Financial Toxicity for Pembrolizumab and Atezolizumab for Metastatic Non-Small Cell Lung Cancer: A Pooled Analysis of Cost-Effectiveness Analyses

Introduction

In recent decades, lung cancer is the most common carcinoma with high incidence and mortality throughout the world, and more than half of the patients were categorized as advanced diseases during the first diagnosis.¹ Immunotherapy developed swiftly, and immune checkpoint inhibitors (ICIs) were promising medical treatments for advanced or metastatic non-small cell lung cancer (NSCLC), especially for the diseases with positive expression of programmed death ligand-1 (PD-L1).^2,3 Tumor proportion score (TPS) is referred to the positivity of PD-L1 expression in tumor cells, and high TPS was associated with a favored prognosis for those who received immunotherapy.

However, the impact of financial burden might not be neglected due to the high cost of the novel therapies, and patients might not be able to afford to continue the previous treatments.^4,5 Immunotherapies represented by Atezolizumab and Pembrolizumab demonstrate excellent efficacy for patients with NSCLC, but their annual treatment costs are significantly higher compared to chemotherapy.⁶ The high expense of cancer treatment could bring great financial pressure, or even bankruptcy to the patients and their families, mainly consisting of the objective economic burdens and subjective perceptions of the poverties. In this way, the concept of financial toxicity was proposed, and it was reported to impair the quality of life and result in increased mortality. The comprehensive score for financial toxicity (COST) was the only validated tool for the financial toxicity assessment, and a prospective investigation that complied with the COST tool identified the definite financial toxicity of pan-cancer treatment in Japan.^4,5,7 Patients with NSCLC are unfavored for immunotherapy due to its high cost, which might lead to impaired survival. In different countries, drug prices further exacerbate financial toxicity.⁸ In China, the drug price negotiation program and the National Reimbursement Drug List (NRDL) initiated in 2018 and led by the government, is a critical policy aimed at reducing the financial burden of medical treatments for patients. Although some advanced drugs and therapies have been included in the NRDL, which has partially reduced medical costs and alleviated financial toxicity, the prices of certain original immune checkpoint inhibitors remain high. Therefore, we aim to explore the financial toxicity of immunotherapy for patients with NSCLC.

Cost-effectiveness analysis was employed to evaluate the association between the survival benefit from immunotherapy and concomitant financial toxicity. Quality-adjusted life years (QALYs) are comprehensive and quantified assessments of health outcomes, including quality of life (QOL), and incremental cost-effectiveness ratio (ICER) is referred to as the cost per QALY gained. Willingness-to-pay (WTP) is the maximum cost that patients are regarded to afford for the therapy, and the comparison of WTP and ICER would help to interpret the survival benefit in the view of economics for immunotherapy. Various countries would set the target WTP in various ways based on their health policies, and it is commonly set as 100,000 or 150,000 US dollars per QALY.⁶ While the cost was generally regarded as cost-effective when the ICER was lower than three times the country’s per-capita gross domestic product (GDP), as suggested by the World Health Organization’s Choosing Interventions that are Cost-Effective project (WHO-CHOICE).⁹

Recently, several studies have proposed the clinical implications of financial toxicity for medical treatment with high expense, and we aimed to investigate the role of financial toxicity in NSCLC after Pembrolizumab or Atezolizumab. We systematically reviewed the previously published studies with cost-effectiveness analysis, and we would also reveal the heterogeneity of financial toxicity stratified by TPS for NSCLC. We hypothesized that financial toxicity could have an adverse impact on survival and might be a crucial indicator in clinical practice for those with NSCLC who received immunotherapy.

Methods

The investigators conducted a systematic literature search for the published economic evaluation of ICIs (Pembrolizumab and Atezolizumab) in the Medline, and Web of Science databases between January 2015 and September 2021. We developed a free-word search in the following terms, Atezolizumab OR Pembrolizumab, non-small cell lung cancer OR lung cancer, and financial toxicity OR cost-effectiveness. All reference lists from the included papers were carefully reviewed to identify relevant studies.

The following inclusion criteria were employed in the selection process: (1) assess the cost-effectiveness of Pembrolizumab or Atezolizumab monotherapy or combined therapies for metastatic NSCLC; (2) several critical economic evaluation parameters were included, including QALY and ICER; (3) the willingness to pay (WTP) was clarified or WTP was mentioned in the study; (4) the papers presented base-case results for economic evaluation. The study would be excluded when it met one of the following criteria: (1) the critical data involving economic evaluation were not available; (2) the paper was not an original article, including (conference) abstract, case report, and review; (3) the paper was not presented in English. Two individual investigators conducted the study selection (WH and JHW), and the discrepancy would be decided by the third investigator (JL).

