Presented at: ASCO Annual Meeting 2021Date: June 4, 2021

A first-in-human phase 1a/b trial of LY3484356, an oral selective estrogen receptor (ER) degrader (SERD)

in ER+ advanced breast cancer (aBC) and endometrial endometrioid cancer (EEC): Results

from the EMBER study

RP2D

RP2D

• No DLTs were observed, and the maximum tolerated dose was not reached.

• TEAEs were mainly grades 1 or 2. Most common TRAEs were nausea (19 [29%]), diarrhea (11 [17%]), and

fatigue (8 [12%]).

• G3 TEAEs occurred in 6 (9%) patients, which were treatment related in 2 (3%) patients (diarrhea [n=1] and

decreased neutrophil count [n=1]).

• SAEs occurred in 3 (5%) patients, only 1 of which was treatment related.

• Dose reductions due to AE occurred in 2 (3%) patients, 1 of which was treatment related.

• No patient discontinued due to an AE. Mean relative dose intensity was 98%.

200 mg QDN=5

400 mg QDN=20

600 mg QDN=20

800 mg QDN=17

1200 mg QDN=3

TotalN=65

Grade Grade Grade Grade Grade GradeAll ≥3 All ≥3 All ≥3 All ≥3 All ≥3 All ≥3

Patients with ≥1 TEAE, n (%) 4 (80) 1 (20) 17 (85) 2 (10) 19 (95) 0 15 (88) 3 (18) 3 (100) 0 58 (89) 6 (9)

Nausea, n (%) 0 0 5 (25) 0 9 (45) 0 7 (41) 0 2 (67) 0 23 (35) 0

Diarrhea, n (%) 0 0 3 (15) 1a (5) 3 (15) 0 5 (29) 0 3 (100) 0 14 (22) 1a (2)

Fatigue, n (%) 1 (20) 0 5 (25) 0 5 (25) 0 3 (18) 0 0 0 14 (22) 0

Arthralgia, n (%) 0 0 3 (15) 0 5 (25) 0 1 (6) 0 0 0 9 (14) 0

UTI, n (%) 0 0 4 (20) 0 3 (15) 0 1 (6) 0 0 0 8 (12) 0

Constipation, n (%) 1 (20) 0 2 (10) 0 1 (5) 0 2 (12) 0 1 (33) 0 7 (11) 0

Headache, n (%) 0 0 2 (10) 0 3 (15) 0 2 (12) 0 0 0 7 (11) 0

200 mg QD

400 mg QD

600 mg QD

800 mg QD

1200 mg QD Total

ORR, n/N (%)aBC, n/N (%) 0/1 2/9 (22) 0/12 0/11 0/2 2/35 (6)EEC, n/N (%) 0/0 0/3 0/0 0/3 0/0 0/6

CBR, n/N (%)aBC, n/N (%) 1/4 (25) 7/9 (78) 1/4 (25) 4/10 (40) 0/0 13/27 (48)EEC, n/N (%) 0/0 2/3 (67) 0/0 0/1 0/0 2/4 (50)

Characteristic 200 mg n=5

400 mgn=20

600 mgn=20

800 mgn=17

1200 mg n=3

TotalN=65

Median age, yrs (range) 66 (45-80) 60 (45-82) 65 (42-80) 55 (35-78) 59 (45-68) 62 (35-82)

ECOG PS, n (%)01

2 (40)3 (60)

14 (70)6 (30)

14 (70)6 (30)

12 (71)5 (29)

1 (33)2 (67)

43 (66)22 (34)

Pathological diagnosis, n (%)aBCEEC

5 (100)0

16 (80)4 (20)

20 (100)0

14 (82)3 (18)

3 (100)0

58 (89)7 (11)

Median prior therapies for aBCa, n (%) 3 (2-6) 3 (0-8) 2 (0-4) 2 (0-7) 1 (1-1) 2 (0-8)

Prior fulvestrant 4 (80) 9 (56) 17 (85) 4 (29) 1 (33) 35 (60)Prior CDK4/6 inhibitors 4 (80) 10 (63) 18 (90) 13 (93) 3 (100) 48 (83)

