results of the GOG 281/LOGS study, which show that trametinib improved progression-free survival compared with the standard‑of-care treatments. The trial was open label with both the patients and investigators aware of the treatment assignment. The primary endpoint was investigator-assessed and as cross over was allowed this may have had implications for those patients originally assigned to the standard of care arm allowing earlier crossover. To account for this the study protocol required objective evidence of progression using RECIST criteria.  Overall survival improvements were numerically in favour of trametinib, although as a high proportion (68%) of patients in the standard-of-care group crossed over to receive trametinib, this may have resulted in confounding, potentially underestimating the survival benefit. Post-hoc sub-group analyses of individual treatments indicated that treatment with trametinib was favoured for all standard of care treatments although some did cross the hazard ratio threshold of 1. Similarly, trametinib treatment was found to be effective irrespective of treatment line.

Clinicians in Wales said that three of the five standard-of-care treatments used in the study, are treatments routinely used in Wales to treat LGSOC that has progressed after at least one previous platinum-containing regimen.  These results are likely to be generalisable to the patient population in Wales

The safety profile of trametinib is known, and no new safety signals were reported in the study. The majority of patients required dose reductions whilst receiving trametinib. More patients discontinued treatment due to toxicity in the trametinib arm but patients were generally on treatment for longer with trametinib than the standard of care group. The difference in rate of small intestinal obstruction between treatment arms was not accounted for by the authors of the paper but may be a complication of the disease itself. The quality of life data from the study showed no significant differences between trametinib and the standard-of-care treatments.

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Patient submissions

AWTTC received two submissions from patient organisations: Ovarian Cancer Action, and Target Ovarian Cancer. The submissions highlight the experiences of patients with ovarian cancer and the challenges they face, focusing on LGSOC. The main points of the submissions are described below.

• Because LGSOC is a rare subtype of ovarian cancer, people diagnosed with LGSOC often feel isolated and without specific support.
• Treatment of LGSOC involves surgery and usually involves removing the ovaries and uterus, leading to loss of fertility and premature menopause. This is particularly difficult as LGSOC tends to affect younger women.
• Patients feel that there are not many treatments available to them. They are told that their disease doesn’t respond well to chemotherapy, but have to undergo chemotherapy and its side effects because there are no other treatments available.
• Most people (over 70%) will experience a recurrence of LGSOC, and as the disease does not respond well to chemotherapy; this creates a sense of uncertainty for patients, who find that difficult to live with. Patients who have had a recurrence said that they found the news of the recurrence more distressing than the initial diagnosis of LGSOC. 
• Patients say that knowing that trametinib was available as an option would give them a ‘mental safety net’ and reduce anxiety around recurrence for them, and their families and carers.
• Being able to take an oral treatment at home would mean less disruption of day-to-day life for patients, and improvements in progression-free survival would help them to return to a more normal routine like work and spending time with friends and family.
• It was noted that this treatment is available in England and that there is a current disparity in access for patients resident in Wales.

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Cost-effectiveness evidence

Background

A literature search conducted by AWTTC identified one published cost-effectiveness analysis, by Piao et al. (2023)¹¹. The analysis aimed to evaluate the cost-effectiveness of trametinib versus standard of care for recurrent LGSOC from the US payer perspective, based on the results of the study GOG 281/LOGS¹¹.

Context

The cost-effectiveness analysis compared cost and effectiveness of trametinib and standard-of-care groups in patients with recurrent LGSOC¹¹. Life-years, quality-adjusted life-years (QALYs), lifetime costs and incremental cost-effectiveness ratios were calculated. The robustness of the model was explored using one-way and probabilistic sensitivity analyses¹¹.

The model contained three health states: progression-free survival (PFS), progressed disease (PD) and death¹¹. The two treatment options were those evaluated in the GOG 281/LOGS study: trametinib and standard-of-care (paclitaxel, pegylated liposomal doxorubicin, topotecan, letrozole, tamoxifen). Treatment continued until unacceptable toxicity or disease progression. The model used a 28‑day Markov cycle and a lifetime horizon. All costs and outcomes were discounted at a rate of 3% annually, and the half-cycle correction was applied in the model. The model used a willingness to pay (WTP) threshold of $150,000, because in the USA the WTP threshold is between $100,000 and $150,000 per QALY for cancer medicines¹¹.

