Learning Objectives. These materials may discuss therapeutic products that have not

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1 Learning Objectives 1. Outline the molecular targets of lung cancer tumor cells and how these mutations can help direct personalized treatments. 2. Examine the types of novel targeted therapies used in advanced non small cell lung cancer (NSCLC). 3. Evaluate safety and adherence issues involved in delivering targeted therapies. 4. Using an evidence based approach, describe how the oncology nurse can improve care using targeted therapies. Disclaimer This slide deck in its original and unaltered format is for educational purposes and is current as of the date of presentation. The content and views presented in this educational activity are those of the authors/presenters and do not necessarily reflect those of Creative Educational Concepts, Inc. or the supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and offlabel 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 or strategies described in this educational activity. 1

2 NSCLC: AN OVERVIEW NSCLC Overview Epidemiology 85% of lung cancer cases Associated with smoking or non smoking history Moderate sensitivity to radiation Low sensitivity to conventional chemotherapy 50% of patients present in the metastatic setting Median overall survival <1 year Signs and Symptoms Cough Most common presenting symptom Dyspnea Chest pain Hoarseness Hemoptysis Weight loss Beckles MA, et al. Chest. 2003; Molina RJ, et al. Mayo Clin Proc. 2008; Cetin K, et al. Clin Epidemiol

3 NSCLC Overview Adenocarcinoma Most common histology 40% of all lung cancer diagnoses Indolent growth Squamous Cell Carcinoma 25% of all lung cancer diagnoses Usually linked to history of smoking Indolent growth Large Cell Carcinoma 10% of all lung cancer diagnoses Rapid growth Adenocarcinoma 40% Wahbah M, et al. Ann Diagn Pathol. 2007; small cell lung treatment pdq#section/_359. NSCLC Mutations Adenocarcinoma Histology Adapted from Chia PL, et al. Clin Epidemiol

4 EGFR MUTANT NSCLC HER Family of Receptors Gespach C, et al. Clin Cancer Res Reprinted with permission 2012 Copyright Clearance Center. All rights reserved. 4

5 HER Family of Receptors Gespach C, et al. Clin Cancer Res Reprinted with permission 2012 Copyright Clearance Center. All rights reserved. EGFR Downstream Effects Harari P, et al. Endocr Relat Cancer Reprinted with permission 2004 Copyright Clearance Center. All rights reserved. 5

6 Mutations in EGFR in NSCLC Exon 19 deletion Exon 21 L858R substitution Exon 18 deletion Exon 20 insertion G719A/S LREA deletion L858R L861X P α C A Exon 18 Exon 19 Exon 20 Exon 21 Adapted from Riely GJ, et al. Clin Cancer Res Mechanism of EGFR Resistance T790M substitution Induces steric hindrance EGFR TKI binding efficacy compromised Cataldo VD, et al. N Engl J Med Reprinted with permission 2011 Massachusetts Medical Society. All rights reserved. 6

7 Mechanism of EGFR Resistance Yu H, et al. Clin Cancer Res Molecular Testing in NSCLC National Comprehensive Cancer Network 1 The NCCN NSCLC Guidelines Panel strongly advises broader molecular profiling with the goal of identifying rare driver mutations for which effective drugs may already be available, or to appropriately counsel patients regarding the availability of clinical trials. Broad molecular profiling is a key component of the improvement of care of patients with NSCLC. CAP/IASLC/AMP 2 Guidelines recommend EGFR and ALK mutation testing before treatment with EGFR TKIs or ALK inhibitors in all patients with lung adenocarcinoma or mixed lung cancer at the time of diagnosis or recurrence, regardless of the clinical characteristics of the patient Leighl NB, et al. J Clin Oncol

