LOXO-305, a Next Generation, Highly Selective, Non ...LOXO-305 is a Highly Potent and Selective Non-Covalent BTK Inhibitor Kinome selectivity Highly selective for BTK Xenograft models

Presented at: 2020 ASH Annual MeetingDate: December 5, 2020

LOXO-305, a Next Generation, Highly Selective, Non-Covalent BTK Inhibitor in Previously Treated Mantle Cell Lymphoma, Waldenström's Macroglobulinemia,

and Other Non-Hodgkin Lymphomas: Results from the Phase 1/2 BRUIN Study

Michael L. Wang1, Nirav N. Shah2, Alvaro J. Alencar3, James N. Gerson4, Manish R. Patel5, Bita Fakhri6,

Wojciech Jurczak7, Xuan Tan8, Katharine Lewis8, Timothy Fenske9, Catherine C. Coombs10, Ian Flinn11,

David Lewis12, Steven Le Gouill13, M. Lia Palomba14, Jennifer Woyach15, John M. Pagel16,

Nicole Lamanna17, Jonathon B. Cohen18, Minal A. Barve19, Paolo Ghia20, Toby A. Eyre21, Ming Yin22,

Binoj Nair22, Donald E. Tsai22, Nora C. Ku22, Anthony R. Mato14, Chan Y. Cheah8

1Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX; 2Medical College of Wisconsin, Brookfield, WI; 3Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL; 4Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA; 5Florida Cancer Specialists / Sarah Cannon Research Institute, Sarasota, FL; 6Division of Hematology and Oncology, University of California, San Francisco, CA; 7Maria Sklodowska-Curie National Research Institute of Oncology, Krakow, Poland; 8Linear Clinical Research and Sir Charles Gairdner Hospital, Perth, Australia; 9Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI; 10Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC;

11Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN; 12Plymouth Hospitals NHS Trust - Derriford Hospital, Plymouth, United Kingdom; 13Service d’hématologie clinique du CHU de Nantes, INSERM CRCINA Nantes-Angers, NeXT Université de Nantes, Nantes, France; 14Memorial Sloan Kettering Cancer Center, New York, NY; 15The Ohio State University Comprehensive Cancer Center, Columbus, OH; 16Center for Blood Disorders and Stem Cell Transplantation, Swedish Cancer Institute, Seattle, WA; 17Herbert Irving Comprehensive Cancer Center,

Columbia University, New York, NY; 18Winship Cancer Institute, Emory University, Atlanta, GA; 19Mary Crowley Cancer Research, Dallas, TX; 20Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele, Milano, MI, Italy; 21Churchill Cancer Center, Oxford University Hospitals NHS Foundation Trust, Old Road, United Kingdom; 22Loxo Oncology at Lilly, Stamford, CT

LOXO-305, a Next Generation, Highly Selective, Non-Covalent BTK Inhibitor in Previously Treated Mantle Cell Lymphoma, Waldenström's Macroglobulinemia,

and Other Non-Hodgkin Lymphomas: Results from the Phase 1/2 BRUIN Study

Presenting Author Disclosures

Research support:

Pharmacyclics, Celgene, Janssen, AstraZeneca, Acerta Pharma, Juno, Loxo Oncology, VelosBio,

BioInvent, Kite Pharma, Verastem, BeiGene, Eli Lilly, InnoCare, Molecular Templates, Oncternal

Advisory/Consultancy:

Pharmacyclics, Celgene, Janssen, AstraZeneca, Acerta Pharma, Pulse Biosciences, Juno, Loxo

Oncology, Kite Pharma, Guidepoint Global, BeiGene, InnoCare, Oncternal, BioInvent, InnoCare, VelosBio

Honoraria/Travel support:

Pharmacyclics, Celgene, Janssen, AstraZeneca, Acerta Pharma, OMI, Targeted Oncology, Oncology

News, Maple Health Group, Dava Oncology, CAHON, Genentech

Figures adapted from Martin et al, 2016 (left) and Cheah et al, 2015 (right). 1Hershkovitz-Rokah et al. Br J. Haemtol. 2018;181:306-19. 2Wang et al. N. Engl. J. Med. 2013;369:507-16. 3Cheah et al. Ann. Oncol.

2015;26:1175-79. 4Martin et al. Blood. 2016;127:1559-63. 5Dreyling et al. Lancet. 2016;387:770-8. 6Epperla et al. Hematol. Oncol. 2017;35:528-35. 7Ondrisova L and Mraz M, Front. Oncol. 2020;10. 8O’Brien et al. Clin

Lymphoma Myeloma Leuk. 2018;18:648-57. 9Byrd et al. Blood. 2019;130(Suppl 1):4326. 10Tam et al. Blood. 2020;136:2038-50.

• Covalent BTK inhibitor resistance in MCL and other lymphomas is incompletely understood1-10

• BTK C481-mutations are uncommon; bypass alterations & epigenetic changes implicated in some patients7

• Overall survival following covalent BTK inhibitor therapy is poor3,4

Outcomes in MCL are Poor Following Covalent BTK Inhibitor Progression

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

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

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.

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 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

MCL

n=61WM

n=26

Otherb

n=66

MCL

n=56WM

n=19

Other

n=55

Safety

population

Efficacy

populationa

CLL/SLL

n=170

CLL/SLL

n=139

Ongoing,

prior to 1st

restaging

n=5

Ongoing,

prior to 1st

restaging

n=7

Ongoing,

prior to 1st

restaging

n=11

Patient Characteristics

Data cutoff date of 27 September 2020. Total % may be different than the sum of the individual components due to rounding. aOther includes DLBCL (n=26), FL (n=12), MZL (n=13), Richter’s Transformation (n=9), other

transformation (n=3), B-PLL (n=2) and Hairy Cell Leukemia (n=1). bECOG PS is missing for 3 patients (2 WM, 1 Other). cCalculated as percent of patients who received prior BTK inhibitor. dOther includes patients who

completed treatment and those who discontinued voluntarily or due to physician’s decision.

