Bosutinib vs Imatinib for Newly Diagnosed Chronic Myeloid Leukemia: Results From the BFORE Trial

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1 Bosutinib vs Imatinib for Newly Diagnosed Chronic Myeloid Leukemia: Results From the BFORE Trial Tim H. Brümmendorf, 1 Carlo Gambacorti-Passerini, 2 Michael Deininger, 3 Michael J. Mauro, 4 Charles Chuah, 5 Dong-Wook Kim, 6 Philipp Le Coutre, 7 Kathleen Jentsch-Ullrich, 8 Cornelius F. Waller, 9 Dominik Wolf, 10 Laurence Reilly, 11 Allison Jeynes-Ellis, 11 Eric Leip, 12 Nathalie Bardy-Bouxin, 13 Andreas Hochhaus, 14 and Jorge E. Cortes, 15 on behalf of the BFORE Study Investigators 1 Universitätsklinikum RWTH Aachen, Aachen, DE; 2 University of Milano-Bicocca, Monza, IT; 3 University of Utah, Salt Lake City, UT, USA; 4 Memorial Sloan Kettering Cancer Center, New York, NY, USA; 5 Singapore General Hospital, Duke-NUS Graduate Medical School, Singapore, SG; 6 Seoul St. Mary s Hospital, Seoul, KR; 7 Charité-Universitätsmedizin Berlin, Berlin, DE; 8 Private Practice, Magdeburg, DE; 9 University Medical Centre Freiburg and Faculty of Medicine, University of Freiburg, Freiburg, DE; 10 Universitätsklinikum Bonn, Bonn, DE; 11 Avillion LLP, London, UK; 12 Pfizer Inc, Cambridge, MA, USA; 13 Pfizer International Operation, Paris, FR; 14 Klinik für Innere Medizin II, Universitätsklinikum Jena, Jena, DE; 15 University of Texas MD Anderson Cancer Center, Houston, TX, USA Abstract A

2 Offenlegung Interessenskonflikte 1. Anstellungsverhältnis oder Führungsposition Universitätsklinikum und RWTH Aachen 2. Beratungs- bzw. Gutachtertätigkeit Novartis, Incyte, Pfizer, Janssen, Merck 3. Besitz von Geschäftsanteilen, Aktien oder Fonds keine 4. Patent, Urheberrecht, Verkaufslizenz Combination of Imatinib with Hypusination inhibitors 5. Honorare Keine 6. Finanzierung wissenschaftlicher Untersuchungen Novartis, Pfizer 7. Andere finanzielle Beziehungen keine 8. Immaterielle Interessenkonflikte keine

3 Introduction BOS is a dual SRC/ABL TKI approved at 500 mg once daily for adults with Ph+ CML resistant/intolerant to prior TKIs Previous studies demonstrated potent activity and manageable toxicity in all phases of CML Ph+ leukemias resistant/intolerant to previous TKIs (phase 1/2) 1-4 Newly diagnosed CP CML (phase 3) 5-7 A higher 12-mo CCyR rate (primary endpoint ) was observed with BOS vs IM in the previous BELA study, but was not statistically significant Improved 12-mo MMR rate and shorter time to response with BOS in BELA Objective: Further assess the efficacy and safety of BOS vs IM for first-line treatment of CP CML BOS=bosutinib; CCyR=complete cytogenetic response; CML=chronic myeloid leukemia; CP=chronic phase; IM=imatinib; MMR=major molecular response; Ph=Philadelphia chromosome; TKI=tyrosine kinase inhibitor. 1. Cortes JE, et al. Blood Khoury HJ, et al. Blood Kantarjian HM, et al. Blood Gambacorti-Passerini C, et al. Am J Hematol Cortes JE, et al. J Clin Oncol Brümmendorf TH, et al. Br J Haematol Gambacorti-Passerini C, et al. Am J Hematol

4 BFORE Study Design Eligibility Ph+ or Ph /BCR-ABL1+ CP CML ECOG PS 0 or 1 Stratification Sokal risk group Geographic region 1:1 N=536 BOS 400 mg once daily (n=268) IM 400 mg once daily (n=268) Primary Endpoint MMR rate at 12 mo Secondary/Other Endpoints MMR rate at 12 mo in ITT CCyR by 12 mo MMR by 18 mo Response duration EFS and OS MMR at 3, 6, 9, 18 mo MR 4, MR 4.5 at 3, 6, 9, 12 mo Time to response Time to transformation Ongoing, open-label, phase 3 study 536 patients were enrolled at 151 centers in 26 countries from July 2014 to August 2015 Expected study duration of 5 years Data presented are up to and including the last randomized patient s 18-mo visit ECOG PS=Eastern Cooperative Oncology Group performance status; EFS=event-free survival; ITT=intent-to-treat; MR=molecular response; OS=overall survival. ClinicalTrials.gov: NCT

5 Analysis Populations Population BOS IM Total Definition ITT All randomized patients mitt* Primary population for efficacy analyses Ph+ patients with e13a2 and/or e14a2 BCR-ABL1 transcript types Safety All randomized patients who received 1 dose Primary endpoint was assessed in the mitt Efficacy (excluding cytogenetic endpoints) was also analyzed in the ITT mitt=modified intent-to-treat. P values from analyses other than the primary endpoint and 12-mo secondary endpoints are for descriptive purposes only, without adjustment for multiple comparisons. *Excludes 12 Ph patients (ie, 0 out of metaphases at baseline; 6 in each arm), 8 patients with atypical transcripts (3 BOS and 5 IM), and 31 patients with unknown Ph status (13 BOS and 18 IM, including 2 IM patients also listed as having atypical transcripts).

