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Beth benderfynodd Grŵp Asesu Meddyginiaethau Cymru’n Un?

Gellir rhoi nivolumab ac ipilimumab gyda'i gilydd i drin math o ganser y croen o'r enw melanoma. Gellir ond cynnig y meddyginiaethau hyn i bobl â melanoma cam 3 y gellir eu tynnu gyda llawdriniaeth, y mae eu melanoma wedi lledaenu i o leiaf un nod lymff, ac sydd â hyd at dri dyddodion o felanoma yn agos at y man lle dechreuodd y melanoma gwreiddiol. Rhoddir Nivolumab ac ipilimumab cyn y llawdriniaeth i helpu i leihau maint y melanoma cyn iddo gael ei dynnu..

Bydd Nivolumab ac ipilimumab 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 Nivolumab ac ipilimumab wedi'u trwyddedu i'w defnyddio cyn llawdriniaeth ar gyfer melanoma, felly gelwir eu defnyddio gyda'i gilydd yn y modd hwn yn ddefnydd 'oddi ar y label'. 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.

I gael rhagor o wybodaeth am felanoma ewch i: Melanoma Focus (Saesneg yn unig)

 

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What did the One Wales Medicines Assessment Group decide?

Nivolumab and ipilimumab can be given together to treat a type of skin cancer called melanoma. These medicines can only be offered to people with stage 3 melanoma that can be removed with surgery, whose melanoma has spread to at least one lymph node, and who have up to three deposits of melanoma close to where the original melanoma started. Nivolumab and ipilimumab are given before the surgery to help shrink the size of the melanoma before it is removed.

Nivolumab and ipilimumab 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.

Nivolumab and ipilimumab are not licensed for use before surgery for melanoma, so using them together in this way 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 melanoma visit: Melanoma Focus

Medicine: nivolumab plus ipilimumab (Opdivo^® plus Yervoy^®)

Indication: neoadjuvant treatment of patients with resectable macroscopic stage III melanoma with ≥1 pathologically proven lymph node metastasis and up to 3 in-transit metastases (OW35)

Meeting date: 9 February 2026

Criterion: Clinical effectiveness and safety

OWMAG opinion OWMAG noted that the NHS Wales Cancer Network Immunotherapy Group had identified an unmet clinical need for a neoadjuvant treatment option for resectable macroscopic stage III melanoma with ≥1 pathologically proven lymph node metastasis and up to 3 in-transit metastases in NHS Wales. Currently, treatment for resectable stage III melanoma in NHS Wales is surgery, followed by adjuvant therapy with either sub-cutaneous (SC) nivolumab every 4 weeks for 13 cycles, IV pembrolizumab every 6 weeks for 9 cycles, or oral dabrafenib plus trametinib daily for 13 x 4-week cycles. The intervention under request is nivolumab IV plus ipilimumab IV every 3 weeks for 2 cycles, followed by surgery. For those patients who have a major pathological response to the neoadjuvant treatment, adjuvant treatment would not be required post-surgery. OWMAG considered the evidence provided by the pivotal NADINA study, which is deemed the most relevant source of evidence pertinent to the assessment. The group noted the favourable event-free survival, pathological response rates and estimated 12-month recurrence-free survival rates in patients who received neoadjuvant nivolumab plus ipilimumab in the NADINA study. The group acknowledged the treatment-sparing potential of neoadjuvant nivolumab plus ipilimumab, as 59% of patients who received this treatment in the NADINA study achieved a major pathological response and did not require adjuvant treatment. OWMAG considered updated data from the NADINA study, presented at conference, which was shared by a clinical expert. They reported that the event free survival (EFS) was 20% higher in the neoadjuvant group versus the adjuvant group, suggesting that the benefits of neoadjuvant treatment are greater than those patients who would have otherwise received adjuvant treatment in accordance with current standard of care (SOC). The group also noted the supporting clinical trials that provide evidence to supplement the NADINA study. OWMAG acknowledged that, although neoadjuvant nivolumab plus ipilimumab is not currently surgery-sparing, a supporting study suggests that it may be feasible for surgery to be safely omitted in patients achieving a major pathological response to neoadjuvant treatment in the future. OWMAG noted that the comparative evidence provided by the NADINA study is limited to one NHS Wales SOC treatment regimen. Due to the similar efficacy and safety profiles of the SOC treatment regimens, the group felt that the study’s findings were generalisable to NHS Wales. OWMAG considered the safety profile of neoadjuvant nivolumab plus ipilimumab. The most frequently reported severe adverse effects were acknowledged, which were raised aspartate aminotransferase, raised alanine aminotransferase, diarrhoea, adrenal insufficiency, and colitis. These were comparable to the expected safety profile for the medicines. OWMAG concluded that the pathological response, EFS, and RFS rates reported in the NADINA and supporting studies suggests that neoadjuvant nivolumab plus ipilimumab is a clinically effective treatment for stage III melanoma. The consistency between the safety findings in the clinical studies and SmPC suggests that the off-label use of nivolumab plus ipilimumab is a tolerable treatment regimen.

