CLINICAL UPDATE ON EGFR-MUTATED NSCLC

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2 Disclaimer This slide deck in its original and unaltered format is for educational purposes and is current as of March The content and views presented in this educational activity are those of the authors and do not necessarily reflect those of Creative Educational Concepts or the supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or employing any therapies described in this educational activity.

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4 CLINICAL UPDATE ON EGFR-MUTATED NSCLC Val R. Adams, PharmD, FCCP, BCOP Associate Professor of Pharmacy Practice and Science Program Director, PGY2 Specialty Residency Hematology/Oncology University of Kentucky College of Pharmacy Lexington, KY

5 Percent Lung Cancer Percent of Cases by Stage 5% 16% Localized (16%) Confined to Primary Site 100% 80% 5-Year Relative Survival 57% 22% Regional (22%) Spread to Regional Lymph Nodes Distant (57%) Cancer Has Metastasized Unknown (5%) Unstaged 60% 40% 20% 0% 55.2% 28.0% 4.3% 7.4% Localized Regional Distant Unstaged Stage

6 Merging Pieces Targeted Therapies Chemotherapy Lung Cancer Immuno-oncology Changing Biology

7 Walgren RA, et al. J Clin Oncol

8 LARGE CELL CARCINOMA Never Smoker Smoker OTHER OR UNSPECIFIED Never Smoker Smoker SQUAMOUS CELL CARCINOMA Never Smoker Smoker ADENOCARCINOMA SMALL-CELL CARCINOMA Smoker Never Smoker Kenfield SA, et al. Tob Control

9 Targetable Mutations Lung Adenocarcinomas Squamous Cell (20%) Large Cell (10%) Adenocarcinoma (70%) NSCLC Heterogeneity KRAS (30%) Unknown (42%) The Fortunate Few EGFR (15%) MEK (1%) Harris T, et al. Discovery Medicine EML4-ALK (5%) HER2 (2%) FGFR4 (2%) BRAF (2%) PIK3CA (1%)

10 Evolving Biology Adenocarcinoma Percent of Lung Cancer from non-smokers Identified EGFR or ALK driven tumors Adenocarcinoma Non-smokers Treatments for EGFR and ALK Meza R, et al. PLoS One. 2015; Köhler J. Frontiers in Medicine

11 First-Line Treatment for Advanced Disease Lung Cancer Biomarkers Histology SCLC NSCLC PD-L1 EGFR ALK None SCLC=Small Cell Lung Cancer; NSCLC=Non-Small Cell Lung Cancer; Squam=Squamous cell histology Non-Squam=All non-squamous cell histologies (most commonly adenocarcinoma) Squam Non- Squam

12 Patient Case SJ is a 61 yo WF who presents with NSCLC HPI: After failing antibiotics a CXR revealed a left lower lobe mass FNA confirmed adenocarcinoma of the lung PMH: N/A FH/SH: Married w/ two sons 28 and 34 (none smoker) Drug History: NKDA PE: Findings consistent with lung cancer otherwise WNL (PS 0-1) Labs: Hepatic, renal, and chemistry levels WNL Radiology: Multiple lesions in the liver stage IV Genetics: KRAS WT, EGFR exon 19 deletion, no ALK rearrangement

13 Progression-free survival (%) OPTIMAL: First-line Erlotinib is Associated with Longer PFS vs. G/C in EGFR Mutant NSCLC OPTIMAL = Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive NSCLC Erlotinib (N=82) Gemcitabine plus carboplatin (N=72) HR 0.16 (95% CI ) Log-rank P< Time (months) Number at risk Erlotinib Gemcitabine + carboplatin G/C = Gemcitabine/Carboplatin Zhou C, et al. Lancet Oncol

14 Progression-Free Survival (Probability) LUX-Lung 3: PFS Favored Afatinib Afatinib Cisplatin/pemetrexed Median (months) HR, 0.58; 95% CI, 0.43 to 0.78, P< No. at risk Afatinib Cisplatin/pemetrexed Time (months) Independent review Intent to Treat Sequist LV, et al. J Clin Oncol

