Second and Third Generation Tyrosine Kinase Inhibitors: How do we Choose?

Dr Jenny Byrne

Nottingham

Imatinib is a wonderful drug!

IRIS 8-Year UpdateOverall Survival (Intent-to-Treat) – Imatinib Arm

% A

live

IRIS 8 year Results

Imatinib is a great drug ……

BUT

Not all patients respond well to Imatinib IRIS data excludes patients who discontinued

‘study’ Imatinib

Outcome for Patients Discontinuing IRIS Trial

All randomized to imatinibAll randomized to imatinib(n= 553; 100%)(n= 553; 100%)

All randomized to imatinibAll randomized to imatinib(n= 553; 100%)(n= 553; 100%)

Discontinued study imatinib*Discontinued study imatinib* (n = 221; 40%) (n = 221; 40%)

Discontinued study imatinib*Discontinued study imatinib* (n = 221; 40%) (n = 221; 40%)

Still receiving study imatinibStill receiving study imatinib (n = 332; 60%) (n = 332; 60%)

Still receiving study imatinibStill receiving study imatinib (n = 332; 60%) (n = 332; 60%)

In CCR In CCR (n = 317; (n = 317;

57%)57%)

In CCR In CCR (n = 317; (n = 317;

57%)57%)

No CCR No CCR (n = 15; (n = 15;

3%)3%)

No CCR No CCR (n = 15; (n = 15;

3%)3%) SafetySafety(n = 43; (n = 43;

8%)8%)

SafetySafety(n = 43; (n = 43;

8%)8%)

Efficacy Efficacy

(n = 82;(n = 82; 15%)15%)

Efficacy Efficacy

(n = 82;(n = 82; 15%)15%)

Other Other

(n = 96(n = 96; ; 17%)17%)

Other Other

(n = 96(n = 96; ; 17%)17%)

AliveAlive(n = 17; (n = 17;

40%)40%)

AliveAlive(n = 17; (n = 17;

40%)40%)

Dead**Dead**(n = 26; (n = 26;

60%)60%)

Dead**Dead**(n = 26; (n = 26;

60%)60%)

AliveAlive(n = 52; (n = 52;

63%)63%)

AliveAlive(n = 52; (n = 52;

63%)63%)

DeadDead(n = 30; (n = 30;

37%)37%)

DeadDead(n = 30; (n = 30;

37%)37%)

AliveAlive(n = 81; (n = 81;

84%)84%)

AliveAlive(n = 81; (n = 81;

84%)84%)

DeadDead(n = 15; (n = 15;

16%)16%)

DeadDead(n = 15; (n = 15;

16%)16%)

**Including primary discontinuation reason ‘Death’ (n=13)

*Patients may have continued imatinib off study.

Up to 40% of patients may ‘fail’ Imatinib

Imatinib Resistance and Intolerance

Some patients do not do well on imatinib...

Imatinib resistance may be defined as: Lack/loss of satisfactory response during imatinib therapy or

progression from chronic to accelerated phase or from chronic or accelerated to blast phase

Imatinib intolerance may be defined as: Side effects requiring either a dose reduction of imatinib to ≤400

mg/day or discontinuation of imatinib due to drug-related toxicity

(Poor adherence / missed doses may also be an issue)

Resistance has been defined as primary or acquired (also known as secondary)

Primary resistance Acquired resistance

Failure to achieve a response Loss of a confirmed response

• Primary haematological resistance

• failure to achieve a CHR• In chronic phase

• failure to return to CP• In advanced disease

• Primary cytogenetic resistance

• failure to achieve a CCyR or MCyR

• Haematological resistance• confirmed loss of a CHR

• Cytogenetic resistance• confirmed loss of a MCyR or

CCyR• Molecular resistance

• increase in BCR-ABL transcripts of more than 1 log

• Often assoc with emergence of a bcr-abl mutation

Hochhaus et al., Hematol Oncol Clin N Am 2004;18:641–56

BCR/ABL mutations are the most frequently

reported mechanism of acquired resistance

• Kinase domain mutations occur in 50-90% of cases of acquired resistance

• Resistance manifests itself through different mechanisms causing• Changes to the stability of the Bcr-Abl conformation• Reduction in binding efficiency of imatinib

Branford et al., Blood 2003;102:276–83; Shah et al., Hematol 2005;183–7; Melo et al., Cancer Lett 2006 (in press)

F486S

P B C A

Q252H/R

E255K/VY253H/F

G250E/A/F

L248V

D241G

M237I

M244V

E279K

E281A

T277A

E276G

K285N

E275K

E355G/D

F359V/C/D/I

V379I

L3641

M351T/L

F382L

G383D

L384M

L387F/M

M388LH396R/P

A397P E453G/K/A/V

E450G/Q/K

Q447R

S438C E459K/Q

A350V

T315I/A/D

A344V

M343T

F317L

S348L

L324Q

G321E

F311L/I/V

C305S

V299L

E292V

L298V

V289A/I

P296H

Adapted from Melo et al (2006)