Criterion: Cost-effectiveness

OWMAG opinion OWMAG did not consider the cost-effectiveness of the treatment, as no cost-effectiveness evidence was identified in the literature and AWTTC did not conduct a cost-effectiveness analysis. OWMAG consider that the likely costs associated with using nivolumab plus ipilimumab for this indication would be reasonable in considering the potential benefit gained from this intervention. Noting that this regimen is cost saving when compared to SOC.

Criterion: Budget impact

OWMAG opinion OWMAG considered the estimated patient numbers provided by clinicians to be reasonable. The addition of neoadjuvant nivolumab plus ipilimumab is anticipated to decrease the spend associated with this patient group in Wales. This is based on an estimated uptake of 41 patients receiving treatment per year and assumes full displacement of comparator adjuvant treatment. This took in to account an estimate of the proportion of patients currently receiving each of the adjuvant treatments in Wales, the proportion of patients who would not obtain a major pathological response and would require adjuvant treatment, grade 3 or  higher adverse events treatment costs as reported across the NADINA and relevant adjuvant clinical studies, monitoring costs and administration costs.  Uncertainty around the number of patients that currently receive each NHS Wales SOC treatment regimen, and who are estimated to receive neoadjuvant nivolumab plus ipilimumab, was acknowledged by OWMAG. OWMAG raised uncertainties around the approach underpinning the budget impact. OWMAG noted that long-term treatment costs are not accounted for, and the adverse event costs are associated with uncertainties. OWMAG noted that variation in the types of adverse events, their severity, and management could increase or decrease the budget impact. However, these factors were deemed to be unlikely to make a material difference on the clear cost benefit in removing the need for adjuvant treatment in those patients who had a major pathological response. Also there is emerging evidence that patients who receive neoadjuvant treatment respond better longer term and therefore are less likely to accrue longer term treatment costs. Whilst understanding the limitations presented, OWMAG consider that the budget impact provides a reasonable estimate of the associated costs to NHS Wales. Recognising that this regimen would be cost saving when compared to SOC, OWMAG consider nivolumab plus ipilimumab to be a reasonable use of NHS resources.

Criterion: Resource use

OWMAG opinion OWMAG recognises that neoadjuvant treatment with nivolumab plus ipilimumab requires additional resources compared to SOC treatment, including a baseline electrocardiogram, an additional Computerised Tomography (CT) scan prior to surgery, and additional pathology reporting post-surgery. Due to the higher rates of severe adverse events that are associated with the neoadjuvant treatment, OWMAG recognised that there may be a greater rate of hospital admissions compared to SOC treatment, resulting in higher resource use in the short term. However, the group agreed that the neoadjuvant treatment may reduce the longer-term burden of adverse events associated with adjuvant treatment in patients who achieve a major pathological response, which would reduce resource use. The group acknowledge that, despite the additional resource requirements associated with neoadjuvant treatment in the short term, the potential to avoid adjuvant treatment in approximate 59% patients would reduce the number of clinic appointments required in the long term. The group discussed the potential surgery-sparing effects of the treatment, which would further reduce the resource burden in the longer term. OWMAG acknowledge that alignment between surgical and oncology multi-disciplinary teams would be essential to ensure that surgery is performed in a timely manner. OWMAG noted that this will be more challenging in north Wales as the surgery takes place in England.

