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
Malignant neoplasms of biliary tract, distal bile duct
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 Oncology’s Magnitude of Clinical Benefit Scale in the non-curative setting; • applied the EML principle for cancer medicines to demonstrate at least 4–6 months overall survival gain in randomized controlled trials; and • appreciated and took into consideration the review of the application undertaken by the EML Cancer Experts group and the Evidence to Decision frameworks that followed the GRADE approach prepared by the Secretariat. The Committee favoured pairings where the evidence strongly supported a large benefit-to-risk ratio. The Committee considered monotherapy more positively than combination therapy for indications where both are approved and a trade-off between additional efficacy, toxicity and cost would typically occur. The Expert Committee recommended the inclusion of: • pembrolizumab, atezolizumab and cemiplimab as first-line monotherapy of metastatic non-small cell lung cancer with high PD-L1 expression (≥ 50%). Listing is recommended for pembrolizumab with a square box as the class representative, and atezolizumab and cemiplimab as specified therapeutic alternatives; • pembrolizumab as first-line monotherapy for deficient mismatch repair/microsatellite instability-high metastatic colorectal cancer; • pembrolizumab, in combination with platinum-based chemotherapy, as first-line treatment of metastatic cervical cancer with PD-L1 expression ≥ 1%. The Committee considered that these recommendations for inclusion provide the best chance of minimizing financial harm and concentrating expenditure into the areas with the most favourable incremental gain in benefit-to-risk ratio. The Committee noted that the use of immune checkpoint inhibitors in adults with solid tumours that have predictive biomarkers (e.g. high PD-L1 expression for non-small cell lung cancer) rather than all patients is the highest priority, to enable greater access in settings where budgetary constraints may require prioritization of scenarios that offer the greatest clinical value. With the recommendation to list pembrolizumab for the above-mentioned indications, the Committee recommended changing the current square box listing of nivolumab as the class representative and pembrolizumab as the specified therapeutic alternative for metastatic melanoma, to make pembrolizumab the class representative with nivolumab as the specified therapeutic alternative. This is intended to signal to countries the possibility of aggregating procurement of a single molecule, pembrolizumab, for multiple cancer indications, which can influence price negotiations with manufacturers. Limiting procurement fragmentation by focusing on a select few immune checkpoint inhibitors is likely to facilitate central purchasing through competitive tendering and better competition from pembrolizumab biosimilars, thereby increasing access. In addition to its recommendations on which immune checkpoint inhibitors to prioritize for inclusion on the EML, the Committee also recognized the value of strategies to improve access, particularly in resource-constrained settings, as presented in the report from the EML cancer experts consultation meeting, and recommended their use. The Committee noted that these strategies were based on evaluation of available evidence and pragmatic considerations. The Committee considered the strategies to improve access to care in two components: clinical strategies and health-system strategies. The Committee acknowledged that, while clinical strategies (over which doctors and patients have greater control) and health-system strategies (requiring government-led policy legislations and reforms) should complement each other, clinical strategies can be implemented immediately and can rapidly benefit access. Clinical strategies – doctors and patients The Committee acknowledged the importance of patients being empowered to make an informed and consensual decision about their treatment, including through information on benefits, harms, accessibility and feasibility of care. This might require comparing alternatives that may differ from each other in one or more of the aforementioned factors. Strategies that can be considered to improve access include: dose optimization according to patient weight (weight-based dosing); rounding down doses to the closest vial size and strength (dose banding); or hybrid dosing regimens that combine the two; and if relevant, vial sharing. Additionally, longer intervals between treatment administration or shorter durations of treatment can also be considered. The Committee also noted that ongoing studies are investigating outcomes with ultra-low-dose immunotherapy. If the results are favourable, ultra-low-dose immunotherapy could be a viable strategy to further improve access. Health-system strategies – policy-makers To enable better value procurement through tendering and competition leading to increased access for individuals and health systems, the Committee recommended that national policies take advantage of similar clinical performance in different immune checkpoint inhibitors, regardless of their biological target (i.e. PD-1 or PD-L1). The Committee opted to recommend four immune checkpoint inhibitors for non-small cell lung cancer using the square box listing, indicating interchangeability at the health-system level for this indication. The recommended medicines have different pharmacological properties but are considered therapeutic alternatives. Where no relevant difference exists in efficacy and safety data, the preferred medicine at the country level should be the one that is generally available at the lowest price. At the country level, the interpretation of the square box should be extensive (i.e. a class effect), potentially covering other equally effective and safe immune checkpoint inhibitors of assured quality where these are offered at an advantageous price. The Committee stressed the importance of effective strategies to encourage rapid entry of biosimilars of immune checkpoint inhibitors into markets. With pembrolizumab listed on the EML for multiple cancers, efforts should be prioritized on accelerating approval and procurement of pembrolizumab biosimilars over those of the other listed molecules. Ensuring a competitive market, with ideally more than four or five alternative suppliers, would foster market maturity, reduce prices, and strengthen the sustainability of access. This strategy is fully aligned with WHO’s broader goal of encouraging generic and biosimilar competition as a