Download Session Slides Olinger

Giving the TKO to Metabolic Adverse
Effects of the TKIs
Alexander Olinger, PharmD
PGY-2 Oncology Pharmacy Resident
Pharmacy Grand Rounds
September 6th, 2016
©2015 MFMER | slide-1
Objectives
• List common tyrosine kinase inhibitors known to
cause metabolic adverse effects (e.g. cardiac,
hypothyroidism, hypo/hyperglycemia)
• Identify signs, symptoms and risk factors for
metabolic adverse effects of tyrosine kinase
inhibitors
• Outline a management strategy for
hypertension, hypothyroidism, or
hypo/hyperglycemia from a tyrosine kinase
inhibitor
©2015 MFMER | slide-2
Presentation Overview
Tyrosine
Kinases and
TKI’s
Hypertension
Glycemic
Control
Hypothyroidism
©2015 MFMER | slide-3
Tyrosine Kinases
• Signaling enzymes
• Activated by ligand (e.g. cytokines)
• ATP  tyrosine residues on signal transduction
molecules
• Phosphorylated proteins promote cellular
response
• Inappropriate activation or up-regulation in cancer
ATP: adenosine triphosphate
Vlahovic G, Crawford J. Oncologist 2003;8:531-8.
©2015 MFMER | slide-4
What is a Tyrosine Kinase?
Tyrosine kinase receptor
Cytokine
P
P
P
P
Cellular response
Tyrosine kinase inhibitor
©2015 MFMER | slide-5
Timeline of the Tyrosine Kinase Inhibitors
TKI approvals
7
Sorafenib, 1st
VEGF TKI
6
5
Gefitinib 1st
EGFR TKI
4
3
2015:
Alectinib,
Lenvatinib,
Palbociclib,
Osimertinib,
Cobimetinib
Imatinib 1st
approved
2
1
0
2000
2005
TKI: Tyrosine kinase inhibitor; EGFR:
endothelial growth factor receptor;
VEGF: Vascular endothelial growth
factor
2010
2015
2020
Wu P, Nielsen TE, Clausen MH. Trends Pharmacol Sci 2015;36:422-39.
©2015 MFMER | slide-6
Adverse Effects of TKI’s
• Dependent on the targeted
• e.g. EGFR and skin rash toxicity
• Down-stream effects from blocking
• e.g. VEGF and decreased nitric oxide production
• Varies between different agents in same class
Cytopenias
Skin rash
Hypertension
LV dysfunction
QT prolongation
Hyperglycemia
Diarrhea
Hyperlipidemia
Electrolyte
abnormalities
Arthralgias
CK elevation
Photosensitivity
Hypothyroidism
VTE
Mucositis
Hypoglycemia
Dy GK, Adjei AA. Ca-Cancer J Clin 2013;63:249-79.
©2015 MFMER | slide-7
Grading of Adverse Events
• NCI CTCAE set recommendations for cancer
clinical trials
• Currently version 4
• Update in progress (version 5)
• Need to be aware of criteria during trials
• Not necessarily in line with current guidelines (e.g. HTN)
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Prehypertension
(120-139/80-89
mm Hg)
Stage 1 (140159/90-99);
recurrent or ≥24
hours; Symptomatic
DBP >20 mm Hg
Stage 2: SBP
≥160 or DBP
≥100 ; more than
1 drug or
intensive therapy
Life
threatening
Death
NCI CTCAE: National Cancer Institute common terminology criteria for
adverse events; SBP: Systolic blood pressure; DBP: Diastolic blood
pressure
NCI CTCAE v4. Accessed online 8/18/16
©2015 MFMER | slide-8
Presentation Overview
Tyrosine
Kinases and
TKI’s
Hypertension
Glycemic
Control
Hypothyroidism
©2015 MFMER | slide-9
VEGF Inhibitors
• Tumors depend on angiogenesis for growth
• VEGF induces angiogenesis
• VEGFIs inhibit VEGFR (especially VEGFR-2)
Drug
Tumor Type (approved)
Axitinib
Renal cell
Cabozantinib
Renal cell, Thyroid
Lenvatinib
Renal cell, Thyroid
Pazopanib
Renal cell, soft tissue sarcoma
Regorafenib
Colorectal, GIST
Sorafenib
Hepatocellular, Renal cell, Thyroid
Sunitinib
GIST, PNET, Renal Cell
Vandetanib
Medullary thyroid
VEGFI: Vascular endothelial growth factor inhibitor; VEGFR: Vascular
endothelial growth factor receptor; GIST: Gastrointestinal stromal
tumor; PNET: Pancreatic neuroendocrine tumor
Small et al. Can J Cardiol 2014;30:534-43.