After identifying the included papers, two investigators (WH and JHW) extracted the data from the involved studies independently, and the difference was assessed and decided by the third investigator (JL). The following items were collected from the papers: the last name of the first author, year of publication, statistical model, cost perspective, treatment therapy, total cost, incremental cost, QALY, incremental QALY, ICER, and WTP. The cost perspective referred to the specific country or area where the authors presented the cost of therapy and conducted the analyses in their research. As for the economic evaluation of the cost, QALY, and ICER, we only extracted data and conducted analyses on the base-case results. All costs had been converted into US dollars to facilitate the comparison of economic outcomes, and the exchange rate of currency conversion was intended to be the average value of the opening price and closing price of the published year of the research. When the WTP was unavailable in the study, it would be estimated as three times the country’s per-capita GDP as conformed to the WHO-CHOICE principle.

We could compare the economic outcomes between the experimental group (ICI monotherapy or combined therapies) and the control group (mainly chemotherapy), including the incremental cost, QALY, and ICER. Afterwards, we would also compare such outcomes in the homogenous treatment subgroup with regard to various PD-L1 expressions. TPS is a general stratification system to show the PD-L1 expression of tumor cells in NSCLC, which would be divided into high expression (>50%) and low expression (1–49%). Moreover, we would review the critical findings from the sensitivity analyses for ICER estimation in each study. The Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist would be employed to check the quality of cost-effectiveness analyses.¹⁰ The CHEERS checklist would inspect seven main parts of the study (title, abstract, introduction, methods, results, discussion, and other relevant information).

The continuous variables were compared with Student’s t-test, and the paired-samples t-test would also be employed between groups. A two-tailed P-value <0.05 was identified as statistically significant. All statistical analyses were conducted in SPSS (version 25.0, IBM, Armonk, NY, USA), GraphPad Prism (version 9.2.3, GraphPad Software, San Diego, CA), and R (version 4.2.0, R Foundation for Statistical Computing, Vienna, Austria) were employed to visualize the statistical findings.

Results

A total of 25 studies met the inclusion criteria, and 30 cost-effectiveness analysis records were included^11–39 (Figure 1). We reviewed the characteristics and economic evaluation index of Pembrolizumab and Atezolizumab among all included studies (Table 1) and described the economic evaluation of Pembrolizumab stratified by the PD-L1 expression (TPS ≥ 50% and 1–49%; Table 2). Among the 30 records, 22 (73.3%) were on Pembrolizumab, eight (26.7%) on Atezolizumab, 17 (56.7%) on the United States payer perspective, and 7 (23.3%) on the Chinese payer perspective. The median WTP of the total population, US population, and Chinese mainland population was 133,032 (range, 26,481–200,000) US dollars, 171,660 (range, 100,000–200,000) US dollars, and 28,274 (range, 26,481–30,828) US dollars, respectively.

Figure 1 The PRISMA flowchart for study selection.

Table 1 The Characteristics of the Included Studies and Economic Evaluation of Pembrolizumab and Atezolizumab Among the Included Total Trial Population

Table 2 The Economic Evaluation of Pembrolizumab Stratified by the PD-L1 Expression (TPS ≥ 50% and 1–49%)

As for the all included studies, the gained QALY (2.1 ± 0.5 years versus [vs] 1.6 ± 0.5 years, P = 0.024; Figure 2a) and incremental QALY (0.87 ± 0.31 vs 0.54 ± 0.35 years, P = 0.041; Figure 2b) of Pembrolizumab were superior to that of Atezolizumab (Table 3). The cost increment compared with the chemotherapy was comparable between Pembrolizumab and Atezolizumab (89883.4 ± 39644.8 dollars vs 124720.3 ± 69709.1 dollars, P = 0.215; Figure 2c), and the ICER of Pembrolizumab was lower than that of Atezolizumab (111758.9 ± 43622.0 US dollars/year vs 292697.1 ± 214854.0 US dollars/year; P = 0.049; Figure 2d).

Figure 2 The variance of quality-adjusted life years (a), incremental quality-adjusted life years (b), increment cost compared to chemotherapy (c), and incremental cost-effectiveness ratio (d) between Pembrolizumab and Atezolizumab. The asterisk indicator, statistically significant difference (P-value < 0.05). Abbreviations: QALY, quality-adjusted life years; ICER, incremental cost-effectiveness ratio; ns, not significant.

Table 3 The Economic Metrics of the Total Population Who Received Pembrolizumab or Atezolizumab, and the Economic Metrics of Those with Pembrolizumab Stratified by PD-L1 Expression

A total of 13 studies compared the economic evaluation of Pembrolizumab grouped by the PD-L1 expression (Table 3), in which nine studies were from the United States payer perspective and four from the Chinese payer perspective. The gained QALY (2.3 ± 0.5 vs 2.2 ± 0.6 years; P = 0.729; Figure 3a), incremental QALY (0.99 ± 0.41 vs 0.93 ± 0.43 years; P = 0.759; Figure 3b), cost increment (86787.2 ± 50,792.6 vs 83278.9 ± 40,328.6 US dollars; P = 0.853; Figure 3c), and ICER (92761.6 ± 46,501.6 vs 106592.8 ± 56,454.1 US dollars/year; P = 0.502; Figure 3d) were all comparable between the PD-L1 expression ≥50% and 1–49%.

