Phase 2: RCT Results Sample Demographics Mean (SD) or N (%) From 2/13/15 - 12/31/16, Age Mean (SD) 53.5 (12.9) we enrolled and Female 94 (53.6) randomized 181 patients Race in a trial comparing oral Caucasian 159 (87.8) chemotherapy mobile Asian 10 (5.5) African American 5 (2.8) app to usual care . Hispanic/Latino/a 4 (2.2) Multiracial 2 (1.1) At baseline, 22% of • Other 1 (0.6) patients reported either Ethnicity forgetting or having Hispanic 4 (2.2) problems remembering Cancer Type Hematologic 60 (33.1) to take oral Lung 33 (18.2) chemotherapy Brain 26 (14.4) Breast 26 (14.4) medication in past week. Other 36 (19.9)
Phase 2: Baseline Symptoms Symptom % Fatigue 88.7 Symptoms reported on Drowsy 76.8 baseline MD Anderson Disturbed Sleep 68.8 Symptom Inventory Memory Problems 63.4 Distressed/Upset 61.7 (MDASI) Dry Mouth 51.1 Feeling Sad 48.6 Numbness/Tingling 47.9 Pain 44.6 Appetite Problems 43.0 Shortness of Breath 38.7 Nausea 37.6 Vomiting 13.4
Phase 2: RCT Results Outcomes by Study Group in Overall Sample Outcome Measure Usual Care Mobile App P- % or M (SE) % or M (SE) value Self-Report Adherence (MMAS) 76.7% 86.2% .19 Pill Bottle/Cap Adherence (MEMS) 79.2% 81.5% .57 Change in Symptom Severity (MDASI) 0.08 (0.15) -0.30 (0.15) .60 Change in Quality of Life (FACT-G) -1.93 (1.13) 0.49 (1.19) .14 Physical Wellbeing 0.11 (0.23) 0.81 (0.48) .29 Social Wellbeing -2.22 (0.50) -0.55 (0.53) .03 Emotional Wellbeing 0.53 (0.40) 0.04 (0.41) .39 Functional Wellbeing -0.40 (0.41) 0.35 (0.43) .22 Change in Satisfaction with Care (FACIT-TS) Explanations -0.34 (0.19) 0.04 (0.20) .17 Interpersonal -0.29 (0.13) 0.07 (0.13) .06 Comprehensiveness -0.89 (0.49) 0.08 (0.52) .18 Trust -0.24 (0.12) -0.24 (0.13) .97
Phase 2: RCT Results MEMS Adherence Moderated by Baseline Self- Reported Adherence
Phase 2: RCT Results Outcomes by Study Group in Patients with Poor Self- Reported Adherence at Baseline (N=35) Outcome Measure Usual Care Mobile App P- % or M (SE) N (%) or M (SE) value Pill Bottle/Cap Adherence (MEMS) 63.9% 86.2% .03 Change in Symptom Severity (MDASI) 0.05 (0.29) -0.04 (0.34) .84 Change in Quality of Life (FACT-G) -2.70 (2.48) 1.36 (3.04) .31 Physical Wellbeing -0.85 (0.97) 1.46 (1.18) .14 Social Wellbeing -1.69 (0.90) -0.53 (1.11) .42 Emotional Wellbeing 0.14 (0.74) -0.001 (0.90) .90 Functional Wellbeing -0.30 (0.81) 0.43 (0.99) .57 Change in Satisfaction with Care (FACIT-TS) Explanations -0.76 (0.45) 0.93 (0.56) .03 Interpersonal -0.29 (0.14) -0.001 (0.18) .22 Comprehensiveness -1.46 (1.01) 1.15 (1.24) .11 Trust -0.43 (0.25) -0.14 (0.31) .48
Phase 2: RCT Results MEMS Adherence Moderated by Baseline Self- Reported Anxiety Symptoms (HADS-Anxiety>7)
Phase 2: RCT Results Outcomes by Group in Patients with Anxiety (N=46) Outcome Measure Usual Care Mobile App P- % or M (SE) % or M (SR) value Self-Report Adherence (MMAS) 68.0% 95.7% . 047 Pill Bottle/Cap Adherence (MEMS) 69.4% 85.5% .044 Change in Symptom Severity (MDASI) 0.02 (0.33) -0.30 (0.36) .52 Change in Quality of Life (FACT-G) -4.56 (2.37) 2.28 (2.60) .06 Physical Wellbeing -0.27 (0.82) 1.92 (0.90) .09 Social Wellbeing -4.07 (1.07) -1.36 (1.18) .10 Emotional Wellbeing 0.63 (0.81) 0.62 (0.89) .99 Functional Wellbeing -0.85 (0.84) 1.10 (0.92) .13 Change in Satisfaction with Care (FACIT-TS) Explanations -0.35 (0.34) 0.20 (0.37) .29 Interpersonal -0.52 (0.23) 0.24 (0.24) .028 Comprehensiveness -1.53 (0.85) 1.10 (0.93) .047 Trust -0.32 (0.28) -0.39 (0.30) .89
Conclusions Patients prescribed oral chemotherapy experience • concerning problems with adherence. A variety of psychosocial and treatment factors are • associated with adherence. Despite the advantages of oral chemotherapy, • symptoms and side effects occur at high rates, especially fatigue, drowsiness and sleep disturbance.
