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Abbreviations
(a/m- NSCLC) advanced/metastatic non-small lung cancer
(Atezo) Atezolizumab
(Cemi) Cemiplimab
(Durv) Durvalumab
(DFS) Disease-free survival
(EFS) Event-free survival
(ICI) Immune check point inhibitors
(Ipi) Ipilimumab
(Nivo) Nivolumab
(Pembro) Pembrolizumab

Introduction
The immune check point inhibitors (ICI) resulted in 2- year overall survival (OS) of patients with advanced advanced/metastatic non-small lung cancer (a/m- NSCLC)1. Costs were equitable with outcomes and dependent on a minimal 50% program death receptor-1 (PD-1) with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic alterations. Costs multiplied with extended use. Recent ICI neoadjuvant trials demonstrated improvement in disease-free-survival (DFS), event- free survival (EFS) and/or pathological response in early lung cancer. Osimertinib, antagonist of EGFR, exon 19 deletions or exon 21 (L858R) substitutions, is approved as neoadjuvant, adjuvant and in a/m- NSCLC treatment 2,3. The current clinical practice is to continue Osimertinib as long as effective and safe. Its 3-year cost was relatively high necessitating placement of $500,000 cap placement 4. We surveyed various neoadjuvant trials aiming to quantify the cost savings of ICI-and targeted therapy in earlier vs advanced stages of multiple solid tumors. 
Methods
Annual 2019-2020 costs of Osimertinib were calculated as monthly optimal dose x 12. The ICI were calculated as dose x mg/m2 or per 80 kg x price x 1-year. Intravenous administration and adverse events treatment costs were not considered.

Results
Pembrolizumab annual cost of $134,796 was the median of 5- evaluated ICI. It is used in 1st-line and as adjuvant at 50% of the 2-year costs 5-7. Extended therapy by 6-12 month added an extra $67,398-$134,796. Few cycles of Nivolumab (Nivo) + one-cycle Ipilimumab (Ipi) in 1st-line treatment, with or without platinum-doublet chemotherapy in stage IV/recurrent NSCLC, resulted in positive outcome8 at $31,425 cost. The 2-year Osimertinib cost in metastatic lung disease was $496,744, adjuvant 1-year $248,372 and neoadjuvant $31,046. Assuming 1000 patients in the United States, treated  by  ICI  x  2.5  years,  cost  would  be $336,990,000. Adding 100 patients treated by Osimertinib x 3-years at $74,511,600, the total would mount to essentially unsustainable $411,501,600. In Europe, with a higher populations number, cost would be more than doubled. Adjuvant Durvalumab (Durv) resulted in long term overall survival (OS) following chemo-radiation therapy in unresectable stage III NSCLC9 at $148,848 cost. Approval of Atezolizumab (Atezo)10 was based on improving the disease-free survival (DFS) using 4 cycles + chemo in resected stage II-IIIA non-small lung cancer (NSCLC) (Impower010). Cost was $35,644 and $89,117savings. 

Table 1: Annual Drug Costs in Lung Cancer

Pembrolizumab is currently utilized as adjuvant therapy in resected IIb or IIc melanoma (KEYNOTE- 716) 11 and for patients with renal cell carcinoma post nephrectomy 12. In the neoadjuvant space, Forde et al reported Nivolumab (Nivo) plus chemotherapy improved event-free survival (EVS) in resectable lung cancer (CheckMate 816) 13 at $31,425, saving $137,423.
Rosner et al 14 recently reported that the recurrence-free rates were 60% and OS 80% using 2-cycles neoadjuvant Nivo in patients with stage 1 to IIIA NSCLC 4-weeks before surgery. The cost was $12,996. Neoadjuvant Durv prolonged survival has been documented in early triple negative breast cancer
15. at $45,464 cost. In cutaneous squamous cell carcinoma 16,17, Cemiplimab (Cemi) in stage II to IV resulted in complete pathological response at $35, 652 vs annual $125,108 cost. In early colorectal cancer (NICHE-2) 18 Nivo 2-cycle + 1-low dose Ipi followed by surgery resulted in major pathological response at $24,927. Results of neoadjuvant generic chemo 19 and brand drugs 20 were recently reported. Treatment costs in stage IV, adjuvant, and neoadjuvant are shown in Table 2 and diagram.