8 Detecting T790M with cfdna Cells release small fragments of cell free plasma DNA (cfdna) into circulation by multiple mechanisms Cell free DNA (cfdna) includes normal and circulating tumor DNA (ctdna) Size: Average base pairs Half life: ~2 hours Diaz LA Jr, et al. J Clin Oncol Reprinted with permission 2014 American Society of Clinical Oncology. All rights reserved cfdna discovery by Mandel and Metais in 1948 Leon et al reported increased concentrations of cfdna in cancer patients; Cancer Res 1977 Stroun et al (Univ. Geneva) described possible mechanisms of cfdna release. Liquid biopsy suggested. RAS mutations were detected in the plasma of pancreatic cancer and leukemia patients. Sorenson et al CEBP 1994; Vasioukhin et al BJH Microsatellite instability was described in cfdna of cancer patients. Nowrouz et al & Chen X et al Nat Med 1996 Multiple ctdna associated alterations in oncogenes were detected in many different tumor types Monitoring tumor by serial ctdna descried in mcrc harboring an APC mutation. Diehl et al Nat Med 2008 Detection of acquired resistance using ctdna described through detection of EGFR T790M mutation in NSCLC receiving anti EGFR Kuang et al Clin Cancer Res Tumor evolution to acquire resistance described in serial ctdna monitoring of CRC. Diaz et al Nature ctdna whole genome sequencing used to describe acquired resistance and evolution of resistant subclones in breast cancer. Murtaza et al Nature 2013 Siravegna G, Bardelli A. Genome Biology

9 Detecting T790M with cfdna EGFR T790M resistance mutation typically found by tissue biopsy, however, tissue biopsy: May present risks May delay therapy May not be feasible Non invasive blood test may be preferred for detecting T790M mutation in cfdna Detecting T790M with cfdna Retrospective review by Oxnard GR, et al. 2016: 70% sensitive in the detection of T790M Similar ORR and PFS with tumor biopsy proven T790M 30% false negative rate Verify with tumor biopsy in cfdna negative patients ENSURE Phase III trial by Wu YL, et al. 2015: Lead to the first FDA approved liquid biopsy test, a companion diagnostic test for erlotinib. 214 patients who had plasma molecular testing: Specificity: 76.7% Sensitivity: 98.2% In September of 2016, the liquid biopsy test was also approved for osimertinib. Oxnard GR, et al. J Clin Oncol. 2016; Wu YL, et al. Ann Oncol. 2015; 9

10 Liquid Biopsy Non invasive Pros Cost Cons Results back in ~2 weeks Specificity is high Addresses heterogeneity of tumor and metastatic sites Helpful when there isn t sufficient tissue or when tissue biopsy cannot be performed Must collect and send to liquid biopsy company Sensitivity not as high as with tissue Not as accurate in early disease Certain chronic conditions may also increase cfdna levels Sholl LM, et al. Arch Pathol Lab Med. 2016; Jiang T, et al. Lung Cancer. 2015; Newman AM, et al. Nat Med TARGETED THERAPIES FOR EGFR MUTANT ADVANCED NSCLC 10

11 The EGFR Mutant Patient 10% Western culture/50% Asian Never smoker Women Adenocarcinoma Non mucinous Timeline of Discovery 1897 Magic Bullet Concept 1946 Nitrogen Mustard 1948 Folic Acid Antagonists Anti metabolites Analogues of DNA 1984 EGFR 1987 Erbb2 gene amplification 1997 Rituximab 1998 Trastuzumab 2001 Alemtuzumab Imatinib 2003 Gefitinib 2004 Bevacizumab Erlotinib Cetuximab 2005 Sorafenib 2006 Sunitinib Dasatinib Panitumumab 2007 Lapatinib 2009 Ofatumumab 2011 Crizotinib Ipilimumab Vandetanib 2012 Regorafenib Cabozantinib Bosutinib 2013 Afatinib 2016 Osimertinib Adapted from Strebhardt K, Ullrich A. Nat Rev Cancer. 2008; information/fda approved drugs/therapeutic area/12/oncology. 11