Conclusions Through a multi-step process involving numerous stakeholders, • we successfully developed a smartphone mobile app to support patients prescribed oral chemotherapy. In the overall sample, the mobile app was generally not • associated with outcomes but lead to improvements in self- reported social wellbeing compared to usual care and marginally significant improvement in satisfaction with interpersonal treatment with clinicians. Intervention effects on outcomes were stronger in patients who • reported poor adherence and high anxiety at baseline.
Acknowledgments Stakeholder Partners Funding Source: PCORI (IHS-1306-03616), Co-Investigators: PI: Greer • Steven Safren, Ph.D. • William Pirl, M.D. • Jennifer Temel, M.D. • Inga Lennes, M.D. • Joanne Buzaglo, Ph.D. • Kamal Jethwani, M.D. Research Coordinators: • Jamie Jacobs, Ph.D. • Nicole Amoyal, Ph.D. • Lauren Nisotel, B.S. • Joel Fishbein, B.A. • James MacDonald, B.A. • Charn Xin C. Fuh, B.S. • Molly Ream, B.A.
Disclaimer Funding Source: PCORI (IHS-1306-03616) The data and statements reported in this presentation are solely the responsibility of the author(s) and do not necessarily represent the views of the Patient- Centered Outcomes Research Institute (PCORI), its Board of Governors or Methodology Committee.
Oral Anticancer Agents: Utilization, Adherence, and Health Care Delivery Wendy Nelson, PhD Behavioral Research Program Division of Cancer Control and Population Sciences LRF October 19, 2017
The views expressed here are those of the presenter and do not represent any official position of the National Cancer Institute or National Institutes of Health. LRF October 19, 2017
Motivation § Targeted oral anticancer (OAC) medications have transformed cancer care § OAC medications offer many potential advantages over traditional IV chemotherapy − Superior effectiveness − Convenient home-based treatment − A sense of control over treatment − Avoid IV infusions, trips to hospital § Potential downsides of OAC medications − Complex treatment regimens, often in addition to other medication regimens − OAC medications require strict adherence to be effective − Patients/caregivers are responsible for symptom management − Financial burden − Difficulties acquiring OAC medication 42
Adherence to OAC Medication is Critical for Achieving a Therapeutic Response § Many oral agents are cytostatic § Optimal adherence: correct drug, correct dose, correct time, correct conditions § Imatinib adherence in CML <80% → no molecular response § Imatinib adherence in GIST → 2-year progression free survival 80% in continuous group vs. 16% in interrupted group § Full dose ibrutinib adherence in CLL → improved PFS in patients missing < 8 days of treatment compared to patients missing > 8 consecutive days of treatment § Suboptimal adherence → toxicity, more physician visits, higher hospitalization rates, unnecessary treatment changes, breakdown in the patient-provider relationship, increased health care expenditures, biased response rates in clinical trials § OAC medication adherence estimates vary widely: 20% - 100% 43
Treatment Schedules Are Complex Sun Mon Tues Wed Thurs Fri Sat Week 1 Lenolidomide Lenolidomide Ixazomib Lenolidomide Lenolidomide Lenolidomide Lenolidomide Lenolidomide Dexamethasone Week 2 Lenolidomide Lenolidomide Dexamethasone Rest Rest Rest Rest Week 3 Rest Rest Ixazomib Lenolidomide Lenolidomide Lenolidomide Lenolidomide Lenolidomide Dexamethasone • Regimens are complex and often in addition to other medications • Adherence is inversely related to dosing complexity • “…clinicians must realize that lack of adherence typically reflects the complexity of the regimen rather than willful or manipulative behavior from the patient.” (2008 National Comprehensive Cancer Network Task Force Report on Oral Chemotherapy) 44
Polypharmacy Characteristics of Medicare Part D Beneficiaries by Type of Oral Cancer Medication Used Characteristics Imatinib Erlotinib Anastrozole Letrozole (N=123) (N=96) (N=2,397) (N=1,078) Mean [SD] Mean [SD] Mean [SD] Mean [SD] 75.3 [6.39] 76.61 [6.55] 75.33 [7.08] 74.76 [7.07] Age 1.93 [1.93] 3.13 [2.53] 2.04 [1.93] 1.99 [1.97] Number of comorbidities 9.75 [6.63] 13.24 [6.00] 7.71 [4.87] 8.03 [4.99] Number of noncancer drugs Kaisaeng et al. Journal of Managed Care & Specialty Pharmacy 2014; 20:669-675 . 45
Polypharmacy § Underappreciated barrier to OAC medication adherence § Potential risks of polypharmacy − Drug-drug interactions (e.g., gefitinib/anticoagulants; imatinib/rifampin; lapatinib/fentanyl) − Drug-food interactions (e.g., ibrutinib/grapefruit, Seville oranges; lapatinib/grapefruit) − Prescribing cascade − Unnecessary treatment change − Increased health care costs (physician visits; hospitalizations) § Why do interventions to improve adherence to OAC medication focus only on the OAC medication? 46
