Drug Costs vs Probability of Survival in Lung Cancer: Impact of Dosage, Duration, and Immune Checkpoint Inhibitor Combinations

Abstract: Clinical guidelines and pathways recommend use of immune checkpoint inhibitors (ICI) in first- and second-line treatment of advanced/metastatic non-small cell lung cancer (amNSCLC). There is an unmet need for simplified methodology to facilitate clear transmission of financial impact of treatment with full disclosure of drug costs and value. The probability of survival (PoS) was previously defined as (1.0-hazard ratio) and used as surrogates of value. The present study provides a practical methodology to weigh costs vs PoS and value of the ICI in amNSCLC. Methods: Yearly costs of pembrolizumab (Pembro), nivolumab (Nivo), and atezolizumab (Atezo) were calculated. Crude dollar value (cV) was computed as costs/PoS. Results: Costs of Pembro 200 mg flat dose was $157,213 compared with 2.0 mg/kg for 80 kg-patient of $125,770. Proportionate savings were noted over the 90 to 50/kg range. Nivo costs were $159,589 and Atezo was $149,770. In first-line, Pembro in programmed death receptor-ligand-1 (PD-L1) > 50% demonstrated PoS 0.40 and cV $393,033. In squamous histology, Pembro+nab-paclitaxel costs were higher than Pembro-paclitaxel by nearly $31,000. PoS was 0.35, essentially similar regardless of the taxane. Pemro+pemetrexed (Peme) combination costs were $278,207. The PoS in PD-L1 < 1.0% was 0.41 and cV $678,554, improving in >50% to 0.58 and cV $479,667. Atezo+bevacizumab (Bev) four-drug combination costs were $281,918, PoS 0.22, and cV $1,305,973. Conclusions: Simplified methodology to gauge cost and value of the ICI was proposed. In first-line squamous amNSCLC, Pembro-taxane demonstrated significant PoS at enhanced cV. The PoS and cV of Pembro-Peme in nonsquamous were unrivaled. Atezo-Bev-4 drugs were costly relative to PoS. The ICI 2-year use increased costs and diminished cV. The impact of dosage, duration, and patent-combinations on ICI costs are highlighted. Strategies to improve value without undue cost control are proposed.

There is an unmet need for simplified methodology to facilitate clear transmission of financial impact of treatment with full disclosure of drug costs and value. In 2015, the term “probability of survival (PoS)” was coined, defined as (1.0-hazard ratio; HR) and used in castrate-resistant prostate cancer to measure value.¹ Overall survival (OS) gains over control with value expressed as cost/OS ratios was later used.² The American Society of Clinical Oncology (ASCO) and the European Society of Clinical Oncology (ESMO) designed platforms assigning points and/or weights to value wherein composite scores were derived from outcome, toxicity, and quality of life (QoL).^3,4 ASCO later revised its value framework using HR.⁵ 

In the present analysis, we surveyed the commonly used and approved drugs in advanced/metastatic non-small cell lung cancer (amNSCLC) lacking the epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase. The HR of death or PoS was the basis of analysis since OS gains were not reached at the closure of some clinical studies. HR are less subject to changes across the time than survival. The analysis was focused on pembrolizumab (Pembro) and atezolizumab (Atezo) in view of the wealth of available outcome data in second- and first-line treatment of amNSLC. Nivolumab (Nivo) was studied only in second-line due to lack of OS or PoS in first-line by December 2018. Pemetrexed (Peme)⁶ and bevacizumab (Bev)⁷ were included as references since they were approved for nonsquamous treatment prior to EGFR recognition. Docetaxel (Doc)⁷ was used as a control in various clinical studies. The main objective was to weigh costs vs PoS and crude dollar value (cV) of the immune checkpoint inhibitors (ICI). A secondary objective was to investigate the impact of dosage, duration, and drug combinations on costs.

Methods

Drug doses, frequency, OS, and HR at the 95% CI were quoted from previously published clinical studies. Parent company 2018 prices in the United States Dollar (USD) were utilized. Costs were calculated for 1 and 2 years with Nivo 240 mg every 2 weeks. Pembro 2.0 mg/kg vs 200 mg total dose, Atezo 1200 mg, Bev 15 mg/kg, and Peme 500 mg/m₂ every 3 weeks were computed. Each drug was measured against its own control. Costs of generic drugs < $1200 were not included. The cV was computed as cost/PoS and relative value (RV) as $100,000/cost/PoS.

