Research article Open Access
Costs and Values of Nivolumab in Advanced/ Metastatic Cancer
Helmy M Guirgis*
Received: April 7, 2017; Accepted: May 2, 2017; Published: May 10, 2017
University of California, Irvine, California, USA
*Corresponding author: Helmy M Guirgis, Clinical professor, University of California, Irvine, California, USA, E-mail: @
Citation: Helmy M Guirgis (2017) Costs and Values of Nivolumab in Advanced/Metastatic Cancer. Cancer Sci Res Open Access 4(2): 1-3.
Background: Nivolumab (Nivo) is a programmed death immune checkpoint antibody widely used to treat cancer. Accepted average incremental cost effectiveness ratio in the United States is 100,000.

Objectives: Compare values (V) of Nivo in advanced/metastatic melanoma, squamous (sq-) and non-sq-non-small-cell lung cancer (NSCLC), renal cell and sq-cell cancer of head and neck (SCCHN).

Methods: Median overall survival gain over control in days (OS), hazard ratios (HR) and prices posted by the parent company were quoted. Values were computed at 4-week as C x HR (4wV) and one-year as C/life-year gain (LYG). Relative values (RV) were calculated as $100,000/C/LYG.

Results: Estimated Nivo 4wC was$10,021. In 1st-line melanoma, OS was not reached, HR 0.42and 4wV 4,209. In 2nd- line renal cell, OS was 162, 4wV 7,315, C/LYG 289,496 and RV 0.35. In sq-NSCLC, OS 96, 4wV was 5,912, C/LYG 488,524 and RV 0.20.In non-sq- NSCLC, OS was 84, 4wV 7,315,C/LYG 558,326 improving in > 10% PD-L1 to 264, 5,512 and 177,650 respectively. In SCCHN, OS was 72, 4wV 7,015 and C/LYG 651,430 improving in PD-L1 >1.0%to123, 5,512 and 381, 287. PD-L1 enrichment significantly increased RV from 0.18 to 0.56 in non-sq- NSCLC and from 0.15 to 0.26 in SCCHN.

Conclusions: The results suggested that HR could serve as adjunct or substitute tools to survival in V-based model. Nivo in 1st-line melanoma, 2nd renal and sq-NSCLC were fair and worth the C. Enrichment of PD-L1 significantly improved V of Nivo in non-sq-NSCLC and SCCHN.

Abbreviations: Adverse events (AEs); Average cost-effectiveness ratios (ACER); Confidence Interval (CI); Cost/Life-year gain (C/LYG); 4-week costs (4wC); 4-week values (4wV); Day (d); Hazard Ratio (HR); Immune check point antibody(ICPA); Incremental cost effectiveness ratio (ICER); Median overall survival gain over control in days (OS); Metastatic (m); Milligram (mg); Non-smallcell- lung cancer (NSCLC); Non-squamous (non-sq-); Quality of life (QoL); Quality- adjusted life- year (QALY); Relative values (RV); Squamous (sq-); Squamous cell carcinoma of the head and neck (SCCHN); Week (w);
Nivolumab (Nivo) is a fully human IgG4 immune checkpoint antibody (ICPA) which disrupts the protein death 1 (PD-1) signaling and restores the antitumor immunity [1]. It is widely used throughout the United Sates (US) to treat various types of cancer.