Pharmacists Pharmacists are uniquely positioned to: § Evaluate a patient’s medications for potential drug-drug and drug-food interactions § Provide medication counseling and information about safe handling of medication § Provide medication reconciliation § Contact the prescribing physician § Assist in procuring the OAC medication in a timely fashion § Help patients obtain financial assistance so they can afford their medication 47
Why do we need this funding opportunity announcement? § Utilization − Little information is available on the adoption of newly approved targeted oral agents − Little information is available on off-label use of oral agents − Are targeted oral agents being prescribed appropriately? § Adherence − Strict adherence is critical to achieving an optimal clinical outcome − Suboptimal adherence may lead to relapse, side-effects, unnecessary treatment changes, increased use of health care resources § Health Care Delivery − Health care systems need to establish new roles, responsibilities, safety standards, patient education strategies for targeted oral therapies − Home-based treatment with targeted oral therapy requires new models of care coordination 48
Purpose § Assess and describe the current state of oral anticancer medication utilization, adherence, and delivery § Identify the structural, systemic, and psychosocial barriers to adherence § Develop models and strategies to improve safe and effective delivery of oral anticancer agents so that clinical outcomes are optimized 49
Utilization Challenges § Understand how OAC medications are being prescribed, used, and monitored − Disparities in access (e.g., rural and underserved populations, insurance) − Off-label use § Potential research questions: − What are the patient and provider characteristics associated with prescribing and use of OAC agents? − Do genetic testing requirements and health insurance coverage affect the utilization of OAC agents? − What are current trends in utilization of newly approved OAC therapies? − What are the patterns of off-label use of OAC medications? 50
Adherence Challenges Understand how cognitive, affective, and motivational processes influence adherence behavior § − Beliefs about the safety and effectiveness of a “pill” − Expectations about side effects, treatment outcome − Depression, anxiety Understand the adherence needs of patients with cognitive, visual, physical, or health literacy limitations § Potential research questions: § − How do patients perceive the risks associated with oral therapy, and how do these risk perceptions influence adherence? − Are there major differences in patterns of adherence depending on the duration or complexity of the treatment regimen? − How do financial considerations (e.g., out-of-pocket costs) influence adherence? 51
Health Care Delivery Challenges § Understand how health care delivery systems are adapting to meet safety standards and the educational needs of patients and caregivers − Symptom management − Coordination of care § Potential research questions: − What system, health care team, provider, and patient-level factors are associated with the safe administration of oral agents? − How can pharmacy care models facilitate coordination of care for patients and health care teams? − What features of health care delivery systems lead to improved safety and adherence? − What models of care help to enhance symptom self-management? 52
Considerations § Studies may be observational/descriptive or include interventions; observational studies should emphasize modifiable factors for future interventions § Studies may focus on utilization, adherence, or health care delivery issues related to oral anticancer agents (no need to study everything) § Consult your Program Director if you have questions 53
Research Priorities § Cross-disciplinary collaborations (e.g., clinical pharmacists, research nurses, social workers, financial navigators) § Studies focused on newer targeted OAC agents § Primary data collection is encouraged 54
Grant Mechanisms – R01 and R21 NIH Research Project Grant NIH Exploratory/Developmental Grant (R01) (R21) PA-17-060 PA-17-061 § Supports discrete, specified, circumscribed § Supports exploratory/developmental research research projects projects § Most commonly used grant mechanism § May be used for pilot or feasibility studies § No specific dollar limit § Preliminary data not required − Advance permission required for >$500K § Direct costs for the two-year project period direct costs in any year may not exceed $275K § 3-5 years of funding § 2 years of funding § Standard receipt dates § Standard receipt dates For more information: grants.nih.gov/grants/funding/funding_program.htm#RSeries 55
Read the funding opportunity announcements carefully § PA-17-060 (R01) https://grants.nih.gov/grants/guide/pa-files/PA-17-060.html § PA-17-061 (R21) https://grants.nih.gov/grants/guide/pa-files/PA-17-061.html § Upcoming R01 application due dates: February 5, 2018; June 5, 2018 § Upcoming R21 application due dates: February 16, 2018; June 16, 2018 § Start the process early! Allow time for registration in Grants.gov and NIH eRA Commons § Verify successful submission by checking the eRA Commons 56
