Presented at: 2020 ASH Annual MeetingDate: December 7, 2020

LOXO-305, A Next Generation, Highly Selective, Non-Covalent BTK Inhibitor In Previously

Treated CLL/SLL: Results From The Phase 1/2 BRUIN Study

Anthony R. Mato1, John M. Pagel2, Catherine C. Coombs3, Nirav N. Shah4, Nicole Lamanna5, Ewa Lech-Maranda6, Toby A. Eyre7, Jennifer A. Woyach8, William G. Wierda9, Chan Y. Cheah10, Lindsey Roeker1, Manish R. Patel11, Bita

Fakhri12, Minal A. Barve13, Constantine S. Tam14, David Lewis15, James N. Gerson16, Alvaro Alencar17, Justin Taylor17, Omar Abdel-Wahab1, Paolo Ghia18, Stephen J. Schuster16, Jessica Chen19, Binoj Nair20, Donald E. Tsai20,

Nora C. Ku20, Matthew S. Davids21, Jennifer R. Brown21, Wojciech Jurczak22

1Memorial Sloan Kettering Cancer Center, New York, USA; 2Swedish Cancer Institute, Seattle, USA; 3University of North Carolina at Chapel Hill, Chapel Hill, USA; 4Medical College of Wisconsin, Milwaukee, USA; 5Herbert Irving Comprehensive Cancer Center, Columbia University, New

York, USA; 6Institute of Hematology and Transfusion Medicine, Warsaw, Poland; 7Oxford University Hospitals NHS Foundation Trust, Churchill Cancer Center, Oxford, UK; 8The Ohio State University Comprehensive Cancer Center, Columbus, USA; 9MD Anderson Cancer Center,

Houston, USA; 10Linear Clinical Research and Sir Charles Gairdner Hospital, Perth, Australia; 11Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota, USA; 12University of California San Francisco, San Francisco, USA; 13Mary Crowley Cancer Research, Dallas, USA; 14Peter MacCallum Cancer Center, Royal Melbourne Hospital, and University of Melbourne, Melbourne, Australia; 15Plymouth Hospitals NHS Trust - Derriford Hospital, Plymouth, UK; 16Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, USA;

17University of Miami Miller School of Medicine, Miami, USA; 18Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele, Milan, Italy; 19Eli Lilly and Company, Indianapolis, IN, USA; 20Loxo Oncology, Inc, a wholly owned subsidiary of Eli Lilly and Co., Stamford, CT, USA; 21Dana-Farber Cancer Institute and Harvard Medical School, Boston, USA; 22Maria Sklodowska-Curie National Research Institute of Oncology, Krakow, Poland

LOXO-305, A Next Generation, Highly Selective, Non-Covalent BTK Inhibitor In Previously

Treated CLL/SLL: Results From The Phase 1/2 BRUIN Study

Presenting Author Disclosures

Research support:

TG Therapeutics, Pharmacyclics, Abbvie, Johnson and Johnson, Acerta / AZ, Regeneron, DTRM

BioPharma, Sunesis, Loxo Oncology, Adaptive

Advisory/Consultancy/DSMB:

TG Therapeutics, Pharmacyclics, Adaptive, Abbvie, Johnson and Johnson, Acerta / AZ, DTRM

BioPharma, Sunesis, Celgene, Verastem

Resistance and Intolerance Limit Covalent BTK Inhibitor Outcomes

Ibrutinib discontinuation from 4 prospective studies1 Ibrutinib acquired resistance in patients with progressive CLL2

1Woyach et al. J Clin Oncol. 2017;35:1437-43. 2Lampson et al. Expert Rev Hematol. 2018;11:185-94. 3Burger et al. Leukemia. 2020;34:878-789. 4Byrd et al. N Engl J Med. 2016;374:323-32. 5Hershkovitz-Rokah et

al. Br J Haematol. 2018;181:306-19. 6Woyach et al. N Engl J Med. 2014;370:2286–94. 7Woyach et al. Blood. 2019;134(Suppl 1):504. 8Xu et al. Blood. 2017;129:2519–25.