Criterion: Other factors

OWMAG opinion There are currently no UK-licenced neoadjuvant treatment options for this indication. In Scotland, the National Cancer Medicines Advisory Group support the off-label use of nivolumab in combination with ipilimumab for the neoadjuvant treatment of resectable stage III melanoma. Therefore, the treatment is available to eligible patients in Scotland. OMWAG were informed by the Melanoma Focus representative that neoadjuvant nivolumab plus ipilimumab is also available to eligible patients in Northern Ireland. From an international standpoint, the European Society for Medical Oncology, the American Society of Clinical Oncology, The National Comprehensive Cancer Network®, and the European Association of Dermato-Oncology recommend both neoadjuvant treatment (followed by adjuvant treatment where required) and resection followed by adjuvant treatment for patients with resectable stage III melanoma.

Final recommendation

OWMAG recommends the use of nivolumab plus ipilimumab for neoadjuvant treatment of patients with resectable macroscopic stage III melanoma with ≥1 pathologically proven lymph node metastasis and up to 3 in-transit metastases. This recommendation is subject to the development of appropriate start/stop criteria.

Summary of rationale

OWMAG recognise that there is a clinical need for a neoadjuvant treatment option for this indication in Wales, particularly as there are currently no UK-licenced treatments available. OWMAG concluded that, based on the evidence provided by the NADINA study, the treatment is likely to reduce the treatment burden for patients, particularly for those achieving a major pathological response. OWMAG acknowledged that a lower treatment burden benefits both the patient, and NHS Wales due to lower medicine acquisition, medicine administration, and healthcare resource costs. The group consider the budget impact presented to demonstrate a reasonable use of NHS resources. The review after 12 months will provide the number of patients who have received this treatment in Wales and more evidence on whether this is an effective treatment for this patient population.

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Key findings

Licence status: Nivolumab plus ipilimumab (Opdivo^® plus Yervoy^®) is not licensed for neoadjuvant treatment of patients with resectable macroscopic stage III melanoma with ≥ 1 pathologically proven lymph node metastasis and up to 3 in-transit metastases; its use for this indication is off-label.

Clinical evidence: The clinical evidence supporting this treatment is primarily provided by the NADINA study (Blank et al. 2024), where 59% of patients treated with neoadjuvant therapy had a major pathological response, with an estimated 12-month recurrence-free survival and event-free survival of 95% and 84%, respectively. The adjuvant treatment arm of this study is considered comparable to current standard of care in Wales, therefore the evidence is considered generalisable.

Safety: No new safety signals have emerged for nivolumab plus ipilimumab for this indication.

Patient factors: Response rates did not differ significantly between BRAF V600 positive and wild-type patient subgroups. A major pathological response was achieved in 59% of patients and adjuvant therapy was not required, highlighting the potential treatment-sparing effect of this neoadjuvant therapy.

Cost effectiveness: No cost-effectiveness evidence was identified for this use of nivolumab plus ipilimumab, and no cost-effectiveness analyses have been undertaken for this indication.

Budget impact: The addition of neoadjuvant nivolumab plus ipilimumab is estimated to decrease the spend associated with this patient group in Wales by [commercial in confidence text removed] per year. This is based on an estimated uptake of 41 patients receiving treatment per year and assumes full displacement of comparator adjuvant treatment.

Impact on health and social care services: As patients achieving a major pathological response would not require adjuvant therapy, the number of outpatient clinic appointments would reduce. A baseline electrocardiogram, an additional computerised tomography (CT) scan prior to surgery, and additional pathology reporting post-surgery would be required for patients receiving neoadjuvant treatment.

Innovation and/or advantages: There are currently no UK-licensed neoadjuvant treatment options for this indication. The treatment is likely to reduce the treatment burden for patients, particularly for those achieving a major pathological response. A lower treatment burden benefits both the patient, and NHS Wales due to lower medicine acquisition, medicine administration, and healthcare resource costs.

