Platinum-doublet chemotherapy was historically the standard first-line treatment for patients with metastatic non-small cell lung cancer (NSCLC) whose tumors lack of epidermal growth factor receptor mutations or anaplastic lymphoma kinase translocations. Research has shown that immune checkpoint inhibitor (ICI) monotherapy for patients with tumor programmed death-ligand 1 (PD-L1) expression ≥ 50% (1), and a single-agent ICI in addition to chemotherapy (2–4) or bevacizumab plus chemotherapy (5) for patients regardless of PD-L1 levels improved overall survival and progression-free survival. However, prices tagged onto these treatments result in financial pressure on health care system.

Nivolumab and ipilimumab are monoclonal antibodies that bind to T-cell’s programmed death-1 and cytotoxic T-lymphocyte antigen 4, respectively, to restore T-cell activity against tumor cells. In 2019, the CheckMate 227 trial showed that first-line treatment with nivolumab plus ipilimumab (N+I) resulted in longer durations of overall survival and progression-free survival than chemotherapy for patients with metastatic NSCLC (6). Specifically, the CheckMate 227 results indicated that N+I were associated with improved survival in pre-specified subgroups including PD-L1 ≥ 1% and PD-L1 < 1%. In 2021, the CheckMate 9LA trial with randomization stratified by PD-L1 ≥ 1% and < 1% revealed that nivolumab plus ipilimumab with two cycles of chemotherapy (N+I+chemotherapy) provided significant improvements in overall survival and progression-free survival versus chemotherapy (7). U.S. Food and Drug Administration (FDA) approved N+I for patients with PD-L1 ≥ 1% (8), and the National Comprehensive Cancer Network panel extended their use for patients with PD-L1 < 1% (9). N+I+chemotherapy was also approved by the FDA for patients regardless of PD-L1 levels later (10).

Although several investigations have shown a single-agent ICI with or without chemotherapy to be cost-effective (11–15), double-agent ICI combinations incur more costs than single-ICI regimens. To date, three studies have estimated the cost-effectiveness of N+I versus chemotherapy and displayed different results (16–18). Another recently published study found that the incremental cost-effectiveness ratio (ICER) of N+I+chemotherapy versus chemotherapy alone was $202,275 per quality-adjusted life year (QALY) (19). However, researchers have not concomitantly compared the cost-effectiveness of chemotherapy, N+I and N+I+chemotherapy. We hypothesized that, compared with traditional platinum-doublet chemotherapy, either N+I or N+I+chemotherapy was not cost-effective regardless of tumor PD-L1 expression levels. Using a simulation model informed with the outcomes data from the CheckMate 227 and CheckMate 9LA trials, we concomitantly compare the costs and effectiveness of chemotherapy, N+I, and N+I+chemotherapy to verify our hypothesis.

This study examined the cost-effectiveness of N+I and N+I+chemotherapy for patients with metastatic NSCLC. We concomitantly compared the two front-line treatments and chemotherapy by abstracting the efficacy and safety data from phase 3 randomized trials (6, 7), and incorporated time-dependent transitional probabilities during the follow-up period for disease progression; thus, our simulation model was able to accurately reflect the effectiveness estimates. Further, instead of simply assigning docetaxel as the second-line chemotherapy for all groups (17), we explicitly modeled the subsequent treatment based on the trial data. We found that first-line N+I and N+I+chemotherapy for metastatic NSCLC were not cost-effective from the U.S. health care sector perspective. Subgroup analyses by different tumor PD-L1 expression levels, and a variety of sensitivity analyses further verified the robustness of the results. Our results provide important information and could help clinical guidelines development when medical community moves toward value-based practice.

Unlike previous investigations which found the ICERs of single-agent ICI regimens versus chemotherapy to be less than $150,000 per QALY (11–15), the ICERs of N+I and N+I+chemotherapy versus chemotherapy alone in our study were far above the willingness-to-pay threshold. Although this finding might be attributed to a higher cost of concomitant use of two ICIs, the ICERs were still higher than the results of three recently published studies (16, 17, 19). One plausible explanation is that we did not include the costs of pemetrexed maintenance therapy after 4 treatment cycles of pemetrexed plus carboplatin chemotherapy, leading to lower cost estimates in our platinum-doublet chemotherapy group. However, pemetrexed maintenance therapy was optional in the trials and could be administered both in the progression-free state of chemotherapy and progressive disease of N+I or N+I+chemotherapy. If we took this issue into consideration and assumed that every non-squamous NSCLC patient received pemetrexed maintenance therapy after pemetrexed plus carboplatin, the ICERs of N+I versus chemotherapy for all patients, patients with PD-L1 ≥ 1%, and patients with PD-L1 < 1% would become $212,823, $220,670, and $200,814 per QALY, respectively, which were still higher than the willingness-to-pay threshold value. In addition, we applied carboplatin plus gemcitabine or pemetrexed as the second-line chemotherapy following progression on N+I+chemotherapy, which would overestimate the ICER of N+I+chemotherapy versus N+I. If we selected docetaxel as the regimen, the ICERs of N+I+chemotherapy versus N+I for all patients and patients with PD-L1 ≥ 1% would become $768,107 and $966,114 per QALY, respectively, indicating N+I+chemotherapy was still not cost-effective. Also, N+I+chemotherapy remained dominated by N+I in patients with PD-L1 < 1%.

