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The Expert Committee, after evaluation, declines to list the medicine proposed in the application.
The Model List of Essential Medicines reports reasons that Committee Members have identified for denying listing.
Rejected
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Rejected
ATC codes: L01FF02
Indication
Other specified malignant neoplasms of bronchus or lung ICD11 code: 2C75.Y
INN
Pembrolizumab
Medicine type
Biological agent
List type
Complementary
Formulations
Parenteral > General injections > IV: 50 mg powder for injection
EML status history
Application rejected in 2019 (TRS 1021)
Application rejected in 2021 (TRS 1035)
Sex
All
Age
Adolescents and adults
Therapeutic alternatives
atezolizumab (ATC codes: L01FF05)
durvalumab (ATC codes: L01FF03)
nivolumab (ATC codes: L01FF01)
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
Tags
Wikipedia
Expert Committee recommendation
The Expert Committee acknowledged the treatment of lung cancer to be complex and recognized the need to provide the best available care within the context of both non-small-cell lung cancers (NSCLC) and small-cell lung cancers. Over the past decade, the treatment regimen for advanced NSCLC has progressed favourably with new treatment regimens involving targeted therapy based on the molecular and biological characteristics of the cancer. For NSCLC with mutation in the epidermal growth factor receptor (EGFR), the Committee recalled the recommendations made in 2019 to include erlotinib, gefitinib and afatinib as therapeutic alternatives for this indication. These medicines are associated with improved quality of life, and prolonged overall survival compared with cytotoxic chemotherapy, in patients with the EGFR driver mutation. The Committee noted that more than 80% of lung cancers are classified as non-small-cell and 15–25% of those cancers have programmed cell death ligand 1 (PD-L1) proteins on the surface of their cells. The Committee acknowledged that immune checkpoint inhibitors – PD-1 and PD-L1 inhibitors – have substantially improved outcomes of NSCLC treatment. Clinical trials with these agents have shown rapid and durable responses in about one fifth of pretreated patients with advanced NSCLC. Even though progression-free survival figures are not impressive, survival outcomes are remarkable. Immune checkpoint inhibitors are associated with a relevant survival benefit well over the established EML threshold for survival (i.e. 4 to 6 months) as first-line treatment in several single studies. The benefit from the checkpoint inhibitors was mostly restricted to patients with PD-L1-positive tumours. Addition of immune checkpoint inhibitors to conventional chemotherapy was associated with a modest increase in toxicity, which may require highly specialized management in selected cases. The Committee noted that even though procurement agencies in some countries have commercial arrangements to obtain a discount on the dose price of PD-1 and PD-L1 inhibitors, the overall price remains very high. The size of the discount varies and is not disclosed publicly in many settings. In best scenarios, the price is around US$ 45 000 per year of treatment, a price that exceeds the median annual household income of even the richest countries and is largely unaffordable in most settings. The high prices, coupled with the significant disease burden and the likely large eligible patient population, will have unsustainable financial implications for many patients and health systems. The costs associated with treatment are complicated by variable and the less remarkable response rate for NSCLC with PD-L1 expression less than 50% as compared with NSCLC with PD-L1 expression greater than 50%, and the uncertainties about the optimal duration of treatment. Some health care systems are adopting a 2-year stopping rule for checkpoint inhibitors. This rule assumes that, if the disease has not worsened, this treatment will provide a lasting, life-time survival benefit. The Committee noted that the duration of any continued treatment effect is unknown, and it is possible that life-time survival benefit can be equally obtained with shorter duration of treatment. There might be resistance from physicians and patients benefiting from treatment to stopping the treatment, which could expose health care systems and/or patients to a substantial economic burden that could severely damage national and/or family budgets. As part of a broader strategy to make these highly priced medicines more accessible and affordable, the Committee would value strategic trials to determine the optimal length of treatment required for these patients or to identify subgroups in whom treatment can be safely shortened. The Committee considered that the use of PD1 and PD-L1 immune checkpoint inhibitors in settings where non-squamous NSCLC is often diagnosed late and there is an underutilization of pretreatment testing to measure PD-L1 expression for predicting a response to immunotherapies might be associated with unintended and harmful consequences. Overall, the Committee considered that the PD-1/PD-L1 immune checkpoint inhibitors to have a favourable benefit-to-harm ratio in treatment of NSCLC, but recommended that they should not be added to the EML at this time due the prohibitively high price of these medicines. The Committee noted that several monoclonal antibodies directed at the PD-1 receptor (e.g. nivolumab, pembrolizumab and pidilizumab) or its ligand PD-L1 (e.g. atezolizumab, durvalumab and avelumab) are used in clinical practice, and others are in different stages of clinical development. The Committee recognized the important role of immune checkpoint inhibitors as a therapeutic class in the treatment of NSCLC. It advised that it would welcome a comprehensive review of all available immune checkpoint inhibitors used in the treatment of NSCLC, providing data on duration of therapy, for consideration by the Expert Committee in 2023. The Committee noted that data on the optimal duration of treatment are likely to consolidate over the next 2 years. The Committee also considered that immune checkpoint inhibitors could be flagged to the Medicines Patent Pool as candidates for consideration for negotiating public health-oriented licences, noting that negotiating such licences can take some time. The outcome of negotiations might provide important insight for future EML consideration on potential accessibility of this class of medicines in low- and middle-income countries. In addition, the Committee noted that WHO prequalification processes for monoclonal antibodies for cancer has resulted in prequalification of two molecules – rituximab and trastuzumab. The Committee considered that immune checkpoint inhibitors would also be candidates for WHO prequalification, to facilitate access to affordable and quality-assured products. The Committee considered that WHO prequalification and voluntary licence agreements are key actions that could facilitate the current regulatory pathways for approval of daratumumab, either originator or biosimilar, at the country level. The Committee also recommended that the high price of PD1 and PD-L1 immune checkpoint inhibitors could be a priority for the proposed EML Working Group addressing pricing and competition issues.
