dose reduction. what do we know and how we do it in ... · front-line randomized trials in cml-cp...
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Dose reduction. What do we know
and how we do it in clinical practice.
Andreas Hochhaus
Hadera I Oct 2018
Front-line Randomized Trials in CML-CP
Trial Drugs References
IRIS IM 400 vs IFN/AraC O’Brien NEJM 2003; Druker NEJM 2006; Hochhaus NEJM 2017
TOPS IM 400 vs IM 800 Cortes JCO 2010
GIMEMA IM 400 vs IM 800 Baccarani Blood 2009
SWOG IM 400 vs IM 800 Deininger Br J Haem 2014
DASISION IM 400 vs DAS 100 Kantarjian NEJM 2010; Cortes JCO 2016
SWOG 0325 IM 400 vs DAS 100 Radich Blood 2012
SPIRIT IM 400+/-AraC or +/- PegIFN vs IM 600 Preudhomme NEJM 2010
CML IV IM 400+/-IFN vs IFN vs IM 800 Hehlmann JCO 2014; Kalmanti Leukemia 2015
ENESTnd IM 400 vs NIL 600 vs NIL 800 Saglio NEJM 2010; Hughes Blood 2014; Hochhaus Leukemia 2016
BELA BFORE
IM 400 vs BOS 500 IM 400 vs BOS 400
Brümmendorf Br J Haem 2015 Cortes ASCO 2017
SPIRIT 2 IM 400 vs DAS 100 O’Brien ASH 2014, EHA 2015
EPIC Radotinib
IM 400 vs Ponatinib 45 IM 400 vs. Radotinib 600 vs. Radotinib 800
Lipton Lancet Oncol 2016 Kwak ASH 2015
Imatinib PDGFR > Kit > Bcr-Abl > Src
(Phos. IC50) 72 nM 99 nM 192 nM >1000 nM
Nilotinib Bcr-Abl > PDGFR > Kit > Src
(Phos. IC50) 19 nM 75 nM 209 nM >1000 nM
Dasatinib Src > Bcr-Abl > PDGFR > Kit
(Phos. IC50) 0.1 nM 1.8 nM 2.9 nM 18 nM
Bosutinib Bcr-Abl > Src > Kit > PDGFRa
(Phos. IC50) 0.5 nM 1.0 nM 6300 nM >10 µM
Target profile of 1st and 2nd generation TKIs
www.cellsignal.com
TKI off-target effects?
Apperley, Lancet 2007
Leukemia cells
Se
ns
itiv
ity
Dru
g d
os
ag
e / c
on
ce
ntr
ati
on
Leukemia cells
Se
ns
itiv
ity
Dru
g d
os
ag
e / c
on
ce
ntr
ati
on
Most resistant cells will be selected and create relapse
TKI drug interactions
Drugs inhibiting CYP3A4 may increase TKI exposure
– ketoconazole, itraconazole, voriconazole
– erythromycin, clarithromycin, telithromycin
– ritonavir, atazanavir, indinavir, nelfinavir, saquinavir, nefazodon,
CYP3A4 inducers may decrease TKI exposure
– dexamethasone, rifampicin, rifabutin, phenytoin, carbamazepin,
phenobarbital
Concomitant use of TKI and CYP3A4 substrate may increase
substrate exposure (narrow therapeutic index!)
– fentanyl, alfentanil
– astemizole, terfenadine
– cyclosporine, sirolimus, tacrolimus
– quinidin, ergot alkaloids, pimozide, cisapride
– simvastatin
Grapefruit juice may increase TKI plasma concentration
Adherance measure by MEMS
(microelectronic monitoring system)
Adherence
• Young age
• Dose increase
• Adverse effects
Marin et al., J Clin Oncol 2010
Relative toxicities of TKIs in independent
second-line trials after imatinib failure
% Severe toxicity Imatinib* (Druker et al.
2006)
Nilotinib (Nicolini et al.
2009;
Dasatinib (Shah et al.,
2008)
Bosutinib (Cortes et al.,
2010)
Myelosuppression ++ + +++ +
Fluid retention ++ - +++ -
Diarrhea + + + +++
Glucose / Lipase - + - -
Druker et al. N Engl J Med. 2006; 355:2408-1
Nicolini et al. Haematologica (EHA Meeting Abstracts) 2009; 94(s2): Abstract 0630
Shah et al. Blood (ASH Annual Meeting Abstracts), Nov 2008; 112: 3225.
Cortes et al. JCO. 2010; ASCO Ann. Meeting Proc. 28, 15S: 6502
* first line
Nilotinib in Newly Diagnosed CML-CP (ENESTnd)
Study Design
N = 846
217 centers
35 countries
*Stratification by Sokal risk score
Follow-up 5 years
Imatinib 400 mg QD (n = 283)
Nilotinib 300 mg BID (n = 282) R A N D O M I Z ED *
Nilotinib 400 mg BID (n = 281)
Saglio G, et al. N Engl J Med. 2010;362(24):2251-2259. Hughes TP, et al. Blood. 2010;116(21):94-95 [abstract 207].