A partitioned survival analysis was done to estimate the movement over time between PFS, PD and death states¹¹. The progression and overall mortality risk for each treatment arm were estimated based on the PFS and overall survival curves from study GOG 281/LOGS. Log‑logistic models provided the best fit for overall survival curve and log-normal models provided the best fit for PFS curve according to the Akaike information criterion (AIC). Age‑specific background mortalities due to other causes were also considered, which were obtained from the US life tables¹¹.

Only direct medical costs were considered, including medicine costs and costs of administration¹¹. Doses were those used in the GOG 281/LOGS study, using a body surface area of 1.86m² to calculate dose size. After disease progression, 69% of patients could cross over to receive trametinib. Medicine and administration costs were based on US data from Centers for Medicare and Medicaid Services. The model included the cost of Grade 3–5 adverse events with an incidence of 5% or more reported in the study. Health-related quality of life was used to adjust the survival time. The utility of PFS was 0.61 and utility of PD was 0.50, derived from published studies^11,12.

As well as one-way and probabilistic sensitivity analyses, a scenario analysis was done, in which it was assumed that the median time for patients in the standard‑of‑care group to receive trametinib after progression was equal to the median time to receive trametinib for patients in the trametinib group¹¹.

Results

Trametinib provided an additional 0.58 QALYs (1.14 life years), and an incremental cost of $248,214 compared with the standard-of-care¹¹. The incremental cost-effectiveness ratio (ICER) was $424,097 per QALY gained compared with the standard-of-care group¹¹.

One-way sensitivity analyses suggested that the model was sensitive to the hazard ratio of overall survival and progression-free survival between the trametinib group and the standard-of-care group, utility of PFS and the cycle cost of trametinib¹¹. Probabilistic sensitivity analyses showed a 6% probability of the trametinib group being cost effective at a willingness-to-pay threshold of $150,000 per QALY gained¹¹.

The study concluded that trametinib was not cost-effective for patients with recurrent LGSOC at the assumed willingness to pay threshold of $150,000 per QALY¹¹. A 39% reduction in the cost of trametinib would make trametinib cost-effective compared to standard-of-care for recurrent LGSOC¹¹.

Cost comparison analysis

In their evidence report, the National Cancer Medicines Advisory Group (NCMAG) in Healthcare Improvement Scotland conducted a cost-comparison analysis using NHSScotland data on costs and standard of care for treatment². AWTTC has applied a similar methodology to conduct a cost comparison analysis using inputs pertinent to the NHS in Wales.

The proposed daily dosing regimen is 2 mg trametinib taken orally once daily as part of a 28-day cycle. The list price for 2 mg trametinib (pack size 30 tablets) is £4,800¹³; however, there is a patient access scheme (PAS) in place, reducing the pack cost to [commercial in confidence figure removed] (excluding VAT).

Treatment with trametinib would continue until disease progression or unacceptable toxicity. Costs are calculated for 8 cycles of trametinib; this was the median number of cycles reported in the GOG281/LOGS study.

Currently, patients in Wales with recurrence of LGSOC are offered various standard‑of-care regimens. Clinicians in Wales indicate that these are either paclitaxel with or without carboplatin, pegylated liposomal doxorubicin (PLD) or letrozole. Dosing details of these regimens and the proportion of patients likely to receive each treatment are given in Table 2. The proportion of patients was informed by clinical expert opinion. The duration of treatment of paclitaxel, letrozole and PLD was informed by median number of cycles from the GOG 281/LOGS study. The duration of treatment for carboplatin plus paclitaxel was assumed to be the standard treatment length of 6 cycles.

Table 2. Standard of care (SOC) comparator treatments in NHS Wales (opens image in new tab) 

The cost comparison between trametinib and the standard‑of‑care comparators used in NHS Wales is given in Table 3. These include medicine acquisition costs, administration costs and monitoring costs. Acquisition costs for comparators are given using both the lowest list price and the NHS Wales contract price if applicable. All acquisition costs exclude VAT. Costs for paclitaxel and PLD were calculated using a body surface area (BSA) of 1.71 m² which is the average BSA for a female patient with cancer in the UK¹⁴. Vial wastage is assumed.