12 First line EGFR TKIs vs Chemotherapy Trial Treatment Mutations PFS ORR (%) NEJ002 N=114 Gefitinib vs Carbo/Pac EGFRm (absence of T790M) 10.8 months vs 5.4 months P< vs 31 P<.001 WJTOG3405 N=51 IPASS N=132 EURTAC N=86 OPTIMAL N=82 Gefitinib vs Cis/Doc Gefitinib vs Carbo/Pac Erlotinib vs standard chemo* Erlotinib vs standard chemo** N=Patients treated with TKI *Cis/Doc, Cis/Gem, Carbo/Doc, Carbo/Gem **Carbo/Gem Del19 & L858R No EGFR status required Del19 or L858R Del19 or L858R 8.4 months vs 5.3 months P< months vs 6.3 months P< months vs 5.2 months P< months vs 4.6 months P< vs 32 P< vs 47 P< vs 15 P value not reported 83 vs 36 P<.0001 Sebastian M, et al. Eur Respir Rev First line EGFR TKIs vs Chemotherapy Trial Treatment Mutations PFS ORR (%) ENSURE N=110 LUX LUNG 3 N=230 LUX LUNG 6 N=242 Independently assessed N=Patients treated with TKI Erlotinib vs Cis/Gem Afatinib vs Cis/Pem Afatinib vs Cis/Gem Del19 or L858R EGFR mutation positive EGFR mutation positive 11 months vs 5.6 months P< months vs 5.5 months P< months vs 6.9 months P= months vs 6.7 months P= months vs 5.6 months P< months vs 5.6 months P< vs 34 P= vs 23 P= vs 44 P= vs 23 P< vs 31 P value not reported Sebastian M, et al. Eur Respir Rev

13 Decision to Treat with EGFR Therapy NCCN Guidelines Version FIRST LINE THERAPY SUBSEQUENT THERAPY Sensitizing EGFR mutation positive EGFR mutation discovered prior to first line chemotherapy EGFR mutation discovered during first line chemotherapy Erlotinib (category 1) or Afatinib (category 1) or Gefitinib (category 1) *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. NOTE: All recommendations are category 2A unless otherwise indicated Asymptomatic T790M testing if Complete progression* planned chemotherapy, including maintenance Symptomatic therapy, or interrupt, followed by erlotinib or afatinib or gefitinib Brain Systemic Isolated lesion Multiple lesions 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 T790M+ T790M 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 Adapted from: EGFR Tyrosine Kinase Inhibitors Gefitinib (1 st Generation) Erlotinib (1 st Generation) Afatinib (2 nd Generation) MOA Indications/ Dosage Dose Adjustments Metastatic NSCLC with EGFR exon 19 deletion or exon 21 L858R substitution mutations (first line): 250 mg PO once daily Renal: No recommendation; minimal renal excretion Hepatic: Withhold in worsening liver dysfunction; discontinue in severe hepatic impairment Strong CYP3A4 inducers: Increase to 500 mg PO daily Reversible inhibition of EGFR Metastatic NSCLC with EGFR exon 19 deletion or exon 21 L858R substitution mutations (first line): 150 mg PO once daily Renal: Hold treatment for grade 3/4 renal toxicity or consider discontinuation Hepatic: Hold or discontinue for bilirubin >3x ULN and/or transaminases >5x ULN Concomitant CYP3A4/CYP1A2 inhibitors or 3A4 inducers Concomitant smoking induces metabolism Highly selective irreversible blocker of EGFR, HER2, and HER4 Metastatic NSCLC with EGFR exon 19 deletion or exon 21 L858R substitution mutations (first line): 40 mg PO once daily Renal o CrCl ml/min 30 mg PO once daily o CrCl <15 ml/min Not studied; avoid use in CrCl <15 ml/min Hepatic: Withhold for >grade 3 hepatic dysfunction and reduce by 10 mg upon improvement to <grade 1 FDA Prescribing Information. 13