©2015 MFMER | slide-10
VEGFI and Hypertension
VEGF
VEGFR
VEGF
inhibitor
P
P
↓RAF
↓Prostacyclin
P
P
↓PI3K
↓c-Src
1. Endothelial
dysfunction
2. Vascular
remodeling
3. Hypertension
↓NO
↓Vasodilatation, ↑ vasoconstriction, cellular injury
PI3K: phosphoinositide 3-kinase; RAF: rapidly accelerated
fibrosarcoma, NO: nitric oxide; c-Src: tyrosine-protein kinase Src
Small et al. Can J Cardiol 2014;30:534-43.
©2015 MFMER | slide-11
VEGFI-Induced Hypertension Characteristics
• ↑ first 24 hours, sustained BP ↑ by day 6
• Sorafenib: Normotensive patients by end of 4 weeks
• 22.2±6.4 mm Hg SBP
• 17.2±6.0 mm Hg DBP
• Effects SBP > DBP
• Dose dependent
• Cessation of therapy  rapid decrease
• Regorafenib: 21 days on, 7 days off
• Hospitalizations when chemotherapy is held
• Often resistant to treatment
BP: Blood pressure; SBP: systolic blood
pressure; DBP: diastolic blood pressure
Azizi M, Chedid A, Oudard S. HN Engl J
Med 2008;358:95-7.
Small et al. Can J Cardiol 2014;30:534-43.
©2015 MFMER | slide-12
VEGFI-Induced Hypertension Risk Factors
Risk Factors
NOT Risk Factors
History of HTN
BMI
>1 VEGFI combination therapy
Race
>65 years of age
Renal function
Smoking
Family history of HTN or CVD
Hypercholesterolemia
BMI: Body mass index; CVD: Cardiovascular disease; HTN:
hypertension
Small et al. Can J Cardiol 2014;30:534-43.
©2015 MFMER | slide-13
VEGFI Hypertension
• Consequences: proteinuria, ↑ CVD, PERS
• Underestimated in clinical trials
• Threshold values ↑ than current guidelines
• Difficult patients typically excluded
• History of hypertension or CVD
• Hypertension sign of positive response?
PERS: Posterior reversible encephalopathy syndrome
Small et al. Can J Cardiol 2014;30:534-43.
©2015 MFMER | slide-14
VEGF-Induced Hypertension Prophylaxis?
• Phase II trial: Cediranib ± hypertensive prophylaxis
• N=126, 30 or 45 mg/day
• Nifedipine was prophylactic agent
• Phase I trials, patients resistant to captopril responded to nifedipine
• Standardized hypertension regimen initiated
• No difference between groups
• Temporary or permanent withdrawal of therapy
• Dose intensity (proportion of planned doses)
• Decreased HTN incidence in comparison to
phase I trial
• 31% and 13% vs 59% and 48% respectively (p=0.02)
Langenberg et al. J Clin Oncol 2009;27:6152-9.
©2015 MFMER | slide-15
VEGFI-Induced Hypertension Monitoring
• Recommendations from National Cancer
Institute in 2012
1. Assess risk for existing CVD and potential
cardiovascular complications prior to start
2. HTN controlled prior to initiation
3. Frequent BP monitoring during first cycle
4. Aggressively manage BP elevations and early
signs/symptoms
• No recommendations regarding therapy
•
JNC 8 guidelines for BP goals
• Be vigilant when off cycle
Steingart et al. Am Heart J 2012;163:156-63.
James et al. JAMA. 2014;311(5):507-520.