Table 3. Costs of trametinib and standard-of-care per patient for first year of treatment (opens image in new tab) 

Administration costs for medicines given by intravenous infusion were sourced from the NHS reference costs 2023/24¹⁵. Monitoring costs for the first year of treatment with trametinib are included which are one ophthalmology outpatient consultation, one electrocardiogram and four echocardiograms.

A weighted average cost for a basket of the NHS Wales standard-of­‑care comparators listed in Table 2 has also been calculated using the proportion of patients estimated for each treatment as the weights.

Additionally, adverse event (AE) treatment costs were estimated for trametinib and for the basket of standard-of-care comparator treatments based on the rates of grade ≥3 adverse events requiring inpatient treatment occurring in >5% of patients reported in the GOG 281/LOGS study. These were diarrhoea (trametinib: 10%, standard‑of‑care: 3%), urinary tract infection (trametinib: 7%, standard-of-care: 5%), small intestine obstruction (trametinib: 9%, standard-of-care: 2%) and colon obstruction (trametinib: 0%, standard-of-care: 3%). AE treatment costs were sourced from the NHS reference costs 2023/24 and multiplied by AE rates. Due to the absence of comparative safety data for one of the comparator treatments (carboplatin + paclitaxel), which was not included in the GOG 281/LOGS study, any additional AEs for this treatment have not been considered in the costings.

A summary of the cost-comparison results for trametinib and the NHS Wales basket of standard-of-care comparator treatments is given in Table 4.

Table 4: Summary of cost-comparison results (opens image in new tab) 

Compared with the standard-of-care basket of comparators used in NHS Wales, trametinib increased medicine acquisition costs per patient by [commercial in confidence figure removed] when comparators were costed at list price and [commercial in confidence figure removed] if NHS Wales contract prices were used. Overall, on including medicine administration, adverse events and monitoring costs, the additional per-patient cost of treatment with trametinib was [commercial in confidence figure removed] (using comparator list prices) and [commercial in confidence figure removed] (when using comparator contract prices) in comparison to standard of care treatments used in NHS Wales. AWTTC considers that the costs using NHS Wales contract prices for comparator treatments provide a better estimate of the expected actual costs.

Limitations of the cost comparison analysis

The first-year monitoring costs for trametinib have been included in the cost comparison, however, in practice, only a small proportion of patients may undergo all tests, thereby reducing the overall monitoring costs.

Monitoring costs for comparator treatments over and above those considered standard for most patients on chemotherapy have not been included. Although rates of grade ≥3 adverse events are reported in the GOG281/LOGS study both for the trametinib group and the standard-of-care group, no further detail is given about proportions requiring treatment and the level of intervention required. Therefore, it is difficult to attribute costs for the treatment of adverse events for either trametinib or standard-of-care comparators with certainty.

The lack of comparative safety of trametinib with one of the standard-of-care comparators used in NHS Wales but not included in the GOG281/LOGS study, means that any adverse events due to this treatment were not included in the cost calculations. Conversely, some adverse events reported in the GOG281/LOGS study and so included in the adverse event treatment costings may be due to standard‑of‑care treatments included in the study but not used in NHS Wales. Thus, adverse event treatment costs for standard‑of‑care comparators may be subject to uncertainty. However, the data presented suggests that rates of grade ≥3 adverse events are broadly similar between the two groups and so it would seem reasonable to assume that adverse treatment costs for trametinib and standard‑of‑care comparator treatments would also be of a similar magnitude.

The administration costs for oral medicines was assumed to be zero. However, oral treatments maybe associated with administration costs that may differ depending on healthcare setting.

Cost effectiveness discussion

There is no direct comparative evidence of cost-effectiveness. The cost-effectiveness analysis conducted from the US payer perspective has limited generalisability to the UK based on differences in treatment and service costs. The utility used in the model was sourced from previous studies, and might not accurately represent the utility in the GOC 281/LOGS study¹¹. Although goodness of fit parameter distribution was tested based on the AIC, there is still inherent uncertainty in the extrapolated survival curve¹¹.