As the movement toward value-based practice, our comparison between N+I+chemotherapy and N+I has important clinical implication. Given the increases in health care spending over time, we acknowledge that the willingness-to-pay threshold of $150,000 per QALY might be under-estimated. While researchers have inferred a higher willingness-to-pay threshold, such as $300,000 per QALY (32), our results indicated that adding chemotherapy over N+I is definitely not cost-effective, and should be discouraged.

In contrast to our intuition, the ICER of N+I versus chemotherapy in patients with PD-L1 ≥ 1% was higher than that in patients with PD-L1 < 1%. This finding could be attributed to a lower survival benefit of N+I versus chemotherapy in PD-L1 ≥ 1% subgroup than that in PD-L1 < 1% subgroup (6). Similar ICER results were also recognized in two previous studies (17, 18). Although exploratory analysis of the trial showed that N+I provided preferable survival benefits in patients with PD-L1 ≥ 50% or high tumor mutational burden, we did not perform these subgroup analyses because of the absence of valid data.

We conducted sensitivity analyses using the chemotherapy group in CheckMate 9LA trial as the reference. In contrast to the base-case results on the CheckMate 227 trial, N+I was weakly dominated by N+I+chemotherapy in all patients and patients with PD-L1 ≥ 1%, and N+I no longer dominated N+I+chemotherapy in patient with PD-L1 < 1%. Possible reasons include that simulations based on the CheckMate 9LA trial modeled a better overall survival of N+I+chemotherapy group than that of N+I group. Nevertheless, either N+I or N+I+chemotherapy remained not cost-effective given a willingness-to-pay threshold of $150,000 per QALY.

Several limitations must be acknowledged in our study. First, we assumed no background mortality and every simulated patient transited from progression-free state to progressive disease before death, which might not capture the deaths resulted from other comorbidities. However, the proportion of deaths attributable to other comorbidities in patients with metastatic NSCLC was only about 6% (33), and our modeled overall survival was similar to the trial results. Second, because the health utility data for all patients in the trial were not available, we used the utility difference in a subgroup of patients with high tumor mutational burden (31) to derive the health utility value for patients receiving N+I or N+I+chemotherapy. Although the effect of different adverse events between treatment groups had been accounted for, patients with high tumor mutational burden were supposed to have a better tumor response to ICIs than those with low tumor mutational burden (34). Consequently, the health utility and quality-adjusted life expectancy in the N+I and N+I+chemotherapy groups might be overestimated and the ICERs be underestimated. Nevertheless, wide variabilities of health utility value were examined in the sensitivity analyses, N+I and N+I+chemotherapy remained not cost-effective. Third, we assumed all treatments were discontinued upon disease progression, whereas nivolumab plus ipilimumab could be used beyond disease progression (6, 7), the costs incurred in N+I and N+I+chemotherapy would thus be underestimated, resulting in lower ICER values. Moreover, we did not account for the waste of drugs while calculating their costs. However, more costs would be applied to N+I and N+I+chemotherapy after addressing these issues, further indicating that N+I and N+I+chemotherapy were not cost-effective.

In conclusion, from the U.S. health care sector perspective, first-line N+I or N+I+chemotherapy was not cost-effective for patients with metastatic NSCLC regardless of tumor PD-L1 expressions levels at a willingness-to-pay threshold of $150,000 per QALY.

Publicly available datasets were analyzed in this study. This data can be found here: N Engl J Med (2016) 375(19):1823-33; N Engl J Med (2018) 378(22):2078-92.

Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

S-CY had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: S-CY and S-YW. Acquisition, analysis, or interpretation of data: S-CY. Drafting of the manuscript: S-CY and S-YW. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: S-CY and NK. Obtained funding: S-CY. Administrative, technical, or material support: NK. Supervision: CG and S-YW. All authors contributed to the article and approved the submitted version.

This work was supported by the Ministry of Science and Technology (110-2314-B-006-100-MY2) and National Cheng Kung University Hospital (NCKUH-11002029). The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

S-CY reports grants from the Ministry of Science and Technology and National Cheng University Hospital during the conduct of the study. S-YW reports grants from Genentech outside the submitted work.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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