Update on the Side Effects of Tyrosine Kinase Inhibitors

Dr Jenny ByrneNottingham University Hospitals Trust

Most Common Adverse Events (by 5 Years)

All Grade AEs Patients, %

Grade 3/4 AE’s Patients %

Superficial Edema 60 2

Nausea 50 1

Muscle cramps 49 2

Musculoskeletal pain 47 5

Diarrhea 45 3

Rash/skin problems 40 3

Fatigue 39 2

Headache 37 <1

Abdominal pain 37 4

Joint pain 31 3

IRIS Study: Most Frequently Reported AEs

• Only Serious Adverse Events (SAEs) were collected after 2005

• Grade 3/4 adverse events decreased in incidence after years 1-2IRIS 8 year update

Imatinib is a Safe Drug....

IRIS SAEs in Year 8 No unique, previously unreported AEs attributed to imatinib

observed over the past 24 months

Since year 5 only 9 SAEs with suspected relationship to imatinib have been reported (2%):

Congestive Heart Failure (n=3): all of the patients had pre-existing cardiac disease prior to study entry

Second malignancy (n=3)*

Myositis (n=1); elevated CK (n=1); multiple sclerosis (n=1)

Pancreatitis (n=1); vomiting (n=1)

Dermatitis (n=1)

*With >400,000 patient years of estimated imatinib exposure, the analysis of clinical safety data from clinical trials and spontaneous reports did not provide evidence for an increased incidence of malignancies for patients treated with imatinib compared to that of the general population

*With >400,000 patient years of estimated imatinib exposure, the analysis of clinical safety data from clinical trials and spontaneous reports did not provide evidence for an increased incidence of malignancies for patients treated with imatinib compared to that of the general population

IRIS 8 year update

But many patients have low level side effects...

Which can affect their quality of life…

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%

ENRICH: Change in Severity of Most Frequently Reported Imatinib-Related Nonhematologic AEs*

Cortes J, et al. Blood. 2012;120(21):[abstract 3782].

ENRICH: Change from Baseline in QoL bCycle*

Cortes J, et al. Blood. 2012;120(21):[abstract 3782].

Nilotinib is Generally Better Tolerated…

But what about Long Term Toxicity...?

ENESTnd: 3-year adverse event data (any grade)

CNS: Central nervous system; GI: Gastrointestinal; PAOD: Peripheral arterial occlusive disease.

1. Larson RA et al. Leukemia 2012 [Epub ahead of print].

*No patient discontinued the study as a result of PAOD. 6/7 patients (85%) with PAOD had pre-existing risk factors at baseline.

Symptomatic QT prolongation

Pancreatitis

Hepatotoxicity

Fluid retention

Effusions

Rash

Significant bleeding

CNS haemorrhage

GI haemorrhage

Ischaemic heart disease

PAOD*

0 10 20 30 40 50 60 70 80 90 100

Patients (%)

Nilotinib 300 mg BID (n=279)

Imatinib 400 mg BID (n=280)

Adverse event onset in third year of therapy

ENESTnd:3-year grade 3/4 laboratory abnormalities

ALT: Alanine aminotransferase; AST: Aminotransferase; Seg.: segmented.

1. Larson RA et al. Leukemia 2012 [Epub ahead of print].

0 10 20 30 40 50 60 70 80 90 100

Patients (%)

AST increased

ALT increased

Bilirubin (total) increased

Lipase (blood) increased

Glucose increased

Haemoglobin

Absolute neutrophils (seg. + bands)

Platelet count (direct)

Nilotinib 300 mg BID (n=279)

Imatinib 400 mg BID (n=280)

Adverse event onset in third year of therapy

11

ENESTnd: arterial Events by 4 Years

Patients, n (%)Nilotinib

300 mg BIDn = 279

Nilotinib400 mg BID

n = 277

Imatinib400 mg QD

n = 280

IHD (3 yrs in brackets) 11 (9) 14 (11) 3 (3)PAOD (3 yrs in brackets) 4 (4) 5 (3) 0

Between years 3 and 4, five new patients had an IHD event (2 in the nilotinib 300 mg BID arm and 3 in the nilotinib 400 mg BID arm), and 2 new patients had a PAOD event (both in the nilotinib 400 mg BID arm)

1 patient in the nilotinib 400 mg BID arm with previously reported PAOD had a newly reported drug-related SAE (arterial stenosis limb) leading to treatment discontinuation

Data cutoff: 27Jul 2012.

