1

The Non-$mall Cost of

Non-Small Cell Lung Cancer

CPT Zachary Leftwich, PharmD PHY-1 Managed Care Pharmacy Resident

Defense Health Agency Pharmacy Operations Division, San Antonio, TX

May 4th 2018

At the end of this session, the learner will be able to: 1. Summarize the pathophysiology of non-small cell lung cancer2. Analyze current guideline recommendations for treating non-small cell lung cancer3. Evaluate similarities and differences between clinical trial results and real-world data

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Assessment questions: 1. Which ALK inhibitor is preferred for first-line in ALK+ NSCLC? a) Alectinib b) Brigatinib c) Crizotinib d) Ceritinib 2. Which agent carries the highest risk of Interstitial lung disease? a) Alectinib b) Brigatinib c) Crizotinib d) Ceritinib 3. Military health system patients on crizotinib experienced longer durations of therapy and better survival than clinical trial patients. True False

Speaker Disclosure: CPT Zachary Leftwich has nothing to disclose concerning possible financial or personal relationships with commercial entities that may have a direct or indirect interest in the subject matter of this presentation.

The findings discussed in this presentation represent the views of the authors, and do not necessarily reflect the views of the Department of Defense (DoD), nor the Departments of the Army, Navy, and Air Force.

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Background

1. Lung Cancer1 a. Represents the second most common form of cancer b. 234,030 new cases, and 154,050 deaths from lung cancer annually c. Average age at the time of diagnosis is 70 years d. Risk factors include: smoking, genetics, radon exposure, pollution, asbestos,

exhaust

2. Non-small cell lung cancer (NSCLC)1 a. Represents around 85% of all lung cancers b. Smoking is the major risk factor c. There are a wide range of prognoses associated with NSCLC. Early stages may be

curable, while later metastatic stages are not i. Five year survival rate for stage IA is 92%

ii. Stage IVA five year survival is 10% d. Typically presents as an adenocarcinoma

3. Anaplastic Lymphoma Kinase (ALK) rearrangement positive non-small cell lung cancer1,2 a. Represents 3-6% of patients with NSCLC b. Most patients are never smokers, or former smokers c. Average age at diagnosis is 52 d. Currently four treatments available for this subset of NSCLC

ALK-positive non-small cell lung cancer pathophysiology

1. Normal Physiology2,3 a. ALK is a tyrosine kinase enzyme that protects lung cells from degradation and

apoptosis when phosphorylated (Fig 1)

2. ALK rearrangement pathophysiology2,3 a. ALK rearrangement is a t (2;5) translocation. This enables phosphoprotein

nucleophosmin to auto phosphorylate without activation by a ligand (Fig 2)

Figure 1. Normal ALK physiology2 Figure 2. ALK rearrangement pathophysiology2

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Treatment methods

1. Historic treatment for advanced metastatic NSCLC consisted of chemotherapy4 a. Preferred chemotherapy options included:

Pemetrexed (500mg/m2) + cisplatin (75mg/m2) Pemetrexed (500mg/m2) + carboplatin (target AUC: 5-6mg/mL/minute)

2. Modern treatment for advanced metastatic NSCLC includes ALK inhibitors5 a. Available ALK inhibitors are listed in Table 1 below5-9

Table 1. Currently available ALK inhibitors

b. Strengths of ALK inhibitor therapy include10-11 i. Less severe adverse reactions compared to chemotherapy

ii. No patient requirement to travel to an infusion clinic iii. All ALK inhibitors are available as oral capsules or tablets

c. Weakness of ALK inhibitor therapy include4 i. Expense of treatment can be cost prohibitive. ALK inhibitor therapy costs

in excess of $10,000 per month ii. There is a limited pool of clinical trial data available due to the recent