Figure 3 The variance of quality-adjusted life years (a), incremental quality-adjusted life years (b), increment cost compared to chemotherapy (c), and incremental cost-effectiveness ratio (d) of Pembrolizumab between tumor proportion score ≥50% and 1–49%. Abbreviations: QALY, quality-adjusted life years; ICER, incremental cost-effectiveness ratio; TPS, tumor proportion score; ns, not significant.

Thirteen (43.3%) analyses of the eight studies were enrolled in our pooled analyses of subgroup analyses of the PD-L1 expression, and the sole study for Atezolizumab was not incorporated in our further analysis. It showed that the ICER was lower than WTP in 43% of the included cost-effectiveness analyses, and the ratio was 54.5% (n = 12) and 12.5% (n = 1) for Pembrolizumab and Atezolizumab, respectively. There was no significant difference between ICER and WTP either for Pembrolizumab (111759 vs 122336 US dollars; P = 0.533) or Atezolizumab (292697.1 vs 117362 US dollars; P = 0.056) among the 30 cost-effectiveness analyses. As for Pembrolizumab, the ICER and WTP were comparable in the Chinese payer perspective (74945 vs 44870 US dollars; P = 0.193), while the ICER was significantly inferior to WTP in the US payer perspective (135091 vs 172138 US dollars; P = 0.017). The ICER and WTP were comparable in the US payer perspective for Atezolizumab (388976 vs 136000 US dollars; P = 0.063).

There were 23 studies (92%) that reported the one-way sensitivity analysis and the extrapolation/utility of overall survival/progression-free survival and total cost of immune checkpoint inhibitors were the main sensitive factors. Among the eight studies on Atezolizumab, six reported the outcomes of sensitivity analysis, and five showed that the cost of Atezolizumab was the critical sensitive factor.

We then check the quality of the included cost-effectiveness analyses conforming to the CHEERS checklist (Figure 4). After a systematic review in accordance with the CHEERS checklist, it revealed a high quality of these included studies. The report of characterizing heterogeneity (56%) and approach (16%) and effect (12%) to engagement with patients and others affected by the study were not satisfactory, while all studies met at least 23 criteria for this checklist.

Figure 4 The heatmap to show whether each included study met the standards of quality assessment (the Consolidated Health Economic Evaluation Reporting Standards checklist), in which the black square was referred to as meeting the item, and the white square represented the lack of this criterion. Abbreviations: Measurement and valuation, etc., measurement and valuation of resources and costs; approach to engagement, etc., approach to engagement with patients and others affected by the study; effect of engagement, etc., the effect of engagement with patients and others affected by the study; study findings, etc., study findings, limitations, generalisability, and current knowledge.

Discussion

Immunotherapy brought unprecedented survival benefits for patients with advanced or metastatic NSCLC, while the financial burden came together with the prognosis improvements.^2–4 The financial toxicity would not be neglected due to the extremely high cost that it might prevent the continuation of effective medical treatment. Previous research would care more about the absolute survival benefits, while there were no perspectives on the directional opinions of cost-effectiveness analysis on the clinical decision of immunotherapy.^2,40 In our research, we conducted a systematic review of economic evaluations on those with advanced or metastatic NSCLC who received Pembrolizumab or Atezolizumab. The comparisons between WTP and ICER suggested that ICIs would lead to financial toxicity in those patients, despite the countries and study patients. The impact of financial toxicity would vary for study drugs, target patient population, and study countries. Thus, the integration of financial toxicity assessment during the process of clinical decision might help patients identify the potential financial toxicity in advance and better arrange the medical treatment for more benefits.

Nowadays, Pembrolizumab and Atezolizumab are considered the first-line treatment for metastatic NSCLC,^41,42 while current research would commonly compare the absolute survival benefit of the medical treatment. Our findings suggested that Pembrolizumab was associated with comparable cost and better QOL-related prognosis than Atezolizumab, and Pembrolizumab showed distinct cost-effectiveness for its lower ICER. Even though the ICER was comparable with WTP for either Pembrolizumab or Atezolizumab in statistical significance, the absolute mean value of the ICER of Atezolizumab was two times higher than its WTP. Atezolizumab was also found lack of cost-effectiveness in other research.³⁴ Considering the heterogeneity of the included study amount, the comparison results between ICER and WTP for Atezolizumab tended to be interpreted carefully. Additionally, as stratified by the countries, Pembrolizumab demonstrated significant cost-effectiveness in the US (P = 0.017) and was acceptable in China (P = 0.193). Due to the limited involved studies on Atezolizumab, we merely conducted the analyses for the US. It seemed to show the tendency of higher ICER than WTP (P = 0.063), while the absolute difference between the two values was nearly two times the WTP. Therefore, these results reminded us of the high cost-effectiveness of Pembrolizumab in those with advanced or metastatic NSCLC.