Background
An application for the inclusion of pembrolizumab, nivolumab and atezolizumab on the EML for treatment of patients with metastatic NSCLC was considered by the Expert Committee in 2019. Listing was not recommended as the Committee considered that the precise place of these medicines in the treatment of this condition was still evolving (i.e. immunotherapy alone or in combination with chemotherapy). The Committee noted the evidence of efficacy in the treatment of patients with metastatic NSCLC with these agents. The Committee observed that the duration of follow-up of the single studies for first-line and second-line immunotherapy in trials for lung cancer was generally shorter than 3 years, and considered that data from longer follow-up would better demonstrate the actual magnitude of benefit. The Committee expressed the hope that by the time of the 2021 Committee meeting, more mature data would be available for metastatic NSCLC and also for use of these agents in locally advanced non-resectable disease, and as adjuvant therapy. Furthermore, the Committee noted that the clinical development of cancer immunotherapy still has some areas of uncertainty about the optimal time for introduction of treatment (first- or second-line), appropriate patient selection and whether or not the use of immune checkpoint inhibitors in combination with other medicines is superior to monotherapy. The Committee expressed concern about the potential impact of oncology medicines on budgets, which could be an impediment to access, and the fact that countries may not be able to list these medicines on their national EMLs because of their high price (1).
Public health relevance
Lung cancer is the leading cause of cancer death worldwide, with an estimated 1.7 million related deaths in 2018 (2). Lung cancer is a highly lethal malignancy, with an economic impact estimated at around US$ 8 billion in lost productivity in the BRICS countries (Brazil, Russia, India, China, and South Africa). Moreover, in the absence of wide coverage of an effective screening programme in place globally, lung cancer diagnoses occur in advanced stages in more than 60% of cases, with high regional variability (3–5). Over 80% of lung cancers are classified as NSCLC (6). Targeted therapies have redefined treatment for patients with genomic alterations in driver oncogenes (e.g. epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase rearrangements, ROS1 rearrangements, BRAF mutations, human epidermal growth factor receptor 2 (HER2) mutations or amplifications and neurotrophic tyrosine kinase (NTRK) 1–3 fusions) to guide the selection of treatments. However, these therapies are ineffective in most patients with NSCLC who have tumours lacking such genetic alterations. Gene-targeted therapies are now estimated to benefit less than 10% of patients with NSCLC, but this proportion might increase rapidly over time (7). Immune checkpoint inhibitor therapy has become part of the standard treatment of patients with advanced and metastatic NSCLC in many high-income settings, based on favourable improvements in clinical outcomes. Immune checkpoint inhibitors target and reactivate immune-competent cells (i.e. T-lymphocytes and antigen-presenting cells) by inhibiting the immunosuppressive ligand PD-L1 or its receptor (PD-1), or by strengthening the immune-activating signals of the immune response (e.g. glucocorticoid-induced tumour necrosis factor receptor-related, proinflammatory interleukins, interferon-gamma) (8).
Benefits
First-line monotherapy in metastatic NSCLC expressing high levels of PD-L1 Pembrolizumab The phase III KEYNOTE-024 study evaluated pembrolizumab as first-line treatment in 500 participants with treatment-naive, advanced NSCLC showing PD-L1 expression ≥ 50%, in the absence of EGFR mutation or anaplastic lymphoma kinase translocations (non-oncogene-driven NSCLC) (9). Participants were randomized to receive 200 mg pembrolizumab every 3 weeks (up to 2 years) or 4–6 cycles of standard platinum-doublet chemotherapy. Efficacy measures favoured pembrolizumab, including progression-free survival (hazard ratio (HR) 0.5, 95% confidence interval (CI) 0.37 to 0.68; P < 0.001) and overall survival (HR 0.6, 95% CI 0.41 to 0.89; P = 0.005). In the intention-to-treat population, based on 189 events of progression or death in the first survival report, the median progression-free survival was 10.3 months (95% CI 6.7 months to not reached) in the pembrolizumab group and 6.0 months (95% CI 4.2 to 6.2 months) in the chemotherapy group. At the time of the second interim analysis, 108 deaths had occurred; 80.2% of participants were alive at 6 months (95% CI 72.9% to 85.7%) in the pembrolizumab group and 72.4% (95% CI 64.5% to 78.9%) in the chemotherapy group. An updated survival report (25.2 months median follow-up) confirmed the superiority of pembrolizumab over chemotherapy: the HR for overall survival was 0.63 (95% CI 0.47 to 0.86; nominal P = 0.002), median overall survival was 30.0 months (95% CI 18.3 months to not reached) in the pembrolizumab arm and 14.2 months (95% CI 9.8 to 19.0 months) in the chemotherapy arm; the Kaplan–Meier estimate of overall survival at 12 months was 70.3% (95% CI 62.3% to 76.9%) for the pembrolizumab group and 54.8% (95% CI 46.4% to 62.4%) for the chemotherapy group (10). In terms of effect size, pembrolizumab provided a gain of median overall survival of 15.8 months and 15.5% at 1 year. After more than 3 years of median follow-up, overall survival in participants in the pembrolizumab arm was 26.3 months versus 14.2 months in the chemotherapy arm (10). The last data available (5 years follow-up 55.1–68.4 months) indicated that participants treated with pembrolizumab exhibited a consistent and significant overall survival improvement (pembrolizumab 31.9% versus chemotherapy 16.3%) and fewer grade 3–5 adverse events (pembrolizumab 31.2% versus chemotherapy 53.3%) (11). The health-related quality of life analysis showed a clinically meaningful and significant improvement (12). Fewer participants treated with pembrolizumab had deterioration in the QLQ-LC13 composite endpoint than participants given chemotherapy (46/151 (31%) versus 58/148 (39%)). Time to deterioration was longer with pembrolizumab than with chemotherapy: median not reached (95% CI 8.5 months to not reached) versus 5.0 months (95% CI 3.6 months