The American (ASCO) and European (ESMO) Societies of Clinical Oncology emphasized the importance of values (V) in the drug economy [2,3]. In the US, the incremental cost-effectiveness ratio (ICER) ranging from $ 50,000 to $ 150,000 per quality adjusted life-year (QALY) is considered acceptable. The National Institute for Health and Care Excellence (NICE) in the United Kingdom (UK) rejected Nivo in 2-nd line non-small-cell lung cancer (NSCLC) while the European Medicines Agency (EMA) approved the drug for the same indication. We previously proposed simplified methodology to weigh drug costs (C) and Vin metastatic (m) castrate-resistant prostate cancer (CRPC) using $ 100,000 as a point of reference [4]. Values of Nivo have not been compared between the various approved indications. Our objectives were to compare the V of Nivo in 1st-line melanoma, and 2nd-line renal cell carcinoma, Squamous (sq)- NSCLC, and non-sq-NSCLC and Squamous cell cancer of the head and neck (SCCHN).
The median overall survival gain of Nivo over control in days (OS), hazard ratios (HR), doses, frequency and protocols were extracted from previously published clinical trials. Prescribing information and prices posted by the parent company were utilized. Costs of Nivo at 2.0 mg/Kg q 2 weeks were assessed. Values were computed at 4-week as C x HR (4wV) and one-year as C/life-year gain (LYG). Relative values (RV) were calculated as $ 100,000/C/LYG.
In early 2016, the 4wC of Nivo2.0 mg/Kg q 2 w were estimated at $ 10,021 at a yearly C of $ 130,273. The recommended total dose of 2.0 mg/Kg has since been changed to a total of 240 mg q 2 weeks and the C has increased by about 7.0%. In 1st-line melanoma, OS was not reached at the closure of the study. The HR was 0.42 and the 4wV 4,209. The OS gain; HR, V and RV of Nivo in 1st- and 2nd-lines [1, 5-8] were shown in Table. The RV in2nd-line renal cancer were 0.35 and in sq-NSCLC 0.20. The PDL1 enrichment significantly increased the RV from 0.18 to 0.56 in non-sq- NSCLC and 0.15 to 0.26 in SCCHN.
The present investigation was prompted by the rising C, diminishing V and decreasing affordability of anticancer drugs [9,10]. Our objective was to compare V of Nivo in various cancer using the same doses, frequency, protocols and C. Nivo, a prototype of PD-1 immune checkpoint antibody(ICPA), was chosen since it prolonged the OS in 1st-line melanoma [5], 2nd-line sq- NSCLC, CheckMate 017 [6], non-sq- NSCLC, CheckMate 057 [1] and renal cell carcinoma, CheckMate 025 [7] and SCCHN [8]. The standard ICER formula based on differences in C per differences in outcome could not be applied in our study since C of Nivo was the same in all the cited indications. Nivo4wCwas within the current estimated average range of the newly approved patent drugs of $ 10,000 - $ 12,000 in the US. The available data on comparative V issues were limited. Nonetheless, the results clearly suggested that Nivo V were fair and worth the dollars spent in 1st-line melanoma and 2nd-line renal and to a lesser extent in sq- NSCLC. Values in 2nd-line non-sq-NSCLC and SCCHN were marginal but significantly improved by PD-L1 enrichment.
HR vs. OS
At the closure of the Nivo study in 1st-line melanoma, OS was not reached and HR was therefore used [5]. Parallel use of both OS and HR was adopted whenever possible throughout our investigation. The HR-based strategy could offer a snapshot approach to measure V in the absence of mature OS data.
Table : Nivo Values in 1st and 2nd lines cancer

Nivo in 1st- and 2nd-line

OS in days (d)
& HR

4wV (4wC x HR)


RV ($100,000/LYG)