Furthermore, we might not overlook the treatment duration setting in the sensitivity analysis, which might result in an inconsistent outcome for ICER. There were no more than five years for the duration (including the extrapolation of overall survival) in the sensitivity analysis of three studies for Atezolizumab.^35,37,38 As concerned by Ondhia, the Economic Guidance Panel reduced the horizon time from ten years to five years in their analyses, which might lead to a conservative cure rate of Atezolizumab and potentially shortened QALY. The concurrent changes would result in an illusory enhanced ICER for Atezolizumab; thus, a longer follow-up of the study population might help disclose the actual improved QALY.³⁵ Moreover, the summary from these one-way sensitivity analyses suggested that apart from improving overall survival or progression-free survival, the total cost of the study drugs is also considered the critical sensitive factor, which would impact the cost-effectiveness of Atezolizumab. In this way, besides the prognosis improvement, the reduction of the total cost was the first and essential approach to attenuate financial toxicity without a doubt.

The PD-L1 expression was a critical indicator for clinical decision and prognosis evaluation,⁴³ while our findings revealed that the prognosis and economic parameters seemed unrelated to the PD-L1 expression for those with Pembrolizumab, including the QALY, total cost, and ICER. However, our findings seemed to be contrary to the prior research that the enrichment of PD-L1 was associated with improved survival and enhanced value.⁶ We deemed that the satisfactory survival improvement in the early and limited research might be a confounding factor for the QALY and ICER estimation. A global, real-world, multicenter study proposed that the PD-L1 expression of nearly one-third of the enrolled patients (n = 702; 30%) was 1–49% and 22% (n = 530) was ≥50% among those with advanced or metastatic NSCLC.⁴⁴ Considering the improved survival of Pembrolizumab among the metastatic NSCLC with low PD-L1 expression levels,⁴⁰ Pembrolizumab was strongly recommended regardless of the PD-L1 expression level due to the comparable QOL-associated prognosis and economic evaluations. Since tumor mutation burden (TMB) was recommended as the immune biomarker,^45,46 TMB might also act as a second stratification factor in further cost-effectiveness analyses.

The involved cost-effectiveness analyses were studies in developed countries except for China, and all studies for the UK, Singapore, and Canada showed no cost-effectiveness of the ICIs. We reasonably speculated that the financial toxicity might also appear in other countries, and it was supposed to be considered in clinical practice and provide mitigating strategies actively.⁴ To our knowledge, this is the first study to explore the role of financial toxicity in the clinical decision of immunotherapy, yet our study has some limitations. First, since the cost of ICIs could be covered by the health care system and patients themselves, the precise financial burden of patients might vary from the geographic region, which could result in bias in calculating the total cost.^4,47 Second, we could notice the heterogeneity of cost-effectiveness analysis conclusions between the general patients and those pertaining to the early-reported clinical trials. That we merely included the studies with high evidence grade could lead to high reliability, while it might result in inherent blemish for the data from clinical trials. As suggested by the previous study, the favored findings in the cost-effectiveness analyses from the partial latest report might be confounded by the model assumptions and could be interpreted as an extraordinarily improved survival with comparatively limited follow-up.²⁵ In this way, further cost-effectiveness analyses might be inclined to the real-world study, which might help to uncover the general performance of financial toxicity on the suffered patients. Third, there was an inherent bias in the current cost-effectiveness analyses that the setting of WTP did not reach a consensus. A study drug with the same price in two countries might lead to a contrary conclusion on whether it was cost-effective or lack of cost-effectiveness. That is, setting a WTP threshold might mislead to a different interpretation of the economic evaluations. Taking China as an example, considering financial toxicity, patients in clinical practice tend to prioritize the cost of drugs when their efficacy is comparable, opting for those with lower financial toxicity. Most targeted therapies have been included in NRDL. In contrast, immune checkpoint inhibitors are not yet covered by China’s drug policies, remaining priced above WTP threshold and posing significant financial toxicity. For advanced NSCLC without driver gene mutations, immunotherapy is often the preferred option, but it is associated with considerable financial toxicity.

Conclusions

Immune checkpoint inhibitors would lead to financial toxicity in patients with advanced or metastatic lung cancer from various countries, and the impact of financial toxicity differed for the study drugs, target patient population, and study countries. The integration of financial toxicity assessment during clinical decision would help these patients get more benefits in the whole course of immunotherapy.