1590
type: MedicalGuidelineRecommendation
type: EssentialMedicineRecommendation
recognizing authority: World Health Organization
guideline date: 2025-05-09
guideline subject: TherapeuticProcedure
  code: MedicalCode
    code value: L01FF03
    coding system: ATC
  drug: durvalumab
  indication: Malignant neoplasms of proximal biliary tract, cystic duct
evidence origin: The Expert Committee recognized that cancer is a growing societal, public health and economic problem globally, and it is responsible for nearly one in three premature deaths from noncommunicable disease. The proportion of patients with advanced stage at first presentation is still substantial. Solid tumours that are amenable to effective therapy using PD-1/PD-L1 immune checkpoint inhibitors are a major cause of the rising burdens with respect to lives lost. The Committee recalled previous applications for immune checkpoint inhibitors. In 2019 nivolumab and pembrolizumab were recommended for listing for treatment of metastatic melanoma, a relatively rare cancer for which these medicines are extremely effective. In 2021 and 2023, applications for immune checkpoint inhibitors for treatment of metastatic NSCLC were not recommended, despite recognition of their relevant efficacy in prolonging life, due to their high costs. The Committee noted the rapid pace of innovation in immuno-oncology and emphasized the importance of reducing inequities in cancer care by increasing access to immune checkpoint inhibitors, adopting multiple strategies. In consideration of the application, the Expert Committee: • appreciated the approach taken by the WHO Collaborating Centre on Evidence Synthesis and Evaluation of Novel Cancer Therapies at the University of Cologne, Germany to identify the PD-1/PD-L1 immune checkpoint inhibitor–indication pairings proposed for EML listing from among the many such medicines that are approved and available, and considered that the approach taken was up-to-date, comprehensive, systematic, transparent and evidence based and provided a solid basis for its decision-making; • noted that all proposed pairings were approved by the European Medicines Agency for first-line treatment of adults for the therapeutic indications for which they are proposed, had evidence from randomized trials and received a score of four or higher on the European Society of Medical O…
evidence origin: Based on a prioritized selection of eight immune checkpoint inhibitors and 12 cancer types, the applicants conducted multiple systematic reviews of randomized controlled trials comparing treatments based on immune checkpoint inhibitors with the established standard of care in the palliative first-line setting. Patient-relevant outcomes of interest were overall survival, progression-free survival, quality of life and higher grade (≥ 3) adverse events. Biliary tract carcinoma irrespective of PD-L1 expression One randomized controlled trial of durvalumab plus chemotherapy versus chemotherapy alone was identified that evaluated treatment of unresectable advanced or metastatic biliary tract carcinoma (TOPAZ-1 (12, 13)). Of 685 randomized participants, 341 received durvalumab plus chemotherapy and 344 received chemotherapy. Durvalumab 1500 mg was administered intravenously on day 1, in combination with gemcitabine 1000 mg/m2 and cisplatin at 25 mg/m2 body-surface area on days 1 and 8, of eight 21-day cycles. After a median follow-up of 22.9 months, there was moderate-certainty evidence that durvalumab-containing regimens likely increase overall survival (hazard ratio (HR) for death 0.76, 95% confidence interval (CI) 0.64 to 0.91; one randomized controlled trial, 685 participants). In absolute terms, 56 versus 47 people per 100, respectively, on durvalumab plus chemotherapy or chemotherapy alone were alive at 1 year, 34 versus 24 people per 100 were alive at 1.5 years, and median overall survival gain was 3.6 months. After a median follow-up of 16.4 months, there was moderate-certainty evidence that durvalumab-containing regimens likely increased progression-free survival (HR for disease progression or death 0.75, 95% CI 0.63 to 0.89; one randomized controlled trial, 685 participants). In absolute terms, 12 versus 6 people per 100 were without disease progression at 1 year. There was moderate-certainty evidence that durvalumab-containing regimens likely have little to no e…
