First-line Atezolizumab Plus Chemotherapy in Treatment of Extensive Small Cell Lung Cancer: A Cost-effectiveness Analysis from China
Introduction Extensive-stage small cell lung cancer (SCLC) is a devastating form of lung malignancy with a poor prognosis, typically resulting in a median overall survival of approximately 10 months. Despite a high initial response rate to first-line chemotherapy, recurrence is rapid in the majority of cases, often leading to death within a few months. Over the past two decades, there has been limited progress in the treatment of SCLC. However, the high tumor mutation burden in SCLC suggests that these tumors may be more immunogenic and could benefit from immune checkpoint inhibitors.
Immune checkpoint inhibitors, such as PD-1/PD-L1 inhibitors and CTLA-4 inhibitors, have shown promise in treating various cancers, including non-small cell lung cancer (NSCLC) and melanoma. Clinical outcomes have been observed in the treatment of extensive-stage SCLC, although single-agent immunotherapy has not significantly improved outcomes. Studies suggest that combining chemotherapy with PD-1/PD-L1 blockade may enhance the antitumor immunity of these inhibitors. The IMpower 133 trial provided initial confirmation that combining atezolizumab with cytotoxic therapy is beneficial and potentially necessary to improve the survival of extensive-stage SCLC patients.
Despite the clinical benefits, the high cost of novel therapies like atezolizumab poses a significant challenge to healthcare systems. Atezolizumab, priced at $11,470 per 1200 mg per cycle, is not financially feasible for most patients. Cost-effectiveness analyses are essential to quantify the clinical benefits and potential costs associated with these new therapies. This study aims to evaluate the cost-effectiveness of first-line atezolizumab combined with chemotherapy versus chemotherapy alone in China.
Methods This economic analysis is based on a literature review and an experimental model, and it did not require approval from an institutional review board or ethics committee. The study utilized data from the IMpower 133 trial, which included 403 untreated extensive-stage SCLC patients randomly assigned to either the atezolizumab combined with chemotherapy group (n = 201) or the placebo plus chemotherapy group (n = 202). Patients received four 21-day cycles of carboplatin and etoposide with atezolizumab (1200 mg per cycle) or placebo, followed by maintenance atezolizumab therapy or placebo until intolerable toxic effects or disease progression occurred.
A Markov model was established to evaluate the cost-effectiveness of different treatment strategies. The model included three mutually transferable health states: progression-free survival (PFS), progressive disease (PD), and death. All patients started in the PFS state and could transition to the PD state or death. The cycle length for transition probabilities was set at 21 days, based on the chemotherapy period. Costs and utility values were calculated at a 3% annual discount rate.
The primary endpoints of the cost-effectiveness analysis were quality-adjusted life-years (QALYs) and the incremental cost-effectiveness ratio (ICER). Secondary endpoints included the average cost-effectiveness ratio (average CE) and net benefit (willingness-to-pay [WTP] benefit-costs). Only direct medical costs were considered, including drug costs, costs of adverse events ≥ grade 3, test costs, supportive care costs, and disease management costs. Utility values were obtained from published literature, representing the quality of life based on disease state and adverse effects.
Results The base case analysis revealed that the combination of atezolizumab with chemotherapy yielded an additional survival benefit of 2 months compared to chemotherapy alone (12.3 months vs. 10.3 months, P = 0.007). The occurrence rate of adverse effects ≥ grade 3 was not significantly different between the atezolizumab and placebo groups (58.1% vs. 57.7%, P > 0.05).
Total costs incurred were $48,129 in the atezolizumab group and $12,920 in the placebo group, resulting in a cost difference of $35,209. However, the QALYs in the atezolizumab group were only 0.072 higher than in the placebo group (0.858 QALYs vs. 0.786 QALYs). The ICER between atezolizumab combined with chemotherapy and chemotherapy alone was $489,013/QALY in China.
Sensitivity analysis indicated that the utilities of the PFS and PD state in the placebo group were the most influential parameters. A probabilistic sensitivity analysis with Monte Carlo simulations revealed that atezolizumab combined with chemotherapy was not cost-effective at a WTP threshold of $25,929/QALY in China, compared with chemotherapy alone.
Discussion The study highlights the lack of significant advances in the treatment of extensive-stage SCLC and the potential of PD-1/PD-L1 inhibitors to improve outcomes. The IMpower 133 trial demonstrated a 2-month survival benefit with the addition of atezolizumab, which is clinically significant given the short median overall survival of extensive-stage SCLC patients. However, the high cost of atezolizumab limits its broad use in clinical practice.
The cost-effectiveness analysis showed that atezolizumab combination therapy is not cost-effective compared to chemotherapy alone at a WTP threshold of $25,929/QALY in China. The study suggests that a discount of more than 80% or payment through company donation/medical insurance on the list price would make atezolizumab combined with chemotherapy cost-effective in China.
Screening appropriate patients is increasingly important for the treatment of extensive-stage SCLC. Biomarkers such as tumor mutation burden (TMB) and PD-L1 expression level may help identify patients who are more likely to benefit from PD-1 or PD-L1 inhibitors. Patients with high TMB and/or PD-L1 positive expression may be more likely to be cost-effective with the addition of atezolizumab.
The one-way sensitivity analysis revealed that utilities were the most influential parameters. The comparison of utilities between the atezolizumab and placebo groups was a relative value, and its influence on the overall outcome was reflected in the improvement of the effectiveness value of atezolizumab compared to placebo. The tornado analysis indicated that the effectiveness values of PFS and OS status in the atezolizumab group had a greater influence on the overall cost-effectiveness.
Limitations of the study include the reliance on published literature for clinical data, such as OS, PFS, and adverse effects, rather than current patient data. Additionally, the study did not consider diverse health insurance policies and company discounts, which could affect the actual cost of atezolizumab. Future studies should use actual clinical data to recalculate values after atezolizumab is officially approved for sale in mainland China.
In conclusion, atezolizumab combination therapy as a first-line treatment is not more cost-effective than chemotherapy alone at a WTP threshold of $25,929/QALY in China. The results of this study provide a decision-making reference for drug pricing and medical insurance companies.
doi.org/10.1097/CM9.0000000000000536
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