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Background

Melanoma is a type of skin cancer arising from melanocytes within the skin. In stage III melanoma, melanoma cells have spread into the skin, lymph vessels, or lymph glands¹. In-transit metastases are melanoma cells that have spread more than 2 cm from the primary melanoma but not as far as the nearest lymph node¹.

The current treatment pathway for resectable macroscopic stage III melanoma in Wales is resection surgery, followed by adjuvant immunotherapy. The NHS Wales Cancer Network Immunotherapy Group (from here, the Group) identified an unmet clinical need for a neoadjuvant treatment option in NHS Wales, which would be treatment sparing for some patients. Therefore, neoadjuvant treatment with nivolumab plus ipilimumab was considered suitable for assessment though the One Wales medicines process.

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Target group

The indication under consideration is resectable macroscopic stage III melanoma with ≥ 1 pathologically proven lymph node metastasis and up to 3 in-transit metastases in adults.

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Marketing authorisation date

Not applicable for this indication, off-label. 

Nivolumab plus ipilimumab (Opdivo^® plus Yervoy^®) is not licensed for the indication under consideration.

[Commercial in confidence text removed].

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Dosing information

The neoadjuvant regimen proposed by the Group is 240 mg of nivolumab plus 80 mg of ipilimumab administered by intravenous infusion every three weeks for a total of two cycles prior to surgery. For patients who achieve a complete pathological response, no further treatment is indicated after surgery. For patients who achieve a partial or non-pathological response, adjuvant treatment is indicated and is determined by the tumour’s BRAF status.

For patients harbouring a BRAF wild-type tumour, the Group propose adjuvant treatment with 480 mg of nivolumab administered intravenously, or 1,200 mg of nivolumab administered sub-cutaneously, every 4 weeks for 11 cycles. For patients harbouring a BRAF V600 mutation-positive melanoma, adjuvant treatment with 150 mg of oral dabrafenib twice daily, plus 2 mg of oral trametinib once daily, for 46 weeks is proposed by the Group. 

Both the neoadjuvant and adjuvant regimens are derived from the pivotal NADINA study². The adjuvant treatment regimens’ doses are consistent with their respective marketing authorisations^3-6.

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Clinical background

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Incidence/prevalence

Overall, the incidence of stage III melanoma gradually increased in Wales between 2011 and 2022⁸. In 2022, there were 1,170 new cases of melanoma of the skin recorded, of which 82 were stage III melanoma at diagnosis⁸.

The Group estimate that 51 patients would be eligible for treatment with neoadjuvant nivolumab plus ipilimumab per year, and a treatment uptake of 80% (41 patients per year).

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Current treatment options and relevant guidance

There are currently no UK-licensed treatment options for the neoadjuvant treatment of resectable stage III melanoma. The National Institute for Health and Care Excellence (NICE) recommends surgery followed by adjuvant treatment with nivolumab or pembrolizumab, or dabrafenib plus trametinib for BRAF mutation-positive patients¹⁰.

Currently, treatment for resectable stage III melanoma in NHS Wales is surgery, followed by adjuvant therapy with either intravenous (IV) or sub-cutaneous (SC) nivolumab, IV pembrolizumab, or oral dabrafenib plus trametinib. Details of the regimens and the proportion of patients estimated to receive each regimen are outlined in Appendix 3.

In Scotland, the National Cancer Medicines Advisory Group (NCMAG) support the off-label use of nivolumab in combination with ipilimumab for the neoadjuvant treatment of resectable stage III melanoma¹¹. In England, the use of off-label neoadjuvant plus adjuvant pembrolizumab treatment for patients with resectable stage III melanoma is under review¹². In Wales, the Group consider the assessment of neoadjuvant nivolumab plus ipilimumab a higher priority than the pembrolizumab regimen, due to its potential to mitigate the need for adjuvant treatment in a large cohort of patients.

From an international standpoint, the European Society for Medical Oncology (ESMO), the American Society of Clinical Oncology (ASCO), The National Comprehensive Cancer Network^® (NCCN), and the European Association of Dermato-Oncology (EADO) recommend both neoadjuvant treatment (followed by adjuvant treatment where required) and resection followed by adjuvant treatment for patients with resectable stage III melanoma^13-16. The choice of neoadjuvant treatment varies between the international guidelines, but the two main options are either neoadjuvant treatment with nivolumab plus ipilimumab followed by adjuvant therapy post-surgery based on pathological response and BRAF V600 mutation status, or neoadjuvant plus adjuvant treatment post-surgery with pembrolizumab.