FDA approval of the agents within the class ALK inhibitor mechanism of action

1. ALK inhibitors exert their effect directly on the anaplastic lymphoma kinase enzyme2,12

a. ALK inhibitors bind to the tyrosine-kinase portion of the ALK enzyme to prevent the binding of ATP (Fig 3)

b. The ALK enzyme is unable to auto phosphorylate without access to the ATP binding site

c. Resistance to ALK inhibitor treatment commonly occurs within one year of treatment due to gene amplification or secondary mutations

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Figure 3. ALK inhibitor mechanism of action2

Role of ALK inhibitors in NSCLC

1. ALK inhibitors extend progression-free survival by slowing cancer progression5

a. ALK inhibitors are the preferred first-line agent in advanced metastatic NSCLC b. Chemotherapy initiation is delayed until the cancer progresses while on ALK

inhibitor treatment c. When cancer progresses during ALK inhibitor therapy, the oncologist may

switch to another ALK inhibitor, or initiate chemotherapy

ALK Inhibitor adverse reactions and pharmacokinetics 1. ALK inhibitor adverse drug reactions are often less severe than chemotherapy

adverse reactions6-11, 13 a. Crizotinib has a higher incidence of vision disorder, diarrhea, and edema

when compared to chemotherapy b. Chemotherapy is associated with a higher frequency of more severe adverse

effects including anemia, neutropenia, leukopenia, and thrombocytopenia c. Interstitial lung disease (ILD) is a rare but serious adverse drug reaction that

can occur while on ALK inhibitor therapy i. Brigatinib is the ALK inhibitor with the highest risk of ILD (9.1%)

ii. Management of ILD varies between drugs, but generally requires a dose reduction or discontinuation of the offending agent

d. All ALK inhibitors are associated with a risk of vision disorder development including: diplopia, photophobia, impaired vision, and reduced acuity14

i. Crizotinib has the highest incidence of vision disorders ii. Switch to another ALK inhibitor upon onset of severe vision loss to

prevent permanent visual impairment e. Crizotinib and ceritinib carry a high risk for nausea, vomiting and diarrhea

i. The rates of nausea, vomiting and diarrhea rival the highly emetogenic chemotherapy alternative to ALK inhibitors

ii. Alectinib and brigatinib are less emetogenic and are options to consider if crizotinib or ceritinib are intolerable

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Table 2. ALK inhibitor adverse drug reactions6-9

2. ALK inhibitors are primarily metabolized hepatically (Table 3)14-17

a. Brigatinib is the only ALK inhibitor that utilizes CYP 2C8 for metabolism b. Ceritinib and alectinib are exclusively excreted in the feces; crizotinib and

brigatinib are also excreted in urine c. The time to response is similar among the agents and range between 1.4-1.8

months13, 18-20

Table 3. ALK inhibitor pharmacokinetics13-20

Time to response= Date of randomization to the date of partial or complete response

Current guideline recommendations

1. Patients diagnosed with advanced metastatic NSCLC should undergo histologic and

molecular testing5 a. Mutation testing should include ALK, epidermal growth factor receptor, C-ros

oncogene, B-Raf, and programmed death-ligand 1 b. ALK inhibitors are first-line therapy in ALK mutation-positive patients who

have not started a course of chemotherapy c. Alectinib is the preferred first-line ALK inhibitor

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Clinical question

What benefit can a patient in a real-world setting expect to receive from crizotinib?

1. Solomon, B et al. (2014)13

PROFILE 1014: First-Line Crizotinib Versus Chemotherapy in ALK-Positive Lung Cancer

Objective Report the results of a comparison between crizotinib and pemetrexed-plus-platinum chemotherapy

Study Design Randomized phase 3, open-label, head-to-head clinical trial

Outcomes Primary Secondary

Progression-Free Survival (PFS)

Objective Response Rate (ORR) Overall Survival (OS)

Treatment Crizotinib 250mg Twice Daily

Pemetrexed (500mg/m2) + Cisplatin: 75mg/m2 OR Carboplatin: AUC: 5 - 6mg/mL/min

Definitions ECOG Score: Eastern Cooperative Oncology Group Score PFS: Median time until death or disease progression OS: Median time from treatment initiation to death