©2015 MFMER | slide-16
VEGFI-Induced Hypertension Treatment
• ACEI: Potentially suboptimal response if severe
• Ang II and renin levels are not ↑ in VEGFI
• Renin and aldosterone levels not elevated in sorafenib
patients (N=20)
• Compelling indication or for renal protection
• CCB: Reduce vascular smooth muscle
contraction
• Dihydropyridine CCBs
• VEGFI induced impairment of NO
• Dose modifications with HTN
ACEI: Angiotensin converting enzyme inhibitor; CCB:
Calcium channel blocker
Small et al. Can J Cardiol 2014;30:534-43.
Veronese et al. J Clin Oncol 2006;24:1363-9.
©2015 MFMER | slide-17
VEGFI-Induced Hypertension Summary
• Decreased NO and prostacyclin → HTN
• Fast onset and offset
• Frequent monitoring during initiation and
cessation
• Treatment: CCB, ACEI and holding therapy
followed by dosage modification
©2015 MFMER | slide-18
Case Question #1
• Which of the following are risk factors for
VEGFI hypertension?
A. Greater than 65 years of age
B. BMI
C. Renal function
D. Family history of HTN or CVD
E. Both B and D
©2015 MFMER | slide-19
Presentation Overview
Tyrosine
Kinases and
TKI’s
Hypertension
Glycemic
Control
Hypothyroidism
©2015 MFMER | slide-20
Overview of Glycemic Effect of TKIs
• Mechanisms still under investigation
• TKIs in same class can be associated with
either hypoglycemia or hyperglycemia
• Example: BCR-ABL inhibitors
Name
Glycemic Effect
Estimated incidence
Imatinib and
Dasatinib
Hypoglycemia
24-47% (0-<1% grades 3 and 4)
Nilotinib
Hyperglycemia
≤50% (7-12% grades 3 and 4)
Dy GK, Adjei AA. Ca-Cancer J Clin
2013;63:249-79.
NCI CTCAE v4. Accessed online©2015
8/18/16
MFMER | slide-21
Hyperglycemia
• ALK inhibitors: Non-small cell lung cancer
• Mechanism unknown
• Ceritinib: Preexisting diabetes/glucose intolerance
• 6 fold increased risk grade 3 and 4
Name
Glycemic Effect
Estimated incidence
Alectinib
Hyperglycemia
All grades, 36% (2% grade
3 and 4)
Crizotinib
No effect
---
Ceritinib
Hyperglycemia
49% (13% grades 3 and 4)
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
<160 mg/dL
fasting
>160-250 mg/dL
>250-500
mg/dL
>500 mg/dL
Death
ALK: Anaplastic lymphoma kinase
Dy GK, Adjei AA. Ca-Cancer J Clin 2013;63:249-79.
NCI CTCAE v4. Accessed online 8/18/16
Lexi-Comp, Inc. (Lexi-Drugs® ). Lexi-Comp, Inc.; August, 30 2016.
Hyperglycemia - Management
• Management not listed in alectinib or
ceritinib protocols
• Consider management similar to American
Diabetes Association guidelines
• Trial of metformin; consider insulin therapy
• Recommendations for ceritinib adjustment
• >250 mg/dL despite adequate treatment
• Hold treatment, decrease dose to 150 mg
• Unable to tolerate 300 mg daily with treatment
• Discontinue therapy
Villadolid J et al. Transl Lung Cancer Res 2015;4:576-83.
Lexi-Comp, Inc. (Lexi-Drugs® ). Lexi-Comp, Inc.; August, 30 2016.
©2015 MFMER | slide-23
Hypoglycemia – Cases in Diabetic Patients
• T1DM
• Sunitinib: 2 cases of cessation of insulin therapy
after 3 and 8 months
• Imatinib: HbA1c 7.2%  5% and 56% ↓ TDI
• T2DM: Case reports with Imatinib, sunitinib,
dasatinib and erlotinib showing decrease or
cessation of antidiabetic treatment
• Rebound after cessation of treatment
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
<LLN - 55
mg/dL fasting
<55-40 mg/dL
<40-30
mg/dL
<30 mg/dL
Death
LLN: Lower limit of normal; TDI: total daily
insulin; T1DM: Type 1 diabetes mellitus;
T2DM: Type 2 diabetes mellitus
Agostino et al. J Oncol Pharm Pract 2011;17:197-202.
