Costs of Extended Use of the Immune Checkpoint Inhibitors in First-line Non-Small Cell Lung Cancer

Cost-effectiveness of drug therapies have been extensively studied.^1,2 However, patients continue to raise valid concerns on drug costs. Reports on drug cost and the impact of extended therapy are preliminary and rare.³ Immune checkpoint inhibitors (ICIs) are relatively expensive, and costs are bound to increase with extended use. Pembrolizumab (Pembro) improved the 5-year overall survival (OS) in first-line advanced/metastatic non-small lung cancer (a/m-NSLC) lacking epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations.^4-6 Some patients preferred to continue therapy beyond two years after achieving sustained partial or complete response. Increased OS by durvalumab (Durv), atezolizumab (Atezo), and pembrolizumab/pemetrexed (Pembro/Peme), and ipilimumab/nivolumab (Ipi/Nivo) have since been reported.^7-15 The purpose of this article was not to compare one drug cost or outcome with another but rather to focus on costs of extended ICI use beyond indications in a/m-NSLC.

The reported OS, hazard ratio (HR) at 95% CI and adverse events (AEs) were quoted. The posted 2020 parent-company prices in US dollars (US$) were used. Doses and frequency of administration were strictly adhered to. Pembro 200 mg, Peme 500mg/m², Atezo 1200 mg, Bev 15 mg/kg and cemiplimab (Cemi), 350 mg every 3 weeks; Durv 10 mg/Kg and Nivo 240 mg every 2 weeks and Ipi 1 mg/Kg every 6 were used. Costs of the generic chemotherapeutic drugs (chemo) including taxanes, doxorubicin, gemcitabine, platin compounds, ICI unused, or wasted amounts were not accounted for.

The costs of six ICI ranged from $103,400 to $168,948 with a mean of $144,080. Adjuvant one-year Durv was used for curative intent in unresectable stage III lung cancer at $148,013 costs (Table 1). Treatment beyond one year was not required.⁷ 

Peme, inhibitor of the folate-dependent enzyme, was widely used in first-line treatment of a/m-NSLC for the last 15 years at one-year costs of $113,793.¹⁶ Pembro has essentially replaced Peme in most of the world at 2-year costs of $334,652.^4-6

Two monotherapy ICIs have since been approved by the US Food and Drug Administration (FDA) in 2020. The first was Atezo, used like Pembro in PD-L1 >50% (IMpower110) at 2-year costs of $308,892.⁹ In the MYSTIQ phase 3 trial, Durv was tested in PD-L1 expression ≥25% of tumor cells vs. chemotherapy.⁸ The 2-year costs were $296,026. At 102-day OS and 0.76 HR, the study did not meet its primary end points.

In 2021, the FDA approved Cemi 350 mg every 3 weeks at $154,896 yearly cost. OS was 234-day gain and HR 0.68, P=.0022.¹⁷

The first ICI-chemo combination developed was Pembro-Peme-platin (Table 2).⁴ The addition of four Peme cycles increased the 2-year costs to $360,912. 

The 2-year costs of Atezo- Bevacizumab (Bev) with one-year Peme, (IMpower150) were $722,977.^18,19 Using the Biosimilar (Bio), costs decreased to $645,857, resulting in $77,120 savings. Using Atezo, Peme without Bev (IMpower130, 132), costs dropped to $422,725 with $300,252.

The OS of the dual Ipi/Nivo was administered until disease progression, unacceptable toxicity, or for a maximum of 2 years of treatment at $544,696 costs.^5,6 The 0.79 HR was not met at PD-L1 ≥1%, and HR was 0.64 at PD-L1 <1%.^13,14

Adding 2-Peme cycles to Nivo/Ipi increased costs by $13,130 to $557,826. The benefit was observed, irrespective of histology or PD-L1 and in patients with liver and/or center nervous involvement.¹⁴

Table 3 summarizes costs and HR of ICI combinations. Direct comparison, however, could not be made. 