Program Contacts Wendy Nelson, PhD Nelsonw@mail.nih.gov 240-276-6971 Adherence Kate Castro, RN, MS, AOCN Kathleen.Castro@nih.gov 240-276-6834 Health Care Delivery Kelly Filipski, PhD Kelly.Filipski@nih.gov 240-276-6841 Utilization 57
U.S. Department of Health & Human Services National Institutes of Health / National Cancer Institute cancercontrol.cancer.gov 1-800-4-CANCER 58
Adherence in the Tyrosine Kinase Inhibitor Era, or How to Run the CML Marathon Michael J. Mauro, MD Leader, Myeloproliferative Neoplasms Program Memorial Sloan Kettering Cancer Center, New York, NY
Background the success story of ABL kinase inhibitors in CML
The history of CML is long, the kinase inhibitor era short 1879 1903 1845 1865 1953 1965 1968 1983 2001 2006 2012 2016 First description of CML Fowlers’s solution -1% arsenic trioxide Staining methods for blood Radiotherapy Busulfan 1998: After seminal preclinical work first clinical trials commence with STI571 Hydroxyurea (imatinib); 1999, target inhibition BMT validated, resistance identified (T315I) Interferon 1845: John Hughes Imatinib Bennett reported a “Case of Dasatinib Hypertrophy of the 1960: Spleen and Liver in Nilotinib 1973: which Death Took Nowell & Hungerford Janet Rowley Place from describe the Bosutinib describes the Suppuration of the Philadelphia Blood” in the 9:22 translocation Ponatinib Chromosome 1983: Nora Heisterkamp Edinburgh Medical and John Groffen, with Journal; Virchow in Generic Imatinib Germany wrote up a others, describe the BCR- similar observation ABL fusion gene product
CML is an increasingly prevalent and survivable cancer lifespan prevalence 200000 180000 160000 Number of Cases 10x greater 140000 steady state number of CML patients in US 120000 by 2050 100000 • Incidence 4700 per year 80000 • Age-matched mortality ratio vs normal population = 1.50 60000 • Accounts for increased US 40000 20000 2000 2005 2010 2015 2020 2025 2030 2035 2040 2045 2050 Huang et al, Cancer 118:3123-3127, 2012. Bower H et al, J Clin Oncol 34:2851-57, 2016. Year
CML IV Study: Comorbidity effect on CML TKI response, transformation As measured by the Charleson Comorbidity Index (CCI) Saußele S et al. Blood 2015;126:42-49
CML IV Study: Comorbidity effect on survival, irrespective of age Charlson Comorbidity Index (CCI) calculated including age Comorbidites trump CML response! Charlson Comorbidity Index (CCI) calculated without age Saußele S et al. Blood 2015;126:42-49
At present, five oral, small molecular kinase inhibitors approved in the US for Ph+ Leukemia: a ‘spoil of riches’; more on the way? 2001 1 st Gen. TKI Novartis (1 st line) Imatinib (STI571) 2007/2010 2007/2010 2 nd Gen. TKIs Novartis BMS (1 st , 2 nd line) (1 st , 2 nd line) Dasatinib (BMS354825) Nilotinib (AMN107) 2012 2012/2015 South Korea Pfizer IL-YANG: (2 nd /3 rd line) (1 st , 2 nd line) only Radotinib (IY5511) Bosutinib (SKI606) (1 st /2 nd /3 rd line 2018?) 3 rd Gen. TKI 4 th Gen. TKI (allosteric): 2012 Ariad ABL001 (2 nd ?/3 rd line) Ponatinib (AP24534)
Know Your Tools: Comparing TKI Toxicity in CML Issue Imatinib Nilotinib Dasatinib Bosutinib Ponatinib Dosing QD/BID, with BID, without QD, w/ or QD, with QD, w/ or food food (2h) w/o food food w/o food Long term Most Extensive; Extensive; Extensive, More limited but safety extensive Emerging Emerging No emerging increasing; toxicity toxicity toxicity Emerging toxicity é thrombocytopenia Heme intermediate least Most severe; ~dasatinb in 2 nd , 3 rd line; toxicity ASA-like ASA-like effect effect; ~nilotinib in 1 st line lymphocytosis é lipase, é bili, é lipase, pancreatitis; Non- Edema, GI Pleural / Diarrhea; é chol, é glu Heme effects, pericardial transaminitis rash; hypertension; ê Phos toxicity Black box: QT effusions Black box: vascular prolongation; occlusion, heart failure, screening req’d and hepatotoxicity Emerging early PAH ? Mild renal Vascular Vascular toxicities question re: (pulmonary effects events events (ICVE, IHD, CHF; ?late arterial (ICVE, IHD, PAD, VTE) renal effects hypertension) PAD)
NCCN Guidelines Version 1.2018 NCCN Guidelines Index Green/Yellow/Red Lights Table of Contents Chronic Myeloid Leukemia Discussion RESPONSE MILESTONES c,e BCR-ABL1 (IS) 3 months 6 months 12 months >12 months >10% f YELLOW RED >1%–10% GREEN YELLOW RED 0.1%–1% GREEN YELLOW <0.1% GREEN CLINICAL CONSIDERATIONS SECOND-LINE AND SUBSEQUENT TREATMENT OPTIONS RED • Evaluate patient compliance and drug interactions Switch to alternate TKI (CML-5) • Mutational analysis and Evaluate for HCT (CML-6) YELLOW • Evaluate patient compliance and drug interactions Switch to alternate TKI (CML-5) or Continue same TKI (CML-F) g • Mutational analysis or Dose escalation of imatinib (to a max of 800 mg) and Evaluate for HCT (CML-6) Continue same TKI (CML-F) h GREEN • Monitor response (CML-F ) and side efgects Patients with Achievement of response milestones must be interpreted within the clinical context. Patients with more than 50% reduction compared to baseline or minimally above the 10% cutofg can continue the same dose of dasatinib or nilotinib for another 3 months.