The NHSScotland cost-comparison analysis used the QALY gain (0.58) from the Piao et al. study to calculate an ICER of £19,386 per QALY gained, based on list prices². If the same QALY gain is applied to the results of the cost comparison analysis for NHS Wales given in Table 4, an ICER of [commercial in confidence figure removed] per QALY gained (using comparator list prices) or [commercial in confidence figure removed] per QALY gained (using comparator NHS Wales contract prices) results, based on the PAS price for trametinib. However, as stated in the NCMAG report, this naïve calculation which is based on simplistic assumption, is for illustrative purposes only and should be interpreted with caution. The calculation for incremental costs accounts for first year of treatment only; hence, it assumes no additional costs for remainder of the modelled lifetime. In addition, the clinical efficacy of the standard‑of‑care comparator treatments used in NHS Wales is assumed to be the same as that observed for the standard-of-care arm in the GOG 281/LOGS study.

In summary, the cost comparison indicated that trametinib is a cost-increasing intervention compared to the usual standard of care treatments offered to patients in Wales with LGSOC that has progressed after at least one previous platinum-based regimen. The clinical evidence supports the clinical effectiveness of trametinib for this patient population but in the absence of direct comparative efficacy between trametinib and comparative standard‑of‑care treatments used in NHS Wales, it is difficult to quantify treatment benefits in relation to costs. Therefore, the actual cost‑effectiveness of trametinib for this indication remains unknown.

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Budget impact

Clinicians in Wales estimate that 13 patients with LGSOC in Wales per year would receive treatment with trametinib. Budget impact has been calculated based on the proposed daily dosing regimen 2 mg trametinib taken orally once daily as part of a 28-day cycle, for 8 cycles. Trametinib would displace standard-of-care treatment options; details of standard-of-care regimens used in NHS Wales and the proportion of patients expected to receive each treatment are given in Table 2.

Medicine acquisition costs, administration, monitoring and adverse event treatment costs for trametinib and the standard-of-care comparators per patient are given in Table 3. Costs for the standard-of-care medicines considered as an NHS Wales standard‑of‑care basket were calculated based on weighted average methodology using proportion of patients for each regimen and are given in Table 4.

For the budget impact, standard-of-care comparator costs have used All Wales contract prices where applicable. Trametinib has been costed at the PAS price available to NHS Wales. Based on results of GOG 281/LOGS study, the median duration of all treatment regimens for this patient population is expected to range from 2 to 10 cycles. Therefore, it is assumed that patients would not continue treatment after Year 1 and so the annual budget impact is assumed to remain the same in subsequent years.

Table 5. Estimated net annual cost for trametinib versus NHS Wales standard of care (opens image in new tab)

The introduction of trametinib to treat recurrent LGSOC in Wales will increase the spend for this patient group. Based on an estimated uptake of 13 patients receiving 8 cycles of trametinib, the annual net budget impact is expected to be [commercial in confidence figure removed] more, assuming full displacement of all NHS Wales standard-of-care treatments.

Budget impact issues

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Equality and health impact assessment

AWTTC have completed an Equality and Health Impact Assessment in parallel with each development stage of the project. This follows the five ways of working for public bodies, and work to achieving the wellbeing goals, outlined in the Well‑Being of Future Generations (Wales) Act 2015. No potential negative impacts were identified.

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Additional factors

Prescribing unlicensed medicines

Trametinib (Mekinist^® ) is not licensed to treat this indication and is therefore prescribed ‘off label’. Prescribers should consult their relevant guidelines on prescribing unlicensed medicines before any off-label medicines are prescribed.  

Care has been taken to ensure the information is accurate and complete at the time of publication. However, the All Wales Therapeutics and Toxicology Centre (AWTTC) do not make any guarantees to that effect. The information in this document is subject to review and may be updated or withdrawn at any time. AWTTC accept no liability in association with the use of its content. 

Information presented in this document can be reproduced using the following citation: All Wales Therapeutics & Toxicology Centre. Evidence Status Report. Assessment of trametinib for the treatment of recurrent low grade serous ovarian carcinoma OW30. 2025.
Copyright AWTTC 2025. All rights reserved.