central pathway to achieving equitable access to high-value cancer treatments. The Committee recognized the need for companion in-vitro diagnostic tests to identify patients eligible for treatment with the recommended immune checkpoint inhibitors. It noted that access to diagnostic capacity is limited in less-resourced settings and may be a barrier to appropriate and optimal use of these medicines. However, the Committee highlighted that this scenario was more variable in middle-income countries, where testing for molecular alterations is more readily available and the price associated with tests is a small fraction of the price associated with treatment. The Committee recognized that the requirement for companion diagnostics adds additional cost but offers a pathway to limit inappropriate use of immune checkpoint inhibitors (i.e. outside of recommended indications) and serves to prevent the waste of resources with non-essential or lower-value use. The Committee considered that countries could apply their own affordability criteria in determining which (if any) of the recommended immune checkpoint inhibitors could be reasonably incorporated into national EMLs and reimbursement schemes. In addition, the Committee considered that countries could apply their own feasibility criteria in assessing health-system readiness for implementing immune checkpoint inhibitors, in terms of diagnostic infrastructure, health-care worker training in immuno-oncology, resources for the management of immune-mediated side-effects and monitoring capabilities, to ensure their safe and effective use. The Committee recognized that the implementation of recommendations concerning immune checkpoint inhibitors will progress at different speeds, largely reflecting the capacity of individual healthcare systems. In low-income countries, limited resources, infrastructure challenges, and demographic factors such as a predominantly young population may significantly delay the adoption of these medicines. By contrast, upper- and lower-middle-income countries are expected to introduce them more rapidly. The Expert Committee did not recommend listing for the following immune checkpoint inhibitors for treatment of the specified conditions: • cemiplimab, durvalumab plus tremelimumab, nivolumab plus ipilimumab, or pembrolizumab – each in combination with chemotherapy – for the treatment of oncogenic-driver wild-type metastatic non-small cell lung cancer regardless of PD-L1 expression; • tislelizumab in combination with chemotherapy for oncogenic-driver wild-type metastatic non-small cell lung cancer with ≥ 50% PD-L1 expression; • nivolumab plus ipilimumab for the treatment of dMMR/MSI-H phenotype metastatic colorectal cancer or metastatic melanoma; • dostarlimab in combination with chemotherapy for dMMR/MSI-H phenotype metastatic endometrial cancer; • pembrolizumab or nivolumab, in combination with chemotherapy, for first-line treatment of metastatic ERBB2-negative gastric or gastro-oesophageal junction adenocarcinoma with ≥ 1% or ≥ 5% PD-L1 expression, respectively; • durvalumab in combination with chemotherapy for first-line treatment of biliary tract cancer regardless of PD-L1 expression; • durvalumab monotherapy, durvalumab plus tremelimumab, or atezolizumab plus bevacizumab for first-line treatment for metastatic hepatocellular carcinoma regardless of PD-L1 expression; • pembrolizumab in combination with chemotherapy for first-line treatment of metastatic head and neck squamous cell carcinoma; • pembrolizumab, nivolumab, or nivolumab plus ipilimumab, each in combination with chemotherapy, for first-line treatment of metastatic oesophageal squamous cell cancer; • nivolumab plus ipilimumab, pembrolizumab plus axitinib, or pembrolizumab plus lenvatinib for the first-line treatment of metastatic renal cell carcinoma regardless of PD-L1 expression; • pembrolizumab in combination with chemotherapy for first-line treatment of triple-negative breast cancer with PD-L1 expression CPS ≥ 10. The reasons for not to recommending inclusion of these pairings included prioritization of monotherapy over combination therapy, magnitude of overall survival gains of fewer than 4–6 months, limited or absence of mature overall survival data, unfavourable benefit-to-risk profiles, uncertainty about optimal immune checkpoint inhibitor and tyrosine kinase inhibitor positioning (i.e. in sequence or in combination) and uncertainty about optimal use across different patient cohorts which may vary with the immunogenicity of tumour types.
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 effect on health-related quality of life (mean difference (MD) from baseline 0.88, 95% CI –1.80 to 3.65; one randomized controlled trial, 646 participants). Cervical cancer with PD-L1 expression ≥ 1% One randomized controlled trial of pembrolizumab plus platinum-based chemotherapy versus platinum-based chemotherapy alone was identified that evaluated treatment of metastatic cervical cancer (Keynote-826 (14–16)). Of 617 participants randomized, 548 had PD-L1 expression of CPS ≥ 1%. After a median follow-up of 39.1 months, there was high-certainty evidence that pembrolizumab-containing regimens increase overall survival (HR for death 0.60, 95% CI 0.49 to 0.74; one randomized controlled trial, 548 participants). In absolute terms, 57 versus 39 people per 100, respectively, on pembrolizumab plus platinum-based chemotherapy or platinum-based chemotherapy alone were alive at 2 years, 46 versus 27 people per 100 were alive at 3 years and median overall survival gain was 11.0 months. There was high-certainty evidence that pembrolizumab-containing regimens increase progression-free survival (HR for disease progression or death 0.60, 95% CI 0.48 to 0.75; one randomized controlled trial, 548 participants). In absolute terms, 52 versus 34 people per 100 were without disease progression at 1 year. There was high-certainty evidence that pembrolizumab-containing regimens have little to no effect on health-related quality of life (MD from baseline 1.30, 95% CI –3.02 to 5.62; one randomized controlled trial, 519 participants). Deficient mismatch repair/microsatellite instability-high colorectal cancer One randomized controlled trial of pembrolizumab monotherapy versus fluoropyrimidine-based chemotherapy was identified that evaluated treatment of deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer irrespective of PD-L1 expression (Keynote-117 (17–19)). Of 307 randomized participants, 153 received pembrolizumab monotherapy and 154 received the comparator treatment (modified FOLFOX6, modified FOLFOX6 plus bevacizumab, modified FOLFOX6 plus