Shrinking International Standard (IS) qPCR the iceberg: Early Molecular Response: <10% or 1-log (10x) drop from 10% Early Molecular Response Early Molecular Response starting level Complete Cytogenetic Response: 1% Complete Cytogenetic Response Complete Cytogenetic Response <1% or 2-log (100x) drop Major Molecular Response: 0.1% <0.1% or 3-log (1000x) drop Major Molecular Response Major Molecular Response 4-log drop (<0.01%) 0.01% MR4 MR4 0.0032% 4.5 log drop, ‘MR4.5’, MR4.5 MR4.5 Complete Molecular Remission: ‘CMR’ ‘CMR’ <0.0032%; below the level of Response eligible for detection for standard labs ‘treatment free remission’ MR5-6? Expectations trials 1 Inferred from MR2.0; IRIS IM400 TIDEL I TIDEL II SPIRIT ENESTnd DASISION 2 MR4.0 rather than MR4.5 (IM400) ENEST/DA (IM600) (IM600) FRANCE (NIL) (DAS) SISION (IM600) >10%@3mo --- 33%/36% 24% 12% --- 9% 16% 87% 1 CCyR @12mo 69% 65%/73% 88% 65% 80% 85% MMR@12mo 40% 27%/28% 47% 64% 49% 55% 46% MMR@24mo 55% 44%/46% 73% 73% 53% 71% 64% 18% 2 22% 2 MR4.5@12mo --- 4%/--- 19% 11% 5% MR4.5@24mo --- 9%/8% --- 34% 26% 2 25% 17% OS@3y 92% 94%/93% --- 96% --- 95% 94%
Criteria for consideration of treatment free remission (TKI cessation): the rules as noted by the NCCN Age ≥18 years. Chronic phase CML. No prior history of accelerated or blast phase CML. On approved TKI therapy (imatinib, dasatinib, nilotinib, bosutinib, or ponatinib) for at least three years. Prior evidence of quantifiable BCR-ABL1 transcript. Stable molecular response (MR4; ≤0.01% IS) for ≥2 years, as documented on at least four tests, performed at least three months apart. No history of resistance to any TKI. Access to a reliable QPCR test with a sensitivity of detection of ≥4.5 logs that reports results on the IS and provides results within 2 weeks. Monthly molecular monitoring for the first six months following discontinuation, bimonthly during months 7–24, and quarterly thereafter (indefinitely) for patients who remain in MMR (MR3; ≤0.1% IS). Consultation with a CML Specialty Center to review the appropriateness for TKI discontinuation and potential risks and benefits of treatment discontinuation, including TKI withdrawal syndrome. Prompt resumption of TKI, with a monthly molecular monitoring for the first six months following resumption of TKI and every 3 months thereafter is recommended indefinitely for patients with a loss of MMR. For those who fail to achieve MMR after six months of TKI resumption, BCR-ABL1 kinase domain mutation testing should be performed, and monthly molecular monitoring should be continued for another six months. Reporting of the following to a member of the NCCN CML panel is strongly encouraged: -Any significant adverse event believed to be related to treatment discontinuation. -Progression to accelerated or blast phase CML at any time.
100 EURO-SKI: Survival without loss of MMR fantastic therapy + n=200; MR4 or greater, >2y (inclusion) 80 Relapses, n=86 good monitoring= Relapse free survival Relapses within 6 months , n=77 60 fantastic outcomes… 40 Relapse mol -free survival at 6 months : 61% (54-68 ) ‘treatment free remission’ 20 Saussele S, et al. EHA . 2014: [abstract LB-6214] 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Months from discontinuation of TKI
Do Adverse Events Occur With TKI Withdrawal? N=200; 222 AEs in 98 patients were reported 57 AEs in 31 patients were related to treatment stop, no grade 4 Patients Patients AEs AEs All Grade Grade 3 All Grade Grade 3 (n) (n) (n) (n) Musculoskeletal pain, joint pain, 23 3 39 6 arthralgia Other (sweating, skin disorders, folliculitis, 8 0 18 3 depressive episodes, fatigue, urticaria, weight loss) Musculoskeletal pain in CML patients after discontinuation of imatinib: a tyrosine kinase inhibitor withdrawal syndrome? J. Richter et al. J Clin Oncol. 2014 Sep 1;32(25):2821-3. Tyrosine kinase inhibitor withdrawal syndrome: a matter of c-kit ? Response to Richter et al. Ph. Rousselot et al. Mahon FX et al, Blood 2014 124:151
Summary I • Highly treatable, functionally curable disease • New paradigm of chronic therapy x years or indefinitely; normal life span expected • Multiple choices of oral agents: • Overlapping and unique side effects • ‘dealer’s choice’ algorithm; careful monitoring, toxicity management, etc. navigation required • Momentum towards ‘treatment free remission’; realistic expectation for smaller minority @ present
Adherence in CML What do we know
Adherence to therapy is a critical factor for achieving deep molecular response linked to treatment free remission • MMR • adherence to imatinib therapy, RR=11.17 (p=0.001) • CMR • adherence to imatinib therapy, RR=19.35 (p=0.004) Marin D, et al. J Clin Oncol 2010; 28(14): 2381–2388.