6 Patient Characteristics (mitt) BOS IM Characteristic (n=246) (n=241) Median age (range), y 52 (18 84) 53 (19 84) Male, % Median time from diagnosis to randomization (range), d* 24 (4 183) 25 (1 183) Prior hydroxyurea/anagrelide, % Sokal risk group, % Low Intermediate High ECOG PS, % Splenomegaly, % 5 10 History of cardiovascular disease, % *Initial date of diagnosis missing for 4 BOS and 2 IM patients. Data missing for 1 patient (IM arm).

7 Treatment Status (Safety) BOS (n=268) IM (n=265) On treatment, % Discontinued treatment, % AE* Related to study treatment 15 9 Not related to study treatment 2 1 Suboptimal response/treatment failure 4 13 Investigator request 1 3 Patient request 2 1 Disease progression to AP/BP 1 2 Death <1 2 Other 1 3 AE=adverse event; AP=acute phase; BP=blast phase. Based on a minimum follow up of 18 months. *Only discontinuations with AE as the primary reason are included. By investigator s assessment. Includes protocol deviation, lost to follow up/failed to return, and other.

8 mitt ITT MMR at 12 mo (primary endpoint) MMR at 18 mo BCR-ABL1 10% at 3 mo CCyR by 12 mo MMR at 12 mo MMR at 18 mo Response Rates % (95% CI) BOS IM OR (95% CI) P Value 47.2 ( ) 56.9 ( ) 75.2 ( ) 77.2 ( ) 46.6 ( ) 56.7 ( ) 36.9 ( ) 47.7 ( ) 57.3 ( ) 66.4 ( ) 36.2 ( ) 46.6 ( ) 1.55 ( ) 1.45 ( ) NA < ( ) 1.57 ( ) 1.50 ( ) < NA=not available; OR=odds ratio. P values for endpoints other than 12-mo MMR and CCyR in the mitt are descriptive only, without adjustment for multiple comparisons.

9 Molecular Response, % Molecular Response Over Time (mitt) 60 P= ,9 BOS IM (n=246) (n=241) ,0 42,3 47,2 36,9 47,7 3 mo 6 mo 9 mo 12 mo 18 mo 3 mo 6 mo 9 mo 12 mo 18 mo Month: 29,5 P= ,4 20,7 18,3 18,3 13,8 P= ,0 11,4 9,8 8,3 8,1 7,1 4,1 4,6 4,5 1,7 2,0 2,9 3,3 0,4 0, MMR MR 4 MR 4.5

10 Cumulative Incidence of MMR (mitt) HR=1.36 (95% CI, ); P<0.01 HR=hazard ratio. Results after 18 months are subject to change due to incomplete follow-up.

11 Multivariable Logistic Regression Model Predicting MMR at 12 Months (mitt) Covariate OR (95% CI) P Value Age 65 vs <65 y 0.74 Women vs men ECOG PS: >0 vs Region 1 vs 3 2 vs Sokal risk group High vs low Intermediate vs low BOS vs IM < Significant predictors shown in yellow. Region 1=US, Canada, and Western Europe; region 2=Eastern Europe, Latin America, and South America; region 3=rest of the world.

12 EFS and OS (mitt) BOS (n=246) Cumulative incidence of progression or death 12 mo 4.1 ( ) 18 mo 4.5 ( ) Kaplan-Meier estimated OS 12 mo 99.6 ( ) 18 mo 99.6 ( ) 13 BOS and 17 IM patients had events* by the 18-month cutoff % (95% CI) IM (n=241) 6.7 ( ) 6.7 ( ) 97.9 ( ) 96.6 ( ) 2 BOS and 9 IM patients died during the study, including 1 and 4 patients, respectively, who died within 28 days of the last dose; no additional deaths in the ITT population *Includes death, transformation to AP/BP, doubling of white blood cell count without complete hematologic response, loss of CCyR, or loss of complete hematologic response.

13 Patients, % Transformation to AP/BP by 18 Months (mitt) 3,0 2,5 2,0 1,5 1,0 0,5 BP AP n=3 (1.2%) n=3 (1.2%) n=1 (0.4%) n=6 (2.5%) 6 (2.4%) BOS and 7 (2.9%) IM patients progressed to AP/BP during the first 18 months of treatment 6 of these patients (3 BOS and 3 IM) met AP criteria within 2 weeks based on basophil count All 6 continued on study drug; 4 achieved MMR and 1 achieved CCyR 0,0 BOS IM No additional transformations in the ITT population

14 Treatment-Emergent AEs (Safety) BOS (n=268) IM (n=265) All Grades Grade 3 All Grades Grade 3 Any TEAE, %* GI Diarrhea Nausea Abdominal pain <1 Musculoskeletal Muscle spasms <1 Myalgia 3 < Liver function ALT increased AST increased Periorbital edema Hematologic Thrombocytopenia Neutropenia Cardiovascular, cerebrovascular, and peripheral vascular events were infrequent in both arms (BOS: 3%, 0%, and 1%; IM: <1%, <1%, and 1%) ALT=alanine aminotransferase; AST=aspartate aminotransferase; GI=gastrointestinal; TEAE=treatment-emergent adverse event. * All-causality AEs with 20% incidence in either arm or a >10% difference between arms based on a follow up of 12 months.