cetuximab, FOLFIRI, FOLFIRI plus bevacizumab, or FOLFIRI plus cetuximab). After a median follow-up of 44.5 months, there was low-certainty evidence that pembrolizumab may increase overall survival (HR for death 0.74, 95% CI 0.53 to 1.03; one randomized controlled trial, 307 participants). In absolute terms, 60 versus 50 people per 100, respectively, on pembrolizumab monotherapy or fluoropyrimidine-based chemotherapy were alive at 3 years, and median overall survival gain was 12.9 months. There was low-certainty evidence that pembrolizumab may increase progression-free survival (HR for disease progression or death 0.59, 95% CI 0.45 to 0.79; one randomized controlled trial, 307 participants). In absolute terms, 57 versus 39 people per 100 were without disease progression at 3 years. There was low-certainty evidence that pembrolizumab may have little to no effect on health-related quality of life (MD from baseline 8.96, 95% CI 4.24 to 13.69; one randomized controlled trial, 292 participants). dMMR/MSI-H endometrial cancer One randomized controlled trial of dostarlimab plus carboplatin and paclitaxel versus carboplatin and paclitaxel was identified that evaluated treatment of dMMR/MSI-H primary advanced or recurrent endometrial cancer (RUBY (20–23)). Of 494 participants randomized, 118 had dMMR-MSI-H tumours. After a median follow-up of 36.6 months, there was low-certainty evidence that dostarlimab-containing regimens may result in a large increase in overall survival (HR for death 0.32, 95% CI 0.17 to 0.63; one randomized controlled trial, 118 participants). In absolute terms, 84 versus 57 people per 100, respectively, in the dostarlimab arm or carboplatin arm were alive at 2 years and 78 versus 46 people per 100 were alive at 3 years. Median overall survival was not reached in the dostarlimab arm and was 31.4 months in the chemotherapy arm. An estimated median overall survival gain of 66.7 months was calculated by the applicants, using the HR and baseline risk estimate from the comparator arm. There was moderate-certainty evidence that dostarlimab-containing regimens likely increase progression-free survival (HR for disease progression or death 0.28, 95% CI 0.16 to 0.50; one randomized controlled trial, 118 participants). In absolute terms, 67 versus 24 people per 100 were without disease progression at 1 year. There was low-certainty evidence that dostarlimab-containing regimens may increase health-related quality of life (MD from baseline 9.38, 95% CI 5.45 to 13.31; one randomized controlled trial, 115 participants). Human epidermal growth factor receptor 2-negative gastric and gastro-oesophageal junction adenocarcinoma with PD-L1 expression CPS ≥ 1/CPS ≥ 5 Two randomized controlled trials of pembrolizumab plus chemotherapy versus chemotherapy alone (Keynote-859 (24, 25) and Keynote-062 (26–28)) and one randomized controlled trial of nivolumab plus chemotherapy versus chemotherapy alone (CheckMate 649 (29–31)) were identified that evaluated treatment of human epidermal growth factor receptor 2 (HER2)-negative gastric or gastro-oesophageal junction adenocarcinoma in patients with PD-L1 expression of CPS ≥ 1 (pembrolizumab) or CPS ≥ 5 (nivolumab). After a median follow-up of 30.2 months, there was low-certainty evidence that pembrolizumab-containing regimens may increase overall survival compared with chemotherapy (HR for death 0.78, 95% CI 0.68 to 0.89; two randomized controlled trials, 1742 participants). In absolute terms, 26 versus 18 people per 100, respectively, on pembrolizumab plus chemotherapy or chemotherapy alone were alive at 2 years, and median overall survival gain was 3.2 months. There was low-certainty evidence that pembrolizumab-containing regimens may increase progression-free survival (HR for disease progression or death 0.77, 95% CI 0.66 to 0.89; two randomized controlled trials, 1874 participants). In absolute terms, 14 versus 8 people per 100 were without disease progression at 2 years. There was low-certainty evidence that pembrolizumab-containing regimens may have little to no effect on health-related quality of life (MD from baseline 1.25, 95% CI –1.07 to 3.58; one randomized controlled trial, 1542 participants). After a median follow-up of 47.4 months, there was moderate-certainty evidence that nivolumab-containing regimens likely increase overall survival compared with chemotherapy (HR for death 0.70, 95% CI 0.61 to 0.81; one randomized controlled trial, 955 participants). In absolute terms, 31 versus 19 people per 100, respectively, on nivolumab-containing regimens or chemotherapy were alive at 2 years and median overall survival gain was 4.8 months. There was low-certainty evidence that nivolumab-containing regimens may increase progression-free survival (HR for disease progression or death 0.70, 95% CI 0.60 to 0.81; one randomized controlled trial, 955 participants). In absolute terms, 21 versus 11 people per 100 were without disease progression at 2 years. There was moderate-certainty evidence that nivolumab-containing regimens likely have little to no effect on health-related quality of life (MD from baseline 6.42, 95% CI 0.67 to 12.17; one randomized controlled trial, 797 participants). Head and neck squamous cell carcinoma with PD-L1 expression combined positive score ≥ 1 One randomized controlled trial of pembrolizumab as monotherapy or in combination with platinum-based chemotherapy versus platinum-based chemotherapy and cetuximab was identified that evaluated treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (Keynote-048 (32–35)). Of 882 randomized participants, 301 received pembrolizumab monotherapy, 281 received pembrolizumab-based chemotherapy and 300 received the comparator treatment. PD-L1 expression combined positive score (CPS) ≥ 1 was equally distributed in intervention and comparator arms and was found in about 85% of participants. Data extracted compared pembrolizumab-based chemotherapy versus cetuximab-based chemotherapy only, as this was the only combination that satisfied the inclusion criteria applied by the applicants. After a median follow up of 45 months, there was moderate-certainty evidence that pembrolizumab-containing regimens likely increase overall survival (HR for death 0.64, 95% CI 0.53 to 0.78; one randomized controlled trial, 477 participants). In absolute terms, 32 versus 17 people per 100, respectively, on pembrolizumab-based chemotherapy or cetuximab-based chemotherapy were alive at 2 years, 21 versus 9 people per 100 were alive at 3 years and median overall survival gain was 6.0 months. After a median follow-up of 11.9 months, there was low-certainty evidence that pembrolizumab-containing