Table 2: Costs of Adjuvant therapy

Diagram

Table 3: Costs of Neoadjuvant therapy

Discussion
The rising costs of oral anti-cancer cancer have raised serious economic concern 21. The relatively high costs of IMpower150 using Atezo and Bevacizumab with chemotherapy in 1st-line metastatic non-squamous a/m-NSCLC (22) have drastically curtailed use. It is vital, therefore, to keep prices affordable to promote patients’ compliance and ultimately increase sales. Cost, cost effectiveness and value 23-25 are intricately connected and ought not be decoupled. Value, cost effectiveness and safety rate first while cost matters second. Cost is a touchy subject, rarely addressed in medical journals.

There is an ongoing war between the host and cancer. Drug resistance is bound to develop. Newer drugs are continuously being developed. Due to sophisticated synthesis and rarity of eligible patients, costs tend to be high. Such drugs are sometimes sold at marginal gain, but with a demonstrable academic achievement. Osimertinib was originally planned to treat T790M mutations. It is presently used to prevent the potential development of such mutations. Without Osimertinib, survival was limited to few months. In general, targeted therapy drugs were 1.52 as costly as ICI 4. The ICI OS is unlikely to be extend beyond 2-year- therapy. Nonetheless, some patients, with their oncologists’ approval, opt to prolong treatment of a/m NSCLC by Osimertinib or ICI beyond 2-years for peace of mind and/or fear of recurrence. It seems that order of administration of therapy significantly alters the outcome. Adjuvant is traditionally administered after surgery whereas radiation and/or chemo prior. Neoadjuvant outcomes seem superior prior to surgery or any other intervention.

Admittedly, neoadjuvant low cost is an expected finding. However, the present work demonstrated that treating 100 United States patients, a small subset of lung cancer; by Osimertinib x 3-years and 1000 by ICI x 2.5 years, would carry a price tag of $411,501,600, an unexpected economic burden. Treatment of other cancers, heart, infectious and other diseases would compound the economic risk, leading to economic collapse of the health system. To put ICI $134,796 cost in comparison, Alzheimer treatment by the newly developed monoclonal antibody costs $26,000 annually. Of note, the expected number of eligible Alzheimer patients is much higher than lung cancer.
Prior to ICI the era, chemotherapy was widely used as adjuvant and neoadjuvant at higher risk of adverse events. This prompted the development of safer paclitaxel nanoparticle albumin-bound at higher cost (Table 1). Chemo is currently presented as payload and shielded by the development of antibody drug conjugates. Neoadjuvant therapy is still at its early phase of discovery and utilization, with a lot of room for more research and expansion. Nivo + chemotherapy was probably the 1st example of approved neoadjuvant trials in resectable lung cancer 11. More research is still needed to clarify the role of chemo and PD-L1. Cost and cap platform 4 and bundling models 26,27 are effective tools to control drug costs. However, they have received minimal endorsements.

Neoadjuvant therapy has been developed by physicians, requiring no governmental approval or pharmaceutical industry participation Their low cost is an added asset since patients at early-stage cancers are usually at their best physical health status and performance. Neoadjuvant use is genrally accepted in lung cancer. In other solid tumors, cost advantages require validation by appropriate modeling for costs with imaging. Nonetheless, the yield of imaging is low in earlier stages. The currently investigated endpoints circulating DNA or minimal residual tumor (MRD) are to be preferred. Such studies ought not delay or constrain use of the early-stage neoadjuvant low-cost advantages. Adding adjuvant after ICI neoadjuvant therapy 28,29 would significantly increase costs. Creative cost- creative avenues could use adjuvant ICI at shorter intervals of 4-6 cycles rather than 1-full-year. Medical schools need to include in their curriculum a course on drug cost mathematics. 
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