CharacteristicsMCL

(n=61)

WM

(n=26)

Othera

(n=66)

Median age (range), years 69 (50-87) 68 (42-84) 68 (27-86)

Female, n (%)

Male, n (%)

14 (23)

47 (77)

8 (31)

18 (69)

26 (39)

40 (61)

ECOG PSb, n (%)

0

1

2

42 (69)

17 (28)

2 (3)

14 (54)

10 (39)

0

18 (27)

43 (65)

4 (6)

Median number prior lines of systemic therapy (range) 3 (1-8) 3 (2-11) 4 (2-10)

Prior therapy, n (%)

BTK inhibitor

Chemotherapy

Anti-CD20 antibody

BCL2 inhibitor

PI3K inhibitor

Lenalidomide

CAR-T

Autologous stem cell transplant

Allogeneic stem cell transplant

57 (93)

56 (92)

60 (98)

9 (15)

1 (2)

12 (20)

3 (5)

15 (25)

3 (5)

18 (69)

23 (89)

24 (92)

3 (12)

1 (4)

1 (4)

0

0

0

24 (37)

63 (96)

65 (99)

12 (18)

13 (20)

18 (27)

9 (14)

7 (11)

2 (3)

Reason discontinued any prior BTKic

Progressive disease

Toxicity/otherd44 (77)

13 (23)

12 (67)

6 (33)

19 (79)

5 (21)

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 (

All MCL Patientsa n=56

Overall Response Rateb, % (95% CI) 52% (38-65)

Best Response

CR, n (%) 14 (25)

PR, n (%) 15 (27)

SD, n (%) 10 (18)

BTK Pre-Treated MCL Patientsa n=52


Best Response

CR, n (%) 13 (25)

PR, n (%) 14 (27)

SD, n (%) 9 (17)

Efficacy of LOXO-305 in Mantle Cell Lymphoma

Data cutoff date of 27 September 2020. Total % may be different than the sum of the individual components due to rounding. Data for 11 MCL patients are not shown in the waterfall plot due to 7 having no target lesions

identified by CT at baseline (including 4 patients who achieved a best response of CR by PET), 1 with no/incomplete post-baseline lesion measurements, and 3 discontinued prior to first post-baseline disease

assessment. *Indicates patients with >50% increase in SPD. 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 and PR. Response status per Lugano criteria.

Efficacy also seen in patients with prior:

• Stem cell transplant: ORR 64% (9/14)

• CAR-T therapy: ORR 100% (2/2)

LOXO-305 Treatment Duration in Mantle Cell Lymphoma

Data cutoff date of 27 September 2020.

• Median follow-up of 6 months (range, 0.7-18.3+ months) for the

efficacy-evaluable patients

• 83% (24 of 29) of responding patients are ongoing and in

response. Only 5 responding patients discontinued (4 for PD, 1

in CR electively discontinued to undergo allogeneic SCT)

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, VGPR, PR, and MR. Response status per IWMM6 criteria.

Efficacy of LOXO-305 in Waldenström’s Macroglobulinemia

All WM Patientsa n=19


Best Response

CR, n (%) 0

VGPR, n (%) 0

PR, n (%) 9 (47)

MR, n (%) 4 (21)

SD, n (%) 3 (16)

BTK Pre-Treated WM Patientsa n=13


Best Response

CR, n (%) 0

VGPR, n (%) 0

PR, n (%) 5 (39)

MR, n (%) 4 (31)

SD, n (%) 1 (8)

Data cutoff date of 27 September 2020. Total % may be different than the sum of the individual components due to rounding. Data for 17 NHL patients are not shown in the waterfall plot due to 6 having no target lesions

identified at baseline, 4 with no/incomplete post-baseline lesion measurements, and 7 discontinued prior to first post-baseline disease assessment. *Indicates patients with >100% increase in SPD. 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 and PR.

Responses were defined according to disease specific guidelines. As of data cutoff, no responses were observed in the efficacy evaluable patients with other tumor types not shown in the table above.

Efficacy of LOXO-305 in Other NHLs

RTa

(n=8)FLa

(n=8)MZLa

(n=9)DLBCLa

(n=25)

Overall Response Rateb, % (95% CI)

75%

(35-97)

50%

(16-84)

22%

(3-60)

24%

(9-45)

Best Response

CR, n (%) 0 2 (25) 0 4 (16)

PR, n (%) 6 (75) 2 (25) 2 (22) 2 (8)

SD, n (%) 1 (13) 1 (13) 7 (78) 2 (8)

LOXO-305 Treatment Duration in Other NHLs

Data cutoff date of 27 September 2020. Other NHLs include B-PLL, and other transformation.

• 77% (10/13) of responding WM patients are ongoing and

in response

• 83% (5/6) of responding RT patients are ongoing and in

response

Conclusions

• LOXO-305 demonstrates promising efficacy in MCL and other NHL patients previously treated with all classes

of available therapy

– Responses were observed across all dose levels

– Efficacy was independent of prior therapy

– Durable responses in BTK pre-treated MCL are particularly notable, given poor outcomes with existing therapeutic

options

• 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 pre-treated patients with MCL and other

NHLs

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

Presentation Opening Slide MCL ASH 2020Slide Number 1

Wang-MCL-ASH2020-FINAL

Documents

LOXO-305, a Next Generation, Highly Selective, Non ...LOXO-305 is a Highly Potent and Selective Non-Covalent BTK Inhibitor Kinome selectivity Highly selective for BTK Xenograft models