regimens may have little to no effect on progression-free survival (HR for disease progression or death 0.82, 95% CI 0.67 to 1.00; one randomized controlled trial, 477 participants). In absolute terms, 16 versus 11 people per 100 were without disease progression at year. There was moderate-certainty evidence that pembrolizumab-containing regimens likely result in little to no difference in health-related quality of life (MD from baseline 0.40, 95% CI -3.80 to 4.60; one randomized controlled trial, 527 participants). Hepatocellular carcinoma irrespective of PD-L1 expression Two randomized controlled trials of atezolizumab plus bevacizumab versus sorafenib (IMbrave 150 (36–38)), and durvalumab as monotherapy or in combination with chemotherapy versus sorafenib (HIMALAYA (39–41)) were identified that evaluated treatment of hepatocellular carcinoma. For the comparison of atezolizumab-containing regimens versus sorafenib, after a median follow-up of 15.6 months, there was moderate-certainty evidence that atezolizumab-containing regimens likely increase overall survival (HR for death 0.66, 95% CI 0.52 to 0.85; one randomized controlled trial, 501 participants). In absolute terms, 55 versus 40 people per 100, respectively, on atezolizumab-containing regimens or sorafenib were alive at 1.5 years and median overall survival gain was 6.9 months. There was moderate-certainty evidence that atezolizumab-containing regimens likely increase progression-free survival (HR for disease progression or death 0.65, 95% CI 0.53 to 0.81; one randomized controlled trial, 501 participants). In absolute terms, 36 versus 21 people per 100 were without disease progression at 1 year. There was moderate-certainty evidence that atezolizumab-containing regimens likely have little to no effect on health-related quality of life (MD from baseline 2.54, 95% CI –1.31 to 6.39; one randomized controlled trial, 481 participants). For the comparison of durvalumab monotherapy versus sorafenib, after a median follow-up of 47.9 months, there was low-certainty evidence that durvalumab may increase overall survival (HR for death 0.86, 95% CI 0.74 to 1.01; one randomized controlled trial, 778 participants). In absolute terms, 38 versus 33 people per 100, respectively, on durvalumab monotherapy or sorafenib were alive at 2 years, 20 versus 15 people per 100 were alive at 4 years and median overall survival gain was 2.3 months. After a median follow-up of 32.4 months, there was moderate-certainty evidence that durvalumab monotherapy likely results in little to no difference in progression-free survival (HR for disease progression or death 1.02, 95% CI 0.88 to 1.19; one randomized controlled trial, 778 participants). In absolute terms, 32 versus 33 people per 100 were without disease progression at 1 year. There was moderate-certainty evidence that durvalumab monotherapy likely has little to no effect on health-related quality of life (MD from baseline 4.30, 95% CI 0.41 to 8.19; one randomized controlled trial, 778 participants). For the comparison of durvalumab plus tremelimumab versus sorafenib, after a median follow-up of 48.2 months, there was moderate-certainty evidence that durvalumab plus tremelimumab likely increases overall survival (HR for death 0.78, 95% CI 0.67 to 0.92, one randomized controlled trial, 782 participants). In absolute terms, 42 versus 33 people per 100, respectively, on durvalumab plus tremelimumab or sorafenib were alive at 2 years, 23 versus 15 people per 100 were alive at 4 years and median overall survival gain was 3.9 months. After a median follow-up of 32.7 months, there was low-certainty evidence that durvalumab plus tremelimumab may increase progression-free survival (HR for disease progression or death 0.90, 95% CI 0.77 to 1.05; one randomized controlled trial, 782 participants). In absolute terms, 37 versus 33 people per 100 were without disease progression at 1 year. There was moderate-certainty evidence that durvalumab plus tremelimumab likely has little to no effect on health-related quality of life (MD from baseline –0.35, 95% CI –4.21 to 3.51; one randomized controlled trial, 782 participants). Malignant melanoma Five randomized controlled trials of ipilimumab plus nivolumab for the treatment of malignant melanoma were identified. Three randomized controlled trials included patients irrespective of PD-L1 expression and BRAF V600 mutation status (ABC (42, 43), CheckMate 067 (44, 45) and CheckMate 069 (46, 47)), and two randomized controlled trials included patients irrespective of PD-L1 mutation status and with BRAF V600-mutant disease (DREAMseq/EA6134 (48, 49) and SECOMBIT (50)). A total of 1537 participants were randomized: 639 to ipilimumab plus nivolumab and 898 to one of the control regimens. Among randomized participants, 346 receiving ipilimumab plus nivolumab and 422 receiving a control regimen had a BRAF V600 mutation. A vast majority of participants included in this review did not have brain metastases. Ipilimumab was administered at a dose of 3 mg/kg and nivolumab at a dose of 1 mg/kg on day 1 of four 3-week cycles. Subsequently, patients received nivolumab 3 mg/kg on day 1 of 2-week cycles. Treatment continued for: up to 2 years of nivolumab administration; until disease progression; until development of unacceptable toxicity; or on withdrawal of consent. Ipilimumab plus nivolumab was compared with: ipilimumab monotherapy 3 mg/kg on day 1 of four 3-week cycles (CheckMate 067 and CheckMate 069); nivolumab monotherapy 3 mg/kg on day 1 of 2-week cycles (ABC and CheckMate 067); BRAF/MEK inhibitor combination dabrafenib 150 mg twice daily and trametinib 2 mg once daily (DREAMseq); and BRAF/MEK inhibitor combination encorafenib 450 mg once daily and binimetinib 45 mg twice daily (SECOMBIT). For the comparison of ipilimumab plus nivolumab versus immune-checkpoint inhibitor monotherapy, after a median follow-up of 34.6 months, there was moderate-certainty evidence that ipilimumab plus nivolumab likely increases overall survival (HR for death 0.68, 95% CI 0.50 to 0.93; three randomized controlled trials, 1133 participants). In absolute terms, 64 versus 52 people per 100, respectively, on ipilimumab plus nivolumab or immune-checkpoint inhibitor monotherapy were alive at 2 years, 49 versus 35 people per 100 were alive at 5 years and median overall survival gain was 12.8 months. After a median follow-up of 35.7 months, there was low-certainty evidence that ipilimumab plus nivolumab may increase progression-free survival (HR for disease progression or death 0.50, 95% CI 0.31 to 0.82; two randomized controlled trials, 1087 participants). In absolute terms, 49 