“ Drugs don ’ t work in patients who don ’ t take them ” C Everett Koop, M.D. former U.S. Surgeon General “The most likely cause of sudden molecular relapse is that the patient stopped therapy” T Hughes, Adelade Cartoon drawn by CML patient (OHSU, Portland, OR) AUS
Pharmacy Record Analysis of 4043 Patients Prescribed Imatinib • Patient adherence with imatinib therapy estimated at 75%. – Only 41% of patients were more than 90% adherent. 3,500 2,921 2,913 2,908 2,883 2,742 3,000 2,617 2,448 2,269 2,500 2,126 1,997 Patients 1,866 1,671 2,000 Dramatic decline in persistency 1,368 – Month 4: near 100% 1,500 – Month 5: 94% 685 1,000 – Month 14: 23% 500 0 0-1 1-2 2-3 3-4 4-5 5-6 6-7 7-8 8-9 9-10 10-11 11-12 12-13 13+ Months Tsang, J-P, Rudychev I, Pescatore SL. J Clin Onc. 2006; 24:330s. Abs 6119.
Long term adherence to imatinib 90 80 Proportion of patients (%) 70 60 50 40.2% 40 30 25.3% 20 13.8% 12.6% 8% 10 0 <80% 80–90% 90–95% 95–99% ≥100% Percentage of intended dose Marin D, et al. J Clin Oncol 2010; 28(14): 2381–2388.
We’ve got issues: Doctor and Patient • Challenging for busy oncologists to • Increasing attention needed to be up to date on fine points of optimize early tolerability and managing a relatively rare cancer monitor late effects for ‘endurance’ such as CML (very diffuse CML care during chronic therapy in US) • Ongoing side effects may tempt • TKI side effects not as dramatic as patients to secretly quit meds; not those form traditional chemo and being taken seriously re: side effects thus may be discounted may frustrate patients • Appointment/MD time short; • Financial burden, inadequate extenders (PAs, etc.) involved and insurance coverage, government nursing time limited/absent to costs, generics versus copies, etc. counsel patients re: oral meds • Medical system and society more • “ Of course they are taking their oriented to time-limited treatment, meds, it is cancer…” not living life fully with cancer as a chronic disease: paradox of having • New paradigm in CML: chronic cancer and still on treatment with maintenance therapy, ?indefinitely no outward change in appearance or at least x several years, unique
Why is toxicity management so important? Adherence to therapy Adherence to therapy, very likely to suffer in given the chronicity of the case of poorly therapy still necessary managed or under- for patients with CML managed side effects: (advice ranges from 3+, ‘self-management’… 5+ to 8-10 yrs+) is one of the strongest predictors of outcome…
6-year probability of MMR according to the measured adherence rate p<0.001 Marin D, et al. J Clin Oncol 2010; 28(14): 2381–2388.
6-year probability of CMR according to the measured adherence rate p=0.002 Marin D, et al. J Clin Oncol 2010; 28(14): 2381–2388.
Imatinib plasma levels, viewed in the setting of an adherence study, were not an independent predictor of molecular response Total population Adherent patients Marin D, et al. J Clin Oncol 2010; 28(14): 2381–2388.
Adherence is critical after dose escalation • In 32 patients who failed to achieve MMR at 18 months the dose of imatinib was increased to 600 mg od • The adherence rate in these 32 patients was 86%, which is significantly lower that that observed in the 55 subjects who remained on 400 mg (98.8%, p=0.02) 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 Adherence >90%, n= 18 Adherence >90%, n= 18 0.9 0.9 0.9 0.9 0.9 p =0.0002 p =0.0002 0.9 0.9 0.9 0.9 p =0.01 p =0.01 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 Probability of 4 log reduction Probability of 4 log reduction Probability of MMR Probability of MMR 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.6 0.6 0.6 0.6 0.6 0.6 0.6 0.6 0.6 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Adherence >90%, n= 18 Adherence >90%, n= 18 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 Adherence ≤90%, n= 14 Adherence ≤90%, n= 14 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 Adherence ≤90%, n= 14 Adherence ≤90%, n= 14 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0 0 0 0 6 6 6 6 12 12 12 12 18 18 18 18 24 24 24 24 30 30 30 30 36 36 36 36 42 42 42 42 48 48 48 48 54 54 54 54 60 60 60 60 66 66 66 66 72 72 72 72 0 0 0 6 6 6 12 12 12 18 18 18 24 24 24 30 30 30 36 36 36 42 42 42 48 48 48 54 54 54 60 60 60 66 66 66 72 72 72 Months from start of imatinib therapy Months from start of imatinib therapy Months from start of imatinib therapy Months from start of imatinib therapy Marin D, et al. J Clin Oncol 2010; 28(14): 2381–2388.