to not reached); HR 0.66, 95% CI 0.44–0.97; P = 0.029). Based on the KEYNOTE-024 trial, confirmed at a 3-year follow-up updated survival analysis, pembrolizumab is considered a new standard in several settings as the first-line option for patients with advanced NSCLC and PD-L1 expression ≥ 50% who do not otherwise have contraindications to immune checkpoint inhibitors: grade of evidence and level of recommendation: I, A; European Society for Medical Oncology’s magnitude of clinical benefit scale (ESMO-MCBS) v1.1 score 5/5. Participants with PD-L1 ≥ 50% drove the overall survival benefit preponderance, as the only subgroup gaining more than 6 months of overall survival. In comparison, no significant increase in overall survival was seen in participants with 1%–49% PD-L1 expression in the exploratory analysis of survival, where overall survival was 13.4 versus 12.1 months in this subpopulation (HR 0.92, 95% CI 0.77 to 1.11). Atezolizumab The IMpower110 study is a phase III, multicentre trial for untreated non-squamous, non-oncogene addicted metastatic NSCLC in participants whose tumour expressed PD-L1 (13). Up to 572 participants were randomized to receive atezolizumab or platinum-based chemotherapy (4 or 6 cycles) once every 3 weeks. At the interim analysis (median follow-up of 15.7 months), atezolizumab monotherapy demonstrated longer overall survival and progression-free survival than the chemotherapy arm. The progression-free survival benefit was respectively 8.1 months versus 5.0 months (stratified HR for disease progression or death, 0.63, 95% CI 0.45 to 0.88). Among participants with EGFR and anaplastic lymphoma kinase wild-type tumours who had high or intermediate PD-L1 expression, progression-free survival was 7.2 months in the atezolizumab group and 5.5 months in the chemotherapy group (stratified HR for disease progression or death 0.67, 95% CI 0.52 to 0.88). The overall survival for atezolizumab compared with chemotherapy arm was respectively 20.2 months versus 13.1 months (HR for death 0.59, 95% CI 0.40 to 0.89; P = 0.01) in the population with high PD-L1 expression, according to preplanned interim analysis. As overall survival testing did not meet its threshold in the wild-type population with PD-L1 expression of ≥ 5% by tumour cells or immune-infiltrating cells), overall survival was not tested in this population. No differences in time to confirmed deterioration were seen between the study arms for cough (HR 0.98, 95% CI 0.48 to 2.03), chest pain (HR 1.02, 95% CI 0.47 to 2.22), dyspnoea (HR 0.96, 95% CI 0.57 to 1.60) and 3-symptom composite score (HR 0.92, 95% CI 0.59 to 1.44). Mean change in physical function from baseline to week 42 was slightly improved with atezolizumab and greater than or similar to chemotherapy. Fatigue and nausea or vomiting scores numerically improved immediately with atezolizumab and were maintained to week 48 (14). Nivolumab The phase III CheckMate 026 trial included in participants with untreated, advanced NSCLC and PD-L1 ≥ 1%, randomized to nivolumab or platinum-doublet standard chemotherapy (15). The trial did not show a superiority of nivolumab over chemotherapy in unselected NSCLC participants. There was no difference in progression-free survival between the treatment groups in the primary efficacy analysis population (participants with a PD-L1 expression ≥ 5%). The median overall survival in the primary efficacy analysis population was 14.4 months (95% CI 11.7 to 17.4 months) in the nivolumab group and 13.2 months (95% CI 10.7 to 17.1 moths) in the chemotherapy group (HR for death 1.02, 95% CI 0.80 to 1.30). Nivolumab was not associated with a longer progression-free survival than chemotherapy. First-line treatment in combination with cytotoxic chemotherapy in metastatic squamous and non-squamous NSCLC, irrespective of tumour PD-L1 expression Pembrolizumab The efficacy and safety of pembrolizumab combined with chemotherapy for untreated advanced non-squamous NSCLC, without sensitizing EGFR/anaplastic lymphoma kinase alterations, regardless of PD-L1 expression, was assessed in the KEYNOTE-189 study (16). A total of 616 participants were randomized to receive four cycles of chemotherapy (pemetrexed + platinum-based compound), with pembrolizumab or placebo administered every 3 weeks for up to 35 cycles in a 2:1 ratio. The co-primary endpoints of this study were progression-free survival and overall survival. After a median follow-up of 10.5 months, the study showed a statistically significant progression-free survival improvement in the group treated with pembrolizumab compared with the placebo group: 8.8 months, 95% CI 7.6 to 9.2 months versus 4.9 months, 95% CI 4.7 to 5.5 months; HR for progression or death 0.52, 95% CI 0.43 to 0.64; P < 0.001). Likewise, there was a statistically significant improvement in overall survival: not reached versus 11.3 months, 95% CI 8.7 to 15.1 months; HR for death 0.49, 95% CI 0.38 to 0.64; P < 0.0010). Following PD-L1 stratification criteria, the pembrolizumab/chemotherapy arm exhibited efficacy across all subgroups analysed: • PD-L1 expression < 1%: 12-month overall survival rate 61.7% versus 52.2%; HR for death 0.59, 95% CI 0.38 to 0.92; • PD-L1 expression 1–49%: 12-month overall survival rate 71.5% versus 50.9%; HR 0.55, 95% CI 0.34 to 0.90; and • PD-L1 expression ≥ 50%: 12-month overall survival rate 73.0% versus 48.1%; HR 0.42, 95% CI 0.26 to 0.68. Response rates were also higher in the pembrolizumab combination group: 47.6% (95% CI 42.6% to 52.5%) compared with 18.9% (95% CI 13.8% to 25.0%) in the placebo combination group (P < 0.001), and consistent across all PD-L1 subgroups, but notably greater in the subgroup PD-L1 ≥ 50% (61.4% versus 22.9%). The KEYNOTE-189 update included a median follow-up of 23.1 months (range 18.6 to 30.9 months) and confirmed a sustained clinical and statistically meaningful benefit in efficacy and safety: median overall survival was 22.0 months (rage 19.5 to 25.2 months) in the pembrolizumab combination group and 10.7 months (range 8.7 to 13.6 months) in the placebo combination group (HR 0.56, 95% CI 0.45 to 0.70), an absolute gain of 10.3 months. The estimated 24-month overall survival rates were 45.5% and 29.9%, respectively. Median progression-free survival was 9.0 months (range 8.1 to 9.9 months) and 4.9 months (range 4.7 to 5.5 months) in the pembrolizumab combination