Mechanism not clear - ? Related to high glucose levelsWorrying – need more data, especially as now approved 1st line

Novartis Communication 25 Feb 2012: Atherosclerotic Related Events

Imatinib 400 mg qdN=280

Nilotinib 300 mg bidN=279

Nilotinib 400 mg bidN=277

Any graden (%)

Grade 3/4 n (%)

Any graden (%)

Grade 3/4 n (%)

Any graden (%)

Grade 3/4 n (%)

Any AREs         4 (1.4) 3 (1.1) 17 (6.1) 11 (3.9) 23 (8.3) 14 (5.1)Risk factors for ARE’s 4/4 (100%) 15/17 (88%) 22/23 (96%)AREs leading to discontinuation 0 0 0 0 10 (3.6) 8 (2.9)Peripheral Arterial Occlusive Disease (PAOD)          0 0 4 (1.4) 3 (1.1) 5 (1.8 ) 1 (0.4)Ischemic Heart disease  3 (1.1) 3 (1.1) 11 (3.9) 6 (2.2) 14 (5.1) 9 (3.2)Ischemic cerebrovascular 1 (0.4) 0 3 (1.1) 2 (0.7) 5 (1.8 ) 4 (1.4)

‘Clinicians should vigorously manage cardiovascular risk factors and AREs according to standard international guidelines regarding treatment of

hypertension, hyperlipidemia, and diabetes as well as smoking cessation’

Is Dasatinib any better...?

DASISION:2-year adverse event data

• Grade 3/4 biochemical abnormalities occurred in ≤3% of patients and with similar frequency in treatment arms except hypophosphataemia (dasatinib: 7%; imatinib 25%)

• Pulmonary arterial hypertension was diagnosed in 3 patients but did not lead to treatment discontinuation

Dasatinib 100 mg QD (n=258)

Imatinib 400 mg QD (n=258)

0 10 20 30 40 50 60 70 80 90 100

Fluid retention

Superficial oedema

Pleural effusion

Myalgia

Nausea

Diarrhoea

Vomiting

Rash

Headache

Fatigue

Neutropenia

Thrombocytopenia

Anaemia

Any

grad

eG

rade

3/4

Patients (%)

1. Kantarjian HM et al. Blood 2012; 119(5): 1123–1129.

Dasatinib and Pleural Effusions

• Occurs in approx. 20% of patients but only 5% Grade 3-4

• Thought to be caused by more potent inhibition of src

• Pleural fluid shows marked lymphocytic infiltrate

• Associated with peripheral blood lymphocytosis

• More common with higher / split doses of dasatinib

• Median time from start of drug to effusion is 5 weeks

• Most occur within 12 months

May resolve with steroid / diuretic combination and temporary stopping of dasatinibOthers require drainage and permanent discontinuation

Pulmonary Arterial Hypertension

• Circulation 2012, Montani et al• French study of 9 cases between 2008-2010• Estimated incidence 0.45% of patients exposed to dasatinib• Src inhibition thought to be implicated in pathogenesis• Late complication occurring 8-48 months after starting dasatinib• More common in females• Median age of patients 51 years• 6/9 patients also had concomitant pleural effusions but PAH

persisted even after effusions resolved• ? Reversible on stopping dasatinib

Evolution of clinical, functional, and hemodynamic parameters after dasatinib discontinuation

Most patients improved after stopping dasatinib but none returned completely to normal

How about the ‘new’ TKIs...?