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Summary of evidence on clinical effectiveness

The All Wales Therapeutics and Toxicology Centre (AWTTC) conducted a literature search during November 2025 to identify evidence concerning the use of nivolumab plus ipilimumab as neoadjuvant treatment for patients with resectable macroscopic stage III melanoma with ≥ 1 pathologically proven lymph node metastasis and up to 3 in-transit metastases.

Searches were performed using the Cochrane library, Central Register of Controlled Trials, EMBASE, MEDLINE and TRIP databases with the following search terms: nivolumab, OPDIVO, ipilimumab, YERVOY, melanoma, neoadjuvant therapy and resect(able). The primary outcomes were pathological response rate, overall survival, progression free survival, event free survival, overall response rate, adverse events/events, quality of life, and resource use.

A literature search identified 313 records which were assessed for eligibility, with 309 excluded following removal of duplicates and screening of title and abstracts. Following eligibility screening, 4 publications were included in the report (Appendix 1). These include the OpACIN study (with one 47-month follow-up study and the PRADO extension cohort) and the NADINA study (Blank et al. 2024) ADDIN EN.CITE.DATA ^2,17-19. Any remaining records were excluded due to unsuitable study designs, small patient numbers, unclear outcome data or conference abstracts.

Of the included studies, the randomised controlled trial by Blank et al. 2024 was deemed the most relevant source of evidence pertinent to the indication in this report and was included in the main analysis. The remaining supporting studies supplement the findings of the NADINA study and are summarised in Appendix 2.

Efficacy

Blank et al. 2024 (NADINA Trial, NCT04949113) conducted a phase III, multicentred, open-label, controlled trial to compare neoadjuvant with adjuvant immunotherapy². The neoadjuvant group comprised of 212 patients (median age of 60 years; range 22-84). The adjuvant group comprised of 211 patients (median age of 59 years; range 19-87). Baseline characteristics were balanced between the groups.

The neoadjuvant group received nivolumab 240 mg intravenously (IV) plus ipilimumab 80 mg IV every 3 weeks for 2 cycles, followed by surgery. Patients achieving a major pathological response did not receive adjuvant treatment. Patients achieving a partial or non-pathological response received adjuvant nivolumab 480 mg IV every 4 weeks for 11 cycles (BRAF wild-type) or adjuvant oral dabrafenib 150 mg twice daily plus trametinib 2 mg once daily for 46 weeks (BRAF V600 mutation-positive). The adjuvant group underwent surgery and received adjuvant treatment with nivolumab IV 480 mg every 4 weeks for 12 cycles, starting between week 6 and 12 (regardless of BRAF status).

The primary outcome was event-free survival (EFS): the time from randomisation to the occurrence of progression to unresectable melanoma before surgery, disease recurrence, or death due to melanoma or treatment. Results are given in Table 1.

At the time of data cutoff, the median duration of follow up was 10.6 months (interquartile range [IQR] 5.2 to 16.8) in the neoadjuvant group and 9.9 months (IQR 4.6 to 16.8) in the adjuvant group.

Table 1. Primary outcome from the NADINA study (opens image in new tab) 

The secondary outcomes were overall survival (OS), recurrence-free survival (RFS), distant metastasis–free survival (DMFS), pathological response, safety measures, and measures of health-related quality of life (HRQoL). Follow-up is ongoing for the assessment of long-term EFS and DMFS, HRQoL, and OS, and outcomes have not yet been published in a peer-reviewed journal.

The pathological response rates and estimated 12-month RFS rates reported for the neoadjuvant group are outlined in Table 2. The assessment of pathological response was conducted according to the International Neoadjuvant Melanoma Consortium criteria by the local pathologist, followed by retrospective central review. A major pathological response (≤ 10% residual viable tumour) was achieved by 59% of patients with 47.2% achieving a pathological complete response (0% residual viable tumour) and 11.8% a pathological near-complete response.