Results

Doc⁷ carries a black-box warning assigned by the Food and Drug Administration. The grade 3-4 adverse events (AEs) of Doc were reported at >20%, Pembro, Nivo, and Atezo were <10%. Except for Doc, the ICI improved the QoL.^8-12 

Drug Costs

Costs of Pembro 2 mg/kg x 80-kg patient were $125,770. The dose was later switched by the parent company to a flat dose of 200 mg at costs of $157,213—higher by $31,443 than the 80-kg-body-weight dose. The 60 kg cost was $94,328 with $62,885 savings per patient. Proportionate savings were noted over the 90 to 50/kg range. The 200-mg dose was uniformly adopted in all first-line results. Nivo costs were $159,589, and Atezo costs were $149,604. There was no significant cost difference between the three ICI.

In second-line, the OS, HR, PoS, and ICI cost are shown in Table 1. Pembro OS gain over Doc was 57 days in programmed death-ligand 1 (PD-L1) >1.0% at 0.29 PoS.⁸ In squamous histology,⁹ Nivo OS gain were 96 days and PoS 0.41. In nonsquamous,¹⁰ OS was 84 days and PoS was 0.27, lower than in squamous histology. Atezo OS ranged from 87 days to 111 days with an average PoS 0.26.^11,12 

In first-line nonsquamous histology (Table 2), Bev costs were $132,314 and PoS 0.21.6. Peme costs were $120,994, and PoS was 0.37 in the Zukin study¹³ and 0.22 in PARAMOUNT.¹⁴ The PoS of Pembro monotherapy in >50% PD-L1 was 0.40 (KEYNOTE-024),^15,16 cV $393,033, and RV 0.25. In KEYNOTE-042, PoS in PD-L1 > 1.0 was 0.19, and in >50% PoS was 0.31.¹⁷ 

The results on ICI-combination therapy are shown in Table 3. In squamous cell (KEYNOTE-407),¹⁸ costs of Pembro+nab-paclitaxel+carboplatin were $189,153. Estimated costs of four doses of generic paclitaxel were $1000 vs nab-paclitaxel of nearly $32,000. Regardless of the taxane used, the 0.36 PoS was not significantly different. 

The PoS of Pembro-Peme-combinations in <1% PD-L1 was 0.41 and improved in > 50% to 0.58.^19,20 The cV ranged from $479,667 to $678,554 and RV 0.22 to 0.18, respectively. The yearly costs of $278,207 were doubled, and cV decreased at 2-year extended therapy.

In IMPOWER 150 study , the 4-drug combination of Atezo+Bev+chemotherapy was tested vs Bev+chemotherapy.²¹ The PoS was modest at 0.22, costs were $281,918, cV $1,281,445, and RV 0.07. The results of the three combinations are shown in Table 3.

Discussion

In the present investigation, the objective was to weigh the ICI costs vs PoS and cV calculated as cost/PoS ratios. To enhance retention and recall, the cV were expressed in RV to $100,000, the average cost-effectiveness ratio in the United States. There was minimal cost difference between the three ICI analyzed. However, significant differences in PoS and cV were noted. The ICI costs were doubled at year 2 of continued therapy.

Patients with newly diagnosed cancer earnestly seek information on the extent of disease, survival, QoL, and treatment costs. Legislation on “surprise billing,” or unexpected medical bills, sent to patients are being formulated.²² Reports on drug costs are scarce and rarely supported by drug companies, and US law prohibits discussion of drug costs during the approval process. The ASCO and ESMO value platforms have been erroneously interpreted as minimizing the role of costs. Defining drug value has been elusive with perspectives differing from patient, society, provider to drug company.²³ Basically, value is either based on cost-effectiveness analysis or outcome per dollar spent.^24-26 The cost of the incremental gain in PoS or OS in prostate and lung cancer were previously reported.^1,2 

Using the methodology of this analysis, ie, use of PoS, may send to patients and families a message of hope rather than fear of death. Rounding-up the cV results to the second digit could eventually facilitate clearer transmission of economic issues to stakeholders. Calculations were carried out in a few minutes once the data were entered, demonstrating the ease of the method.

