Reports of a clinical benefit from gefitinib maintenance therapy after first-line platinum-based chemotherapy in clinical trials caused great excitement among both oncologists and patients. However, the widespread and long-term use of gefitinib comes with a dramatically increased burden on health resources, which is a concern for health policy decision makers. The need for a precise economic assessment of gefitinib maintenance use in this clinical setting is becoming urgent.
This work is the first study to address the cost-effectiveness of gene-guided gefitinib maintenance treatment after standard chemotherapy for patients with advanced EGFR mutation-positive NSCLC. Genotyping for EGFR mutations with the subsequent gefitinib maintenance treatment of patients with confirmed mutations yielded an average ICER of $57,066.40 per additional QALY gained against control strategy. This ratio is largely attributable to the higher costs associated with the acquisition of gefitinib, whereas the costs of EGFR genotyping and the costs of managing progressed disease had little influence. Finding of scenario analyses in Table 3 indicated that gefitinib would be more cost-effective (ICER without GPAP, $92,968.5/QALY at 1 year to $57,066.4/QALY at 10 year ) with the longer timeframe because the health benefit related to progression free survival yielded by gefitinib could be more obviously displayed (incremental progression free LYs, 2.2 at 1 year to 0.7 at 10 year; incremental overall LYs, 0.16 at 1 year to 0.74 at 10 year; incremental QALYs, 0.12 at 1 year to 0.46 at 10 year ), especially after two years. At one year, more patients in gefitinib arm was still in the state of progression-free survival and more patients in control arm had moved into progressed survival, which resulted in the gap between the incremental progression free LYs and the incremental overall LYs in gefitinib strategy comparing with control strategy. Pemetrexed switch maintenance treatment has been widely recommended for patients with advanced NSCLC. A pharmacoeconomic analysis from a US payer and the Swiss Health Care System perspective showed that the pemetrexed switch maintenance treatment resulted in an incremental cost of $122,371 per additional life year gained and $138,500 per additional QALY gained in patients with nonsquamous cell histology [22, 35]. In comparison with pemetrexed switch maintenance treatment, gene-guided gefitinib maintenance has a much more favorable ICER, which is considerably contributed by the more favorable PFS time of gefitinib than pemetrexed in patients with EGFR mutations (16.6 months vs. 4.4 months) [8, 11]. These results suggest that gefitinib maintenance tailoring for patients with EGFR mutations could deliver health benefits at a lower cost than pemetrexed switch maintenance therapy. This finding comes in line with the two recent economic studies, which provided the favorable economic evidence to support the first-line therapy with gefitinib for patients with EGFR mutation-positive and traditional chemotherapy for those with EGFR mutation-negative after mutation testing [36, 37].
Although gefitinib maintenance yielded greater health benefits, the ICER did not approach the willingness-to-pay thresholds of $16,349.10 and $38,733.30 (3× the per capita GDPs of China and Shanghai in 2011, respectively). If the Gefitinib Patient Assistance Program were available to Chinese patients, the Gefitinib strategy might be a cost-effective alternative because the probability of cost-effectiveness reached nearly 51% at a threshold of $16,349.10 (Figures 4 and 5). For local governments in China, the per capita GDP differs significantly among the 32 provinces. In regions with a higher economic development level (3× the per capita GDP > $16,349.10), local health decision makers could consider covering gefitinib in their local supplemental medical service.
The ability of gefitinib to prevent disease progression in patients with EGFR mutation-positive tumors was a major determinant of clinical and economic outcomes. A one-way sensitivity analysis found that the most two sensitive parameters were the HR of PFS for the Gefitinib strategy in patients with EGFR mutations and the utility of progression free survival regardless of the use of the GPAP. This finding suggests that improving the quality of life, i.e., achieving the progression free state, could increase the cost-effectiveness of gefitinib maintenance treatment. At the same time, in patients who have a low risk of disease progression, such as adenocarcinoma histology, gefitinib maintenance treatment might be more cost-effective. The cost of gefitinib was another influential factor. When the price of gefitinib per 250 mg decreased by 50%, the ICERs for the Gefitinib strategy decreased to $29,493.40 and $8,792.60 per additional QALY gained without or with the GPAP, respectively. Although the PSA results indicated that the GPAP leads to the cost-effective probability of the Gefitinib strategy, approaching 51% at 3× the per capita GDP of China, a reduction in the price of gefitinib or a more preferential patient assistance program (i.e. pay for shorter than six months of gefitinib, after which they receive donations of gefitinib until the end of their treatment) might be the best strategies to achieve a more favorable ICER.
It is important to note that the current analysis did not evaluate the cost-effectiveness of gefitinib maintenance treatment for the whole cohort without EGFR genotyping. If all patients received gefitinib maintenance, the health outcome of 50% of the patients would not have improved because no statistically significant difference was found between the Gefitinib and Control strategies in patients who were EGFR mutation negative . The cost of gefitinib for the whole cohort in the first 21-day cycle was nearly $1663.10, including $831.50 expended by patients who were EGFR mutation negative, which was higher than the cost of EGFR genotyping ($507.90) for the whole cohort. Thus, it was obvious that gefitinib maintenance without EGFR genotyping was not cost-effective when compared with gefitinib maintenance with EGFR genotyping and would become less cost-effective with a lower frequency of EGFR mutations due to the increased cost of gefitinib for patients who are EGFR mutation negative. We noticed that the frequency of EGFR mutations ranged from 8% in Caucasian patients to 30% in Asian patients. As a result, we concluded that gene-guided gefitinib maintenance treatment is superior to non-gene-guided treatment [38–40].
Other limitations of the study should also be considered. First, the present model did not include other EGFR-targeted agents used as maintenance treatments, such as erlotinib, to assess the incremental cost-effectiveness in comparison with gefitinib because no head-to-head trial data are currently available. Second, we did not conduct a budget impact analysis for the addition of gefitinib maintenance treatment on society. The annual incidence of lung cancer in China is approximately 300,000 cases . Because the PFS of advanced NSCLC was nearly 58.9% after four cycles of standard chemotherapy and the frequency of EGFR mutations was 50%, gefitinib might be prescribed as a maintenance treatment to more than 88,000 patients each year . Based on our model results, gefitinib maintenance treatment would result in a gain of approximately 24,700 QALYs and would increase expenditures by approximately $1,399 and $395 million without and with GPAP, respectively. Third, the current analysis incorporated PSF and OS data after cancer progression from different trials. Although the sensitivity of the OS data after cancer progression was little (Figure 2), the analysis should be updated when the overall survival of gefitinib maintenance therapy was available. Forth, some model inputs were obtained from literature published abroad due to a lack of Chinese data, such as the utility values. Fifth, the sensitivity and specificity of different genotyping facilities was not accounted. A new economic analysis of different genotyping facilities testing for EGFR mutations is necessary in the future. Finally, to simplify our evaluation, we did not include other adjuvant therapies, such as the traditional Chinese herbals for lung cancer. However, because the results of this analysis reflected the common clinical conditions of advanced NSCLC in China, we believe that this analysis can serve as an important reference for health policy decision makers.