Table 2. Pathological response rates to neoadjuvant arm reported in the NADINA study (opens image in new tab) 

Progression was reported in 2.4% of patients, and surgery was omitted or not yet performed in the remaining 4.2%.

BRAF mutation status did not appear to markedly influence EFS or pathological response. The estimated 12-month EFS was 83.5% (99.9% CI, 70.3 to 99.2) and 83.9% (99.9% CI, 70.1 to 99.9) in patients with a BRAF V600 mutation and BRAF wild-type melanoma, respectively. A major pathological response was achieved by 53.8% and 65.3% of patients with a BRAF V600 mutation and BRAF wild-type melanoma, respectively.

Safety

Discussion

The primary outcome for the NADINA study was met, demonstrating that neoadjuvant nivolumab plus ipilimumab improved 12-month EFS compared to adjuvant nivolumab (83.7% versus 57.2%). Adjuvant treatment was not required in 59% of patients in the neoadjuvant group who achieved a major pathological response, and the estimated 12-month RFS was 95.1% for these patients. BRAF mutation status did not appear to markedly influence EFS or pathological response.

Median follow-up was approximately 10 months for the NADINA study, a relatively short duration. However, the findings align with the efficacy reported in the preceding OpACIN-neo and PRADO studies which are associated with longer follow up^17-19. Although the preceding single-arm studies differ slightly in population and treatment regimens from NADINA (see Appendix 2 for details), there is sufficient comparability to provide supportive evidence for the treatment under consideration.

A major pathological response was achieved by 63.3% and 61% of applicable patients in the OpACIN-neo and PRADO studies, respectively^17-19. The PRADO trial reported a 24-month RFS rate of 93%, 64% and 71% in patients who achieved a major, partial, and non-pathological response, respectively¹⁷. A survival update of the OpACIN-neo study reported an estimated 3-year EFS rate and RFS rate of 77% and 79%, respectively¹⁹. Unlike the NADINA and PRADO studies, the RFS analysis was not subdivided according to pathological response category.

The most frequently reported treatment-related grade 3-4 AEs reported in all three studies are consistent with the SmPC for nivolumab and ipilimumab. As per the NADINA study, the most frequently reported systemic treatment-related grade 3 or higher AE in the PRADO study were increased ALT (7%), increased AST (6%), diarrhoea (5%) and colitis (4%)¹⁷. In the OpACIN-NEO study, none of the grade 3 or higher immune-related AE were observed in more than one patient in the applicable treatment group, which included increased ALT, increased AST, and diarrhoea^18,19.

In the NADINA study, AEs were reported more often for the neoadjuvant treatment group compared to the adjuvant group. This finding aligns with nivolumab’s SmPC, which reports that immune‑related adverse reactions have occurred at higher frequencies when nivolumab was administered in combination with ipilimumab compared with nivolumab as monotherapy.

Overall, favourable pathological response, EFS, and RFS rates reported in the NADINA and supporting studies suggests that neoadjuvant nivolumab plus ipilimumab is a clinically effective treatment for stage III melanoma. The consistency between the safety findings in the clinical studies and SmPC suggests that the off‑label use of nivolumab plus ipilimumab is generally a tolerable treatment regimen.

Service impact

As adjuvant treatment can be omitted in patients who achieve a major pathological response, neoadjuvant nivolumab plus ipilimumab is likely to reduce the number of outpatient appointments required by the patient population.

The PRADO study showed that therapeutic lymph node dissection and adjuvant treatment could be omitted in patients who achieved a major pathological response following neoadjuvant treatment with nivolumab plus ipilimumab. The patient outcomes were encouraging, as reported above and in Appendix 2. Therefore, neoadjuvant nivolumab plus ipilimumab may offer further benefits to patients and the service in the future due to its potential to be surgery-sparing. A phase II study (NCT06754904) aims to investigate the surgery-sparing potential of neoadjuvant nivolumab and ipilimumab further, which is due to complete in 2032²⁰.