K357R

5417Y

There is a Clear Need to Monitor Response to Therapy Carefully: ELN Guidelines 2013Time Optimal Response Warning Failure

Baseline n/a High risk or CCA/Ph+, major route

n/a

3 months BCR-ABL1 ≤ 10% and/or Ph+ ≤ 35%

BCR-ABL1 >10% and/or Ph+ 36-95%

No CHR and/or Ph+ >95%

6 months BCR-ABL1 <1% and/or Ph+ 0 (CCyR)

BCR-ABL1 1-10% and/or Ph+ 1-35%

BCR-ABL1 >10% and/or Ph+ >35%

12 months BCR-ABL1 ≤ 0.1% (MMR)

BCR-ABL1 >0.1-1%

BCR-ABL1 >1% and/or Ph+ >0

Anytime Stable or improving MMR

ACA/Ph- (-7 or 7q-) Loss of CHR, loss of CCyR, confirmed loss of MMR, mutations, ACA in Ph+ cells Baccarani M, et al. Blood 2013: 122: 872–884

Importance of achieving optimal response of ≤ 10% BCR-ABLIS at 3 months

Significant difference in 8-year overall survival (OS) rates in a real-world s

7

Early response is predictive of survival

• Achieving ≤ 10% BCR-ABL at 3 months correlates with significantly higher rates of improved PFS and OS 1

Marin et al. 2012

P < 0.001

Important to ‘Get the Drugs in’ to Achieve Optimal responses: Missed Doses Do Matter!

Chance of achievement of RQ-PCR <0.1% at 12 months decreases with decreased average dosing

Imatinib Dasatinib

Dosing in 1st

12 monthsAchievement of MMR

at 12 months (ITT)Achievement of MMR

at 12 months (ITT)

100% 125/227 (55.1%) 129/187 (69.0%)

95-99.9% 14/27 (51.9%) 20/29 (69.0%)

80-95% 3/10 (30.0%) 17/37 (45.9%)

<80% 6/18 (33.3%) 13/29 (44.8%)

Which 2nd line drug should we choose for our patients?

Up to 40% of patients may ‘fail’ 1st line Imatinib

Up to 20% may ‘fail’ Nilotinib / dasatinib 1st line

Imatinib

Dasatinib-1st and 2nd line

Nilotinib- 1st and 2nd line

Bosutinib- 2nd/3rd line if other TKIs not appropriate

Ponatinib- T315I or if no other TKI indicated

2000 2010 20152005

Development License NICE approved

Off patent2016

TKIs in CML

CDF

Licensed Drugs in CML

N

NON

NH

NC O

O

ClCl

Bosutinib

- 500 mg once a day

Dasatinib-More potent-100 mg once daily

Ponatinib-Most potent-30 mg once daily

- 400 mg twice a day

Treating CML is Not Easy! PATIENT FACTORS

Patients are not all the same! Different ages, comorbidities, sensitivity to side effects Compliance

DISEASE FACTORS CML is not a homogeneous disease! Different biological properties affecting sensitivity to different

drugs Different mutations

DRUG FACTORS The different drugs are not all equal! Different toxicities Varying efficacy against different mutations

Aim is to match the correct patient with the correct drug for their CML!

Not that easy as in the UK we are not able to access all the drugs freely

What do the Guidelines Say?ELN Guidelines 2013 – 2nd Line TreatmentA change of therapy is mandatory for resistance or toxicityIf there is intolerance, any other available TKI can be used, including imatinib second-line after a second-generation TKI first-line.For resistance, the logic sequence is: [1] from imatinib to any other available and approved TKI (dasatinib, nilotinib, bosutinib, ponatinib), [2] from nilotinib to other TKIs (dasatinib, bosutinib, ponatinib), and [3] from dasatinib to other TKIs (nilotinib, bosutinib, ponatinib).Regrettably, there are no studies comparing different TKIs in second-line. Therefore, the choice of the second-line TKI is guided by some patient characteristics, mainly age and comorbidities, by the type of side effects with the first TKI, and by the presence of BCR-ABL1 kinase mutations, and also by drug availability and cost, and by doctor experience.

No Clear Winner with Respect to Efficacy

No trials have directly compared the drugs

Factors that need to be borne in mind when choosing 2nd line treatments

Any known mutationsKnown toxicities of the drugsPatient related comorbidities

What drugs are funded by the NHS!