NCI CTCAE v4. Accessed online 8/18/16 ©2015 MFMER | slide-24
Proposed Mechanisms for Hypoglycemia
Target
Mechanism
Drug example
C-Abl
Inhibition may protect against apoptosis in
β-cells
Imatinib, dasatinib
PDGFR
Protect against insulin resistance
Imatininb, dasatinib,
sorafenib, sunitinib
VEGFR2
↓ islet remodeling, ↓T cell migration into
islets, ↓insulitis severity
Sorafenib, sunitinib
EGFR
Improvement in glucose tolerance and
reduction in insulin resistance
Erlotinib
C-Abl : Abelson tyrosine kinase
PDGFR: Platelet derived growth factor
VEGFR2: Vascular endothelial growth factor receptor 2
EGFR: Endothelial growth factor
Agostino et al. J Oncol Pharm Pract 2011;17:197-202.
©2015 MFMER | slide-25
Hypoglycemia
• Retrospective chart review of 70 patients
• CML, PhCr + ALL, RCC, GIST
• 17 T2DM, 61 non-diabetic patients
• Imatinib  dasatinib, sunitinib  sorafenib
• Values only collected during basic metabolic
panels
• No finger sticks
CML: Chronic myeloid leukemia; GIST: Gastrointestinal stromal tumor; PhCr + ALL: Philadelphia
chromosome positive acute lymphoblastic leukemia;
RCC: Renal cell carcinoma
Fountas et al. J Oncol Pharm Pract 2011;17:197-202.
©2015 MFMER | slide-26
Hypoglycemia – Non-Diabetic Patients
Name (N=61)
Mean BGΔ after
initiation (%)
Mean BGΔ
after Cessation (%)
Imatinib (39)
-9mg/dL (8.4)
Not reported
Dasatinib (8)
-52mg/dL (37.9)
+29mg/dL (34.1)
Sunitinib (30)
-15 mg/dL (12.8)
+14mg/dL (13.7)
Sorafenib (23)
-12 mg/dL (12.2)
+10 mg/dL (10)
BGΔ: blood glucose change
Agostino et al. J Oncol Pharm Pract 2011;17:197-202.
©2015 MFMER | slide-27
Hypoglycemia – Diabetic Patients
Name (N=17)
Mean BGΔ during
treatment (%)
Mean BGΔ
After Cessation (%)
Imatinib (6)
-9mg/dL (4.7)
Not reported
Dasatinib (1)
-52mg/dL (23.9)
+30 mg/dL (18)
Sunitinib (7)
-14 mg/dL (9.4)
+14mg/dL
(not reported)
Sorafenib (5)
-12 mg/dL (7.5)
+11 mg/dL (7.9)
• 47% of patients decreased or stopped diabetic medications during
therapy
• 1 patient admitted to ED for hypoglycemia (sunitinib, BG = 22 mg/dL)
• Limitations: small sample size, confounders (e.g. weight loss) not
collected, retrospective chart review
Agostino et al. J Oncol Pharm Pract 2015;26:643-56.
©2015 MFMER | slide-28
Hypoglycemia - Management
• Non-diabetic patients: Close monitoring not
needed
• Patients in trial not symptomatic
• Diabetic patients
• Increased blood glucose monitoring
during initiation
• Vigilance during discontinuation of therapy
©2015 MFMER | slide-29
Glycemic Control Summary
Hyperglycemia
Hypoglycemia
• Alectinib and ceritinib
• Sunitinib, sorafenib,
imatinib, dasatinib and
erlotinib
• Mechanism: unknown
• Close monitoring of
diabetic patients
• Mechanism: improved
glucose tolerance and
protection of islet cells
• Adjust dose or hold
therapy if unable to control • Close monitoring of
diabetic patients
©2015 MFMER | slide-30
Presentation overview
Tyrosine
Kinases and
TKI’s
Hypertension
Glycemic
Control
Hypothyroidism
©2015 MFMER | slide-31
VEGFI-Induced Hypothyroidism Mechanism
Image from Cao Y. Nat Rev Endocrinol 2014;10:530-9.