versus 24 people per 100 were without disease progression at 2 years. There was moderate-certainty evidence that ipilimumab plus nivolumab likely results in little to no difference in health-related quality of life (MD from baseline -1.08, 95% CI –3.44 to 1.28; one randomized controlled trial, 758 participants). For the comparison of ipilimumab plus nivolumab versus BRAF/MEK inhibitors for BRAF V600-mutant disease, after a median follow-up of 32.2 months, the evidence was very uncertain about the effect of ipilimumab plus nivolumab on overall survival (HR for death 0.73, 95% CI 0.42 to 1.27; one randomized controlled trial, 138 participants). In absolute terms, 73 versus 65 people per 100, respectively, on ipilimumab plus nivolumab or BRAF/MEK inhibitors were alive at 2 years and 64 versus 54 people per 100 were alive at 5 years. Median overall survival was not reached in either group. The evidence was very uncertain about the effect of ipilimumab plus nivolumab on progression-free survival. Pooled 2-year progression-free survival rates were 40.1% versus 23.9% (two randomized controlled trials, 403 participants). Health-related quality of life was not reported. Oncogenic driver wild-type non-small cell lung cancer with high PD-L1 expression (tumour proportion score ≥ 50%) Five randomized controlled trials of atezolizumab (IMpower 110 (51, 52) and IPSOS (53)), cemiplimab (EMPOWER-Lung1 (54–56)) and pembrolizumab (Keynote-024 (57–59) and, Keynote-042 (60, 61)) were identified that evaluated treatment, as monotherapy, of non-small cell lung cancer without oncogenic driver mutations (EGFR, ALK) and PD-L1 expression ≥ 50%. All studies were global, multicentre, unblinded phase III randomized controlled trials comparing immune-checkpoint inhibitor monotherapy with the established standard of care for non-small cell lung cancer, with the exception of IPSOS, which was conducted in a patient setting where no clearly established standard treatment exists (patients ineligible for platinum-based chemotherapy). Patients with squamous cell or non-squamous cell tumours that were negative for EGFR or ALK driver mutations were eligible for inclusion. After median follow-up of 60.7 months, there was moderate-certainty evidence that pembrolizumab monotherapy likely increases overall survival compared with platinum-based doublet chemotherapy (hazard ratio (HR) for death 0.66, 95% CI 0.57 to 0.76; two randomized controlled trials, 904 participants). In absolute terms, 45 versus 30 people per 100, respectively, on pembrolizumab monotherapy or platinum-based doublet chemotherapy were alive at 2years and 22 versus 10 people per 100 were alive at 5 years and median overall survival gain was 6.3 months. There was low-certainty evidence that pembrolizumab monotherapy may increase progression-free survival (HR for disease progression or death 0.66, 95% CI 0.39 to 1.12; two randomized controlled trials, 904 participants). In absolute terms, 35 versus 21 people per 100 were without disease progression at 1 year. There was low-certainty evidence that pembrolizumab monotherapy may increase health-related quality of life (MD from baseline 7.85, 95% CI 2.51 to 13.19; one randomized controlled trial, 297 participants). After median follow-up of 35.6 months, there was low-certainty evidence that atezolizumab monotherapy may increase overall survival compared with chemotherapy (HR for death 0.79, 95% CI 0.54 to 1.09; two randomized controlled trials, 280 participants). In absolute terms, 39 versus 30 people per 100, respectively, on atezolizumab monotherapy or chemotherapy were alive at 2 years and median overall survival gain was 3.7 months. There was low-certainty evidence that atezolizumab monotherapy may increase progression-free survival (HR for disease progression or death 0.63, 95% CI 0.48 to 0.84; two randomized controlled trials, 280 participants). In absolute terms, 34 versus 18 people per 100 were without disease progression at 1 year. Health-related quality of life for atezolizumab was not reported. After median follow-up of 35.0 months, there was moderate-certainty evidence that cemiplimab monotherapy likely increases overall survival compared with platinum-based doublet chemotherapy (HR for death 0.63, 95% CI 0.52 to 0.77; one randomized controlled trial, 712 participants). In absolute terms, 50 versus 34 people per 100, respectively on cemiplimab monotherapy or platinum-based doublet chemotherapy were alive at 2 years, 40 versus 23 people per 100 were alive at 3 years and median overall survival gain was 8.0 months. There was moderate-certainty evidence that cemiplimab monotherapy likely increases progression-free survival (HR for disease progression or death 0.56, 95% CI 0.47 to 0.67; one randomized controlled trial, 712 participants). In absolute terms, 24 versus 8 people per 100 were without disease progression at 1 year. There was moderate-certainty evidence that cemiplimab monotherapy likely results in little to no difference in health-related quality of life (MD from baseline 5.03 (95% CI 2.11 to 7.96; one randomized controlled trial, 563 participants). Oncogenic driver wild-type non-small cell lung cancer irrespective of PD-L1 expression Eight randomized controlled trials of (i) pembrolizumab plus platinum-based chemotherapy (Keynote-021 (62, 63), Keynote-189 (64–66) and Keynote-407 (67–69)); (ii) cemiplimab plus platinum-based chemotherapy (EMPOWER-Lung3 (70–72)); (iii) ipilimumab plus nivolumab plus chemotherapy (CheckMate 9LA (73–75)); (iv) durvalumab plus tremelimumab plus chemotherapy (POSEIDON (76, 77)); and (v) tislelizumab plus platinum-based chemotherapy (RATIONALE-307 (78–80) and RATIONALE-304 (81–84)), each versus platinum-based doublet chemotherapy, were identified that evaluated treatment of non-small cell lung cancer without oncogenic driver mutations (EGFR, ALK) irrespective of PD-L1 expression. All studies were global multicentre phase III randomized controlled trials, except for Keynote-021, which was a phase I/II randomized controlled trial. Keynote-189, Keynote-407 and EMPOWER-Lung3 were double-blinded, comparing immune-checkpoint inhibitor-based regimens with an active chemotherapeutic backbone and placebo. Keynote-021, CheckMate 9LA, POSEIDON and CheckMate 9LA were unblinded. All studies followed the same basic structure of comparing the addition of an immune-checkpoint inhibitor or immune-checkpoint inhibitor-doublet to platinum-based chemotherapy with platinum-based chemotherapy alone. After a median follow-up of 59.8 months, there was moderate-certainty evidence that pembrolizumab-containing regimens likely increase overall survival compared with