and placebo combination groups, respectively (HR 0.48, 95% CI 0.40 to 0.58), with estimated 24-month progression-free survival rates of 20.5% and 1.5%. Notably, the study update confirmed the benefit for overall survival and progression-free survival across all PD-L1 tumour proportion scores (17). The KEYNOTE-407 trial assessed the efficacy and safety of pembrolizumab plus chemotherapy (carboplatin and either paclitaxel or nab-paclitaxel) compared with placebo plus chemotherapy (carboplatin and either paclitaxel or nab-paclitaxel) in participants with untreated, advanced squamous NSCLC, without sensitizing EGFR/anaplastic lymphoma kinase alterations, and regardless of PD-L1 tumour proportion score (18). The median overall survival was 15.9 months (95% CI 13.2 months to not reached) in the pembrolizumab combination group and 11.3 months (95% CI 9.5 to 14.8 months) in the placebo combination group (HR for death 0.64, 95% CI 0.49 to 0.85; P < 0.001), and a 1-year Kaplan–Meier estimate of 65.2% in the pembrolizumab arm versus 48.3% in the placebo arm. Overall, the results show an overall survival gain of 4.6 months, reducing death by 36% and favouring the addition of pembrolizumab compared to standard of care chemotherapy. The overall survival benefit extends to all PD-L1 expression subgroups, including PD-L1 < 1%. The progression-free survival benefit was 6.4 months (95% CI 6.2 to 8.3 months) in the pembrolizumab combination group and 4.8 months (95% CI 4.3 to 5.7 months) in the placebo combination group (HR for disease progression or death 0.56, 95% CI 0.45 to 0.70; P < 0.001). First-line consolidation therapy for locally advanced, unresectable NSCLC with PD-L1 expression ≥1% Durvalumab The efficacy of durvalumab was evaluated in the PACIFIC trial, a double-blind study in 713 participants with locally advanced, unresectable NSCLC, irrespective of tumour PD-L1 expression (19). Participants had completed at least two cycles of definitive platinum-based chemotherapy with radiation therapy within 1 to 42 days before start of the study. Participants were randomized to receive durvalumab (476 participants) or placebo (237 participants) every 2 weeks for up to 12 months or until unacceptable toxicity or confirmed disease progression. The study showed a significant improvement in progression-free survival in the durvalumab-treated group compared with the placebo group (HR 0.52, 95% CI 0.42 to 0.65; P < 0.0001) as well as in overall survival (HR 0.68, 95% CI 0.53 to 0.87; P = 0.00251). As of 31 January 2019, 48.2% of the participants had died (44.1% and 56.5% in the durvalumab and placebo groups, respectively). The median duration of follow-up was 33.3 months. The updated overall survival remained consistent with that previously reported (stratified HR 0.69, 95% CI 0.55 to 0.86). The median overall survival was not reached with durvalumab but was 29.1 months with placebo. The 12-, 24- and 36-month overall survival rates with durvalumab and placebo were 83.1% versus 74.6%, 66.3% versus 55.3% and 57.0% versus 43.5%, respectively. All secondary outcomes examined showed improvements consistent with previous analyses (20). A significant benefit from durvalumab was observed only in the subgroup withPD-L1 > 1%, both for overall survival (HR 0.53, 95% CI 0.36 to 0.77; median overall survival not reached versus 29.1 months) and progression-free survival (HR 0.46, 95% CI 0.33 to 0.64; median progression-free survival 17.8 versus 5.6 months). In the PD-L1-negative subgroup, no statistically significant improvement was seen in either overall survival (HR 1.36, 95% CI 0.79 to 2.34) or progression-free survival (HR 0.73, 95% CI 0.48 to 1.11). An exploratory post hoc analysis of outcomes grouped by tumour cell PD-L1 expression from the PACIFIC trial included 709 participants who had received at least one dose of durvalumab (473 participants) or placebo (236 participants) (21). After a median follow-up of 33.3 months, durvalumab was associated with a progression-free survival benefit across all PD-L1 expression subgroups, and improved overall survival across all subgroups except PD-L1 < 1%: • PD-L1 ≥ 25% (HR 0.50, 95% CI 0.30 to 0.83; median not reached versus 21.1 months), • PD-L1 < 25% (HR 0.89, 95% CI 0.63 to 1.25; median 39.7 versus 37.4 months), • PD-L1 ≥ 1% (HR 0.59, 95% CI 0.41 to 0.83; median not reached versus 29.6 months), • PD-L1 1%–24% (HR 0.67, 95% CI 0.41 to 1.10; median 43.3 versus 30.5 months), • PD-L1 unknown (HR 0.60, 95% CI 0.43 to 0.84; median 44.2 versus 23.5 months), • PD-L1 < 1% (HR 1.14, 95% CI 0.71 to 1.84; median 33.1 versus 45.6 months). A recent 4-year overall survival update (20 March 2020, median follow-up 34.2 months (range 0.2–64.9)) confirmed a sustained benefit with durvalumab compared with placebo for progression-free survival (stratified HR 0.55, 95% CI 0.44 to 0.67; median 17.2 versus 5.6 months) and overall survival (stratified HR 0.71, 95% CI 0.57 to 0.88; median 47.5 months versus29.1 months). The 48-month overall survival rates for durvalumab versus placebo were 49.6% versus 36.3% and progression-free survival rates were 35.3% versus 19.5% (20,22). Second-line treatment for advanced NSCLC, after failure of platinum-containing standard chemotherapy Pembrolizumab, nivolumab and atezolizumab have been approved by the United States Food and Drug Administration and the European Medicines Agency for use in the second-line treatment setting, based on phase III studies showing improved overall survival compared with docetaxel (the standard of care in second-line treatment for patients with NSCLC who have not responded to platinum-containing first-line chemotherapy (23,24). Overall, no major differences were found in efficacy or safety among these three therapies to inform a best single option and no direct comparative studies have been conducted. There are two key distinctions between the three approved therapies, which can affect choice and use. • PD-L1 expression in the tumour. Nivolumab and atezolizumab are approved in patients with previously treated, advanced NSCLC, irrespective of PD-L1 expression, while pembrolizumab is approved only in patients with PD-L1 expression > 1%. • Schedule of administration. Pembrolizumab is approved to be given in the dose of 200 mg every 3 weeks or 400 mg every 6 weeks and nivolumab is approved to be given in the dose of 240 mg once every 2 