It should be noted that the methodology failed to incorporate health-related QoL and toxicity. Fortunately, the ICI class was reported to improve the QoL with grade 3-4 AEs of < 10%. The methodology is not intended for medical economists and clinical researchers but rather for busy community oncologists, pharmacists, and nurses. The PoS did not capture the rate and depth of response to the ICI. Scarcity of drug comparative studies and subset analysis could undermine the validity of the results. No drug comparison could be made since HR and PoS are dependent on the study design, selection of the population, performance status, and confidence intervals. 

The cost-saving results of Pembro using weight-based dosage over the 200-mg flat fit-all dose were consistent with Goldstein et al findings.²⁷ The 160 mg total dose in an 80-kg patient reduced the costs by $31,443. Proportionate savings were noted over the 90 to 50 kg range.

In first-line, the results confirmed the positive impact of PD-L1 >50% on Pembro monotherapy. However, the PoS and RV in KEYNOTE-024^15,16 were higher than in KEYNOTE-042.¹⁷ 

The addition of chemotherapy to the ICI enhanced the outcome in multiple major clinical studies. Pembro-Peme combination was initially reported for amNSCLC by Langer et al¹⁹ and later confirmed by Gandhi et al.²⁰ Their results confirmed the narrative that chemotherapy-ICI combinations have synergistic effects, probably secondary to neo-antigen release and immune cell activation. Pemro-Peme combination resulted in unprecedented 0.41 to 0.58 PoS, depending on PD-L1 status. The cV ranged from $678,554 to $478,667, and RV ranged from 0.14 to 2.0, respectively. Costs should decrease when Peme becomes available as a generic. Costs of Atezo-Bev 4-drug combination in IMpower150 were considered expensive relative to modest PoS and cV.²¹ 

Pembro added to paclitaxel or nab-paclitaxel was recently described as the combination of choice in squamous cell histology.¹⁸ The liposomal nab-paclitaxel reduced the incidence of peripheral neuropathy but increased costs over the generic paclitaxel by nearly $31,000. The PoS were 0.36, irrespective of the taxane used. The squamous type is noted for male predominance with higher incidence of smoking and rates of mutations. Of interest, the PoS of Nivo in second-line was higher in squamous than nonsquamous type.

At present, the tumor mutation burden (TMB)²⁸ is being explored as potential predictive marker in addition to PD-L1. In an exploratory analysis of phase 3 CheckMate 026 trial of patients with a high TMB (defined as ≥243 mutations/Mb), Nivo in first-line improved the progression-free survival over chemotherapy.²⁹ Results of Nivo/Ipilimumab on OS using TMB are promising.³⁰ The search continues for standardized, reliable, and rapid TMB tests.

Conclusion

The present investigation presents a practical methodology to weigh drug costs vs PoS and cV with focus on the ICI. There was minimal cost difference between the three ICI analyzed. However, significant differences in PoS and cV were noted. The ICI costs were doubled at 2-year of continued therapy. The impact of dosage, duration, and patent-combinations on ICI costs was highlighted. Strategies were proposed to reduce drug costs, enhance PoS, and improve cV without undue cost limits or control. 

References

1. Guirgis HM. The value of anticancer drugs in castrate-resistant metastatic prostate cancer: economic tools for the community oncologist. J Community Support Oncol. 2015;13(10):362-366. doi:10.12788/jcso.0148

2. Guirgis HM. The impact of PD-L1 on survival and value of the immune check point inhibitors in non-small-cell lung cancer; proposal, policies and perspective.
J ImmunoTher Cancer. 2018;6(1):15. doi:10.1186/s40425-018-0320-3

3. Schnipper LE, Davidson NE, Wollins DS, 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 

4. Cherny NI, Sullivan R, Dafni U, 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 (ESMO-MCBS): Ann Oncol. 2015;26(8):1547-1573. doi:10.1093/annonc/mdv249

5. Schnipper LE, Davidson NE, Wollins DS, et al. Updating the American Society of Clinical Oncology Value Framework: revisions and reflections in response to comments. J Clin Oncol. 2016;34(24):2925-2934. doi:10.1200/JCO.2016.68.2518

6. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355(24):2542-2550. doi:10.1056/NEJMoa061884

7. Shepherd FA, Dancey J, Ramlau R, et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-base chemotherapy. J Clin Oncol. 2000;18(10):2095-2103. doi:10.1200/JCO.2000.18.10.2095 

8. Herbst RS, Baas P, Kim D-W, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-postive, advanced non-small-cell lung cancer (KEYNOTE -010): a randomised controlled trial. Lancet. 2016;387(10027):1540-1550. doi:10.1016/S0140-6736(15)01281-7

