In recent years, the emergence of ICIs has greatly changed the treatment strategy of lung cancer, raising a great interest in oncologists and patients. There were two studies evaluated the efficacy of ICIs in the first-line treatment of ES-SCLC, Both in CASPIAN[31] and Impower133[32]trials, first-line immunotherapy plus chemotherapy showed satisfied efficacy. Based on these clinical trials, published research studied the cost-effectiveness of new immunotherapy strategies. According to the data of CASPIAN trial, our published research demonstrated that durvalumab in combination with platinum–etoposide was not a cost-effective option in the first-line treatment of patients with extensive-stage SCLC in the U.S. According to the data of Impower133 trial, Qiu Li[33] and Ling Yu Li[18] conducted cost-effectiveness analysis and concluded that atezolizumab plus chemotherapy to chemotherapy was not a cost-effective choice in the first-line treatment of extensive-stage SCLC from an American and Chinese perspective, respectively. The common point of these studies is that the price of PD-L1 antibody was always the greatest factor affecting the outcomes. Given the updated survival data of the Keynote-604 trial recently published, the cost-effectiveness of pembrolizumab plus chemotherapy in the first-line treatment for patients with ES-SCLC is necessary to be updated accordingly. Therefore, we performed the first cost-effectiveness analysis of pembrolizumab plus chemotherapy versus chemotherapy in first-line setting for patients with ES-SCLC.
Our analysis proved that pembrolizumab plus chemotherapy was not cost-effective in the first-line treatment of ES-SCLC at a WTP threshold of $150,000 per QALY,resulting in an additional 0.18 QALYs and ICER of $ $647,509 per QALY versus chemotherapy. One-way sensitivity analysis showed that the cost of pembrolizumab was the most influential factor.Further analysis found that when the cost of pembrolizumab was reduced by 80.3%, the immunotherapy became cost-effective at an ICER of $149,904/QALY. Therefore, changing the price of pembrolizumab is an effective feasible strategy to achieve efficient use of pembrolizumab plus chemotherapy. The acceptability curves also demonstrated this finding that a paucity of certainty was achieved by pembrolizumab plus chemotherapy at the WTP threshold of $150,000 in the US. The results of probabilistic sensitivity analysis showed that the probability of pembrolizumab plus chemotherapy was cost-effective vs chemotherapy was 0%. The subgroup cost-effectiveness analysis demonstrated that pembrolizumab plus chemotherapy was not a cost-effective treatment across all patients subgroups. Our analysis will be essential to guide policymaking and payment in health care and provided drug pricing decision-makers with the reference to reprice pembrolizumab.
Unfortunately, the detailed expression of PD-L1 and tumor mutational burden (TMB) were not shown in the Keynote-604 trial. In many other studies, PD-L1 expression and TMB were of great value as biomarkers for the efficacy of ICIs treatment, which can improve clinical benefits[34–41]. Anti-PD-1 /PD-L1 antibody is effective in patients with high expression of PD-L1 and high TMB (TMB-H), especially in patients with non-small cell lung cancer (NSCLC), melanoma, renal cell carcinoma, etc[42, 43]. In our previous studies, we showed that first-line treatment with pembrolizumab was a cost-effective strategy when compared to platinum-based chemotherapy in locally advanced or metastatic NSCLC patients with high expression of PD-L1(TPS ≥ 50%)[44]. Regardless of the PD-L1 expression levels nivolumab plus ipilimumab was cost-effective in NSCLC patients with TMB-H[45]. It seems that the significance of using predictive markers to properly screen patients and achieve cost-effective strategies is a concern of clinicians and administrators[46]. Therefore, more detailed information about biomarkers is needed in future studies, including PD-L1 expression, TMB, microsatellite instability (MSI) and deficient DNA mismatch repair(dMMR), etc.
Significantly, despite the survival benefits displayed in certain clinical trials, ICIs were not cost-effective in most cases. Consequently, it is a great challenge that to approve new drugs solely based on cost-effectiveness of drugs without considering the dynamic evolution of survival curves and using predictive markers.
There are some limitations in our study. Firstly, our study is based on the Keynote-604 trial, the only clinical trial that estimated the efficacy of pembrolizumab plus EP or EP as first-line therapy in patients with ES-SCLC. Any bias within the trial will be reflected in our study. Secondly, the long-term efficacy of pembrolizumab plus EP in the model was extrapolated from the clinical data from the Keynote-604 trial, which is inevitably subject to uncertainty. Third, the Keynote-604 trial did not provide the Kaplan-Meier curve for each subgroup, making it impossible to run the model completely for each subgroup. The original group balance produced by randomization may not exist in the subgroups. Thus, the results of the subgroup analyses should be interpreted with caution. Fourth, we revised the utility value by the disutility of AEs, which will lead to the inaccuracy of the utility value. Fifth, the costs of grade 1/2 AEs and immune-related AEs were excluded, which might overestimate the benefits of pembrolizumab plus chemotherapy. Finally, the compliance of patients was not considered in our study, while a large number of studies have shown that compliance has a significant impact on cost-effectiveness for cancer patients.