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An NCRI randomised study comparing dasatinib with imatinib in patients with newly diagnosed CML Stephen OBrien, Corinne Hedgley, Sarah Adams, Richard Clark, Jane Apperley, Letizia Foroni, Chris Pocock, Tessa Holyoake, Jenny Byrne, Caroline

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An NCRI randomised study comparing dasatinib with imatinib in patients with newly diagnosed CML

Stephen O’Brien, Corinne Hedgley, Sarah Adams, Richard Clark, Jane Apperley, Letizia Foroni, Chris Pocock, Tessa Holyoake, Jenny Byrne, Caroline Hodgson, Wendy Osborne, Mhairi Copland, John Goldman

The Newcastle Hospitals NHS Foundation Trust

www.spirit-cml.org

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814 patients recruited

Recruitment closed Feb 2013

172 hospitals set up 145 recruited patients

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Acknowledgements

Data analysis and presentation Stephen O’Brien, Corinne Hedgley, Sarah Adams Trial management and data collection Newcastle Corinne Hedgley, Lynn Seeley, Caroline Hodgson, Ruth Bescoby, Carrie Page, Angela Fallows, Laura Brown, Wendy Banks, Meg Buckley, Leanne Woolmer, Wendy Osborne PCR & DNA/RNA biobanking Letizia Foroni, Gareth Gerrard, Hammersmith Cell biobanking Tessa Holyoake, Alan Hair, Glasgow Study Management Committee SO’B, CH, Richard Clark, Liverpool; Jane Apperley, Hammersmith, Mhairi Copeland (Chair of CML WG) Data Monitoring Committee John Goldman, Keith Wheatley, Graham Dark Sponsor Newcastle Hospitals NHS Foundation Trust Funder Bristol Myers Squibb Chief Investigator Stephen O’Brien Sites n=172. Thanks to all our investigators and site staff. Patients n=814. A huge thank you to all participating patients.

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Imatinib Dasatinib Nilotinib Bosutinib Ponatinib 2000 2010 2015 2005

Development License NICE approved

Off patent 2016

TKIs in CML

CDF

(radotinib)

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Background

Imatinib still used as first line therapy
2nd generation TKIs generally produce higher rates of

major molecular response

Dasision study* (n= 519) MR3 (MMR) at 3 years:
Imatinib 55%

69% still on treatment

Dasatinib 69%

71% still on treatment

No differences in OS at 3 years
Some concerns about long term safety of 2nd gen
SPIRIT 2 (n=814) is largest comparative dasatinib trial

*Jabbour et al. Blood (2014); 123: 494-500

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SPIRIT 2: study design

Chronic phase CML

within 3 months of diagnosis

R

Arm A Imatinib 400 Arm B Dasatinib 100 Randomised, open label Primary endpoint: 5 year EFS

Secondary: cytogenetic, PCR response, toxicity n=814 N=407 N=407

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Inclusion criteria

1. Male or female patients ≥ 18 years of age.
2. Patients must have all of the following:

i) be enrolled within 3 months of initial diagnosis of chronic phase CML ii) confirmation of the Philadelphia chromosome or variants of (9;22) translocations; iii) (a) < 15% blasts in peripheral blood and bone marrow; (b) < 30% blasts plus promyelocytes in peripheral blood and bone marrow; (c) < 20% basophils in peripheral blood, (d) ≥ 100 x 109/L platelets iv) no evidence of extramedullary leukaemic involvement, with the exception

f hepatosplenomegaly.
3. Written voluntary informed consent.