9. Brahmer J, Reckamp KL, Bass P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373(2):123-135. doi:10.1056/NEJMoa1504627 

10. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced non-small-cell lung cancer. N Engl J Med. 2015;373(17):1627-1639. doi:10.1056/NEJMoa1507643

11. Fehrenbacher L, Spira A, Ballinger M, et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicenter, open-label, phase 2 randomized controlled trial. Lancet Oncol. 2016;387(10030):1837-1846. doi:10.1016/S0140-6736(16)00587-0

12. Rittmeyer A, Barlesi F, Water Kamp D, et al. Atezolizumab versus docetaxel in patients with previously treated non-small cell lung cancer (OAK): a phase 3, open-label, multicentre randomized controlled trial. Lancet. 2017;389(10066):255-265. doi:10.1016/S01-40-6736(16)32517-X

13. Zukin M, Barrios CH, Pereira JD, et al. Randomized phase III trial of single-agent pemetrexed versus carboplatin and pemetrexed in patients with advanced non-small-cell lung cancer and Eastern Cooperative Oncology Group Performance status of 2. J Clin Oncol. 2013;31(23):2895-2902. doi:10.1200/JCO.2012.48.1911

14. Paz-Arez L, de Marinis F, Dediu M, et al. PARAMOUNT: Final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013;31(23):2895-2902. doi:10.1200/JCO.2012.47.1102

15. Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small cell lung cancer. N Engl J Med. 2015;372(21):2018-2028. doi:10.1056/NEJMoa1501824

16. Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016;375(19):823-1833. 

17. Mok TSK, Wu Y, Kudaba I, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet. 2019;393(10183):1819-1830. doi:10.1016/S0140-6736(18)32409-7

18. Paz-Ares L, Luft A, Vincente A, et al. Pembro plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med. 2018;379(21):2040-2051. doi:10.1056/NEJMoa1810865

19. Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016;17(11):1497-1508. doi:10.1016/S1470-2045(16)30498-3

20. Gandhi L, Rodriguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018;378(22):2078-2092. doi:10.1056/NEJMoa1801005

21. Kowanetz M, Socinski MA, Zou W, et al. IMpower150: Efficacy of atezolizumab (atezo) plus bevacizumab (bev) and chemotherapy (chemo) in 1L metastatic nonsquamous NSCLC (mNSCLC) across key subgroups. Abstract presented at: American Association for Cancer Research Annual Meeting 2018; April 14-18, 2018; Chicago, IL. Abstract CT076.

22. Scott D. Exclusive: the new bipartisam House bill to stop surprise medical bills, explained. Vox. May 14, 2019. https://www.vox.com/policy-and-politics/2019/5/14/18622825/surprise-medical-bills-trump-house-health-care-legislation. Accessed May 28, 2019.

23. Goodman C, Kline R. Stakeholders agree: “value” in cancer care depends on perspective. ASCO Post. 2018;9(16):9-10.

24. Russell LB, Gold MR, Siegel JE, Daniels N, Weinstein MC. The role of cost-effectiveness analysis in health and medicine. Panel on cost-effectiveness in health and medicine. JAMA. 1996;276(14):1172-1177. 

25. Siegel JE, Weinstein MC, Russell LB, et al. Recommendations for reporting cost effectiveness analyses. Panel on cost-effectiveness in health and medicine. JAMA. 1996;276(16):1339-1341. 

26. Tsevat J, Moriates C. Value-based health care meets cost-effectiveness analysis. Ann Int Med. 2018;169(5):329-332.

27. Goldstein DA, Gordon N, Davidescu M, et al. A phamacoeconomic analysis of personalized dosing vs fixed dosing of pembrolizumab in firstline PD-L1-positive non-small cell lung cancer. J Natl Cancer Inst. 2017;109(11). doi:10.1093/jnci/djx063

28. Helwick C. In patients with non-small cell lung cancer, tumor mutation load emerging as biomarker for immunotherapy. ASCO Post. 2017;8(21):11.  

29. Carbone DP, Reck M, Paz-Ares L, et al. First-line nivolumab in stage IV or recurrent non-small-cell lung cancer. N Engl J Med. 2017;376(25):2415-2426. doi:10.1056/NEJMoa1613493

30. Hellmann MD, Ciuleanu TE, Pluzanski A, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med. 2018;378(22):2093-2104. doi:10.1056/NEJMoa1801946