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References

1. NHS England. Clinical commissioning policy. Trametinib in recurrent or progressive low grade serous ovarian cancer (adults).  Nov 2023. Available at: https://www.england.nhs.uk/publication/clinical-commissioning-policy-trametinib-in-recurrent-or-progressive-low-grade-serous-ovarian-cancer/. Accessed Apr 2025.
2. NHS Scotland, and Healthcare Improvement Scotland. National Cancer Medicines Advisory Group (NCMAG) programme: NCMAG118 trametinib. Advice Document v1.0.  Oct 2024. Available at: https://www.healthcareimprovementscotland.scot/publications/ncmag118-trametinib-advice-document-october-2024/. Accessed Apr 2025.
3. National Institute for Health and Care Excellence. NICE Guideline, NG161. COVID-19 rapid guideline: delivery of systemic anticancer treatments.  Mar 2020 (updated Aug 2022). Available at: https://www.nice.org.uk/guidance/ng161. Accessed Apr 2025.
4. Novartis Pharmaceuticals UK Ltd. Mekinist^®. 2 mg film-coated tablets. Summary of Product Characteristics.  Dec 2024. Available at: https://www.medicines.org.uk/emc/product/5072/smpc. Accessed Apr 2025.
5. Gonzalez-Martin A, Harter P, Leary A et al. Newly diagnosed and relapsed epithelial ovarian cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Annals of Oncology. 2023;34(10):833-848.
6. Gershenson DM, Miller A, Brady WE et al. Trametinib versus standard of care in patients with recurrent low-grade serous ovarian cancer (GOG 281/LOGS): an international, randomised, open-label, multicentre phase 2/3 trial. The Lancet. 2022;399:541-553.
7. Gockley A, Melamed A, Bregar AJ et al. Outcomes of women with high-grade and low-grade advanced-stage serous epithelial ovarian cancer. Obstetrics & Gynecology. 2017;129(3):439-447.
8. Public Health Wales. Cancer Reporting Tool Wales.  Mar 2025. Available at: https://publichealthwales.shinyapps.io/Cancer_Reporting_Tool_PHW/. Accessed Apr 2025.
9. National Institute for Health and Care Excellence. Technology Appraisal TA389. Topotecan, pegylated liposomal doxorubicin hydrochloride, paclitaxel, trabectedin and gemcitabine for treating recurrent ovarian cancer.  Apr 2016. Available at: https://www.nice.org.uk/guidance/ta389. Accessed Apr 2025.
10. Armstrong DK, Alvarez RD, Backes FJ et al. Ovarian cancer, version 3.2022. Featured updates to the NCCN guidelines. Journal of the National Comprehensive Cancer Network. 2022;20(9):972-980.
11. Piao H, Wu M, Qin S et al. Trametinib for patients with recurrent low-grade serous ovarian cancer: a cost-effectiveness analysis. Gynecologic Oncology. 2023;168:17-22.
12. Nica A, Lee JYJ, Hong NL et al. Cost-effectiveness of maintenance hormonal therapy in patients with advanced low grade serous ovarian cancer. Gynecologic Oncology. 2021;160(1):206-213.
13. BMJ Group and the Royal Pharmaceutical Society. British National Formulary. Mar 2025. Available at: https://www.medicinescomplete.com/mc/bnf/current/. Accessed Apr 2025.
14. Sacco JJ, Botten J, Macbeth F et al. The average body surface area of adult cancer patients in the UK: a multicentre retrospective study. PLoS One. 2010;5(1):e8933.
15. NHS England. 2023/24 National Cost Collection Data Publication.  Nov 2024. Available at: https://www.england.nhs.uk/publication/2023-24-national-cost-collection-data-publication/. Accessed Feb 2025.
16. Haddaway NR, Page MJ, Pritchard CC et al. PRISMA2020: An R package and Shiny app for producing PRISMA 2020-compliant flow diagrams, with interactivity for optimised digital transparency and Open Synthesis. Campbell Systematic Reviews. 2022;18(2):e1230. Accessed Apr 2025.

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• Original assessment: OWMAG recommendation with starting and stopping criteria June 2025 PDF 74KB
• Original assessment: OWMAG decision rationale June 2025 PDF 56KB
• Original assessment: Evidence Status Report June 2025 PDF 187KB
• Original assessment: Equality and Health Impact Assessment June 2025 PDF 144KB