Due to the higher rates of grade 3–4 AEs that are associated with neoadjuvant treatment, there may be a greater rate of hospital admissions compared to standard of care (SOC) treatment. The budget impact of this, in addition to additional service requirements required by neoadjuvant treatment, are detailed in the budget impact section. Although neoadjuvant treatment is associated with a greater risk of grade 3–4 AEs in the short term, the treatment may reduce the longer-term burden of AEs associated with adjuvant treatment in patients who achieve a major pathological response.

Study design and generalisability to NHS Wales

The NADINA study is a phase III randomised controlled trial informed by the findings of the earlier OpACIN-neo and PRADO phase II studies². Stratified randomisation of patients minimised selection bias and ensured that confounding factors were accounted for e.g. age or BRAF mutational status, giving the trial design good credibility. However, the ‘open-label’ design of this study increased the risk of performance and reporting bias among the patients and researchers.

The NADINA study compared neoadjuvant treatment with adjuvant nivolumab, administered intravenously. In NHS Wales, SOC adjuvant nivolumab is administered subcutaneously. However, due to the comparable pharmacokinetics, objective response rates and safety profile of nivolumab when given both intravenously and subcutaneously, it can be assumed that the findings are generalisable to the NHS Wales population who receive SOC adjuvant nivolumab treatment.

The NADINA study compares neoadjuvant treatment with adjuvant nivolumab. As clinicians estimate that only 10% of patients in NHS Wales currently receive SOC adjuvant nivolumab, with the remainder receiving pembrolizumab or dabrafenib plus trametinib, the generalisability of the findings to the wider NHS Wales population appears limited.

Although there are no published studies directly comparing the efficacy of each adjuvant treatment option, indirect comparisons suggest comparable effectiveness. Long-term follow up of the pivotal studies that supported the use of nivolumab and pembrolizumab in the adjuvant treatment of stage III melanoma (both BRAF-mutation positive and wild-type) reported similar RFS rates. A follow-up of the CheckMate 238 study reported a 4-year RFS rate of 51.7% (95% CI; 46.8 to 56.3, median follow-up 51.1 months, IQR 41.6 to 52.7) for nivolumab²¹. The KEYNOTE-054 follow-up reported a 5-year RFS rate of 55.4% (95% CI; 50.8 to 59.8, median follow-up 4.9 years) for pembrolizumab²². Furthermore, a propensity score matched survival analysis by Bloem et al. 2025 reported that no significant differences in outcomes were observed between patients with stage III BRAF-mutation positive melanoma treated with adjuvant immunotherapy versus dabrafenib plus trametinib²³. Due to the likely comparable efficacy of the SOC adjuvant treatments prescribed in NHS Wales, it can be assumed that the findings of the NADINA study are generalisable to NHS Wales.

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Patient organisation submission

The patient organisation Melanoma Focus has provided a submission to support this assessment. The main points of the submission are listed below:

• Melanoma is a highly curable cancer if diagnosed at an early stage, however if the disease progresses to stage IV with the usual spread of the disease to lungs, liver, bone and/or brain, distressing symptoms may occur.
• It is therefore important to minimise the likelihood of patients with stage III melanoma from progressing to stage IV in order to increase patients’ chances of survival or [improve] prognosis.
• The biggest fear for patients with stage III melanoma is their disease spreading to the brain, which causes significant anxiety. Caring for a loved one with melanoma can be emotionally draining as carers often have the same anxieties and fears. This is particularly concerning as there is often a considerable financial burden as many patients are economically active.
• The adjuvant treatments used routinely in the UK include pembrolizumab or nivolumab, which are immune checkpoint inhibitors, and dabrafenib in combination with trametinib, which is a targeted therapy treatment against the BRAF mutation that is present in about 40% of melanomas.
• The NADINA phase 3 neoadjuvant trial showed that by giving 2 cycles of ipilimumab and nivolumab prior to surgery in patients with high-risk stage 3 melanoma, the risk of the melanoma returning is reduced by an additional 28% after a median 9.9 month follow up. 
• This study provided the option to stop treatment dependent upon response and 60% of patients did not require further adjuvant treatment, allowing patients to continue with their lives without the need for a year of treatment and the risk of further side effects.