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Exclusion criteria

1. Ph-negative, BCR-ABL-positive, disease not eligible
2. Any prior treatment for CML (hydroxycarbamide and

anagrelide permitted)

3. Prior chemotherapy, including PBSC mobilisation
4. Prior autograft or allograft
5. ECOG Performance Status Score ≥ 3
6. >2x ULN liver, renal function; >1.5x ULN coag; warfarin OK
7. Uncontrolled medical disease; known HIV pos; major surgery

within 4 weeks

8. Patients who are: pregnant; breast feeding; not on appropriate

contraception

9. Other malignancy within the past five years (except BCC)

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Endpoints

Primary:

5 year event free survival (EFS)

– Assessed for all patients March 2018 Secondary:

Rate of complete cytogenetic response (CCR)
Rate of Major Molecular Response

– (MMR, MR3, BCR-ABL/ABL ratio<0.1%)

Toxicity
Treatment failure rates (TFR) after 5 years
Rates of complete haematologic response (CHR)
Overall survival at two and 5 years

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Patients enroled

Characteristic Imatinib n=407 (%) Dasatinib n=407 (%) Total n=814 (%) Age Median 53.0 53.0 53.0 Range 18.0-87.0 18.0-89.0 18.0-89.0 Gender Female 165 (40.5) 157 (38.6) 322 (39.6) Male 241 (59.2) 249 (61.2) 490 (60.2) NK 1 (0.2) 1 (0.2) 2 (0.2) Available data for Sokal 242 (59.6) 246 (60.6) 488 (60.1) Follow up (months) Median 35.0 35.0 35.0 Range 7 – 65 8 – 68 7 - 69

Aug 2008 to Feb 2013 814 in 54 months: 15 per month

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What happened to the patients?

Imatinib n=407 (%) Dasatinib n=407 (%) Total n=814 (%) Consent withdrawl/protocol violation 1 (0.2) 1 (0.2) 2 (0.2) Treated 406 (%) 406 (%) 812 (%) All deaths, any cause 12 (3.0) 14 (3.4) 26 (3.2) Ongoing 249 (61.3) 291 (71.7) 540 (66.5) Discontinued 157 (38.7) 115 (28.3) 272 (33.5)

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Patients who discontinued

Imatinib n=157 (%) Dasatinib n=115 (%) Total n=272(%) Consent withdrawn 4 (1.0) 9 (2.2) 13 (1.6) Death, any cause 7 (1.7) 4 (1.0) 11 (1.4) Accelerated phase 3 (0.7) 2 (0.5) 5 (0.6) Blast crisis 7 (1.7) 4 (1.0) 11 (1.4) Failure to achieve CCR after 24 months 3 (0.7) 1 (0.2) 4 (0.5) Failure to achieve MCR after 12 months 20 (4.9) 3 (0.7) 23 (2.8) Intolerance - non haem tox 48 (11.8) 67 (16.5) 115 (14.2) Intolerance - haem/lab tox 11 (2.7) 10 (2.5) 21 (2.6) Loss of CHR 4 (1.0) 4 (0.5) Loss of MCR 8 (2.0) 2 (0.5) 10 (1.2) Lost to follow up 1 (0.2) 1 (0.1) Other 4 (1.0) 10 (2.5) 14 (1.7) Suboptimal respose (cytogenetic, haematological, molecular, mutation detected) 37 (9.1) 3 (0.7) 40 (4.9)

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Adverse events

All grades Imatinib n=406 (%) Dasatinib n=406 (%) Fluid retention 12 (3.0) 11 (2.7) Oedema 7 (1.7) 4 (1.0) Pleural effusion 3 (0.7) 77 (19.0) Required chest drain 13 (3.2) 13 of 77 is 16.9% Myalgia 32 (7.9) 23 (5.7) Nausea 124 (30.5) 91 (22.4) Vomiting 49 (12.1) 46 (11.3) Diarrhoea 119 (29.3) 96 (23.6) Fatigue 102 (25.1) 119 (29.3) Headache 52 (12.8) 101 (24.9) Rash 69 (17.0) 97 (23.9) Dyspnoea, no pleural effusion 32 (7.9) 69 (17.0)

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Comparative AEs

Fluid retention Oedema Pleural effusion Myalgia Nausea Vomiting Diarrhoea Fatigue Headache Rash Pulmonary (arterial) hypertention Dyspnoea (exertional) with no pleural effusion