15 Summary of Safety Data All-grade TEAEs: BOS 98% and IM 97% GI events and ALT/AST elevations more common with BOS Diarrhea common (70%); only 2 patients discontinued BOS because of this AE Musculoskeletal TEAEs more common with IM (BOS 30% vs IM 59%) Grade 3 TEAEs: BOS 56% and IM 43% ALT increase (19%) and thrombocytopenia (14%) most common with BOS Neutropenia (12%) most common with IM Dose interruptions (56% vs 36%) and reductions (35% vs 17%) due to TEAEs more common with BOS Median duration of dose delay: BOS 23 d, IM 15 d Median duration of dose reduction: BOS 105 d, IM 104 d Median dose intensity: BOS 392 mg/d, IM 400 mg/d Treatment discontinuations due to TEAEs*: BOS 14% vs IM 9% Most commonly ALT/AST elevations for BOS (5%) and myelosuppression for IM (2%) Dose escalation for suboptimal response: BOS 17% vs IM 28% *AEs leading to discontinuation are from a follow up of 12 months.

16 Conclusions BFORE met its primary endpoint, with a significantly higher 12-mo MMR rate with BOS vs IM (47% vs 37%; P=0.02) MMR rates were consistent at 12 mo in the ITT population (47% vs 36%; P=0.01) MMR benefit was maintained at 18 mo with a higher rate observed with BOS (57% vs 48%; P=0.04) Responses occurred earlier with BOS Safety data were consistent with known profiles with no new toxicities BOS was associated with a higher incidence of GI events and transaminase elevations and a lower incidence of musculoskeletal events Results suggest the lower BOS dose (400 mg) is associated with better tolerability and improved outcomes BOS could become a new first-line treatment option in CML

17 recg3/4 G0/1 recg3/4 G0/1 CML-7 (BODO) Study: Step-in Dosierungsphase G2 Zieldosis: Kont. 500 mg/tag G2 14 Tage 400 mg/tag Startdosis: 14 Tage 300 mg/tag

18 Acknowledgments We would like to thank the BFORE study patients and their families, as well as all of the study investigators, nurses, and site staff Tim H. Brümmendorf, 1 Carlo Gambacorti-Passerini, 2 Michael Deininger, 3 Michael J. Mauro, 4 Charles Chuah, 5 Dong-Wook Kim, 6 Philipp Le Coutre, 7 Kathleen Jentsch-Ullrich, 8 Cornelius F. Waller, 9 Dominik Wolf, 10 Laurence Reilly, 11 Allison Jeynes-Ellis, 11 Eric Leip, 12 Nathalie Bardy-Bouxin, 13 Andreas Hochhaus, 14 and Jorge E. Cortes, 15 on behalf of the BFORE Study Investigators This study was sponsored by Avillion under a collaborative development agreement with Pfizer Inc. Editorial support was provided by Johna Van Stelten, PhD, of Complete Healthcare Communications, LLC, and was funded by Pfizer

19 Back-Up Slides

20 Cumulative Incidence of CCyR (mitt) HR=1.33 (95% CI, ); P<0.01 Results are subject to change after 18 mo due to incomplete follow-up.

21 Cumulative Incidence of MMR (ITT) HR=1.37 (95% CI, ); 1-sided P<0.01 Results are subject to change after 18 mo due to incomplete follow-up.

22 Vascular TEAEs (Safety) BOS (n=268) IM (n=265) All Grades Grade 3 All Grades Grade 3 Any vascular event, % <1 Cardiovascular 3 1 <1 0 Angina pectoris 1 <1 <1 0 Myocardial ischemia Acute coronary syndrome <1 <1 0 0 Coronary artery disease <1 <1 0 0 Coronary artery occlusion <1 <1 0 0 Cerebrovascular 0 0 <1 <1 Cerebrovascular accident 0 0 <1 <1 Peripheral vascular Angiopathy < Capillary fragility < Deep vein thrombosis < Venous thrombosis limb < Iliac artery occlusion 0 0 <1 0 Peripheral coldness

23 Laboratory Abnormalities (Safety) BOS (n=268) IM (n=265) All Grades Grade 3/4 All Grades Grade 3/4 Any abnormality, % ALT increased AST increased Increased amylase Decreased calcium Increased creatine kinase Increased creatinine Increased glucose Decreased potassium Increased lipase Decreased phosphate Few patients discontinued because of transaminase elevations ALT increased: BOS 5% vs IM 0% AST increased: BOS 2% vs IM 0%