Bosulif (bosutinib) and Iclusig (ponatinib) both now licensed for 2nd

line in the USA and are coming...

Can we Predict their Side Effects..?

Imatinib

(Phos. IC50)

PDGFR

72 nM >Kit

99 nM >BcrAbl

221 nM >Src

>1000 nM

Nilotinib

(Phos. IC50)

BcrAbl

20 nM >PDGFR

75 nM >Kit

209 nM >Src

>1000 nM

Dasatinib

(Phos. IC50)

Src

0.1 nM >BcrAbl

1.8 nM >PDGFR

2.9 nM >Kit

18 nM

Bosutinib

(Phos. IC50)

Src

3 nM >BcrAbl

85 nM >PDGFR

>3000 >Kit

>10000 nM

Ponatinib

(Phos. IC50)

BcrABl1

0.37 nM>

PDGFR

1.1 nM>

Src

5.4 nM>

Kit

12.5 nM

1. Manley PW, et al. Proc Am Assoc Cancer Res 2007;48:772.2. Weisberg E, et al. Cancer Cell 2005;7:1129.3. Remsing Rix LL, et al. Leukemia 2009;23:477.4. O’Hare T. et al (2009) Cancer Cell. 16: 401-412

Target kinases for the 5 Tyrosine Kinase Inhibitors

Adverse Event, n (%)All Grades(n = 288)

Grade 3–4(n = 288)

Diarrhea 243 (84) 26 (9)

Nausea 128 (44) 5 (2)

Vomiting 102 (35) 9 (3)

Rash 98 (34) 25 (9)

Abdominal pain 64 (22) 3 (1)

Fatigue 62 (22) 2 (1)

Pyrexia 60 (21) 1 (<1)

Cough 45 (16) 0

Headache 42 (15) 0

Arthralgia 38 (13) 1 (<1)

Decreased appetite 36 (13) 2 (1)

Nasopharyngitis 34 (12) 0

Constipation 32 (11) 1 (<1)

Asthenia 31 (11) 5 (2)

Bosutinib Study 200 (2nd Line): Treatment-emergent Adverse Events

Brümmendorf et al. Oral presentation, EHA 2010; abstr 1136.

Parameter Diarrhea Nausea Vomiting

Patients with event, n (%) 243 (84) 128 (44) 102 (35)

Median time to onset, d 2 5 8

Median duration, d 27 10 3

Resolved, n (%) 206 (85) 117 (91) 98 (96)

Received concomitant medication, n (%) 165 (68) 52 (41) 35 (34)

Required dose reduction, n (%) 13 (5) 6 (5) 7 (7)

Required dose interruption, n (%) 35 (14) 10 (8) 15 (15)

Discontinued treatment, n (%) 6 (3) 2 (2) 4 (4)

Bosutinib Study 200 (2nd Line): Gastrointestinal Adverse Events

Brümmendorf et al. Oral presentation, EHA 2010; abstr 1136.

Start with low dose and build up gradually. Warn patients & give loperamide!

Laboratory Abnormality, n (%) Grade 3–4 (n = 288)

Hypermagnesemia 35 (12)

Elevated ALT 30 (10)

Hypophosphatemia 23 (8)

Elevated lipase 23 (8)

Elevated uric acid 17 (6)

Elevated AST 14 (5)

Hypocalcemia 10 (3)

Hypomagnesemia 10 (3)

Hyperglycemia 9 (3)

Elevated INR 7 (2)

Bosutinib Study 200 (2nd Line): Other Grade 3–4 Laboratory Abnormalities

ALT, alanine aminotransferase; AST, aspartate aminotransferase; INR, international normalized ratio.Brümmendorf et al. Oral presentation, EHA 2010; abstr 1136.