Statistics Hazard ratios: Cox regression analysis Time to endpoints analysis: Kaplan-Meier method (PFS/OS) Objective response rate: Pearson chi-square test

Patient Population Total patients (343) | crizotinib (172) | chemotherapy (171) Stratified by: ECOG score, Asian race, presence of brain metastases

Inclusion Criteria

• Age>18 • Diagnosed advanced, recurrent, or metastatic ALK(+) NSCLC • No previous systemic treatment • Response Evaluation Criteria in Solid Tumors (RECIST) measurable • Eastern Cooperative Oncology Group (ECOG) score of 0-2 • Adequate hepatic, renal, and bone marrow function

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Baseline Patient Characteristics

Measure Crizotinib (n=172) Chemotherapy (n=171)

Median Age (Range) 52 (22-76) 54 (19-78)

ECOG Score n (%) 0-1: 161 (94%) 2: 10 (6%)

0-1: 163 (95%) 2: 8 (5%)

Brain Metastases: n (%) 45 (26%) 47 (27%)

Smoking status: n (%) Never smoked: 106 (62) Former smoker: 56 (33) Current smoker: 10 (6)

Never smoked: 112 (65) Former smoker: 54 (32) Current smoker: 5 (3)

Results

Result Crizotinib (n=172) Chemotherapy (n=171)

Progression-Free Survival Median Months, (95% CI)

10.9 Months (8.3 - 13.9)

7 Months (6.8 - 8.2)

Hazard Ratio (95%CI) 0.45 (0.35-0.6) -

Objective Response Rate %, (95% CI) 74% (67 - 81) 45% (37 - 53)

12 Month Mortality 16% (28/172) 21%

Duration of Therapy Median Months, (Range)

10.9 Months (0.4 - 34.3)

4.1 Months (0.7 - 6.2)

Duration of Response Median Months, (95% CI)

11.3 Months (8.1 - 13.8)

5.3 Months (4.1 - 5.8)

Patients Remaining at Data Cutoff 79 62

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Author’s Conclusion

• Results were independent of: ̶ Type of platinum treatment ̶ Performance status ̶ Patient ethnicity ̶ Presence of brain metastases

• Overall survival did not differ significantly between treatments • Crizotinib is superior to chemotherapy with respect to PFS,

ORR, reduction of symptoms, and quality of life In patients with previously untreated ALK+ NSCLC

Reviewer’s Critique

Strengths • Phase 3 clinical trial • Head-to-head vs. standard of care • Relatively large scale study

Limitations

• Open Label • Crossover could have boosted chemotherapy mortality results • Overall survival data is immature • Funded by Pfizer • Only 18/343 patients were ECOG 2. Authors claim performance

status had no effect on outcomes

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2. Peters, s et al. (2017)20

ALEX: Alectinib Versus Crizotinib in Untreated ALK-Positive Non-Small Cell Lung Cancer

Objective Investigate alectinib compared with crizotinib in patients with untreated, advanced ALK+ NSCLC.

Study Design Randomized, open-label, phase 3, head-to-head clinical trial

Outcomes

Primary Secondary

Progression-Free Survival (PFS) Objective Response Rate (ORR) Overall Survival (OS) Time to CNS Progression

Treatment Alectinib 600 mg Twice daily

Crizotinib 250mg Twice Daily

Definitions ECOG Score: Eastern Cooperative Oncology Group Score PFS: Median time until death or disease progression OS: Median time from treatment initiation to death

Statistics Hazard ratios: Cox regression analysis Time to endpoints analysis: Kaplan-Meier method (PFS/OS) Objective response rate: Clopper-Pearson method

Patient Population Total patients (303) |alectinib (152) | crizotinib (151) Stratified by: ECOG score, Asian race, presence of brain metastases