15 Probability of Progression-free Survival IPASS Trial: PFS Favored Gefitinib EGFR-Mutation-Positive Hazard ratio, 0.48 (95% CI, ) P<.001 Events: Gefitinib, 97 (73.5%) Carboplatin plus paclitaxel, 111 (86.0%) Carboplatin plus paclitaxel Gefitinib 0.0 No. at Risk Gefitinib Carboplatin plus paclitaxel Months since Randomization Mok TS, et al. N Engl J Med

16 First-Line Gefitinib, Afatinib or Erlotinib? Afatinib Erlotinib Gefitinib Improvement in PFS vs. chemo 4.2 months 4.5 months 3.5 months Response rate 56% 58% 67% Activity in T790 mutant clones Common Grade 3 or 4 toxicity Rash 16% 13% 3% Diarrhea 14% 5% 4% Fatigue 1% 6% < 1% P-gp substrates EGFR binding Irreversible Reversible Reversible Food effect (take on empty stomach) AUC=Area under the curve; F=Bioavailability Decrease AUC by 39% Increase F from ~60% to ~100% No change FDA Prescribing Information; Sequist LV, et al. J Clin Oncol. 2013; Rossell R, et al. Lancet Oncol. 2012; Mok TS, et al. N Engl J Med

17 Osimertinib FDA accelerated approval based on 2 single arm open label trials NSCLC patients with an EGFR mutation (T790M) EGFR testing was performed with the FDA approved companion diagnostic EGFR mutation test Dose determined to be 80mg PO daily

18 Best Percentage Change from Baseline in Target-Lesion Size Osimertinib Efficacy D*D* D D D D DDDD DD D D 20 mg 40 mg 80 mg 160 mg 240 mg DD DDD D D D D D DD D D D D D D D D EGFR T790M detected in 62% of patients, negative in 28%, unknown in 10% Overall Response Rate = 51% - Median PFS = 9.6 months Jänne PA, et al. N Engl J Med

19 Osimertinib vs. Chemotherapy - AURA3 Mok TS, et al. N Engl J Med

20 Tissue for Genetic Testing Since this an acquired mutation it requires repeat T790M analysis. FDA approved liquid biopsy test (a companion diagnostic test for osimertinib) can be performed with plasma and there is a correlative process for tissue. Note: circulating plasma DNA for testing can be below the limit of detection. Hence a follow-up tissue biopsy might occur. Oxnard GR, et al. J Clin Oncol. 2016; Mok T, et al. N Engl J Med. 2017; Wu YL, et al. Ann Oncol. 2015; FDA Prescribing Information;

21 Resistance to EGFR TKIs Nguyen KH, et al. Clin Lung Cancer

22 First Line Osimertinib? Pooled data from two Phase I expansion cohort studies with 80 or 160mg PO daily look promising N=60 Median PFS=19.3 mo (95% CI 13.7 NC) Confirmed ORR=77% (95% CI 64 87) Disease control rate=97% (95% CI ) Dose reduction 80mg=10%; 160 mg = 47% Most common toxicity=diarrhea, stomatitis, and paronychia (at 80 mg, no grade 3 or 4) Ramalingam S, et al. European Lung Cancer Conference. Abstract LBA1_PR

23 Osimertinib Toxicity At the approved dose of 80mg - 79% had a drug related AE. The most common: diarrhea (33%), rash (32%), nausea (18%), pruritus (17%), constipation (17%), and decreased appetite (16%) Grades 3-5 were uncommon: Dyspnea 1%, Anemia 3%, Decreased appetite 1%, Diarrhea 1% Janne PA, et al. N Engl J Med

24 Individualized NSCLC Therapy Has Arrived, Now What? Current Role and Future Opportunities for Specialty Pharmacy and Managed Care Philip Schwieterman, PharmD, MHA Pharmacy Director Oncology and Infusion Pharmacy UK HealthCare and Markey Cancer Center Lexington, KY

25 Cost and Utilization Trends Spending on Oncology Medicines (US $ Bn) Monoclonal Antibodies Protein Kinase Inhibitors Other Targeted Therapies Cytotoxics

26 Monthly and Median Costs of Cancer Drugs Monthly and Median at the Costs Time of Cancer of FDA Drugs Approval at the Time of FDA ( ) Approval Monthly Cost of Treatment (2014 Dollars, log scale) $ $10000 $1000 $100 $10 $ Year of FDA Approval Individual Drugs Median Monthly Price (per 5 year period) Source: Peter B. Bach, MD, Memorial Sloan-Kettering Cancer Center.