weeks, whereas atezolizumab can be given in the doses of 840 mg every 2 weeks, 1200 mg every 3 weeks, or 1680 mg every 4 weeks, based on current approvals by the European Medicines Agency. Pembrolizumab The KEYNOTE-010 trial randomized 1033 participants with previously treated squamous and non-squamous NSCLC with PD-L1 expression of at least 1% to receive pembrolizumab (tested at two doses, 2 mg/kg or 10 mg/kg, every 3 weeks) or docetaxel (75 mg/m2 every 3 weeks) (25). Overall survival was longer for the pembrolizumab group than the docetaxel group: 2 mg/kg (HR 0.71, 95% CI 0.58 to 0.88; P < 0.001); 10 mg/kg (HR 0.61, 95% CI 0.49 to 0.75; P < 0.001), with a 2-year overall survival rate of 14.5% versus 30.1% (2 mg/kg group). Median overall survival was 14.9–17.3 for the 2 mg/kg and 10 mg/kg arms, compared with 8.2 months for the chemotherapy arm. The safety profile favoured pembrolizumab with a smaller percentage of participants with grade 3–5 adverse events (16%) than in the chemotherapy arm (35%), and decreased appetite (14%) and fatigue (14%) for immune checkpoint inhibitors, and neutropenia (14%), alopecia (33%), anaemia (13%) and oral mucositis (14%) for chemotherapy. No relevant differences in the safety of pembrolizumab were seen between participants given 2 mg/kg or 10 mg/kg. Long-term outcomes from KEYNOTE-010 were recently published (26). Pembrolizumab continued to show improved overall survival compared with docetaxel in the PD-L1 ≥ 50% and PD-L1 ≥ 1% groups (HR 0.53, 95% CI 0.42 to 0.66; P < 0.00001 and HR 0.69, 95% CI 0.60 to 0.80; P < 0.00001, respectively) after a 42.6-month median follow-up. Estimated 36-month overall survival rates for PD-L1 expression ≥ 50% and PD-L1 expression ≥ 1% groups were 34.5% (pembrolizumab) versus 12.7% (docetaxel) and 22.9% versus 11.0%, respectively. Grade 3–5 treatment-related adverse events occurred in 16% versus 37% of participants in the pembrolizumab and docetaxel groups, respectively. Of 690 participants, 79 completed 35 cycles per 2 years of pembrolizumab: 12-month overall survival and progression-free survival rates after completing treatment were 98.7% (95% CI 91.1% to 99.8%) and 72.5% (95% CI 59.9% to 81.8%), respectively. Nivolumab In the CheckMate-017 trial, 272 participants with squamous NSCLC were randomized to receive nivolumab or docetaxel (27). The median overall survival was 9.2 months (95% CI 7.3 to 13.3 months) in the nivolumab group and 6.0 months (95% CI 5.1 to 7.3 months) in the docetaxel group. In the CheckMate-057 trial, 582 participants with non-squamous NSCLC (e.g. adenocarcinoma) were randomized to nivolumab or docetaxel (28). In a recent update of the CheckMate-017 and CheckMate-057 trials, the pooled 2-year overall survival favoured nivolumab in both squamous NSCLC (29%, 95% CI 24% to 34% versus 16%, 95% CI 12% to 20%) and non-squamous NSCLC (23%, 95% CI 16% to 30% versus 8%, 95% CI 4% to 13%) (29). In the pooled analysis of overall survival in the intention-to- treat population (854 participants) with squamous (272 participants (31.9%)) and non-squamous (582 (68.1%)) NSCLC, median overall survival was 11.1 months (95% CI 9.2 to 13.1 months) with nivolumab versus 8.1 months (95% CI 7.2 to 9.2 months) with docetaxel (HR 0.72, 95% CI 0.62 to 0.84). Higher PD-L1 expression levels were associated with greater overall survival benefit with nivolumab (HR 0.42, 95% CI 0.28 to 0.63) in participants with PD-L1 ≥ 50%, but a benefit was still observed in participants with PD-L1 < 1% (HR 0.78, 95% CI, 0.61 to 0.99). Consistent with the primary analyses, nivolumab showed a better 2-year overall survival benefit than docetaxel in participants with squamous NSCLC regardless of PD-L1 expression level. However, in participants with non-squamous NSCLC, higher levels of PD-L1 were associated with a greater overall survival benefit with nivolumab, but NSCLC patients with PD-L1 < 1% still derived greater benefit from immune checkpoint inhibitors than chemotherapy: in participants with PD-L1 ≥ 50%, the HR for overall survival on the basis of 2 years minimum follow-up was 0.38 (95% CI 0.24 to 0.60) for participants with non-squamous NSCLC. Pooled data from four clinical studies of nivolumab in participants with previously treated NSCLC (CheckMate 017, 057, 063 and 003) showed 4-year overall survival with nivolumab was 14% for all participants (664 participants), 19% for those with PD-L1 expression > 1% and 11% for those with PD-L1 expression < 1%. Nivolumab continued to show long-term overall survival and progression-free survival benefit compared with docetaxel, with 5-year survival rates of 13.4% versus 2.6% and progression-free survival rates of 8% versus 0%. Survival after a response at 6 months on nivolumab or docetaxel was longer than after progressive disease at 6 months: HR for overall survival 0.18 (95% CI 0.12 to 0.27) for nivolumab and HR 0.43 (95% CI 0.29 to 0.65) for docetaxel. For stable disease versus progressive disease, HR for overall survival was 0.52 (95% CI 0.37 to 0.71) for nivolumab and HR 0.80 (95% CI 0.61 to 1.04) for docetaxel. Long-term data did not show any new safety signals (30). Atezolizumab The phase III OAK trial evaluated atezolizumab versus docetaxel in 850 participants with previously treated, advanced squamous and non-squamous NSCLC (31). Overall survival was improved in participants given atezolizumab (median overall survival 13.8 months, 95% CI 11.8 to15.7 months) compared with participants given docetaxel (9.6 months, 95% CI 8.6 to 11.2 months), with HR 0.73 (95% CI 0.62 to 0.87; P = 0.0003). Subgroup analysis showed a greater magnitude of benefit in patients with higher PD-L1 expression, both assessed on tumour cells or immune-infiltrating cells: the net benefit gain with tumour cells 1/2/3 or immune-infiltrating cells 1/2/3 was +5.4 months (HR 0.74, 95% CI 0.58 to 0.93; P = 0.0102) and +5.5 months with tumour cells 2/3 or immune-infiltrating cells 2/3 (HR 0.67, 95% CI 0.49 to 0.90; P = 0.0080). Data for patient-reported outcomes in the OAK study found that atezolizumab delayed the time to deterioration in patient physical function and role function compared with docetaxel. No significant differences in time to deterioration were observed between treatment arms for health-related quality of life, although the point estimate numerically favoured atezolizumab (HR 0.94, 95% CI 0.72 to 1.24) (32).