platinum-based doublet chemotherapy (HR for death 0.66, 95% CI 0.58 to 0.74; three randomized controlled trials, 1298 participants). In absolute terms, 48 versus 33 people per 100, respectively, on pembrolizumab-containing regimens or platinum-based doublet chemotherapy were alive at 2 years, 22 versus 10 people per 100 were alive at 5 years and median overall survival gain was 6.3 months. There was high-certainty evidence that pembrolizumab-containing regimens increase progression-free survival (HR for disease progression or death 0.55, 95% CI 0.48 to 0.64; three randomized controlled trials, 1298 participants). In absolute terms, 43 versus 21 people per 100 were without disease progression at 1 year. There was moderate-certainty evidence that pembrolizumab-containing regimens may result in little to no difference in health-related quality of life (MD from baseline 5.00, 95% CI 2.13 to 7.87; two one randomized controlled trials, 1156 participants). After a median follow-up of 28.4 months, there was moderate-certainty evidence that cemiplimab-containing regimens likely increase overall survival compared with platinum-based doublet chemotherapy (HR for death 0.65, 95% CI 0.51 to 0.82; one randomized controlled trial, 466 participants). In absolute terms, 43 versus 27 people per 100, respectively, on cemiplimab-containing regimens or platinum-based doublet chemotherapy were alive at 2 years and median overall survival gain was 6.9 months. There was high-certainty evidence that cemiplimab-containing regimens increase progression-free survival (HR for disease progression or death 0.55, 95% CI 0.44 to 0.68; one randomized controlled trial, 466 participants). In absolute terms, 37 versus 16 people per 100 were without disease progression at 1 year. There was high-certainty evidence that cemiplimab-containing regimens do not increase health-related quality of life (MD from baseline 0.61, 95% CI –2.23 to 3.45; one randomized controlled trial, 466 participants). After a median follow-up of 54.5 months, there was low-certainty evidence that ipilimumab plus nivolumab-containing regimens may increase overall survival compared with platinum-based doublet chemotherapy (HR for death 0.74, 95% CI 0.63 to 0.87; one randomized controlled trial, 719 participants). In absolute terms, 37 versus 26 people per 100, respectively, on ipilimumab plus nivolumab-containing regimens or platinum-based doublet chemotherapy were alive at 2 years, 20 versus 11 people per 100 were alive at 5 years and median overall survival gain was 3.9 months. There was moderate-certainty evidence that ipilimumab plus nivolumab-containing regimens likely increase progression-free survival (HR for disease progression or death 0.70, 95% CI 0.59 to 0.83; one randomized controlled trial, 719 participants). In absolute terms, 31 versus 19 people per 100 were without disease progression at 1 year. There was moderate-certainty evidence that ipilimumab plus nivolumab-containing regimens have little to no effect on health-related quality of life (MD from baseline 4.70, 95% CI –3.26 to 12.66; one randomized controlled trial, 646 participants). After a median follow-up of 63.4 months, there was low-certainty evidence that durvalumab plus tremelimumab-containing regimens may increase overall survival compared with platinum-based doublet chemotherapy (HR for death 0.77, 95% CI 0.65 to 0.92; one randomized controlled trial, 675 participants). In absolute terms, 31 versus 22 people per 100, respectively, on durvalumab plus tremelimumab-containing regimens or platinum-based doublet chemotherapy were alive at 2 years, 13 versus 7 people per 100 were alive at 5 years and median overall survival gain was 3.5 months. After a median follow-up of 10.3 months, there was moderate-certainty evidence that durvalumab plus tremelimumab-containing regimens likely increase progression-free survival (HR for disease progression or death 0.72, 95% CI 0.60 to 0.86; one randomized controlled trial, 675 participants). In absolute terms, 23 versus 13 people per 100 were without disease progression at 1 year. Health-related quality of life was not reported. After a median follow-up of 16.4 months, there was low-certainty evidence that tislelizumab-containing regimens may increase overall survival compared with platinum-based doublet chemotherapy (HR for death 0.80, 95% CI 0.62 to 1.02; two randomized controlled trials, 694 participants). In absolute terms, 75 versus 69 people per 100, respectively, on tislelizumab-containing regimens or platinum-based doublet chemotherapy were alive at 1 year and median overall survival gain was 4.5 months. There was high-certainty evidence that tislelizumab-containing regimens increase progression-free survival (HR for disease progression or death 0.51, 95% CI 0.40 to 0.66; two randomized controlled trials, 694 participants). In absolute terms, 37 versus 14 people per 100 were without disease progression at 1 year. There was moderate-certainty evidence that tislelizumab-containing regimens likely result in little to no difference in health-related quality of life (MD from baseline 3.70, 95% CI –0.06 to 7.46; two randomized controlled trials, 687 participants). Oesophageal squamous cell carcinoma with PD-L1 expression CPS ≥ 1/CPS ≥ 10 One randomized controlled trial of pembrolizumab plus chemotherapy versus chemotherapy alone (Keynote-590 (85–87)) and one of nivolumab plus chemotherapy or ipilimumab plus nivolumab versus chemotherapy alone (CheckMate 648 (88, 89)) were identified that evaluated treatment of advanced oesophageal squamous cell carcinoma. The review included only the subgroup of participants in Keynote-590 with PD-L1 expression CPS ≥ 10, and the subgroup of participants in CheckMate 648 with PD-L1 expression on tumour cells (TC) ≥ 1%, in line with the prioritization framework. After a median follow-up of 22.6 months, there was low-certainty evidence that pembrolizumab plus chemotherapy may increase overall survival compared with platinum-based chemotherapy in patients with PD-L1 expression CPS ≥ 10 (HR for death 0.57, 95% CI 0.43 to 0.75; one randomized controlled trial, 286 participants). In absolute terms, 34 versus 15 people per 100, respectively, on pembrolizumab plus chemotherapy or platinum-based chemotherapy were alive at 2 years and median overall survival gain was 6.6 months. There was low-certainty evidence that pembrolizumab-containing regimens may increase progression-free survival (HR for disease progression or death 0.53, 95% CI 0.40 to 0.60; one randomized controlled trial, 286 participants). In absolute terms, 17 versus 4 people per 100 were without disease progression at 2 