56% BTK

mutants

16% BTK &

PLCG2 mutants

20% BTK &

PLCG2 not

identified

• Ibrutinib discontinuation rates at 5 years

• Front line = 41%3

• Relapsed/refractory = 54%1

• BTK C481 mutations are the dominant reason for progressive

CLL after covalent BTK inhibitors1-8

• BTK C481 mutations prevent covalent BTK inhibitors from

effective target inhibition1-6

LOXO-305 is a Highly Potent and Selective Non-Covalent BTK Inhibitor

Kinome selectivityHighly selective for BTK

Xenograft modelsIn vivo activity similarly efficacious as ibrutinib in WT; superior in C481S

BID, twice-daily; BTK, Bruton tyrosine kinase. Illustration reproduced courtesy of Cell Signaling Technology, Inc. (www.cellsignal.com). 1Brandhuber et al. Clin. Lymphoma Myeloma Leuk. 2018;18:S216. 2Mato et al.

Blood. 2019:134 (Suppl 1):501.

LOXO-305 30 mg/kg BID

• Nanomolar potency against WT & C481-mutant BTK in cell and

enzyme assays1,2

• >300-fold selectivity for BTK vs 370 other kinases1

• Due to reversible binding mode, BTK inhibition not impacted by

intrinsic rate of BTK turnover1

• Favorable pharmacologic properties allow sustained BTK inhibition

throughout dosing interval1

vehicle

Ibrutinib 50 mg/kg BID

Phase 1/2 BRUIN Study: Design, Eligibility and Enrollment

Data cutoff date of 27 September 2020. aEfficacy evaluable patients are those who had at least one post-baseline response assessment or had discontinued treatment prior to first post-baseline response assessment. bOther includes DLBCL, FL, MZL, Richter’s transformation, B-PLL, Hairy Cell Leukemia, and other transformation. All response data presented based on investigator assessment.

• Age ≥18

• ECOG PS 0-2

• CLL or other B-cell NHL

• Active disease and in need of

treatment

• Previously treated

Eligibility

• 28-day cycles

• Intra-patient dose escalation

allowed

• Cohort expansion permitted at

doses deemed safe

Phase 1 3+3 design

• Safety/tolerability

• Determine MTD &

recommended phase 2 dose

• Pharmacokinetics

• Efficacy according to ORR &

DOR based on disease criteria

(iwCLL, IWWM, Lugano)

Key endpoints

Phase 1

Escalation + Expansion

(25 to 300 mg QD)

n=203

Phase 2

(200 mg QD)

n=120

n=323

CLL/SLL

n=170

MCL

n=61WM

n=26

Otherb

n=66

CLL/SLL

n=139

MCL

n=56

WM

n=19

Other

n=55

Safety

population

Efficacy

populationa

Ongoing, prior

to 1st restaging

n=31

CLL/SLL Patient Characteristics

Characteristics n=170

Median age, years (range) 69 (36-88)

Female, n (%)

Male, n (%)

61 (36)

109 (64)

ECOG PSa, n (%)

0

1

2

87 (51)

69 (41)

13 (8)

Median number prior lines of systemic therapy

(range)

BTK pre-treated

3 (1-11)

4 (1-11)

Prior therapy, n (%)

BTK inhibitor

Chemotherapy

Anti-CD20 antibody

BCL2 inhibitor

PI3K inhibitor

Lenalidomide

Autologous stem cell transplant

Allogeneic stem cell transplant

CAR-T

146 (86)

140 (82)

153 (90)

57 (34)

36 (21)

14 (8)

0

3 (2)

10 (6)

Reason discontinued any prior BTKi, n (%)b

Progressive disease

Toxicity/otherc98 (67)

48 (33)

Baseline Molecular Characteristicsd

Mutation status, n (%)

BTK C481-mutant

BTK Wildtype

PLCG2-mutant

25 (27)