Prior chemotherapy 1 (20) 7 (44) 4 (20) 3 (21) 0 15 (26)

ESR1 mutationb detected in ctDNA, n (%) 2 (50) 7 (44) 8 (50) 3 (20) 0 20 (37)

Measurable disease at baseline, n (%) 2 (40) 14 (70) 12 (60) 14 (82) 2 (67) 44 (68)

Komal L. Jhaveri1, Elgene Lim2, Erika P. Hamilton3, Cristina Saura4, Tarek Meniawy5, Rinath Jeselsohn6, J. Thaddeus Beck7, Peter A. Kaufman8, Sarah Sammons9, Kalyan Banda10, Meena Okera11, Kan Yonemori12, Kathleen K. Harnden13, Sung-Bae Kim14, Joohyuk Sohn15, Cynthia X. Ma16, Phillippe G. Aftimos17, Xuejing A Wang18, Suzanne R.L. Young18, and Muralidhar Beeram19

1Memorial Sloan Kettering Cancer Center, New York, NY, USA; 2Garvan Institute of Medical Research, Darlinghurst, Australia; 3Sarah Cannon Research Institute and Tennessee Oncology, PLLC, Nashville, TN, USA; 4Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain; 5Sir Charles Gairdner Hospital and Linear Research Institute, Nedlands, WA, Australia; 6Dana Farber Cancer Institute, Boston, Massachusetts, USA; 7Highlands Oncology Group, Springdale, AR, USA; 8University of Vermont Medical Center and UVM Cancer Center, Burlington, VT, USA; 9Duke Cancer Institute, Durham, NC, USA; 10Fred Hutchinson Cancer Research Center and University of Washington, Seattle, Washington, USA; 11Ashford Cancer Centre, Adelaide, Australia; 12Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan;

13Inova Schar Cancer Institute, Fairfax, Virginia, USA; 14Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; 15Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea; 16Washington University School of Medicine in St Louis, St Louis, Missouri, USA; 17Institut Jules Bordet, Universite Libre de Bruxelles, Brussels, Belgium; 18Eli Lilly and Company, Indianapolis, IN, USA; 19START Center for Cancer Care, San Antonio, TX, USA

A first-in-human phase 1a/b trial of LY3484356, an oral selective estrogen receptor (ER) degrader (SERD) in ER+ advanced breast cancer (aBC) and endometrial endometrioid cancer (EEC): Results from the EMBER study

Sponsored by Loxo Oncology at LillyASCO Annual Meeting, Virtual, June 4 – 8, 2021 Presenter: Komal L. Jhaveri, jhaverik@mskcc.org

# 1050

• LY3484356 was well tolerated and had a favorable safety profile with PK exposure supporting QD dosing. No cardiac safety signal (bradycardia/QTc prolongation).

• LY3484356 400 mg QD was selected as the RP2D for future studies.

• LY3484356 showed anti-tumor activity (CBR, ≥48%) in patients with advanced/ metastatic ER+, HER2- BC and ER+ EEC, who were heavily pre-treated with available standard of care treatments, with: Durable objective activity in fulvestrant-refractory disease. Clinical benefit observed irrespective of ESR1 mutation status. 79% (31/39) of patients with SD/PR continuing with ongoing treatment.

• Further trials of LY3484356 are ongoing/planned: A phase 1b dose expansion of LY3484356 (as monotherapy and in combination

with everolimus, abemaciclib, alpelisib, or trastuzumab) (EMBER; NCT04188548).

A phase 1, open-label, preoperative window study evaluating the biological effects of LY3484356 in post-menopausal women with stage I-III ER+, HER2-breast cancer (EMBER-2; NCT04647487).

A randomized, open-label, phase 3 study of LY3484356 vs investigator’s choice of endocrine therapy, in patients with ER+, HER2- locally advanced or metastatic breast cancer previously treated with endocrine therapy (EMBER-3).

BACKGROUND

• The estrogen receptor (ER) is the key therapeutic target for ER+/HER2-breast cancer.