Melanoma UK are another patient organisation who represent individuals affected by melanoma across the UK and were supportive of this assessment. Their submission states that patients with stage III melanoma voice concerns regarding limited treatment options and experience anxiety surrounding the risk of recurrence after surgery. From a patient perspective, access to effective neoadjuvant therapy would represent an important opportunity to improve long-term outcomes and reduce uncertainty that many patients experience.

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Cost-effectiveness evidence

No cost-effectiveness evidence was identified for this indication. A cost effectiveness analysis was not undertaken by AWTTC.

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Budget impact

In the absence of cost-effectiveness data and analysis, a comprehensive budget impact was undertaken which considered medicine acquisition, medicine administration, healthcare resource, and adverse event costs.

Treatment regimens for the proposed nivolumab plus ipilimumab neoadjuvant treatment and for SOC pathways are detailed in Appendix 3. Medicine acquisition costs were based on the confidential Patient Access Scheme (PAS) prices for each medicine. Treatment durations were informed by the NADINA study and validated with clinical expert opinion. The administration costs were based on the costs of delivering parenteral chemotherapy in line with the NHS England National Cost Data Publication²⁴.

Healthcare resource costs were sourced from the NHS England National Cost Data Publication. Clinical experts determined that a baseline electrocardiogram, an additional Computerised Tomography (CT) scan prior to surgery, and additional pathology reporting post-surgery would be required for patients receiving neoadjuvant treatment²⁴. The cost of one consultant-led multi-professional attendance was included for each cycle in both the NHS Wales SOC and neoadjuvant treatment arms.

The AE costs comprised the most frequently reported systemic treatment-related grade 3 or higher AEs in the NADINA study: raised ALT, raised AST, diarrhoea, adrenal insufficiency, and colitis². The cost of these adverse events for the adjuvant treatments was derived from the NADINA (nivolumab monotherapy and nivolumab plus ipilimumab), COMBI-AD (dabrafenib plus trametinib), and KEYNOTE-054 (pembrolizumab) studies, using the individual AE rates reported by each study^2,22,25. The cost of a short, non-elective inpatient stay was considered appropriate to represent the adverse event costs (£753), which was sourced from the NHS England Cost Collection Index 2024/25²⁴.

Table 3 details the costs associated with each treatment regimen, per patient. Table 4 outlines the total cost the treatment under consideration and SOC treatment, according to the proportion of patients that are estimated to receive each treatment (as per clinician input and results of the NADINA study). Clinicians estimate that 51 patients will be eligible for treatment per annum. Of the eligible group, 41 patients (80%) are estimated to go on to receive treatment.

The NHS Healthcare Resource Group codes and associated costs that were used in the budget impact section are summarised in Appendix 4.

Table 3. Costs per patient, per regimen, per year (opens image in new tab) 

Table 4. Costs per patient population, per regimen, per year (opens image in new tab) 

Table 5 outlines the total costs associated with SOC treatment and the treatment under consideration for eligible patients in NHS Wales. Table 5 highlights that the main source of cost saving is the avoidance of adjuvant treatment in 59% of patients receiving neoadjuvant treatment and the higher medicine acquisition cost of the NHS Wales SOC treatments.

Table 5. Comparison of costs for the treatment under consideration and its comparators (opens image in new tab) 

Discussion

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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. It is not expected that nivolumab plus ipilimumab will have a significant potential negative impact on people based on the protected characteristics of the Equality Act 2010.

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Additional factors

Prescribing unlicensed medicines

Nivolumab plus ipilimumab 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. Off-label nivolumab plus ipilimumab (Opdivo^® plus Yervoy^®) for the neoadjuvant treatment of patients with resectable macroscopic stage III melanoma with ≥1 pathologically proven lymph node metastasis and up to 3 in-transit metastases. Reference number: OW35. 2026.
Copyright AWTTC 2026. All rights reserved.

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References

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• Original assessment: OWMAG recommendation with starting and stopping criteria March 2026 PDF 105KB
• Original assessment: OWMAG decision rationale March 2026 PDF 34KB
• Original assessment: Evidence Status Report March 2026 PDF 194KB
• Original assessment: Equality and Health Impact Assessment March 2026 PDF 129KB