Reason for request

New indication

Key points

Favourable opinion for reimbursement in the first-line treatment of adult patients with unresectable malignant pleural mesothelioma. 

What therapeutic improvement?

Therapeutic improvement compared to pemetrexed and platinum-based chemotherapy.

Role in the care pathway?

Concerning the management of malignant pleural mesothelioma, analysis of prognostic factors reveals the favourable influence of an early stage (in particular, the absence of extrapleural lymph node involvement), epitheloid histology, female gender, adjuvant therapy (radiotherapy and chemotherapy) and the “complete” nature (maximalist surgery aimed at achieving macroscopically complete resection) of surgical resection on patients having undergone surgery. There is no standardised therapeutic strategy for stages in which surgical resection is possible. Surgical excision of the lung (pneumonectomy) makes it possible to envisage irradiation of the affected hemithorax, the aim being to reduce the frequency of local recurrences. Intensity modulated techniques, tomotherapy or arc therapy are strongly recommended in order to limit the risk of complications. Early prophylactic irradiation of the transparietal procedure openings may be proposed as an option to reduce the risk of parietal recurrence, although the European guidelines are not conclusive with respect to the benefit of this. Finally, radiotherapy can be used for palliative purposes due to its analgesic efficacy.

Malignant pleural mesothelioma is a tumour with relatively low sensitivity to chemotherapy. However, the early introduction of chemotherapy in unresectable forms appears to be preferable to delaying initiation until the development of symptoms in patients who are asymptomatic at the time of diagnosis. The anti-tumour activity of polychemotherapy is superior to that of monotherapy and highlights the pivotal role of cisplatin, which clearly emerges as the most active drug substance in terms of response rates. Since 2003, the cisplatin-pemetrexed combination has been considered to be the standard chemotherapy treatment for advanced forms of MPM and should be offered as first-line therapy for patients under the age of 75 years whose general condition is maintained. The MAPS clinical study conducted by the IFCT-GFPC also demonstrated an improvement in overall survival in these patients following the addition of bevacizumab to the cisplatin-pemetrexed combination, but bevacizumab currently has no MA in this indication.

Role of the medicinal product in the care pathway

The OPDIVO/YERVOY (nivolumab/ipilimumab) combination is a first-line treatment for unresectable malignant pleural mesothelioma (MPM). It has demonstrated its superiority in terms of overall survival compared to the cisplatin-pemetrexed combination. However, there is no data available having compared it to the bevacizumab (off-label) + cisplatin-pemetrexed combination, which has demonstrated an improvement in overall survival versus the cisplatin-pemetrexed combination in the first-line treatment of MPM.

Given the initially increased risk of death and progression (first 5 months for deaths and first 8 months for tumour progression) in patients having received the nivolumab/ipilimumab combination, compared to those having received chemotherapy, the Committee recommends cautious use of dual immunotherapy in patients at high risk of progression/early death. The Committee considers that the therapeutic decision should be taken after a documented proposal resulting from a multidisciplinary team meeting.



Clinical Benefit


The Committee considers that the clinical benefit of the YERVOY (nivolumab/ipilimumab) combination is substantial in the MA indication.

Clinical Added Value



  • demonstration of the superiority of the nivolumab + ipilimumab combination compared to chemotherapy alone (pemetrexed + platinum), in terms of overall survival, with an individual estimate of an absolute improvement of 4 months, HR = 0.74 [CI6%: 0.60-0.91], deemed to be clinically relevant in a randomised, open-label phase 3 study,

And despite:

  • the time to observation of an improvement in overall survival of more than 5 months (crossing over of survival curves at 5 months);
  • the difficulty in differentiating between the proportion attributable (efficacy and toxicity) to each immunotherapy (nivolumab/ipilimumab), and hence the specific value of the combination of these two drugs compared to monotherapy (nivolumab or ipilimumab) related to the design of the CHECKMATE 743 study;
  • the toxicity profile of nivolumab + ipilimumab, marked by:
    • the development of an immunological AE (mentioned in the SPC: the occurrence was more frequent when nivolumab was administered in combination with ipilimumab, compared to nivolumab as monotherapy), and infusion-related reactions;
    • the need to definitively stop treatment for 29.3% of patients in the nivolumab + ipilimumab group versus 20.4% in the chemotherapy group;

the Transparency Committee considers that the OPDIVO/YERVOY (nivolumab/ipilimumab) combination provides a minor clinical added value (CAV IV) compared to pemetrexed and platinum-based chemotherapy in the first-line treatment of adult patients with unresectable malignant pleural mesothelioma.

Avis économique

Ce produit a fait l'objet d'un avis économique rendu par la Commission d'évaluation économique et de santé publique le 29 mars 2022.

L’avis économique porte sur une indication superposable à celle demandée au remboursement, à savoir le traitement de première ligne en association à ipilimumab des patients adultes atteints d’un mésothéliome pleural malin non résécable, et couvre environ 80% de la prise en charge de l’indication, représentée par les deux traitements actuellement les plus prescrits. Sous les hypothèses retenues par l’industriel, nivolumab en association à ipilimumab est associé à un RDCR de 222 582 €/QALY gagné  versus l’association pemetrexed + sels de platine sur 7 ans.

L’impact budgétaire associé à l’introduction de nivolumab en association à ipilimumab représente une augmentation des dépenses de l’assurance maladie dans l’indication de 201%, pour une population cible de 5 807 patients cumulés sur 5 ans. Cet impact budgétaire est principalement porté par le poste d’acquisition des traitements qui augmente de 588% et qui représente 78% des dépenses totales. 

> Opdivo - Avis économique (pdf)


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