evidence origin: Biliary tract carcinoma irrespective of PD-L1 expression There was high-certainty evidence that durvalumab-containing regimens result in little to no difference in grade ≥ 3 adverse events (risk ratio (RR) 0.98, 95% CI 0.91 to 1.06; one randomized controlled trial, 680 participants). Cervical cancer with PD-L1 expression ≥ 1% There was moderate-certainty evidence that pembrolizumab-containing regimens likely increase grade ≥ 3 adverse events (RR 1.09, 95% CI 1.01 to 1.19; one randomized controlled trial, 616 participants). dMMR/MSI-H colorectal cancer There was low-certainty evidence that pembrolizumab monotherapy may reduce grade ≥ 3 adverse events (RR 0.72, 95% CI 0.61 to 0.85; one randomized controlled trial, 296 participants). dMMR/MSI-H endometrial cancer There was low-certainty evidence that dostarlimab-containing regimens may increase grade ≥ 3 adverse events (RR 1.20, 95% CI 1.06 to 1.36; one randomized controlled trial, 487 participants). HER2-negative gastric and gastro-oesophageal junction adenocarcinoma with PD-L1 expression CPS ≥ 1/CPS ≥ 5 There was low-certainty evidence that pembrolizumab-containing regimens may increase grade ≥ 3 adverse events (RR 1.11, 95% CI 1.01 to 1.23; two randomized controlled trials, 2066 participants). There was low-certainty evidence that nivolumab-containing regimens may increase grade ≥ 3 adverse events (RR 1.35, 95% CI 1.23 to 1.49; one randomized controlled trial, 1549 participants). Head and neck squamous cell carcinoma with PD-L1 expression CPS ≥ 1 There was moderate-certainty evidence that pembrolizumab-containing regimens likely result in little to no difference in grade ≥ 3 adverse events (RR 1.02, 95% CI 0.95 to 1.10; one randomized controlled trial, 563 participants). Hepatocellular carcinoma irrespective of PD-L1 expression For the comparison of atezolizumab plus bevacizumab versus sorafenib, there was very-low-certainty evidence that atezolizumab plus bevacizumab may result in little to no difference in grade ≥…
evidence origin: No evidence was presented in the application on costs or cost–effectiveness of the various interventions. A separate report, prepared by Arianna Schouten, Knowledge Ecology International, presented an analysis of financial implications of pembrolizumab and nivolumab and the potential impact of their inclusion on the EML (108). The report highlighted that immune checkpoint inhibitors are still prohibitively expensive, especially in low- and middle-income countries. The report explored the financial and policy landscape surrounding these medicines and discussed strategic pathways that can support improved affordability and access. Key patents for pembrolizumab and nivolumab are set to expire between 2028 and 2033, and subsequent market entry of biosimilars presents an important opportunity to reduce costs. Pembrolizumab has broader indications and a stronger biosimilar pipeline, and so is expected to face greater pricing pressure, potentially leading to price reductions of up to 60%. Nivolumab, with fewer indications and a less competitive pipeline, may see more moderate reductions of between 25% and 40%. However, biosimilar entry may be delayed by evergreening strategies employed by originator companies. These include the development of subcutaneous formulations (109), which can secure new patents and extend market exclusivity beyond the original expiry dates – potentially up to 2039 in the case of pembrolizumab. These strategies affect competition and may hinder timely access to biosimilars, especially in high-revenue markets. Policy-makers must weigh the trade-offs between supporting biosimilar intravenous formulations and newer subcutaneous versions that may prolong exclusivity. The report highlighted that despite sharing many common treatment indications and potentially acting as within-class treatment alternatives, there has been limited within-class market competition, with spending on individual immune checkpoint inhibitors remaining relatively stable over tim…
section: 8.2.3. Immunomodulators
  type: Section
  parent item: 8.2. Antineoplastics and supportive medicines
    type: Section
    parent item: 8. Immunomodulators and antineoplastics
drug unit: Parenteral > General injections > IV: 50 mg per mL in 2.4 mL vial concentrate solution for infusion; 50 mg per mL in 10 mL vial concentrate solution for infusion
patent information: Main patent is active in several jurisdictions. For more information on specific patents and license status for developing countries visit www.MedsPaL.org
list: ComplementaryList
population: Population
  age: AdolescentAndAdult
  sex: Female
  sex: Male
  condition: Malignant neoplasms of proximal biliary tract, cystic duct
included in emlc: false
status for indication: ApplicationRejected
therapeutic equivalence in class: false

durvalumab
type: Drug
type: Medicine
non proprietary name: durvalumab
active ingredient: durvalumab
ingredient: durvalumab
drug unit: Parenteral > General injections > IV: 50 mg per mL in 2.4 mL vial concentrate solution for infusion; 50 mg per mL in 10 mL vial concentrate solution for infusion
guideline: 1464
guideline: 1573
guideline: 1574
guideline: 1575
guideline: 1576
guideline: 1590
status: ApplicationRejected

Malignant neoplasms of proximal biliary tract, cystic duct
type: MedicalIndication
code: MedicalCode
  code value: 2C14.Z
  coding system: ICD-11