There is a pressing need to control drug costs for economic and humanitarian reasons. High costs disproportionately target the poor and disadvantaged. In significance, costs trail behind value, outcome, quality of life, and safety. Nonetheless, value, if unaffordable, are essentially worthless. In the present investigation, the integrity of cost comparison would remain intact, regardless of potential changes in posted price, dollar, or coin use. Extended therapy of ICI combinations for 2 years and beyond was analyzed. The 2-year costs were selected as the basis of comparison. Costs of AEs treatment were not included since differences in AEs between the various members were minimal. The generic taxanes, doxorubicin, and platin compounds were not considered in view of their low costs.

Using adjuvant Durv in unresectable stage 3, one year of $148,013 costs seemed well worth the dollars spent considering the impressive 363 days OS gain and 0.53 HR.⁷ Though used for curative intent, adjuvant Durv served as an appropriate cost comparator with other ICI used for ≥2 years.

The monotherapy Pembro 2-year costs were $334,652 and exceedied $836,630 after 5 years. The reported OS gain was 474 days and 0.63 HR.⁶ In the absence of clear strategy on duration of therapy, insured and/or financially capable patients continue therapy irrespective of costs.

Monotherapy Atezo, approved in 2020, demonstrated 213 day OS gain and 0.59 HR in 50% PD-L1.⁹ Long follow-up 5 five-year survival of Atezo are needed. The FDA also approved Durv at 0.76 HR in PD-L1 >25% in tumor cells.⁸ The study did not reach its preplanned threshold. Nonetheless, it revealed the complexities and signaled the significance of the burden tumor mutation.

A late addition to the ICI used in a/m-NCLC with PD-L1 >50% space was Cemi, (EMPOWER-Lung 1 Trial).¹⁵The yearly cost was $154,896, well within average ICI cost in our study. The 234-day OS gain and HR 0.68; P=.0022 were essentially close to Pembro. Further confirmation and long-term results are needed.

The combination Pembro-Peme at 2-year costs of $360,652 resulted in positive outcome, regardless of PD-L1 and waived the PD-L1 50% requirement.¹²

Atezo/Bev-Peme demonstrated 0.78 HR, improving in liver metastasis to 0.54 (IMpower150) at 2-year costs of $722,977.^10,11 Using Bev-Bio, costs dropped to $532,064 with $77,120 savings. Synthesis of biosimilars to the vascular endothelial growth factor inhibitors Bev is probably a costly endeavor, technically demanding and time-consuming process. Using Atezo without Bev, the cost dropped to $422,725, bringing the cost closer to Pembro-Peme.¹⁹

The dual ICI Ipi/Nivo was chemo-sparing in a/m-NSLC at $554,696 costs of. Of note, Ipi/Nivo positive outcome was shown in PD-L1 <1% and >1%, thus suited for PD-L1–negative patients.^13,14 Ipi/Nivo was later used in combination with two Peme cycles for up to 2 years at $557,826 costs. The OS was not reached in updated analysis. Of interest, there was no benefit in nonsmokers, (CHECKMATE-9LA).¹⁴

Cross comparison of OS, HR, and costs could not be made since each clinical study had its population, control, and narrative. The HR of Pembro-Peme was reported as 0.42-0.49, Atezo/Bio-Bev-chemo 0.78, and Ipi/Nivo-Chemo 0.66.

Peme is expected to lose patency in the upcoming years and become cheaper and more affordable in first-line treatment in economically less fortunate parts of the world.¹⁵

Policies and perspective on ICI costs and value in a/m-NSLC continue to emerge.^20-22 High costs negatively impact access.²⁴ For example, drug prices are lower in Germany when compared with those in the United States.^18,24 The present investigation demonstrated that cost differences between the individual members of the ICI class are nonsignificant. What matters more is the unsustainable high costs of prolonged therapy. Such costs provide the rationale and incentive for cost-constraint policies. Bundling of ICI costs has been previously proposed.²² Applied to extended use, bundling would soften the economic impact on the health care system and patients. ICI costs are largely determined by duration of therapy. Pembro costs beyond 2 years call for guidance on therapy duration and emphasize the need for cost constraint policy.

Authors: Helmy M Guirgis, MD, PhD¹

Affiliations: ¹Cancer Free Foundation, Dana Point, California

Address correspondence to:
Helmy Guirgis
cancerguir@gmail.com