66 (73)

4 (4)

High Risk Molecular Findings, n (%)

17p deletion

TP53 mutation

17p13 deletion + TP53 mutant

IGHV unmutated

11q deletion

20 (25)

27 (30)

18 (22)

71 (88)

15 (19)

Data cutoff date of 27 September 2020. Total % may be different than the sum of the individual components due to rounding. aPatients with missing ECOG PS status: n=1. bCalculated as percent of patients who received

prior BTK inhibitor. cOther includes patients who completed treatment and those who discontinued voluntarily or due to physician’s decision. dMolecular characteristics were determined centrally, in those patients with

sufficient sample to pass assay quality control. 91 patients were tested for BTK and PLCG2, 81 patients for 17p13 deletion, 91 patients for TP53, 81 patients for 17p13 deletion + TP53, 81 patients for IGHV and 81

patients for 11q deletion.

LOXO-305 Pharmacokinetics

Data cutoff date of 27 September 2020. Concentration at 24 hours was inferred from the pre-dose concentrations.

Plasma exposures exceeded BTK IC90 throughout

dosing interval at doses ≥100mg QD

Plasma exposures were

dose-dependent and linear

Horizontal line represents the plasma level at which the unbound

LOXO-305 concentration corresponds to BTK-WT and BTK C481S

IC90 based on cellular assays.

25 mg QD (n=5)50 mg QD (n=6)100 mg QD (n=9)150 mg QD (n=19)200 mg QD (n=35)250 mg QD (n=24)300 mg QD (n=19)

LOXO-305 Safety Profile

No DLTs reported and MTD not reached

5 of 323 patients (1.5%) discontinued due to treatment-related AEs

200mg QD selected as recommended Phase 2 dose

Data cutoff date of 27 September 2020. Total % may be different than the sum of the individual components due to rounding. aThe AEs listed are the most common that occurred at any grade in at least 10% of the

patients, regardless of attribution. bAEs of special interest are those that were previously associated with covalent BTK inhibitors. cBruising includes contusion, petechia, ecchymosis and increased tendency to bruise.

Hemorrhage includes hematoma, epistaxis, rectal hemorrhage, subarachnoid hemorrhage, upper gastrointestinal hemorrhage, vitreous hemorrhage and wound hemorrhage. Rash includes rash maculo-papular, rash,

rash macular, rash erythematous, rash popular, rash pruritic and rash pustular. dSubarachnoid bleed sustained during a bicycle accident, considered by investigator as unrelated to LOXO-305. eBoth events considered

by investigators as unrelated to LOXO-305 due to a history of prior atrial fibrillation in each.

All doses and patients (n=323)

Treatment-emergent AEs, (≥10%), n (%)a Treatment-related AEs, n (%)

Adverse Event Grade 1 Grade 2 Grade 3 Grade 4 Any Grade Grades 3/4 Any Grade

Fatigue 40 (12%) 22 (7%) 3 (1%) - 65 (20%) 2 (

Efficacy of LOXO-305 in CLL/SLL

Data cutoff date of 27 September 2020. Data for 13 CLL/SLL patients are not shown in the waterfall plot due to 4 having no target lesions identified at baseline, 5 with no/incomplete post-baseline lesion measurements,

and 4 discontinued prior to first post-baseline disease assessment.

All 6 8 10

0

20

40

60

80

100

Follow-up time sincestart of treatment (months)

Be

st

Re

sp

on

se

(%

)

63%

n=139 n=79 n=49 n=29

71%

86%

68%

PR

PR-L

SD

NE

PD

Overall Response Rate Increases

Over Timec

Data cutoff date of 27 September 2020. Total % may be different than the sum of the individual components due to rounding. aEfficacy evaluable patients are those who had at least one post-baseline response

assessment or had discontinued treatment prior to first post-baseline response assessment. bORR includes patients with a best response of CR, PR, and PR-L. Response status per iwCLL. cIncludes the efficacy-

evaluable CLL/SLL patients at the time of data cutoff. Data at each timepoint includes the efficacy-evaluable CLL/SLL patients who had the opportunity to be followed for at least the indicated amount of time.