14 EGFR Tyrosine Kinase Inhibitors Gefitinib (1 st Generation) Erlotinib (1 st Generation) Afatinib (2 nd Generation) Common: Acneiform rash, diarrhea, fatigue, anorexia, paronychia Common: Acneiform rash, diarrhea, fatigue, anorexia, cough, dyspnea, paronychia Common: Acneiform rash, paronychia, pruritus, diarrhea, decreased appetite, stomatitis Adverse Effects Serious: GI perforation, bleeding events, cardiac events, severe skin reactions, hepatotoxicity, pulmonary toxicity Emetic Potential: Minimal (<10%) Serious: GI perforation, bleeding events, cardiac events, severe skin reactions, hepatotoxicity, pulmonary toxicity Emetic Potential: Minimal (<10%) Serious: Cardiovascular toxicity (decreased LVEF), cutaneous reactions, diarrhea/stomatitis, hepatotoxicity, keratitis, pulmonary toxicity Emetic Potential: Minimal (<10%) Drug/Food Interactions Substrate of BCRP, CYP2D6, CYP3A4 Inhibits BCRP, CYP2C19, CYP2D6 Administer with or without food Substrate of CYP1A2 (minor) and CYP3A4 (major) Administer 1 hour before or 2 hours after a meal (empty stomach) Substrate & inhibitor of BCRP and P gp Administer 1 hour before or 2 3 hours after a meal (empty stomach) Monitoring EGFR mutation status; LFTs and renal function, electrolytes, other signs of toxicity EGFR mutation status; LFTs and renal function, electrolytes, other signs of toxicity EGFR mutation status; LFTs and renal function, skin toxicity, diarrhea FDA Prescribing Information; Efficacy Among First line EGFR TKIs CTONG0901 Erlotinib vs gefitinib in EGFR TKI naïve and EGFR TKI progressive patients with exon 19 or 21 EGFR mutations No statistically significant difference in PFS or OS Similar toxicity profiles Erlotinib and gefitinib were both superior in exon 19 mutation patients in terms of ORR (62.2% vs 43.5%; P=.003) and OS (22.9 months vs 17.8 months; P=.022) WJOG5108L Erlotinib vs gefitinib in EGFR TKI naïve patients with EGFR mutations No statistical difference in PFS, ORR, or OS between the two groups Toxicities were similar among both groups Yang J, et al. Br J Cancer. 2017; Urata Y, et al. J Clin Oncol

15 Efficacy Among First line EGFR TKIs LUX LUNG 7 Afatinib vs gefitinib EGFR TKI naïve patients with EGFR sensitizing mutations Median PFS TTF Median OS Gefitinib 10.9months P=.017 Afatinib 11months 11.5 months 13.7 months P= months 27.9 months P=.258 However, there were significantly more toxicities with afatinib when compared to gefitinib Paz Arez, L et al. Ann Oncol Resistance to EGFR Therapy Eventually Happens Median PFS 10.8 vs 5.4 months Maemondo M, et al. N Engl J Med Reprinted with permission 2010 Massachusetts Medical Society. All rights reserved. 15

16 Third Generation EGFR Inhibitor Osimertinib Selective for resistant/mutant forms of EGFR over wild type (~200 times greater potency) Also inhibits HER2, HER3, HER4 FDA accelerated approval in 2015 Treatment of metastatic EGFR T790M mutation positive NSCLC After progression on or after EGFR TKI therapy Dose: 80 mg once daily Cross D, et al. Cancer Discov. 2014; FDA Prescribing Information. Osimertinib (AZD9291) Progression Free Survival by T790M Jänne PA, et al. N Engl J Med Reprinted with permission 2015 Massachusetts Medical Society. All rights reserved. 16

17 Osimertinib vs Chemotherapy in T790M Mok T, et al Recent phase 3 study comparing osimertinib to platinumpemetrexed in T790M patients who progressed while on first line EGFR TKI therapy. Intent to Treat Population Patients with CNS Metastases No. of Patients Median PFS mo (95% CI) No. of Patients Median PFS mo (95% CI) Osimertinib ( ) Platinumpemetrexed ( ) Osimertinib ( ) Platinumpemetrexed ( ) Mok T, et al. N Engl J Med EGFR TKI TOXICITIES 17

18 Toxicities of EGFR TKI Therapy All Grade Adverse Events Percentage of Patients Experiencing (%) NR 29 Afatinib NR Erlotinib NR=Not Reported Compiled from FDA Prescribing Information; current as of September Toxicities of EGFR TKI Therapy All Grade Adverse Events Percentage of Patients Experiencing (%) Gefitinib 47 7 NR NR 5 NR 42 Osimertinib NR=Not Reported Compiled from FDA Prescribing Information; current as of September