Primary endpoint: MMR at 12 months Key secondary endpoint: Durable MMR at 24 months Other endpoints: CCyR, time to MMR and CCyR, EFS, PFS,
time to AP/BC, OS
71%, P < .0001
67%, P < .0001
44%
By 24 months
100
90
80
70
60
50
40
30
20
10
0
% W
ith
MM
R
0 3 6 9 12 15 18 21 24 27 30 33
Time Since Randomization (Months)
55%, P < .0001
51%, P < .0001
27%
By 12 months
Δ 24%-28%
Δ 23%-27%
Nilotinib 300 mg BID
Nilotinib 400 mg BID
Imatinib 400 mg QD
282
281
283
n
*ITT population.
Hughes TP, et al. Blood. 2010;116(21):94-95 [abstract 207].
Data cut-off: 20 Aug 2010.
BID, twice daily; QD, once daily.
Nilotinib in Newly Diagnosed CML-CP (ENESTnd): 24 Month Data
Cumulative Incidence of MMR*
Cardiovascular events on nilotinib vs. imatinib
Hochhaus et al. ENESTnd, Leukemia 2016
0 10 20 30 40
Months
%
100
Dasatinib 100 mg QD
Imatinib 400 mg QD
20
10
0
By 24 months
17%
8%
P=0.002
DASISION: Cumulative incidence of
BCR-ABLIS ≤0.0032% (MR4.5)
Kantarjian et al., ASCO 2011
Cortes et al. J Clin Oncol 2016
Adverse events Dasatinib vs. Imatinib
van Erp et al., Cancer Treatment Reviews 2009; 35:692-706
Half live of various TKIs
Shah et al., Cancer Cell 2008
Dasatinib: Transient inhibition of BCR-ABL
R
5 *100mg + 2 * 0mg (5+2)
7 *100mg
24 months
TS = n * G (CTCAE v.4.03)
CML Tx naive
CML TKI resistant
CML TKI intolerant
Non-Inferiority N = 306 60 trial centers 5 Jahre
≤ 4 weeks HU, Imatinib or Dasatinib
6 12 18
3-monthly molecular monitoring BCR-ABLIS
Screening
SA-1 SA-2
SA: Safety analysis (DMC) TS: Toxicity Score cum. MR 24 ms: cumulative molecular response by 24 ms.
cum. MR 24 ms
Dasatinib Holiday for Improved Tolerability (DasaHIT)
Cortes, et al. Blood. 2018;132:393–404.
56
49
35
26
20
72 70
58
45
38
60
54
40
30
24
0
20
40
60
80
100
Resistant/intolerant (n=203) T315I (n=64) All CP-CML (n=267)
PACE: Response to ponatinib in patients with CP-CML
after failure to previous TKIs
MCyR CCyR MMR MR4 MR4.5
Ponatinib:Estimated duration of MMR (response at any time) for CP-CML patients
Cortes, et al. Blood. 2018;132:393–404.
Examples of AE terms included in category
-Angina pectoris -Myocardial infarction
-Coronary artery disease
CARDIAC
Examples of AE terms included in category
-Cerebrovascular accident
-Cerebral infarction -Carotid artery
stenosis
CEREBRAL
Examples of AE terms included in category
-Peripheral arterial occlusive disease -Peripheral artery
stenosis -Peripheral ischemia
PERIPHERAL CARDIAC (AE 14%/SAE 11%)
CEREBRAL (AE 12%/SAE 10%)
PERIPHERAL (AE 11%/SAE 9%)
Examples of AE terms included in category
-Deep vein thrombosis -Pulmonary embolism -Retinal vein occlusion
VTE VTE (AE 5%/SAE 4%)
Venous: (5%)* Arterial: (29%)*
Ponatinib: arterial occlusive events and
venous thromboembolism
SOURCE: Cortes, et al. Am Soc Clin Oncol 2016:Abstr 7013. ARIAD Pharmaceuticals, Inc. Data on file as of Aug 2015.
*Events occurring in patients with CP-CML; 4-year follow-up.
†Dose reduction and/or interruption.
No. of events (%)
Median time to onset, days (range)
Median AE duration, days
Discontinuation due to AE, n (%)
Dose modification, n (%)†
39 (14) 33 (12) 31 (11)
394 (15–1355) 681 (12–1339) 505 (8–1300)
27 30 315
4 (10) 6 (18) 2 (6)
21 (53) 9 (27) 8 (26)
PACE: exposure-adjusted incidence of
new AOEs over time
0 to <1 year 1 to <2 years 2 to <3 years 3 to <4 years
SOURCE: Cortes, et al. Am Soc Clin Oncol 2016:Abstr 7013.