years. There was low-certainty evidence that pembrolizumab-containing regimens may have little to no effect on health-related quality of life (MD from baseline -1.95, 95% CI –7.72 to 3.82; one randomized controlled trial, 274 participants). After a median follow-up of 39.5 months, there was low-certainty evidence that nivolumab plus chemotherapy may increase overall survival compared with platinum-based chemotherapy in patients with PD-L1 expression TC ≥ 1% (HR for death 0.59, 95% CI 0.46 to 0.76; one randomized controlled trial, 315 participants). In absolute terms, 29 versus 12 people per 100, respectively, on nivolumab plus chemotherapy or platinum-based chemotherapy were alive at 2 years, 26 versus 10 people per 100 were alive at 3 years, and median overall survival gain was 6.3 months. There was moderate-certainty evidence that nivolumab plus chemotherapy likely increases progression-free survival (HR for disease progression or death 0.67, 95% CI 0.51 to 0.89; one randomized controlled trial, 315 participants). In absolute terms, 21 versus 10 people per 100 were without disease progression at 1 year. There was moderate-certainty evidence that nivolumab plus chemotherapy likely has little to no effect on health-related quality of life (MD from baseline 3.44, 95%–CI –0.03 to 6.91; one randomized controlled trial, 522 participants). After a median follow up of 39.7 months, there was low-certainty evidence that ipilimumab plus nivolumab may increase overall survival compared with platinum-based chemotherapy in patients with PD-L1 expression TC ≥ 1% (HR for death 0.62, 95% CI 0.48 to 0.80; one randomized controlled trial, 315 participants). In absolute terms, 27 versus 12 people per 100, respectively, on ipilimumab plus nivolumab or platinum-based chemotherapy were alive at 2 years, 24 versus 10 people per 100 were alive at 3 years and median overall survival gain was 5.6 months. There was low-certainty evidence that ipilimumab plus nivolumab may have little to no effect on progression-free survival (HR for disease progression or death 1.04, 95% CI 0.79 to 1.36; one randomized controlled trial, 315 participants). In absolute terms, 9 versus 10 people per 100 were without disease progression at 1 year. There was moderate-certainty evidence that ipilimumab plus nivolumab likely has little to no effect on health-related quality of life (MD from baseline 1.91, 95% CI -1.70 to 5.51; one randomized controlled trial, 529 participants). Renal cell carcinoma irrespective of PD-L1 expression Two randomized controlled trials of ipilimumab plus nivolumab versus sunitinib (BOINIKK (90–92), CheckMate 214 (93–95)) and two randomized controlled trials of pembrolizumab plus axitinib or lenvatinib versus sunitinib (Keynote-426 (96–100), CLEAR (101–104)) were identified that evaluated treatment of renal cell carcinoma. For the comparison of ipilimumab plus nivolumab versus sunitinib, after a median follow-up of 92.6 months, there was low-certainty evidence that ipilimumab plus nivolumab may increase overall survival (HR for death 0.72, 95% CI 0.62 to 0.84; two randomized controlled trials, 1178 participants). In absolute terms, 69 versus 60 people per 100, respectively, on ipilimumab plus nivolumab or sunitinib were alive at 2 years, 48 versus 36 people per 100 were alive at 5 years and median overall survival gain was 13 months. There was low-certainty evidence that ipilimumab plus nivolumab may result in little to no difference in progression-free survival (HR for disease progression or death 0.96, 95% CI 0.66 to 1.40; two randomized controlled trials, 1169 participants). In absolute terms, 45 versus 43 people per 100 were without disease progression at 1 year. There was low-certainty evidence that ipilimumab plus nivolumab may increase health-related quality of life (MD from baseline 6.28, 95% CI 2.60 to 9.96; one randomized controlled trial, 923 participants). For the comparison of pembrolizumab plus axitinib or lenvatinib versus sunitinib, after a median follow-up of 59.2 months, there was low-certainty evidence that pembrolizumab-containing regimens may increase overall survival (HR for death 0.83, 95% CI 0.72 to 0.94; two randomized controlled trials, 1573 participants). In absolute terms, 72 versus 67 people per 100, respectively, on pembrolizumab-containing regimens or sunitinib were alive at 2 years, 44 versus 37 people per 100 were alive at 5 years and median overall survival gain was 9.6 months. After a median follow-up of 37.1 months, there was moderate-certainty evidence that pembrolizumab-containing regimens likely increase progression-free survival (HR for disease progression or death 0.54, 95% CI 0.33 to 0.86; two randomized controlled trials, 1573 participants). In absolute terms, 64 versus 43 people per 100 were without disease progression at 1 year. There was moderate-certainty evidence that pembrolizumab-containing regimens likely have little to no effect on health-related quality of life (MD from baseline −0.34, 95% CI −2.78 to 2.10; two randomized controlled trials, 1546 participants). Triple-negative breast cancer with PD-L1 expression ≥ 10% One randomized controlled trial of pembrolizumab plus chemotherapy versus chemotherapy was identified that evaluated treatment of advanced/metastatic triple-negative breast cancer (Keynote-355 (105–107)). Of 847 participants randomized, 323 had PD-L1 CPS ≥ 10% and among those with PD-L1 CPS ≥ 10, 220 received pembrolizumab plus chemotherapy and 103 received chemotherapy. Chemotherapy was the investigator’s choice of nab-paclitaxel, paclitaxel or gemcitabine plus carboplatin. After a median follow-up of 44.1 months, there was low-certainty evidence that pembrolizumab-containing regimens may increase overall survival compared with chemotherapy alone (HR for death 0.73, 95% CI 0.55 to 0.95; one randomized controlled trial, 323 participants). In absolute terms, 45 versus 34 people per 100, respectively, on pembrolizumab regimens or chemotherapy were alive at 2 years, 34 versus 23 people per 100 were alive at 3 years and median overall survival gain was 6.0 months. There was low-certainty evidence that pembrolizumab-containing regimens may increase progression-free survival (HR for disease progression or death 0.66, 95% CI 0.50 to 0.88; one randomized controlled trial, 323 participants). In absolute terms, 38 versus 23 people per 100 were without disease progression at 1 year. There was moderate-certainty evidence that pembrolizumab-containing regimens likely have little to no effect on health-related quality of life (MD from baseline –1.80, 95% CI –7.33 to 3.73; one randomized controlled trial, 317 participants).