19 Toxicities of EGFR TKI Therapy >Grade 3 Adverse Events Percentage of Patients Experiencing (%) NR 4 Afatinib NR Erlotinib 8 <1 0 <1 < NR=Not Reported Compiled from FDA Prescribing Information; current as of September Toxicities of EGFR TKI Therapy >Grade 3 Adverse Events Percentage of Patients Experiencing (%) Gefitinib NR NR 0.1 NR Osimertinib NR=Not Reported Compiled from FDA Prescribing Information; current as of September

20 ROLE OF THE ONCOLOGY NURSE NCI CTCAE Grading Guideline Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Mild Moderate Severe or medically significant but not immediately lifethreatening Life threatening consequences Death Asymptomatic or mild symptoms; Clinical or diagnostic observations only; Intervention not indicated Minimal, local or noninvasive intervention indicated; Limiting ageappropriate instrumental ADL Hospitalization or prolongation of hospitalization indicated; Disabling; Limiting selfcare ADL Urgent intervention indicated Death related to AE Instrumental ADL preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. Self Care ADL bathing, dressing and undressing, feeding self, using the toilet, taking medications and not bedridden _QuickReference_5x7.pdf. 20

21 EGFR Inhibitor Rash EGFRs are present in follicular epithelium, sebaceous glands, and dermal capillaries, explaining the skin toxicities seen with EGFR TKIs. Generally presents on face, scalp, chest and back Can range from mild to severe Hirsh V. Curr Oncol Grading Tools for EGFR Rash The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) is typically used for clinical trial grading of adverse events. The Multinational Association of Supportive Care in Cancer (MASCC) has published the EGFR Inhibitor Toxicity Tool (MESTT), as an event specific grading system that can be used to standardize assessment, optimize the use of EGFR inhibitors and enable researchers to conduct more informative, controlled studies. 21

22 NCI CTCAE Rash Grading Scale Rash acneiform* *A disorder characterized by an eruption of papules and pustules, typically appearing on face, scalp, upper chest, and back Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Papules and/or pustules covering <10% BSA, which may or may not be associated with symptoms of pruritus or tenderness Papules and/or pustules covering 10 30% BSA, which may or may not be associated with symptoms of pruritus or tenderness; associated with psychosocial impact; limiting to instrumental ADL Papules and/or pustules covering >30% BSA, which may or may not be associated with symptoms of pruritus or tenderness; limiting self care ADL; associated with local superinfection, with oral antibiotics indicated Papules and/or pustules covering any % BSA, which may or may not be associated with symptoms of pruritus or tenderness; associated with extensive superinfection, with IV antibiotics indicated; lead to life threatening consequences Death _QuickReference_5x7.pdf. MASCC Rash Grading Scale Papulopustular eruption (Grading individually for face, scalp, chest, or back) Grade 1 Grade 2 Grade 3 1A: Papules or pustules <5 OR 1 area of erythema or edema <1 cm in size 1B: Papules or pustules <5 OR 1 area of erythema or edema <1 cm in size AND pain or pruritus 2A: Papules or pustules 6 20 OR 2 5 areas of erythema or edema <1 cm in size 2B: Papules or pustules 6 20 OR 2 5 areas of erythema or edema <1 cm in size AND pain, pruritus or effect on emotions or functioning 3A: Papules or pustules >20 OR >5 areas of erythema or edema <1 cm in size 3B: Papules or pustules >20 OR >5 areas of erythema or edema <1 cm in size AND pain or pruritus or effect on emotions or functioning Lacouture ME, et al. Support Care Cancer