Harms
Pembrolizumab In Keynote-024, treatment-related adverse events occurred in 73.4% of participants in the pembrolizumab group and 90.0% of participants in the chemotherapy group. In the pembrolizumab and chemotherapy groups respectively, 26.6% and 53.3% of adverse events were grade 3 (moderate-severe) to grade 5 (toxic death), which resulted in a higher treatment discontinuation rate because of these adverse events in the chemotherapy group (10.7% versus 7.1%). Despite longer mean treatment duration in the pembrolizumab group (11.1 versus 4.4 months), grade 3‒5 treatment-related adverse events were less frequent with pembrolizumab than chemotherapy after 3 years follow-up (10). The most common treatment-related adverse events in the pembrolizumab arm were hypo- and hyperthyroidism (in 9% and 8% of participants, all grade 1 and 2), diarrhoea (in 14.3%), fatigue (in 10.4%) and pyrexia (in 10.4%). For chemotherapy, bone marrow toxicity (anaemia in 44.0%) and traditional systemic treatment-related adverse events were observed (nausea in 43.3% and fatigue in 28.7%); anti-emetic premedication was allowed per protocol, consistent with institutional and international guidelines for moderately to highly emetogenic platinum-containing chemotherapy regimens in the standard of care arm. The most frequent adverse events in the KEYNOTE-189 trial were nausea (55.6% in the pembrolizumab arm versus 52% in the placebo arm, grade 3 in 3.5% in both arms), anaemia (46.2% versus 46.5%, grade ≥ 3 in 16.3% versus 15.3%), fatigue (40.7% versus 38.1%, grade ≥ 3 in 5.7% versus 2.5%). Rates of treatment-related adverse events were similar for carboplatin and cisplatin. The proportion of participants who discontinued all trial drugs because of treatment-related adverse events was greater in the pembrolizumab arm than the placebo arm (13.8% versus 7.9%). Overall, the immune-related treatment-related adverse events of interest occurred in the pembrolizumab arm (any grade, 22.7%; grade ≥ 3, 8.9%) or placebo (any grade, 11.9%; grade 3, 4.5%) group. The most frequent immune-related treatment-related adverse events in the pembrolizumab arm were hypothyroidism (any grade, 6.7%; grade ≥ 3, 0.5%), pneumonitis (any grade, 4.4%; grade 3, 2.7%), hyperthyroidism (any grade, 4%; grade ≥ 3, 0%), infusion reaction (any grade, 2.5%; grade ≥ 3, 0.2%), and colitis (any grade, 2.2%; grade 3, 0.7%) (17). In the KEYNOTE-407 trial of pembrolizumab in combination with chemotherapy, 98.2% of participants in the pembrolizumab arm versus 97.9% in the placebo arm experienced any grade of treatment-related adverse events, where anaemia, alopecia and neutropenia were the most common in both arms. Treatment-related adverse events of grade ≥ 3 occurred in 69.8% of participants in the pembrolizumab arm and 68.2% in the placebo arm; anaemia and neutropenia occurred in more than 10% of the participants. Pneumonitis and autoimmune hepatitis were the grade ≥ 3 adverse events that occurred more frequently in the pembrolizumab arm, with percentages similar to those observed in the KEYNOTE-189 trial (18). Atezolizumab In the IMpower110 Study, treatment-related adverse events occurred in both the atezolizumab and chemotherapy arms: any grade in 90.2% of participants in the atezolizumab arm versus 94.7% of participants in the chemotherapy arm; grade 3 and 4 in 30.1% versus 52.5%; and grade 5 in 3.8% versus 4.2%. The most frequent grade 3 and 4 adverse events were anaemia, neutropenia and thrombocytopenia. Hepatic laboratory abnormalities, rash and hypothyroidism were the most reported immune-mediated treatment-related adverse events (≥ 5% in both groups). Grade 3 or 4 immune-mediated treatment-related adverse events occurred in 6.6% of participants in the atezolizumab arm and 1.5% in the chemotherapy arm, with no grade 5 event reported (13). For patient-reported outcomes in the OAK study, fewer participants receiving atezolizumab experienced grade 3 or 4 treatment-related adverse events (14.9%) than did participants receiving docetaxel (42.4%); no grade 5 treatment-related adverse events related to atezolizumab were observed (32). Durvalumab In the PACIFIC study, the most frequent treatment-related adverse events were cough (40.2% in the durvalumab arm versus 30.3% in placebo), upper respiratory tract infections (26.1% versus 11.5%) and rash (21.7% versus 12.0%). The most frequent grade 3–4 treatment-related adverse event was pneumonia (6.5% versus 5.6%). The overall incidence of grade 3 or 4 treatment-related adverse events was 12.8% in the durvalumab arm and 9.8% in the placebo arm (19). Overall, durvalumab is most associated with immune-mediated treatment-related adverse events. In the combined safety database with durvalumab monotherapy (1889 participants with multiple tumours types), immune-mediated pneumonitis occurred in 79 (4.2%) participants, including grade 3 in 12 participants (0.6%), grade 4 in one patient (< 0.1%) and grade 5 in five participants (0.3%). Durvalumab does not induce antibody-dependent cell-mediated cytotoxicity. Other immune-related treatment-related adverse events reported in less than 1% of participants treated with durvalumab monotherapy in clinical trials were myasthenia gravis, myocarditis, myositis, polymyositis, meningitis, encephalitis and Guillain–Barre syndrome. No overall differences in safety were reported between elderly (≥ 65 years) and younger participants. Preliminary real-world data of durvalumab consolidation after chemoradiotherapy compared with regular follow-up after chemoradiotherapy found the incidence of grade 3 radiation pneumonitis was higher in the group treated with durvalumab (14.3% versus 2.5%) (33). Nivolumab In the CheckMate-017 trial in patients with squamous NSCLC, treatment-related adverse events, including hematologic and non-haematological events, occurred less frequently with nivolumab than with docetaxel: in the nivolumab group, 58% of participants had events of any grade, of which 7% were grade 3 or 4; in the docetaxel group, 86% of participants had events