Study 200 (2Study 200 (2ndnd Line): Grade 3–4 Line): Grade 3–4 Hematologic Laboratory AbnormalitiesHematologic Laboratory Abnormalities

Laboratory Abnormality, n (%) Grade 3–4 (n = 288)

Thrombocytopenia 71 (25)

Neutropenia 48 (17)

Anemia 35 (12)

Brümmendorf et al. Oral presentation, EHA 2010; abstr 1136.

Generally less haematological toxicity than other 2nd line agents – may be useful for patients who cannot tolerate other TKIs due to low counts

Bosutinib Study 200 (2nd Line): Other Adverse Events of Interest

• Pleural effusion

– Observed in 10 (3%) patients (all grades)

– Grade 3–4 pleural effusion reported in 1 (<1%) patient

• Effects on QTcF interval

– On treatment, 25 (9%) patients had grade 1–2 prolongation and 1 (<1%) patient had grade 3–4 prolongation

– At treatment completion, 2 (2%) patients had grade 1–2 prolongation and none had grade 3–4 prolongation

Brümmendorf et al. Oral presentation, EHA 2010; abstr 1136.

Ponatinib PACE Study: Treatment Emergent AEs

*Combines the terms erythematous, macular and papular rash14

≥ 20% any grade Total

CP-CML (N=270) Total Population (N=449)

Any Grade %

Grade 3/4 %

Any Grade%

Grade 3/4%

Non-hematologic

Rash* 43 4 38 4Abdominal pain 40 9 38 9Headache 40 3 35 2Dry skin 40 2 35 2Constipation 38 2 34 2Fatigue 27 1 27 2Pyrexia 23 1 27 2Nausea 24 1 26 1Arthralgia 26 3 25 2Hypertension 23 7 21 7Lipase increased 23 11 19 12Pancreatitis 7 6 6 5Amylase increased 7 1 7 2Hematologic

Thrombocytopenia 44 34 42 34Neutropenia 18 16 24 21Anemia 14 8 20 14

Ponatinib Phase 2 PACE Study:Treatment Emergent Serious AEs

15

• Serious adverse events of arterial thromboembolism, including arterial stenosis, were observed in patients with cardiovascular risk factors

SAEs in >6 Patients Total CP-CML (N=270) n (%)

Total Population (N=449)n (%)

Non-hematologicPancreatitis 17 (6) 24 (5)Abdominal pain 10 (4) 18 (4)Lipase increased 5 (2) 7 (2)Diarrhea 3 (1) 7 (2)Myocardial infarction 8 (3) 14 (3)Cardiac failure 5 (2) 13 (3)Atrial fibrillation 8 (3) 12 (3)Hypertension 6 (2) 8 (2)Coronary artery disease 6 (2) 6 (1)Pneumonia 7 (3) 22 (5)Pyrexia 7 (3) 15 (3)Sepsis 2 (1) 8 (2)Dehydration 2 (1) 6 (1)Cellulitis 2 (1) 6 (1)HematologicAnemia 5 (2) 13 (3)Febrile neutropenia 1 (<1) 13 (3)Thrombocytopenia 4 (1) 13 (3)Pancytopenia 1 (<1) 6 (1)Neutropenia 2 (1) 6 (1)

Iclusig Given FDA Approval but with Black Box Warning (Dec 2012)

• Important for haematologists to be aware of these toxicities

• Ponatinib forms part of the new SPIRIT 3 trial for newly diagnosed patients

Summary

• No drug is side effect free!• Side effect profile depends on the degree of inhibition of the kinases• Side effects rarely recur on switching to different TKI• Long term toxicity may be emerging but more data needed• Choice of drug needs careful consideration for each patient• Refractory patients: main consideration must be to achieve disease

control• Intolerant patients: ideally choose drug depending on other

comorbidities / risk factors (if funding allows)– Diabetes / cardiovascular risk factors: ? avoid nilotinib / ponatinib– Pulmonary issues: ? Avoid dasatinib– Low blood counts: consider bosutinib

• May need to brush up on cardiology skills!