Favours dasatinib Favours imatinib

Difference 95% CIs

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Lab AEs

Imatinib 406 (%) Dasatinib 406 (%) Total 812 (%) All grades Grade 3/4 All grades Grade 3/4 All grades Grade 3/4 Anaemia 362 (89.2) 105 (25.9) 372 (91.6) 124 (30.5) 734 (90.4) 229 (28.2) Neutropenia 187 (46.1) 40 (9.9) 208 (51.2) 44 (10.8) 395 (48.6) 84 (10.3) Thrombocytopenia 194 (47.8) 17 (4.2) 280 (69.0) 51 (12.6) 474 (58.4) 68 (8.4) Elevated ALT 148 (36.5) 6 (1.5) 180 (44.3) 328 (40.4) 6 (0.7) Elevated creatinine 81 (20.0) 13 (3.2) 71 (17.5) 17 (4.2) 152 (18.7) 30 (3.7)

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PCR milestones (used in SPIRIT 3)

Imatinib (n=406) Dasatanib (n=406) Total (n=812) 3 month samples 305 (100%) 304 (100%) 609 (100%) PCR <10% (MR1) 147 (48.2) 235 (77.3) 382 (62.7) 12 month samples 340 (100%) 358 (100%) 698 (100%) PCR <1.0% (MR2) 240 (70.6) 301 (84.1) 541 (77.5) 18 month samples 274 (100%) 291 (100%) 565 (100%) PCR <0.1% (MR3) 137 (50.0) 163 (56.0) 300 (53.1)

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PCR response and pleural effusion

Imatinib n=406 Dasatinib n=406 Total n=812 Available 18 month PCR 274 (100%) 291 (100%) 565 (100%) PCR <0.1% (MR3) 137 (50.0) 163 (56.0) 300 (53.1) No pleural effusion Available 18 month PCR 272 (100%) 233 (100%) 505 (100%) PCR <0.1% (MR3) 137 (50.4) 125 (53.6) 262 (51.9) With pleural effusion Available 18 month PCR 2 58 60 PCR <0.1% (MR3) 38 (65.5) 38 (63.3)

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Conclusions

Largest randomised trial of dasatinib vs imatinib

– n=814 – median follow up 3 years

Both drugs generally well tolerated

– 540 of 812 (66.5%) continue on study medication – GI tox, pleural effusions – No difference in cardiovascular events

786/812 (96.8%) remain alive overall
Comparative response, survival to follow
Dasatinib might allow more patients to reduce dose, stop
Dasatinib supply free of charge until at least 2018

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Key questions in CML

1. 10% at 3 months seems important. Can we improve
utcome by switching drugs?
2. Imatinib is going to be around for a while. Can we work
ut how best to use it?
3. Can we give CML patients less treatment, minimise

toxicity and stop treatment? – Quality of life, toxicity – Economics – Survival not compromised; ‘cure’

4. What’s the most cost effective way to treat CML?
5. Can we personalise treatment?

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www.spirit-cml.org

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R

Imatinib Nilotinib Group up I Group up N Imatinib Ponatinib Ponatinib Nilotinib Stage ge 1

Randomise ise

(500 to each group)

Stage ge 2

Sele lecti ctive ve switch tch

(3 mont nths hs or la later er)

Stage ge 3

Reduce ce dose se, stop

(aft fter r minim imum 3 years rs)

Primary y endpoin int

MR3 at 3 years rs

Imatinib Ponatinib Ponatinib Nilotinib Aim to reduce and stop

(if MR3 for at least 1 year)

www.spirit-cml.org

n=500 n=500

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An NCRI randomised study comparing dasatinib with imatinib in patients with newly diagnosed CML

Stephen O’Brien, Corinne Hedgley, Sarah Adams, Richard Clark, Jane Apperley, Letizia Foroni, Chris Pocock, Tessa Holyoake, Jenny Byrne, Caroline Hodgson, Wendy Osborne, Mhairi Copland, John Goldman

The Newcastle Hospitals NHS Foundation Trust