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 ≥ 3 adverse events (RR 1.11, 95% CI 0.97 to 1.28; one randomized controlled trial, 485 participants). For the comparison of durvalumab monotherapy versus sorafenib, there was low-certainty evidence that durvalumab monotherapy may reduce grade ≥ 3 adverse events (RR 0.73, 95% CI 0.64 to 0.85; one randomized controlled trial, 762 participants). For the comparison of durvalumab plus tremelimumab versus sorafenib, there was moderate-certainty evidence that durvalumab plus tremelimumab likely results in little to no difference in grade ≥ 3 adverse events (RR 0.98, 95% CI 0.87 to 1.10; one randomized controlled trial, 762 participants). Malignant melanoma For the comparison of ipilimumab plus nivolumab versus immune-checkpoint inhibitor monotherapy, there was high-certainty evidence that ipilimumab plus nivolumab increases grade ≥ 3 adverse events (RR 2.37, 95% CI 2.03 to 2.77; three randomized controlled trials, 1137 participants). For the comparison of ipilimumab plus nivolumab versus BRAK/MEK inhibitors for BRAF V600-mutant disease, there was low-certainty evidence that ipilimumab plus nivolumab may increase grade ≥ 3 adverse events (RR 1.26, 95% CI 0.94 to 1.69; two randomized controlled trials, 394 participants). Oncogenic driver wild-type non-small cell lung cancer with high PD-L1 expression (TPS ≥ 50%) There was moderate-certainty evidence that pembrolizumab monotherapy likely reduces grade ≥ 3 adverse events (risk ratio (RR) 0.49, 95% CI 0.37 to 0.66; two randomized controlled trials, 1555 participants). There was low-certainty evidence that atezolizumab monotherapy may reduce grade ≥ 3 adverse events (RR 0.81, 95% CI 0.54 to 1.22; two randomized controlled trials, 996 participants). There was low-certainty evidence that cemiplimab monotherapy may reduce grade ≥ 3 adverse events (RR 0.89, 95% CI 0.76 to 1.03; one randomized controlled trial, 699 participants). Oncogenic driver wild-type non-small cell lung cancer irrespective of PD-L1 expression There was moderate-certainty evidence that pembrolizumab-containing regimens likely result in little to no difference in grade ≥ 3 adverse events (RR 1.08, 95% CI 1.00 to 1.16; three randomized controlled trials, 1286 participants). There was moderate-certainty evidence that cemiplimab-containing regimens likely increase grade ≥ 3 adverse events (RR 1.39, 95% CI 1.06 to 1.81; one randomized controlled trial, 465 participants). There was low-certainty evidence that ipilimumab plus nivolumab-containing regimens may increase grade ≥ 3 adverse events (RR 1.21, 95% CI 1.05 to 1.40; one randomized controlled trial, 707 participants). There was moderate-certainty evidence that durvalumab plus tremelimumab-containing regimens likely result in little to no difference in grade ≥ 3 adverse events (RR 1.05, 95% CI 0.92 to 1.21; one randomized controlled trial, 664 participants). There was very-low-certainty evidence that tislelizumab-containing regimens may increase grade ≥ 3 adverse events (RR 1.11, 95% CI 0.93 to 1.34; two randomized controlled trials, 687 participants). Oesophageal squamous cell carcinoma with PD-L1 expression CPS ≥ 1/CPS ≥ 10 There was low-certainty evidence that pembrolizumab plus chemotherapy may result in little to no difference in grade ≥ 3 adverse events (RR 1.03, 95% CI 0.97 to 1.10; one randomized controlled trial, 740 participants). There was low-certainty evidence that nivolumab plus chemotherapy may increase grade ≥ 3 adverse events (RR 1.33, 95% CI 1.11 to 1.61; one randomized controlled trial, 614 participants). There was low-certainty evidence that ipilimumab plus nivolumab may reduce grade ≥ 3 adverse events (RR 0.91, 95% CI 0.73 to 1.13; one randomized controlled trial, 626 participants). Renal cell carcinoma irrespective of PD-L1 expression For the comparison of ipilimumab plus nivolumab versus sunitinib, there was low-certainty evidence that ipilimumab plus nivolumab may reduce grade ≥ 3 adverse events (RR 0.82, 95% CI 0.64 to 1.04; two randomized controlled trials, 1223 participants). For the comparison of pembrolizumab plus axitinib or lenvatinib versus sunitinib, there was moderate-certainty evidence that pembrolizumab-containing regimens likely increase grade ≥ 3 adverse events (RR 1.11, 95% CI 1.04 to 1.18; two randomized controlled trials, 1546 participants). Triple-negative breast cancer with PD-L1 expression ≥ 10% There was moderate-certainty evidence that pembrolizumab-containing regimens likely result in little to no difference in grade ≥ 3 adverse events (RR 1.06, 95% CI 0.97 to 1.15; one randomized controlled trial, 843 participants).
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 time. Factors identified that may contribute to the lack of within-class market competition include market segmentation based on indication, the role of biomarkers and limited direct head-to-head comparative studies of individual immune checkpoint inhibitors. Current pricing levels often exceed national cost–effectiveness thresholds and may still exceed these thresholds despite potential price reductions following biosimilar entry. Thus, the report emphasizes the importance of a multifaceted strategy to address price and competition and improve affordability and access. Additional strategies include a supportive policy environment favouring the uptake of biosimilars, pooled procurement mechanisms to make use of collective bargaining and reduce prices, and voluntary and compulsory licensing to overcome patent barriers and facilitate early access. The report concludes that inclusion of immune checkpoint inhibitors on the WHO EML can play an important role in catalysing global and national efforts to achieve equitable access by signalling the public health importance of immune checkpoint inhibitors and legitimizing and enabling policy and procurement strategies. Price and cost–effectiveness data for the proposed immune checkpoint inhibitors were collected by the WHO Secretariat and included in the Evidence to Decision framework documents prepared by the Secretariat. Overall, the wholesale and retail prices for the proposed immune checkpoint inhibitors are still high across different World Bank income settings. Resource requirements to implement immune checkpoint inhibitor treatment were judged to be large for all medicine–indication pairings. Cost–effectiveness studies were identified for each medicine–indication pairing but were limited to high-income and upper-middle-income settings. The reported incremental cost–effectiveness ratios were usually higher than corresponding willingness-to-pay thresholds, with few exceptions (e.g. pembrolizumab for dMMR/MSI-H colorectal cancer (110–113)).
8.2. Antineoplastics and supportive medicines
Main patent is active in several jurisdictions. For more information on specific patents and license status for developing countries visit www.MedsPaL.org