No
. of
pat
ien
ts w
ith
eve
nts
pe
r 1
00
pat
ien
t-ye
ars
Do
se inten
sity (mg
/d)
15.5 15.7
10.4 9.6
32.7 31.4
25.5
19.7
0
5
10
15
20
25
30
35
40
45
0
2
4
6
8
10
12
14
16
18
mg/d mg/d
mg/d
mg/d
Summary of Exposure-Adjusted Incidence Rates for Newly Occurring AOEs* in All Patients
Interval†
**In the safety population †Later intervals exclude patients with prior events; ongoing patients may have a different risk than those at study start
• This univariate analysis of the PACE population shows that the relative risk for serious AOEs differs by risk category; some conditions are associated with higher risk
• Before starting treatment with ponatinib, a patient’s CV status should be assessed, including history and physical examination, and CV risk factors should be actively managed
PACE: Relative Risk of Serious AOEs by Risk
Category
RR (95% CI)
0.0 1.0 2.0 3.0 4.0 5.0 6.0
Hypertension* (n=240) 2.6 (1.6–4.1)
Ischemic cardiac disease† (n=101) 2.4 (1.6–3.5)
Diabetes‡ (n=72) 2.1 (1.4–3.2)
Hypercholesterolemia§ (n=229) 2.0 (1.3–3.0)
Age ≥65 years (n=155) 1.8 (1.2–2.6)
Male (n=238) 1.6 (1.0–2.4)
Non-ischemic cardiac disease† (n=193) 1.4 (0.9–2.0)
Obesity|| (n=109) 1.2 (0.8–1.8)
Risk factor
*Includes medical history, prior concomitant medication, and/or baseline blood pressure gr ≥2. †Includes medical history and/or prior concomitant medication. ‡Includes medical history, prior concomitant medication, and/or baseline glucose gr ≥2. §Includes medical history, prior concomitant medication, and/or baseline triglycerides gr ≥1. ||Includes medical history and/or baseline BMI ≥30 kg/m2.
SOURCE: ARIAD Pharmaceuticals, Inc. Data on file as of Aug 2015. Previously presented by Cortes, et al. Eur Hematology Assoc Ann Mtg 2015:Abstr P234
RR (95% CI)
NOTE: Node size in graph represents patient numbers; line signifies derived 95% CI.
PACE safety population
Multivariate analysis of arterial occlusive events by
dose intensity
SOURCE: Hochhaus, et al. J Clin Oncol 2014;32(5s):abstr 7084.
Probability of arterial occlusive events vs dose intensity in subset of PACE* patients (n=446)
15 mg/day
30 mg/day
45 mg/day
0.2
0.1
0.3
0.0
Esti
mat
ed p
rob
abili
ty
Fit 95% CI
• Each 15 mg/day reduction in average daily dose intensity is predicted to lead to approximately a 33% reduction in the risk of arterial occlusive events
• Multivariate analyses suggested that dose reduction/interruption may be a strategy for reducing risk
Dose intensity
*Post hoc retrospective analysis; estimation by reduced multivariate model. The optimal dose has not yet been identified.
Company-sponsored trial: OPTIC
(a dose-ranging study)
Ponatinib 45 mg
once daily*
Ponatinib 15 mg
once daily*
Adult patients with CP-CML resistant to ≥2 TKIs and without significant CV history
Primary endpoint: MCyR by 12 months; N=450
Discontinue from study if no MCyR by 12 months OR
Continue treatment up to 2 years or until loss of response or intolerance
1:1:1 randomization
Ponatinib 30 mg
once daily*
An international randomized phase 2 trial to characterize the
efficacy and safety of three starting doses of ponatinib
Dose reduction to 15 mg once daily
upon achievement of MCyR or MR2 at 3, 6, 9, or 12 months
*Dose reductions due to AEs permitted.
All compounds are either investigational or being studied for potential new use. Efficacy and safety have not been established. This information is
presented only for purposes of providing an overview of clinical trials and should not be construed as a recommendation for use.
Optimal TKI-Dose ?
Drug
Salvage therapy Frontline
Initial
approval Current Should be
Initial
attempt Approved Should be
Imatinib 400 mg
QD
400 mg
QD --
400 mg
QD
400 mg
QD
600-800
mg QD
Dasatinib 70 mg
BID
100 mg
QD
50-100
mg QD?
100 mg
QD
100 mg
QD
70 mg QD?
100 mg
5x/w.?
Nilotinib 400 mg
BID
400 mg
BID
300-400
mg QD?
300-400
mg BID
300 mg
BID
300 mg
BID
Bosutinib 500 mg
QD
500 mg
QD
400 mg
QD?
500 mg
QD
400 mg
QD
400 mg
QD
Ponatinib 45 mg
QD
45 mg
QD
30 mg
QD?
45 mg
QD -- --
Dose reduction
Standard dose
Regular initial
reduction
Minimum dose to avoid
resistance
Imatinib 400 mg/d 300 mg/d 300 mg/d
Nilotinib 2x300 mg/d 450 mg/d 400 mg/d
Dasatinib 100 mg/d 80 mg/d 70 mg 5*/week
Bosutinib 400 mg/d 300 mg/d 300 mg/d
Ponatinib 30 mg/d 15 mg/d 15 mg/d