23 EGFR Inhibitor Rash Can present as early as 2 weeks into treatment. Patient should be evaluated for rash weekly during the first six weeks of treatment. An assessment of oral adherence should occur regularly throughout the entire course of treatment. Patients should be counseled on the prevalence of rash and its link to drug efficacy. Rash can be debilitating for patients and potentially lead to adherence issues. Therefore, prevention strategies must be discussed. Hirsh V. Curr Oncol MASCC Rash Prevention and Treatment Guidelines Preventive Topical Systemic Treatment Topical Systemic Recommended Hydrocortisone 1% cream with moisturizer and sunscreen BID Minocycline 100 mg daily Doxycyline 100 mg BID Alclometasone 0.05% cream Fluocinonide 0.05% cream BID Clindamycin 1% Doxycycline 100 mg BID Minocycline 100 mg daily Isotretinoin at low doses (20 30 mg/d) Not Recommended Pimecrolimus 1% cream Tazarotene 0.05% cream Sunscreen as single agent a EGFR inhibitor study MASCC = Multinational Association of Supportive Care in Cancer Level of Evidence II a Recommendation Grades Tetracycline 550 mg BID II a A Vitamin K1 Cream IV a C Acitretin IV a C C Comments Doxycycline is preferred in patients with renal impairment. Minocycline is less photosensitizing. Fluocinonide 0.05% cream BID should not be used on the face for more than 2 weeks at a time. Isotretinoin is photosensitizing and can cause xerosis. Monitor lipids and liver enzymes with retinoids. Lacouture ME, et al. Support Care Cancer

24 Paronychia With EGFR Inhibitors Wear comfortable shoes Trim nails without aggressive manicuring in order to avoid micro abrasions that may lead to infection Wear gloves while cleaning Inflammation topical corticosteroids or tetracycline Excessive tissue granulation electrocautery, silver nitrate and nail avulsion If infection occurs, tissue must be cultured in order to guide antibiotic therapy Lacouture ME, et al. Support Care Cancer Schirmer Test for Dry Eye Used to determine whether the eye produces enough tears to keep it moist. The test is performed by placing filter paper inside the lower lid of the eye. After a few minutes, the paper is removed and the length of the paper that has become wet is measured. 24

25 Diarrhea Most likely to occur within 4 weeks of therapy initiation. Patient should be evaluated weekly during this time. Important to rule out other causes (other medications, diet, etc.) May lead to reduced adherence, nutritional deficiencies, and decreased quality of life. Hirsh V. Curr Oncol NCI CTCAE Diarrhea Grading Scale Diarrhea Grade 1 Grade 2 Grade 3 Grade 4 Increase of <4 stools per day over baseline Increase of 4 6 stools per day over baseline Increase of >7 stools per day over baseline Incontinence Hospitalizatio n indicated Limits selfcare activities of daily living Lifethreatening consequences Urgent intervention needed _QuickReference_5x7.pdf. 25

26 Non Pharmacological Strategies for Diarrhea Diet BRAT diet (bananas, rice, apple sauce, toast) Remove greasy, spicy and fried foods Fluid 3 4 L/day to prevent dehydration Potentially probiotics Hirsh V. Curr Oncol Management of Diarrhea Example Protocol from Memorial Sloan Kettering Cancer Center Severity (CTCAE v.4) Grade 1 in absence of nausea, vomiting, fever, neutropenia or dehydration Grade 2 in absence of nausea, vomiting, fever, neutropenia or dehydration Grade 3 4or Grade 1 2 with one of the following symptoms: nausea, vomiting, fever, neutropenia or dehydration Intervention Continue drug at current dose and monitor for change in severity Initiate loperamide (4 mg x 1, then 2 mg q 4 6 hrs) Discontinue lactose containing products, alcohol, supplements, caffeine Drink 8 10 glasses of fluid Eat small, frequent, light meals Consider treatment protocol recommendations Reassess after hours; if diarrhea worsen or do not improve proceed to next step When diarrhea resolves, continue drug at same dose Discontinue loperamide after 12 hours diarrhea free interval If intolerable, hold drug until diarrhea resolves and monitor for change in severity Continue loperamide 2 mg every 4 6 hrs Add diphenoxylate/atropine 2.5 mg every 6 hours, consider Tincture of Opium 6 mg QID Reassess after hours; if reactions worsen or do not improve proceed to next step; Refer to clinic or UCC When diarrhea resolves, restart study drug at same dose and continue dietary modification Hold drug and monitor for change in severity Continue loperamide 2 mg every 6 hrs and dietary/hydration recommendations Add diphenoxylate/atropine 2.5 mg every 6 hours, consider Tincture of Opium 6 mg QID Refer to clinic or ER for IV hydration and evaluation If diarrhea worsens or do not improve admit to hospital for management When diarrhea resolves, restart study drug at reduced dose, consider prophylactic antidiarrheal use and continue dietary modifications 26