1st- line: Nivo vs. dacarbazine,

OS not reached
HR 0.42




2nd- line: Nivo vs. everolimus,
Renal cell

HR 0.73
P = 0.002




Nivo vs. docetaxel, sq-NSCLC

HR 0.59
P = 0.00025




Nivo vs. docetaxel, non-sq-

NSCLC-CheckMate 057


Subset analysis in >10% PD-L1

HR 0.73
P = 0.0016

HR 0.27













Nivo vs. investigator’s choice,


Subset analysis in >1.0 PD-L1


HR 0.70
P = 0.0101


HR  0.55

















Overall survival generally considered the ultimate measure of clinical benefit was used throughout the present investigation; The C/LYG was measured relative to 100,000, an accepted average cost-effectiveness ratio (ACER) in the US. The safety of patients treated by Nivo have been well documented [1, 5 -7]. The reported Nivo gr ¾ adverse events (AEs) were in general less than 5.0% in all the cited clinical studies. Costs and values were calculated in a few minutes once the data was collected. The RV approach could facilitate clear transmission of economic issues between physicians and patients [11]. Patients as consumers would like to know in advance the C incurred to better manage their budgets. Using this simplified model, upfront costs and values could be promptly disclosed to patients.
A correction factor would be needed to adjust for the C of AEs treatment of drugs as Doc and dacarbazine. Cost treatment of AEs [12] could be costly and “toxic” [13]. In a recent phase III trial in previously treated NSCLC, all-grade treatment-related AEs were less frequent with Nivo than with docetaxel [14].
Duration of Treatment
The costs and values of Nivo were calculated for one year. In the Checkmate-057 study of non-sq- NSCLC [1], the median duration of response was >17 months. Currently the optimal duration of therapy has not been defined. Continued treatment until disease progression or intolerance has been recommended.
A simplified survival and HR- based model was presented to evaluate V of Nivo in various cancers. Values were defined as C x HR and as C per the incremental increase in OS gain over control in days. The 4wV served as an early screening measure of V. In view of Nivo well-documented safety and favorable impact on quality of life, the results were expressed relative to $ 100,000, the average acceptable C/QALY in the US. Values of Nivo in 1stline melanoma, 2nd-line renal cell and to a lesser extent sq-NSCLC were fair and worth the dollars spent. The marginal V in non-sq- NSCLC and SCCHN significantly improved by PD-L1 enrichment.
  1. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med. 2015;373(17):1627-39. doi: 10.1056/NEJMoa1507643
  2. Schnipper LE, Davidson NE, Wollins DS, Courtney Tyne, Douglas WB, Diane B, et al. American Society of Clinical Oncology statement: A framework to assess the value of cancer treatment options. J Clin Oncol. 2015;33(23): 2563-2577. doi: 10.1200/JCO.2015.61.6706
  3. Cherny NI, Sullivan R, Dafni U, Kerst JM, Sobrero A, Zielinski C, et al. A standardized, generic, validated approach to stratify the magnitude of clinical benefit that can be anticipated from anti-cancer therapies. The European Society for Medical Oncology: Magnitude of Clinical Benefit Scale (ESM-MCBS).  Ann Oncol. 2015;26(8):1547- 1573. doi: 10.1093/annonc/mdv249
  4. Guirgis HM. Value of Anticancer Drugs in Castrate-Resistant Metastatic Prostate Cancer; Economic Tools for the Community Oncologist. JCSO. 2015;13(10):362-366.
  5. Robert C, Long GV, Brady B, Caroline Dutriaux, Michele Maio, Laurent Mortier, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med.2015;372(4):320-330.
  6. Brahmer J, Reckamp KL, Bass P, Crinò L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small- Cell lung Cancer. N Eng J Med.2015;373(2):123-135.  doi: 10.1056/NEJMoa1504627
  7.  Motzer RJ, Escudier B, McDermott DF, Saby George, Hans JH, Sandhya Srinivas, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373:1803-1813. doi: 10.1056/NEJMoa1510665
  8. Robert L, Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD,  et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck.  N Engl J Med. 2016; 375(19):1856-1867. doi: 10.1056/NEJMoa1602252
  9. Kelley RK, Venook AP.  Nonadherance to Imatinib during an economic downturn. N Engl J Med. 2010;363(6):596-598. doi: 10.1056/NEJMc1004656
  10. Dusetzina SB,  Winn AN,  Abel GA,  Huskamp HA,  Keating NL.  Cost sharing and adherence to tyrosine kinase inhibitors for patients with chronic myeloid leukemia.  J Clin Oncol. 2013; 32(4):306-311.  doi: 10.1200/JCO.2013.52.9123
  11. Henrikson NB, Shankaran V. Improving price transparency in cancer care. JOP. 2016;12(1):44-47. doi: 10.1200/JOP.2015.006171
  12. Ubel PA, Abernethy AP, Zafar SY. Perspective, Full disclosure- out of pocket costs as side effects. N Engl J Med. 2013; 369: 1484-1486.  doi: 10.1056/NEJMp1306826
  13.  Niraula S, Amir E, Vera-Badillo F, Bostjan Seruga, Alberto Ocana, Ian F. Tannock. Risk of Incremental Toxicities and Associated Costs of New Anticancer Drugs: A Meta-Analysis. J Clin Oncol. 2014;32(32):3634-3642. doi: 10.1200/JCO.2014.55.8437
  14. Venkatachalam M. Estimated costs of managing treatment-related adverse events (TREAs) of nivolumab in the Checkmate 017 and CheckMate 057 phase III non-small-cell lung cancer (NSCLC) trials, Poster 6617, ASCO Annual Meeting, 2016 Chicago IL.
Listing : ICMJE   

Creative Commons License Open Access by Symbiosis is licensed under a Creative Commons Attribution 3.0 Unported License