Inclusion Criteria • Age>18 • Diagnosed advanced, recurrent, or metastatic ALK(+) NSCLC • No previous systemic treatment • Response Evaluation Criteria in Solid Tumors (RECIST) measurable • Eastern Cooperative Oncology Group (ECOG) score of 0-2 • Adequate hepatic, renal, and bone marrow function

Baseline Patient Characteristics

Measure Alectinib (n=152) Crizotinib (n=151)

Median Age (Range) 58 (25-88) 54 (18-91)

ECOG Score n (%) 0-1: 142 (95%) 2: 10 (7%)

0-1: 141 (93%) 2: 10 (7%)

Brain Metastases: n (%) 64 (42%) 58 (38%)

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Smoking Status: n (%) Nonsmoker: 92 (61) Former smoker: 48 (32) Current smoker: 12 (8)

Nonsmoker: 98 (65) Former smoker: 48 (32) Current smoker: 5 (3)

Results

Result Alectinib (n=152) Crizotinib (n=151)

Progression-Free Survival Median Months, (95% CI)

25.7 Months (19.9 - NE)

10.4 Months (7.7 – 14.6)

Hazard Ratio (95%CI) 0.50 (0.36 - 0.70) -

Objective Response Rate %, (95% CI) 82.9% (76 – 88.5) 75.5% (67.8 – 82.1)

12 Month Mortality 15.6% (24/152) 17.5% (26/151)

Duration of Therapy Median Months, (Range)

17.9 Months (0 - 29)

10.7 Months (0 - 27)

Duration of Response Median Months, (95% CI) NE 11.1 Months

(7.9 - 13)

Patients Remaining at Data Cutoff 84 46

Author’s Conclusion

• Progression-free survival was significantly longer with alectinib than with crizotinib

• Time to CNS progression was significantly longer with alectinib • Grade 3 - 5 adverse events were more frequent with crizotinib

than with alectinib

Reviewer’s Critique

Strengths • Phase 3 clinical trial • Head-to-head vs. standard of care • Large scale study • Addressed effect of ECOG performance status on outcomes

Limitations • Open Label • Overall survival data is immature • Only 20/303 patients were ECOG 2

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Real-world utilization in the Military Health System (MHS)

1. TRICARE is the health plan that serves over 9.4 million active duty and retired military members and their families

a. Prescriptions are dispensed from retail pharmacies, military treatment facilities, and a mail order pharmacy

b. The pharmacy expenditure exceeds $7.6 billion annually, and includes the drugs covered under the outpatient pharmacy benefit

c. The Defense Health Agency (DHA) oversees the execution of the budget and the management of the formulary for the Department of Defense (DoD)

1. Leftwich, Z, Lugo M, Trice, S, Khoury R. (2018)

Real-World Utilization of Oral Non-Small Cell Lung Cancer & Ovarian Cancer Agents in the Military Health System

Objective Describe similarities and differences in duration of therapy, mortality and time to treatment change between clinical trial data and the MHS population

Study Design Retrospective pharmacy claims analysis

Outcomes

Primary Secondary

Duration of therapy (DOT) Twelve month mortality

Time to treatment change

Treatment ALK Inhibitors: crizotinib, ceritinib, alectinib, brigatinib

Definitions ECOG Score: Eastern Cooperative Oncology Group Score DOT: Median time until treatment discontinuation Twelve month mortality: Proportion of patients who did not survive 12 months of treatment

Statistics Twelve month mortality: Kaplan-Meier method *The authors did not perform statistical comparisons between groups due to the presence of confounders between patient populations

Patient Population N= 217

(crizotinib group)

Crizotinib: 217 Ceritinib: 6 Alectinib: 13 Brigatinib: 0

Inclusion Criteria • Required ICD-9 or 10 code from Oct 2012 to Oct 31 2017 for: • Lung cancer (ALK inhibitors)