Overall Response Rate in all CLL/SLL

patients and BTK pre-treated subgroup

All CLL/SLL Patientsa n=139

Overall Response Rateb, % (95% CI) 63% (55 – 71%)

Best response

CR, n (%) 0

PR, n (%) 69 (50%)

PR-L, n (%) 19 (14%)

SD, n (%) 45 (32%)

BTK Pre-Treated CLL/SLL Patientsa n=121

Overall Response Rateb, % (95% CI) 62% (53 – 71%)

Best Response

CR, n (%) 0

PR, n (%) 57 (47%)

PR-L, n (%) 18 (15%)

SD, n (%) 41 (34%)

Efficacy of LOXO-305 in CLL/SLL

LOXO-305 Treatment Duration in CLL/SLL

Data cutoff date of 27 September 2020.

• Median follow-up of 6 months (range, 0.6-17.8+) for the efficacy-evaluable

patients

• 94% (83 of 88) of responding patients are ongoing and in response. Only 5

responding patients discontinued (4 for PD, 1 patients in PR electively

discontinued to undergo transplantation)

LOXO-305 Efficacy Regardless of BTK Experience and Other Prior Therapy

Data cutoff date of 27 September 2020. aEfficacy evaluable patients are those who had at least one evaluable post-baseline assessment or had discontinued treatment prior to first post-baseline assessment.

Prior therapy

BTK C481 mutation status

Reason for prior BTKi

discontinuation

Median Lines of

Prior Therapy,

median (range)

3 (1-11)

4 (1-11)

5 (2-11)

4 (2-11)

5 (2-11)

4 (2-11)

5 (2-11)

6 (3-11)

6 (4-10)

4 (1-10)

3 (1-9)

4 (1-11)

3 (1-8)

3 (1-10)

Treated, n

170

146

57

36

54

113

48

14

10

66

25

98

48

25

Efficacy-

evaluablea, n

139

121

48

30

45

93

39

12

10

65

24

79

42

25

0 25 50 75 100

mut

wt

Toxicity/other

Progression

CAR-T

Chemotherapy + CD20 + BTK + BCL2 + PI3K

Chemotherapy + CD20 + BTK + BCL2

Chemotherapy + CD20 + BTK

BTK + BCL2

PI3K

BCL2

BTK, 10 months follow-up

BTK

All efficacy-evaluable patients

ORR, % (95% CI)

Duration of Response and Progression-Free Survival in CLL/SLL

Progression-Free SurvivalDuration of Response

Data cutoff date of 27 September 2020.

Conclusions

• LOXO-305 demonstrates promising efficacy in CLL/SLL patients previously treated with all classes of

available therapy

– Responses were observed across all dose levels

– Efficacy was independent of BTK C481 mutation status, the reason for prior BTKi discontinuation (i.e. progression

vs intolerance), or other classes of prior therapy received (including covalent BTK inhibitors, BCL2 inhibitors, and

PI3K-delta inhibitors)

• Favorable safety and tolerability are consistent with the design of LOXO-305 as a highly selective and non-

covalent BTK inhibitor

– No DLTs were observed and no MTD was identified

– Notable covalent BTKi-associated toxicities were rarely observed

– Longer follow-up is needed to better understand the LOXO-305 safety profile associated with chronic administration

• LOXO-305 is well tolerated and exhibits promising efficacy in heavily pretreated CLL/SLL patients

NCT 03740529

Acknowledgements

• BRUIN trial patients, their families and caregivers

• BRUIN trial investigators and study staff

• Medical writing assistance was provided by Susan P. Whitman, PhD, an employee of Loxo Oncology., Inc,

a wholly owned subsidiary of Eli Lilly and Company

NCT 03740529

Mato-CLL-ASH2020-FINALPresentation Opening Slide CLL ASH 2020Slide Number 1