Poor adherent patients have a higher probability of losing the CCyR and a lower EFS 1.0 1.0 1.0 1.0 1.0 1.0 p<0.0001 p<0.0001 0.9 0.9 0.9 0.9 0.9 0.9 Cumulate incidence of loss of CCyR Cumulate incidence of loss of CCyR Cumulate incidence of loss of CCyR 0.8 0.8 0.8 0.8 0.8 0.8 Probability of imatinib failure Probability of imatinib failure Probability of imatinib failure Adherence rate ≤85%, n=18 Adherence rate ≤85%, n=18 0.7 0.7 0.7 0.7 0.7 0.7 Adherence rate >85%, n=69 Adherence rate >85%, n=69 0.6 0.6 0.6 p<0.0001 p<0.0001 0.6 0.6 0.6 0.5 0.5 0.5 0.5 0.5 0.5 0.4 0.4 0.4 0.4 0.4 0.4 0.3 0.3 0.3 0.3 0.3 0.3 0.2 0.2 0.2 0.2 0.2 0.2 Adherence rate ≤85%, n=18 Adherence rate ≤85%, n=18 0.1 0.1 0.1 0.1 0.1 0.1 Adherence rate >85%, n=69 Adherence rate >85%, n=69 0.0 0.0 0.0 0.0 0.0 0.0 0 0 0 6 6 6 12 12 12 18 18 18 24 24 24 0 0 0 6 6 6 12 12 12 18 18 18 24 24 24 Months from enrolment Months from enrolment Months from enrolment Months from enrolment Months from enrolment Months from enrolment Marin D, et al. J Clin Oncol 2010; 28(14): 2381–2388.
ADAGIO: About One Third of CML Patients Report Poor Adherence to Imatinib • 169 CML patients treated with imatinib prospectively followed for 90 days 100 Baseline Follow-up Patients Who Reported in 80 67% 64% Past 4 Wks (%) 60 40 22% 25% 16% 13% 20 3% 2% 1% 2% 0 Adherent Dose Not Consecutive Dose Dose Taken Doses Not Taken Reduced Taken > 2-Hr Delay Overall adherence and nonadherence by behavior, self-reported Noens L, et al. Blood. 2009;13:5401-5411.
Microelectronic Monitoring System (MEMS 6 Trackcap) CML Study • Records the time of opening the container • Most reliable method of measuring adherence • Marin study: patients told that adherence was measured by pill counts, not told about bottle cap electronic chip Marin D, et al. J Clin Oncol 2010; 28(14): 2381–2388.
The Ideal: 100% adherence as recorded by MEMS Marin D, et al. J Clin Oncol 2010; 28(14): 2381–2388.
The Reality: ‘Catching up’ to empty the bottle, as recorded by MEMS Marin D, et al. J Clin Oncol 2010; 28(14): 2381–2388.
The Reality: Poor adherence due to drug holiday, as recorded by MEMS Marin D, et al. J Clin Oncol 2010; 28(14): 2381–2388.
The Reality: Poor adherence and Human Nature, as recorded by MEMS Marin D, et al. J Clin Oncol 2010; 28(14): 2381–2388.
The dosing of medication may be very erratic as well Marin D, et al. J Clin Oncol 2010; 28(14): 2381–2388.
Achievement of a molecular response is related to the adherence to imatinib therapy 6-year probability of response Adherence rate n MMR (%) 4-log (%) CMR (%) p=0.01 p=0.02 p=0.02 100% 36 91.1 79.9 46.7 <99% 51 58.6 38.6 22.7 p<0.001 p<0.001 p=0.002 >95% 57 94.5 77.2 45.2 <95% 30 29.3 15.0 8.2 p<0.001 p<0.001 p=0.002 >90% 64 93.7 76.0 43.8 <90% 23 13.9 4.3 0 p<0.001 p=0.001 p=0.007 >85% 69 85.8 69.2 40.8 <85% 18 11.8 5.6 0 p=0.001 p=0.005 p=0.04 >80% 75 81.2 63.8 37.1 <80% 12 0 0 0 MMR=major molecular response; CMR=complete molecular response. Marin D, et al. J Clin Oncol 2010; 28(14): 2381–2388.
Conclusion to the Marin Study: Adherence and the achievement of MMR are the only independent predictors for outcome 1.0 1.0 p<0.0001 0.9 0.9 MMR, n=53 p=0.003 Cumulate incidence of loss of CCyR 0.8 0.8 Probability of imatinib failure CCyR, no MMR, Adherence Rate ≤85%, n=11 0.7 0.7 CCyR, no MMR, Adherence Rate >85%, n=23 0.6 p<0.0001 p<0.0001 0.6 0.5 0.5 0.4 0.4 0.3 0.3 p<0.0001 MMR, n=53 0.2 0.2 p=0.0009 CCyR, no MMR, Adherence Rate ≤85%, n=11 0.1 0.1 CCyR, no MMR, Adherence Rate >85%, n=23 0.0 0.0 0 6 12 18 24 0 6 12 18 24 Months from enrolment Months from enrolment Marin D, et al. J Clin Oncol 2010; 28(14): 2381–2388.