27 Drugs don t work if people don t take them. C. Everett Koop, Former US Surgeon General Definitions Adherence/Compliance Adherence is preferred but both terms are imperfect, and, unfortunately, can stigmatize patients Definitions of adherence World Health Organization the extent to which a patient s behavior corresponds with agreed recommendations from a health care provider International Society for Pharmacoeconomics and Outcomes Research the degree or extent of conformity to the recommendation about day to day treatment by the provider with respect to the timing, dosage, frequency and duration of time from the initiation to discontinuation of therapy. Adherence is often defined to be taking 80% or more of a medication as prescribed This is an arbitrary number Adherence is impacted by multiple factors Cramer JA, et al. Value Health. 2008; 27

28 Shift to Oral Cancer Treatments Advantages Patient convenience No need for IV access Can achieve sustained drug levels Minimal disruption in daily life Patient preference Disadvantages Distances patient from provider Changes the way patients are monitored Safeguards for prescription or administration may be lacking Patients have more responsibility for their own care Adherence to Oral Chemotherapy Reminder Triggers Pill boxes (traditional/electronic), diaries Event reminders (eg, take medications together, take with meals) Cell phones/alarms Symptom Management Provider Support and Surveillance Weekly phone calls Refill reminder postcard Notify caregiver of patient concerns Referral to counselor Support group Patient assistance program Schneider SM, et al. Semin Oncol Nurs

29 Role of the Oncology Nurse in Palliative Care Oncology nurses have the responsibility to encourage planning and informed choices based on the needs and values of patients. Oncology nurses are in a unique position to advocate for patients regarding access to and delivery of quality palliative care. Studies have shown that cancer patients benefit from early palliative care Temel JS, et al 151 patients with metastatic NSCLC. Those with early palliative care had a better quality of life, less depression and a longer median survival than those in the control standard care group. Temel JS, et al. N Engl J Med. 2010; policy/positions/practice/palliative care. Future Generation EGFR Inhibitors EGF816 NCT , NCT , NCT , NCT ASP8273 NCT , NCT , NCT , NCT , NCT AC0010 NCT , NCT , NCT , NCT

30 Abbreviations AE = Adverse Event ALK = Anaplastic lymphoma kinase APC = Adenomatous polyposis coli gene BID = Twice daily BP = Base pairs BRCP = Breast cancer resistance protein cfdna = Cell free DNA CRC = Colorectal cancer CrCl = Creatinine clearance CT = Computed tomography CTCAE v.4 = Common Terminology Criteria for Adverse Events version 4.0 ctdna = Circulating tumor DNA CYP = Cytochrome P450 D = Day EGFR = Epidermal growth factor receptor ER = Emergency room FDA = Food and Drug Administration GI = Gastrointestinal HER = Human epidermal growth factor receptor IHC = ImmunoHistoChemistry IV = Intravenous KRAS = Kristen Rat Sarcoma LFTs = Liver function tests LLL = Left lower lobe LN = Lymph node LVEF = Left ventricular ejection fraction Abbreviations mab = Monoclonal antibody MASCC = Multinational Association of Supportive Care in Cancer mcrc = Metastatic colorectal cancer Mets = Metastasis Mg = Milligram ml/min = Milliliters per minute MRI = Magnetic Resonance Imaging NCCN = National Comprehensive Cancer Network NR = Not reached NSAID = Non steroidal antiinflammatory drug NSCLC = Non small cell lung cancer ORR = Objective response rate PET = Positron emission tomography PFS = Progression free survival PgP = P glycoprotein PO = By mouth Q = Every QID = Four times daily RAS = Renin angiotensin system gene RT = Radiation therapy SUV = Standardized uptake value TKI = Tyrosine kinase inhibitor TTF = Time to Treatment Failure TTF 1 = Thyroid transcription factor 1 UCC = Urgent care center ULN = Upper limit of normal 30