Efficacy against Different Mutations

Efficacy against Double Mutations

Even more difficult when there are 2 mutations

Side Effects due to the TKIs are caused by their ‘Off-Target’ 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

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

Most of the drugs have unwanted effects on other cellular proteins leading to their side effects

Choice of Drug: Relative Toxicities

Imatinib Nilotinib Dasatinib Bosutinib

Oedema ++ + + -

Diarrhoea ++ + + +++(transient)

Rash + ++ + +

Headache + ++ ++ +

Glucose - ++ - +

Lipase - + - +

QT prolongation - + + +

Hepatotoxicity + + - +

Haem toxicity + ++ ++ +

Pleural effusions - - ++ (20%) + (3%)

Pulm hypertension - - + (0.5%) ?+

PAOD and IHD - + (6%) - -

risk benefit

Need to balance

Choice of Drug - Comorbidities

Drug Try to Avoid in

Nilotinib-Worsens blood glucose levels-Cardiovascular risk factors

DiabeticsPatients with history of cardiovascular problems eg angina, stroke

Dasatinib-Pleural effusions-Pulmonary hypertension

Chronic lung diseases

Difficult times…

We may not be able to use the drugs we want to due to funding issues

NICE & the CDF- Recent changes

Currently approved 2nd Line Treatments

• Second-line therapy for adults with CP/AP Ph+ CML who are resistant to treatment with standard-dose imatinib or who have imatinib intolerance2

Nilotinib*

• Second-line therapy for adults with CP Ph+ CML who are resistant to or intolerant of at least one prior treatment including imatinib

Nilotinib5

NICE SMC

1. NICE. Technology appraisal 251. 2. NICE. Technology appraisal 241.

3. SMC. No. 709/11. 4. SMC. No. 01/02.

5. SMC. No. 440/08.

*If the manufacturer makes nilotinib available with the discount agreed as part of the patient access schemeDasatinib and high dose Imatinib not approved (2012)

NB: Can still get other drugs for certain patients via the Cancer Drugs Fund

Cancer Drugs Fund (CDF) New drugs have to prove their safety, quality and efficacy NICE: clinical effectiveness – how well does something work in

comparison with what we already use? AND cost effectiveness – how much more life or quality of life do we get for the extra money spent?

A positive NICE appraisal has to be funded by the NHS: as the budget is fixed, something else has to be axed or delayed

Main issue with NICE - too slow, so in 2007 government set up CDF to improve access to cancer drugs in the UK

Each drug is scored for impact on survival, quality of life, toxicity and ‘unmet need’ (is it the only systemic therapy for that disease?)

14/15 expenditure on November list £390m and £420m in 15/16 84 separate drug indications in the CDF in November 14 and as

overspent the lowest scoring 45 indications assessed in this recent prioritisation process and 18 removed (including CML drugs)

Due to finish April 2016 – not quite sure what next!

Available TKIs: NICE and National CDF1st Line CP 2nd Line CP 3rd / 4th Line CP

Imatinib (NICE) (after IFN) X

Nilotinib (NICE) (NICE) X

Dasatinib X x If IM intol / ref ANDNIL intol (but not refractory)

Bosutinib X X If NIL AND DAS intol (but not refractory)

Ponatinib X XUnless T315I

XUnless T315I

Not all patients will respond to 2nd line drugs

40- 50% of patients requiring a 2nd line treatment will ‘fail’ There is some evidence for 3rd line treatment using an alternative drug

but funding is an issue Other option is a stem cell transplant (which is funded)

CHR MCyR CCyR

Nilotinib 2nd Line Responses

Bosutinib 3rd Line Results

Response, n (%)

IM + D Resistant(n = 36)

IM + D Intolerant(n = 51)

IM + NI Resistant(n = 27)

Median follow-up (range), mo 14.8(2.7–47.3)

28.7(0.3–49.7)

12.2(2.0–48.0)

Hematologic response

Evaluable patients 36 50 27

Complete 22 (61) 40 (80) 21 (78)

Cytogenetic response

Evaluable patients 34 38 24

Major 10 (29) 14 (37) 7 (29)

Complete 3 (9) 13 (34) 4 (17)

Partial 7 (21) 1 (3) 3 (13)

Molecular response

Evaluable patients 25 47 16

Major 2 (8) 17 (36) 1 (6)

Khoury et al. Oral presentation 892, ASH 2010.

Ponatinib Results

Licensed post 1st line if other drugs not suitable

Efficacy of 3rd Line Drugs

Lipton et al (Ariad sponsored)

Evidence suggests ponatinib more effective than bostunib

What do the Guidelines Say re 3rd Line?

• There are no evidence-based, reliable, specific recommendations for the patients who fail two or even three TKIs.

• These patients form a heterogeneous group• Can try any of the remaining TKIs• Consider SCT in eligible patients. • Ponatinib is likely to be more efficient than

any other TKI, but there are no comparative studies

Summary The second generation drugs are effective for many patients

who are resistant to or intolerant of Imatinib Not clear which one is the best Responses may be durable Side effect profiles of the drugs differ and rarely overlap Generally safer than transplants Should be offered to patients who fail / can’t take Imatinib Choice of drug should depend on mutation analysis, side

effects & patient comorbidities BUT not all drugs are funded Not a cure all! Some patients won’t respond Limited choice for 3rd line treatment in the UK Transplantation remains an alternative option