of any grade, of which 55% were grade 3 or 4. The safety profile was consistent with the class side-effects with no new signals of safety. The most frequently reported treatment-related adverse events with nivolumab were fatigue and asthenia, and for docetaxel were neutropenia (33%); 10% febrile neutropenia), fatigue (33%), alopecia (22%), nausea (23%) and peripheral neuropathy (11%). Treatment discontinuations due to adverse events were reported in 3% and 10% of participants in the nivolumab and chemotherapy arms, respectively (27). In the CheckMate-057 trial, the safety profile and pattern of adverse events in participants with non-squamous NSCLC were consistent with the data from the participants with squamous NSCLC. Treatment-related adverse events of any grade were observed in 69% and 88% of participants in the nivolumab and docetaxel arms, respectively. Grade 3–4 adverse events were observed in 10% of participants in the nivolumab arm and 54% of participants in the docetaxel arm. Discontinuation rates were 5% in the nivolumab arm and 15% in the docetaxel arm (28).
Cost / cost effectiveness
A cost–effectiveness analysis of pembrolizumab as first-line treatment in patients with high PD-L1 expression was conducted using data from Keynote 024, from the perspective of a United States third-party public health care payer (36). Pembrolizumab would be expected to result in an incremental cost of US$ 98 281 per quality-adjusted life year (QALY) gained or an incremental cost of US$ 78 873 per life year gained. Including the cost of PD-L1 testing had a very small effect on the model results. With a 5-year time horizon, the ICER was US$ 99 998/LY and US$ 122 024/QALY; with a 10-year time horizon, the incremental cost–effectiveness ratio was US$ 83 065/life year and US$ 103 101/QALY. Base-case results indicated that, compared with standard of care over a 20-year time horizon, pembrolizumab would be expected to result in an additional 1.31 life years gained and an additional 1.05 QALYs gained. For pembrolizumab in combination with chemotherapy for first-line treatment of metastatic non-squamous NSCLC, the National Institute for Health and Care Excellence (NICE) technology appraisal guidance (TA557, 10 Jan 2019) calculated that the incremental cost–effectiveness ratio was less than £ 50 000 per QALY gained and concluded that incremental cost–effectiveness ratios were not all clearly within the range usually considered a cost-effective use of resources. At that time, NICE decided not to recommend pembrolizumab combination for routine use in adults with untreated, metastatic, non-squamous NSCLC whose tumours have no EGFR- or anaplastic lymphoma kinase-positive mutations (37). Updated guidance (TA683, 10 March 2021), considering updated overall survival data, concluded that the most plausible estimates of cost–effectiveness for pertuzumab in combination with chemotherapy were within what NICE considers a cost-effective use of resources and recommended the combination as an option for untreated, metastatic non-squamous NSCLC with a 2-year stopping rule (38). For pembrolizumab in combination with chemotherapy for first-line treatment of metastatic squamous NSCLC, NICE technology appraisal guidance (TA600, 11 Sept 2019) concluded that the long-term overall survival benefit with pembrolizumab combination therapy was uncertain because of the very short duration of the interim data from KEYNOTE-407. The committee decided that the incremental cost–effectiveness ratio was not within the range usually considered a cost-effective use of resources and that further overall survival data are required to reduce cost–effectiveness uncertainty (39). A decision-analytic microsimulation model was developed to compare chemoradiotherapy with chemoradiotherapy followed by durvalumab consolidation therapy until progression or a maximum of 1 year for potential budgetary consequences. Among 2 million simulated patients, durvalumab consolidation therapy was cost-effective compared with no consolidation therapy at a willingness-to-pay threshold of US$ 100 000 per QALY, with an estimated incremental cost–effectiveness ratio of US$ 67 421 per QALY. Durvalumab consolidation therapy would contribute an additional US$ 768 million to national cancer spending in the first year, decreasing to US$ 241 million in year 5. Durvalumab consolidation therapy indicates that expensive immunotherapies can be cost-effective because treating with immunotherapy earlier during cancer progression can provide significant value, despite having a substantial budgetary consequence (40). In another study, a Markov model based on the 3-year follow-up data of the PACIFIC trial was used to compare consolidation durvalumab with observation, using published utility values. The study assessed costs for treatment strategies from the perspective of the Swiss health care payers. In the unselected and PD-L1-positive patients, durvalumab showed incremental effectiveness ratios of Sw.fr. 88 703 per QALY gained and Sw.fr. 66 131 per QALY gained, respectively. Durvalumab was cost-effective at a willingness-to-pay threshold of Sw.fr. 100 000 per QALY gained in almost three quarters of simulations in the probabilistic sensitivity analysis (41). For durvalumab as consolidation therapy after platinum-based chemoradiation in locally advanced unresectable NSCLC, NICE technology appraisal guidance (TA578, 1 May 2019) noted that durvalumab had the potential to be cost-effective compared with standard care, but more evidence from the ongoing PACIFIC trial was needed to address uncertainties associated with the duration of treatment effect and the rate of disease progression (42). Some pharmaceutical manufacturers have set up access programmes to facilitate availability of checkpoint inhibitors in low- and middle-income countries. However, few details are available in the public domain on the exact characteristics of these programmes, including tiered pricing strategies, or on the effect of these programmes on equitable access and affordability.