©2015 MFMER | slide-33
Hypothyroidism and TKIs
Drug
Targets
Cancer Type
Hypothyroidism
Mechanism
Sunitinib
VEGFR1-3, FLT3,
PDGFR
GIST, PNET,
renal cell
carcinoma
Destructive thyroiditis,
VEGF binding prevention
 decreased blood flow,
inhibited thyroid
peroxidase
Sorafenib
VEGFR1-3, Raf
Kinases, PDGFR
HCC, RCC,
Thyroid cancer
VEGF binding prevention
 decreased blood flow
Axitinib
VEGFR1-3
RCC
VEGF binding prevention
 decreased blood flow
Imatinib,
nilotinib
BCR-ABL
CML
Induced hepatic
microsomal enzymes
•
•
•
•
Others: Pazopanib and vandetanib (VEGFR)
Less common in sorafenib and nilotinib
Pre-existing therapy: Increased levothyroxine metabolism
May or may not be reversible
PNET: Pancreatic neuroendocrine tumor;
HCC: Hepatocellular carcinoma
Torino et al. Nat Rev Clin Oncol 2009;6:219-28.
©2015 MFMER | slide-34
Hypothyroidism from TKIs: Characteristics
Currently on Treatment?
Average time
to onset
Frequency of thyroid
dysfunction
Yes, Levothyroxine
< 2 weeks
21-100%
No
4-16 weeks for
sorafenib, 4-94
weeks for sunitinib
18-85% (<1-2% grade ≥3)
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Asymptomatic;
intervention not
indicated
Symptomatic; thyroid
replacement indicated;
limiting
instrumental ADL
Severe
symptoms;
limiting self
care ADL;
hospitalization
indicated
Life-threatening
consequences;
urgent
intervention
indicated
Death
• Fatigue, constipation, weight gain, dry skin, muscle weakness
• High TSH (mild >4 mU/L, hypothyroidism >10 mU/L)
• Low T4 (<5 mU/L)
Hamnvik et al. J Natl Cancer Inst 2011;103:1572-87.
NCI CTCAE v4. Accessed online 8/18/16
©2015 MFMER | slide-35
Hypothyroidism - Treatment
• Risk versus benefit
• Asymptomatic (TSH 5-10 mU/L), no treatment needed
• Check TSH at baseline
• Currently on levothyroxine
• Every 4 weeks until stable, Then every 2 months
• No current therapy
• Recheck every 4 weeks for 4 months
• Then every 2-3 months
• Monitor after discontinuation of therapy
Torino et al. Nat Rev Clin Oncol 2009;6:219-28.
Hamnvik et al. J Natl Cancer Inst 2011;103:1572-87.
©2015 MFMER | slide-36
TKI induced Hypothyroidism Summary
• Agents
• VEGFI: Axitinib, pazopanib, sorafenib, sunitinib,
vandetanib
• BCR-ABL: Imatinib, nilotinib
• Baseline hypothyroidism is greatest risk factor
• Treatment: Levothyroxine
• Frequent monitoring during initiation and
cessation of therapy
©2015 MFMER | slide-37
Question #2
• Which of the following agent(s) are most likely
to cause both hypothyroidism and
hypoglycemia?
A. Sunitinib
B. Axitinib
C. Pazopanib
D. Imatinib
E. Both A and D
©2015 MFMER | slide-38
Question #3
• Which of the following statements is true
regarding management of metabolic effects of
TKIs?
A.
B.
C.
D.
Close monitoring of blood glucose should be done in nondiabetic patients starting sunitinib
Based on its mechanism, a trial of CCB inhibitors should be
tried over ACEI for VEGFI-induced hypertension
Prophylaxis with CCBs was shown to reduce held doses and
discontinuations VEGFIs
A patient with a TSH of 6.7 on sunitinib should always initiate
levothyroxine therapy
©2015 MFMER | slide-39
Summary
• Healthcare providers should be aware of
metabolic adverse effects of TKIs
• Initiation and when discontinuing
• VEGFI-induced hypertension
• No prophylaxis
• CCB 1st, ACEI 2nd then trial others
• Hypoglycemia and Hyperglycemia: Close
monitoring in diabetics
• Hypothyroidism: Close monitoring first 4 cycles
• Patients on levothyroxine  increased dose likely
• More research is needed
©2015 MFMER | slide-40