Complexities, Actions, Algorithms CV toxicity, switching TKIs, management deficits
SIMPLICITY Study Overview: Landmark Observational Study in CML Strategic Objective: Determine effectiveness of available CP-CML treatments, understand impact of CML and treatment on QoL and evaluate HRU and associated cost burden in real-world setting Inform clinical practice Eligibility: Primary Research Objective Retrospective (imatinib) • Newly-diagnosed CP-CML N=252 • To better understand the use of dasatinib and patients other TKIs in first-line CML in a real world setting Prospective (nilotinib) • Receiving 1 st line imatinib, N=408 Secondary Research Objectives dasatinib or nilotinib Prospective (imatinib) • Evaluate patient benefit of CML treatment • ≥18 years at time of diagnosis N=416 • Determine healthcare resource utilization • Not participating in a CML Prospective (dasatinib) N=418 clinical trial 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 Improve outcomes for CP-CML patients Enrollment Enrollment End of (Retrospective (Prospective study cohort) cohort) follow-up Data Collection • • • • Demographics Clinical characteristics Bone marrow aspirates Hospitalizations • • • • Vital signs TKI treatment Blood tests QoL outcomes • • • • Physical exam Comorbidities Molecular response Treatment adherence • • • • CV assessments Spleen assessment Cytogenetics Discontinuation 3
SIMPLICITY: Lack of Adherence to Monitoring Guidelines in Clinical Practice About 1 in every 5 patients are not tested for MR at 12 months and almost half are not tested for CyR Patients not tested for CyR at 12 months 1 Patients not tested for MR by 12 months 1 Overall (N=862) Overall 51% 17% (N=862) US US 38% 13% (n=573) (n=573) Europe Europe 58% 19% (n=289) (n=289) Age <65 years at initiation of first-line TKI, patients who had switched from first-line TKI and those seen in academic centres were more likely to be monitored by 12 months (p<0.05) 2 1. Goldberg SL, Cortes J, Gambacorti-Passerini C, et al. Cytogenetic and molecular testing in patients with chronic myeloid leukemia (CML) in a prospective observational study (SIMPLICITY). J Clin Oncol. 2014;32:5s (suppl; abstr 7050). 2. Goldberg SL, Cortes J, Gambacorti-Passerini C, et al. Predictors of performing response monitoring in patients with chronic-phase chronic myeloid leukemia (CP-CML) in a prospective observational study (SIMPLICITY). J Clin Oncol. 2014;32:(suppl 30; abstr 116).
SIMPLICITY: Patients Discontinuing First-Line TKI Quarter of SIMPLICITY patients discontinue TKI treatment in first 12 months 862 pts with at least 12 months of follow-up discontinuing treatment (%)* Imatinib 30% Pts who Proportion of patients (n=400) discontinued index Tx: Dasatinib 17% (n=230) 24% (N=207) Nilotinib 21% (n=232) *P<0.001 Hehlmann R, Cortes J, Gambacorti-Passerini C et al. Tyrosine kinase inhibitor (TKI) switching experience from SIMPLICITY, a prospective observational study of chronic phase chronic myeloid leukemia (CP-CML) patients in clinical practice. 19 th European Hematology Association (EHA) Annual Meeting; June 12–14, 2014, Milan, Italy: abstract P883.
SIMPLICITY: Reasons for Treatment Discontinuation Intolerance most common reason for TKI discontinuation in first 12 months 862 pts with at least 12 months of follow-up Hehlmann R, Cortes J, Gambacorti-Passerini C et al. Tyrosine kinase inhibitor (TKI) switching experience from SIMPLICITY, a prospective observational study of chronic phase chronic myeloid leukemia (CP-CML) patients in clinical practice. 19 th European Hematology Association (EHA) Annual Meeting; June 12–14, 2013, Milan, Italy: abstract P883
SIMPLICITY: Switching Patterns in Pts Discontinuing in First Year Second-line TKI choices vary by region; in the US, DAS was most common second-line TKI, while in Eu, the second-line TKI choice was more equally distributed 862 pts with at least 12 months of follow-up Imatinib Dasatinib Nilotinib FIRST-LINE (n=119) (n=40) (n=48) SECOND-LINE DAS NIL IM NIL DAS IM All patients 45% 32% 40% 17% 33% 29% SECOND-LINE IM NIL DAS NIL DAS IM Pts in Europe 33% 0% 36% 42% 25% 12% SECOND-LINE DAS NIL IM NIL DAS IM Pts in US 58% 26% 41% 21% 35% 32% Hehlmann R, Cortes J, Gambacorti-Passerini C et al. Tyrosine kinase inhibitor (TKI) switching experience from SIMPLICITY, a prospective observational study of chronic phase chronic myeloid leukemia (CP-CML) patients in clinical practice. 19 th European Hematology Association (EHA) Annual Meeting; June 12–14, 2014, Milan, Italy: abstract P883
ENRICH STUDY: Changes in Toxicity and QoL in Patients Switched from Imatinib to Nilotinib - 45 / 52 patients had a total of 182 low-grade (grade 1/2), imatinib-related, nonhematologic AEs at baseline. - Of the 182 AEs, 130 were grade 1 and 52 were grade 2. 71.4% ASH 2012
ENRICH: Change in Severity of Most Frequently Reported Imatinib-Related Nonhematologic AEs* Cortes J, et al. Blood . 2012;120(21):[abstract 3782].
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