• Prescription (Rx) claims for ALK inhibitors during the same timeframe, and all prior prescriptions

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Baseline Patient Characteristics

Measure Crizotinib (n=181)

Median Age: Years, (Range) 69 (20-91)

ECOG Score: n (%) No restriction

Brain Metastases: n (%) No Data

Smoking Status: n (%) No Data

Results

Result Crizotinib

12 Month Mortality 47.5% (86/181)

Duration of Therapy Median Months, (Range)

3 Months (1-60)

Time to Treatment Change Median Months, (Range)

4.2 Months (1-59)

Patients Remaining at Data Cutoff 72

Author’s Conclusion

• Crizotinib had a higher 12-month mortality in the MHS compared to clinical trial results

• Crizotinib had a shorter duration of therapy in the MHS compared to clinical trial results

• ECOG score and median patient age may be confounders in the comparison of real-world to clinical trial patients

• Proper statistical comparisons require chart reviews which could limit value-based contracting feasibility for price reduction

Strengths • Real-world patient data • Large sample • limited patient exclusion

Limitations • Statistical comparison was not appropriate due to differences and confounders in patient populations

• Effect of ECOG performance score on results is unknown • Chemotherapy initiation and adherence metrics are not

readily available

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Summary

1. Comparison of real-world MHS data to clinical trial results is summarized in table 4

Table 4. Results comparison13, 20

Conclusion

1. Crizotinib duration of therapy and mortality presented in clinical trials are inconsistent with the findings from the MHS population13, 20

a. The median duration of therapy was shorter in the MHS population (3 months) vs. the clinical trial populations of the PROFILE 1014 and ALEX trials (10.7 months and 10.9 months, respectively)

b. Twelve-month mortality was 30% higher in the MHS (47.5%) compared to the PROFILE 1014 (16%) and ALEX trials (17.5%)

c. The differences between clinical trial results and MHS findings are attributed to two potential confounders

i. The PROFILE 1014 and ALEX trials restrict inclusion based on ECOG score. MHS does not restrict the use of ALK inhibitors based on level of disability

ii. Median patient age was higher in the MHS (69 years) than PROFILE 1014 (52 years) and ALEX (54 years)

d. The confounders reveal fundamental differences in baseline characteristics of each group. For this reason, the authors did not conduct statistical comparison between populations

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Final recommendations

1. Despite unfavorable real-world results, ALK inhibitors are recommended as first-line

treatment in advanced metastatic NSCLC a. ALK inhibitors effectively extend progression-free survival and duration of

response compared to chemotherapy and have fewer severe adverse reactions b. Real-world patients experienced shorter durations of therapy and higher

mortality than presented in clinical trials c. Although the presented real-world results are not favorable, age and ECOG score

appear to influence outcomes d. Younger patients with an ECOG score of 0-1 appear to benefit most from ALK

inhibitor therapy e. Future studies are needed to assess the impact of age and ECOG score on ALK

inhibitor efficacy

2. This study revealed numerous challenges of comparing real-world data to clinical trial data, and the incorporation of results into potential value-based contracting solicitations

a. As a health plan, evaluating only the population that meets clinical trial inclusion criteria would exclude real patients that received medication appropriately

b. The statistical comparison of all real-world patients to clinical trial patients may be inappropriate due to population differences

c. The challenges of this type of comparison will have to be addressed by future research in order to pursue value-based contracting

3. Future steps include a. Extending the analysis to other ALK inhibitors once utilization increases b. Conduct a Cost Effectiveness Analysis to analyze the relative cost and benefit of

the ALK inhibitors

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Appendices

Appendix A. Abbreviations

Appendix B. MHS crizotinib survival curve

ALK Anaplastic Lymphoma Kinase OS Overall SurvivalNSCLC Non-Small Cell Lung Cancer PFS Progression Free Survival

AUC Area Under the CurveECOG Score

Eastern Cooperative Oncology Group Performance Score

WAC Price Wholesale Acquisition Price DOT Duration of TherapyILD Interstitial Lung Disease MHS Military Health SystemORR Objective Response Rate PARP Poly ADP Ribose Polymerase

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References:

1. Non-small cell lung cancer. The American Cancer Society. Available at: Cancer.org/cancer/non-small-cell-lung-cancer. Accessed April 24, 2018.