WHO guidelines
WHO guidelines for treatment of NSCLC are not currently available. The ESMO clinical practice guidelines for metastatic non-small-cell lung cancer (last updated in September 2020) include the following recommendations (34). First-line treatment of EGFR- and anaplastic lymphoma kinase-negative NSCLC, PD-L1 ≥ 50% Pembrolizumab is considered a standard first-line option for patients with advanced NSCLC and PD-L1 expression ≥ 50% who do not otherwise have contraindications to use of immunotherapy (such as severe autoimmune disease or organ transplantation) [I, A; European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS) v1.1 score: 5]. Atezolizumab represents a promising first-line treatment option in patients with PD-L1-high (following the specific definition of TC3 or IC3 per trial design) NSCLC [I, A; not EMA-approved], with the formal caution of a subgroup analysis compared with trial design and ITT using only TC > 50% [I, B]. First-line treatment of EGFR- and anaplastic lymphoma kinase-negative NSCLC, regardless of PD-L1 status Based on the results from KEYNOTE-189, pembrolizumab in combination with pemetrexed and a platinum-based ChT [chemotherapy] should be considered a standard option in metastatic non-squamous NSCLC [I, A; ESMO-MCBS v1.1 score: 4]. Results from KEYNOTE-407 place the combination of pembrolizumab plus carboplatin and paclitaxel or nab-P [nab-paclitaxel] as a standard choice in patients with metastatic squamous NSCLC [I, A; ESMOMCBS v1.1 score: 4]. Second-line treatment of NSCLC without actionable oncogenic driver Pembrolizumab, atezolizumab and nivolumab “represent reasonable standard therapy for most patients with advanced, previously treated, PD-L1-naive NSCLC” [I, A; ESMO-MCBS v1.1 score: 5]. First-line consolidation therapy for locally advanced, unresectable NSCLC with PD-L1 expression ≥ 1% ESMO clinical practice guidelines for early-stage and locally advanced (non-metastatic) non-small-cell lung cancer (last updated May 2020) (35) recommend consolidation administration of durvalumab in patients with unresectable stage III NSCLC with PD-L1 ≥ 1% and whose disease has not progressed following platinum-based chemoradiotherapy [I, A; ESMO-MCBS v1.1 score: 4].
Availability
Pembrolizumab (trade name Keytruda, Merck), atezolizumab (trade name Tecentriq, Genetech) and nivolumab (trade name Opdivo, Bristol Myers Squibb) have regulatory approval in multiple countries for the treatment of metastatic NSCLC. They have primary patent protection until 2028, 2029 and 2026, respectively. Durvalumab (trade name Imfinzi, AstraZeneca) has regulatory approval in multiple countries for the treatment of locally advanced, unresectable NSCLC as consolidation therapy after platinum-based chemotherapy. It has primary patent protection until 2030.
Other considerations
The EML Cancer Medicines Working Group advised that it supported the inclusion of pembrolizumab on the EML for first-line treatment of metastatic NSCLC in selected patients with PD-L1 expression ≥ 50% based on evidence of a relevant and meaningful survival benefit. Considering the other PD-1/PD-L1 monoclonal antibodies, atezolizumab has also shown evidence of benefit in this setting (first-line, PD-L1 expression ≥ 50%), but the data are not as robust as they are for pembrolizumab. Recent meta-analyses suggest, however, similar performance of the different PD-1/PD-L1 antibodies (43,44), so other monoclonal antibodies within the same class could be considered as possible alternatives for selection at the country level to provide opportunities for better procurement and tendering. The Working Group did not support the listing at this time of PD-1/PD-L1 immune checkpoint inhibitors for use in stage 3 locally advanced disease, second-line in the metastatic setting, or as maintenance therapy. Regarding cost–effectiveness, the Working Group noted that cost–effectiveness has not been proven using the list prices available in countries, but rather at discounted prices negotiated with health system payers. The effect on health system budgets of supplying these treatments will be very high in many countries. Weight-based dosing of pembrolizumab (2 mg/kg) may be preferred over fixed dosing because it is less costly, and without loss of benefit. Molecular and immunohistochemistry diagnosis is a vital component for using immunotherapy in NSCLC and involves at least PD-L1 staining, and analysis of EGFR and anaplastic lymphoma kinase. Validated immunohistochemistry companion tests defined for the regimens described are available. The authors of a recent study validating the three different available biomarkers for NSCLC (22C3, SP263 and SP142), asserted that their study “consolidates the analytical evidence for interchangeability of the 22C3, 28-8, and SP263 assays and lower sensitivity of the SP142 assay” (45). To address the feasibility of adopting the regimens mentioned above, the following factors need to be evaluated: the existing and required workforce and their expertise; capacity-building standards; governance for access to the medicines’ chain; and the financial aspects of offering timely, high-quality, accurate and reliable pathology diagnosis and treatment without catastrophic or excessive expenditure for the patient or health system. Comments were received from the WHO Department of Noncommunicable Diseases. The technical department advised that the inclusion of immune checkpoint inhibitors for the treatment of NSCLC would have substantial implications for the EML and access to cancer medicines globally. The technical department noted that their clinical effect, ability to address major disease burden at the population level and the accumulation of the existing clinical data would favour their inclusion on the EML. It noted, however, that there were also important concerns that needed to be addressed, such as the establishment of a framework to better inform their selection in national EMLs given the negative implication their inclusion may have on access including inability to safely deliver the treatment, the diversion of resources away from other essential medicines, and the financial hardship for patients who must make out-of-pocket payments. The technical department noted that further data from low- and middle-income countries would help the technical team and Expert Committee better understand the feasibility of the use of immune checkpoint inhibitors for treatment of NSCLC in resource-limited settings and implications of their approval and selection. The technical department concluded that while the inclusion of checkpoint inhibitors for NSCLC may be warranted, strong consideration should be given to the development of such a framework in this review cycle or for the next Expert Committee in 2023.
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