27 Aligning Cost and Care Delivery Reimbursement Models Bundled/ Capitated Payments Patient Centered Oncology Payments CMS Proposed Part B Model CMS Oncology Care Model Care Delivery Models Affordable Care Act Quality Oncology NCCN Value Practice Pathways Initiative ASCO Value Framework ICER

28 Costs and Savings in Oncology Care Savings Offset Additional Payments Under Patient-Centered Oncology Payment (PCOP) $ Hospital Admits ED Visits Testing PCOP Savings Hospital Admits ED Visits Testing Payer Receives Net Savings Oncology Practice Reduces Avoidable Hospital Admissions Drug Costs Drug Costs Oncology Practice Follows Appropriate Use Criteria for Drugs, Tests, and Imaging Care Mgt Current Practice Services Other Revenue Infusion E&M Care Mgt Current Practice Services Other Revenue Care Mgt New Patient Infusion E&M Oncology Practice Receives Higher Payments Than Today for Costs of Existing and New Services COSTS PAYMENT COSTS PAYMENT

29 The Cost of Poor Adherence Improve Care Coordination Enhance Patient Engagement and Education Utilize Counseling and Medication Management Expand Screening and Assessment Invest in HIT Infrastructure Employ Quality Measurement Establish Financial Incentives

30 A Factor of Poor Adherence

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32 Specialty Pharmacies The Rise of Health System Specialty Pharmacy The Benefits 35 URAC Accredited Health-System Specialty Pharmacies Integrates components of Accountable Care Organizations Mitigates multiple redundancies 20 Shared health records 15 Support both Rx and Medical Coverage Adherence rates higher* Quicker access to therapy Jul-10 July-12 August-15 January-17 8 Location, Location, Location *Hanson RL, et al. Am J Health Syst Pharm. 2014;

33 Adherence Chemotherapy Double Checks Infusion Coordination Pharmacist s Role in the Oncology Patient Care Team Oral Chemotherapy Programs Dose Optimization Toxicity Management Pharmacist Prior Authorization Support Nausea / Vomiting Free Drug Programs Pain Management Biosimilars

34 Health System Daily Pharmacist Model Clinical Trials and Precision Medicine Resident/ Students (11) Oral Chemo (2) Clinic (7) Inpatient Clinical (3) Infusion (3) (2) UK HealthCare Inpatient Ops (3) (Number of Pharmacists)

35 Aiming for Optimal Patient Outcomes Case-based Treatment Strategies Josiah D. Land, PharmD, BCOP Clinical Pharmacy Specialist Thoracic Medical Oncology Team Memorial Sloan Kettering Cancer Center New York, NY

36 Patient DD May 2014: 63 yo AAF with recent diagnosis of lung cancer presents to the thoracic oncology clinic for treatment options HPI: December 2013: chest pain related to moving furniture attributed to musculoskeletal in nature March 2014: continued chest pain not relieved by prn naproxen further workup by PCP

37 Patient DD: Workup CT chest: 4.5 x 4.1 x 4.1 cm RUL mass encasing RUL bronchus and abutting distal trachea+ RUL/RML nodules PET scan: RUL hypermetabolic mass + multiple RUL satellite nodules + bony metastasis to sternum + pleural implant + FDG avid small pleural effusion CT Head: NED RUL mass biopsy Primary lung adenocarcinoma: CK7+/TTF-1+/Napsin A+/P63+/CK20- Molecular Pathology: +EGFR exon 21 L858R substitution mutation