2. Alectinib: an Anaplastic Lymphoma Kinase (ALK) Inhibitor. Personalized medicine in oncology; 2016. Available at: personalizedmedonc.com/article/alectinib-an-anaplastic-lymphoma-kinase-alk-inhibitor. Accessed April 24, 2018.

3. Mourali, J et al. Anaplastic Lymphoma Kinase Is a Dependence Receptor Whose Proapoptotic Functions Are Activated by Caspase Cleavage. Mol. Cell. Biol. 2006;26 (16): 6209-6222.

4. Klein, R et al. Cost-Effectiveness of Pemetrexed Plus Cisplatin as First-Line Therapy for Advanced Nonsquamous Non-small Cell Lung Cancer. J Thorac Oncol. 2009;4 (11): 1404-14.

5. Ettinger, D et al. NCCN Clinical practice guidelines in oncology: Non-Small Cell Lung Cancer. National comprehensive cancer network. Available at: www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed April 28, 2018.

6. Xalkori (Crizotinib) [package insert]. Pfizer. NY; 2016. 7. Zykadia (Ceritinib) [package insert]. Novartis Pharmaceutical Corporation. NJ; 2017. 8. Alecensa (Alectinib) [package insert]. Genentech. Tokyo, Japan; 2017. 9. Alunbrig (Brigatinib) [package insert]. ARIAD Pharmaceuticals. Cambridge, MA; 2017. 10. Cisplatin. Lexi-Comp Online. Wolters Kluwer Health, inc. Riverwoods, IL. Available at: online.lexi.com.

Accessed 24 April 2018. 11. Carboplatin. Lexi-Comp Online. Wolters Kluwer Health, inc. Riverwoods, IL. Available at: online.lexi.com.

Accessed 24 April 2018. 12. Wilson, F. A Functional Landscape of Resistance to LK inhibition in Lung Cancer. Cancer Cell. 2015;27(3):

397–408 13. Solomon, B et al. First-Line Crizotinib versus Chemotherapy in ALK-Positive Lung Cancer. New England

Journal of Medicine. 2014;371;23. 14. Crizotinib Lexi-Comp Online. Wolters Kluwer Health, inc. Riverwoods, IL. Available at: online.lexi.com.

Accessed 28 April 2018 15. Ceritinib Lexi-Comp Online. Wolters Kluwer Health, inc. Riverwoods, IL. Available at: online.lexi.com.

Accessed 28 April 2018 16. Alectinib Lexi-Comp Online. Wolters Kluwer Health, inc. Riverwoods, IL. Available at: online.lexi.com.

Accessed 24 April 2018 17. Brigatinib Lexi-Comp Online. Wolters Kluwer Health, inc. Riverwoods, IL. Available at: online.lexi.com.

Accessed 24 April 2018 18. Mok et al. ASCEND-2: A single-arm, open-label, multicenter phase II study of ceritinib in adult patients

(pts) with ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC) previously treated with chemotherapy and crizotinib (CRZ). J Clin Oncol. 2016; 34:2866-2873.

19. Kim, D et al. Brigatinib in Patients With Crizotinib-Refractory Anaplastic Lymphoma Kinase–Positive Non–Small-Cell Lung Cancer: A Randomized, Multicenter Phase II Trial. J Clin Oncol. 2017; 35:2490-2498.

20. Peters, S et al. Alectinib versus Crizotinib in Untreated ALK-Positive Non–Small-Cell Lung Cancer. N Engl J Med. 2017;377;9