38 Patient DD PMH: none PSH: lipoma removal Allergies: NKDA SH: never smoker, rare EtOH, married x 41 years, 2 adult children FH: father (alive) prostate cancer; paternal grandmother (deceased) head/neck cancer Health Maintenance 2013: GYN exam WNL 2/2014: mammogram WNL Home Medications Naproxen 250 mg BID prn Ibuprofen 400 mg PO Q4H prn

39 Patient DD Diagnosis: Stage IV EGFR mutant lung adenocarcinoma metastatic to bone and pleura Treatment Decision(s)

40 NCCN Guidelines Version FIRST-LINE THERAPY Sensitizing EGFR mutation positive EGFR mutation discovered prior to first-line chemotherapy Erlotinib (category 1) or Afatinib (category 1) or Gefitinib (category 1) Progression See Subsequent Therapy (NSCL-19) EGFR mutation discovered during first-line chemotherapy Complete planned chemotherapy, including maintenance therapy, or interrupt, followed by erlotinib or afatinib or gefitinib Adapted from:

41 Patient DD: Treatment Course 6/12/14: initiated Erlotinib 150 mg PO daily 7/28/14: partial response in lung, pleura, bone 11/7/14: continued response in lung, lymph nodes, pleura 2/ /2016: stable disease 12/2016: CT CAP shows POD in RUL primary lesion, increased pleural disease, new osseous lytic mets in pelvis Treatment Decision

42 Assess Adherence! Drugs don t work if people don t take them. C. Everett Koop, Former US Surgeon General

43 NCCN Guidelines Version Progression* T790M testing** Asymptomatic Symptomatic Brain Systemic *Beware of flare phenomenon in subset of patients who discontinue EGFR TKI. If disease flare occurs, restart EGFR TKI. **If tissue biopsy is not feasible, plasma biopsy should be considered. Consider reflex to tissue-based testing, if plasma test is negative for the T790M mutation. Isolated lesion Multiple lesions T790M+ T790M- SUBSEQUENT THERAPY Consider local therapy Osimertinib (if T790M+) (Category 1) or Continue erlotinib or afatinib or gefitinib Consider local therapy Osimertinib (if T790M+) (Category 1) or Continue erlotinib or afatinib or gefitinib Consider local therapy Continue erlotinib or afatinib or gefitinib or See subsequent therapy for multiple lesions, below Progression Osimertinib (Category 1), if not previously given See first-line therapy options for adenocarcinoma and squamous cell carcinoma or PD-L1 expression positive (>50%), see first-line therapy See subsequent therapy for multiple lesions, below See subsequent therapy for multiple lesions, below Adapted from:

44 Patient DD: Treatment Course 1/4/2017: inpatient admission for sacral canal cord compression Medically managed with supportive care/radiation oncology ctdna pending for T790M status prior to admission 1/14/2017: ctdna positive for EGFR T790M resistance mutation Treatment Decision Osimertinib 80 mg once daily

45 Patient DD: Wrap Up 1/17/2017: patient initiated Osimertinib 80 mg PO once daily Patient counseling: Most common side effects: diarrhea, rash, nail changes, dry skin Can be taken with or without food Medication is restricted to a specialty pharmacy, patient and family must increase vigilance with regard to ongoing refills Follow-up with thoracic medical oncology

46 Financial Toxicity? Patient Perspective

47 Potential Financial Timeline Date Therapy(s) Age Insurance 5/2014 Oncology referral and workup 63 Commercial Plan Medication Therapy Out of Pocket Expenses Deductible, Premiums, Copays, Co-Insurance 6/2014 Erlotinib 63 Commercial Plan Tier 4 ($250/mo) 3/2015 Erlotinib 64 Commercial Plan Copay Card ($25/mo) 9/2015 Erlotinib 65 Medicare A, B, and D 1/2016 Erlotinib 66 Medicare A, B, and D 1/2017 Osimertinib 67 Medicare A, B, and D Coverage Gap ($3,000) Catastrophic Coverage Foundation Support available ($4,000) New Plan Year Foundation Support?