• Novel degraders of ER may overcome endocrine therapy resistance while providing consistent oral pharmacology and convenience of administration.1-3

• ER is also expressed in ~80% of endometrioid endometrial cancers (EEC) and endocrine therapy (ET) may be effective in patients with ER+ EEC.4-5

• LY3484356 is a novel, orally bioavailable SERD with pure antagonistic properties, which result in sustained inhibition of ER-dependent gene transcription and cell growth.6

• Preclinically, LY3484356 monotherapy shows favorable efficacy and pharmacokinetic (PK) properties, including activity in ESR1 mutant models.6

• T1/2 was 25-30 hours.

• Dose proportional increases in LY3484356 exposures were observed across all evaluated doses.

• Steady state LY3484356 plasma concentrations in patients exceeded the EC80 range achieved in preclinical BC xenograft studies and the steady state fulvestrant Cmax.7

• EMBER (NCT04188548) is a global first-in-human phase 1a/b, open-label study. Phase 1a evaluated the dose-escalation of oral LY3484356 monotherapy.

– Primary objective was to determine the recommended phase 2 dose (RP2D) of LY3484356.

– Secondary objectives were to assess safety, PK, and anti-tumor activity of LY3484356.

• Dose-escalation followed an i3+3 design with 5 dose levels (200 mg –1200 mg) evaluated.

– LY3484356 was administered orally, once daily, in 28-day cycles.

– 3-4 patients were evaluated in each cohort for dose-limiting toxicity (DLT) during cycle 1 (28 days).

– Cohorts could then backfill up to a total of 20 patients per dose level (n=100 maximum).

• Key Inclusion criteria:

– ER+/HER2- aBC

Up to 3 prior regimens in the advanced/metastatic setting were allowed.

– ER+ EEC

Patients must have progressed after prior platinum-based therapy or be deemed unsuitable or declined platinum-based therapy.

Patients must not have received prior fulvestrant or aromatase inhibitor therapy.

References1. Soleja M, et al. Expert Opin Pharmacother 2019 20:1819-1829; 2. Robertson JFR, et al. Clin Pharmacokinet 2004 43:529-538; 3. Gombos A. Curr Opin Oncol 2019 31:424-429; 4. Backes FJ, et al. Gynecol Oncol 2016 141:312–317; 5. van Weelden WJ, et al. Front Oncol 2019 9:359; 6. Bhagwat S, et al. Proceedings of the AACR 2021 abstr:1236; 7. Fulvestrant FDA label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021344Orig1s039lbl.pdf.

AcknowledgementsWe thank the EMBER trial patients, their families and caregivers, trial investigators and study staff. Medical writing assistance was provided by Susan P. Whitman, PhD, an employee of Loxo Oncology at Lilly.Copies of this poster obtained through Quick Response (QR) Code are for personal use only and may not be reproduced without permission from ASCO® and the author of this poster

• Antitumor activity was assessed per RECIST v1.1 by:

– Objective response rate, ORR:

Defined as confirmed complete response [CR] or partial response [PR]).

Evaluable patients had measurable disease and at least 1 post-baseline tumor assessment or discontinued prior.

– Clinical benefit rate, CBR:

Defined as CR or PR, or SD ≥24 weeks.

Evaluable patients were enrolled ≥24 weeks prior to data cut.

• Serial plasma samples were obtained for PK and ctDNA (Guardant360, Guardant Health), and available tumor tissue was collected for central ER & HER2 testing (by IHC).

• Data cut off date for this analysis was April 7, 2021.

CONCLUSIONS

• Median duration of treatment was 60 days (range 7-449). 35 patients remain on treatment.

STUDY DESIGN

METHODS

• Objective responses were seen with longer durations of treatment (both PRs occurred after 24 weeks of therapy).

• Both patients with PRs had received at least 3 prior regimens for metastatic disease.

• In patients with available serial ctDNA data (n=21), 86% (18/21) had early declines in overall ctDNA (as measured by change in allele frequencies of all somatic mutations reported at C2D1 compared to baseline).

• The degree of this decline was generally deeper in patients who experienced clinical benefit versus those who did not.

RESULTSTable 1. Patient and disease characteristics

Figure 1. Pharmacokinetics

Table 2. TEAEs reported in >10% of all patients

Figure 2. Duration of treatment

Figure 4. ctDNA dynamics by ESR1 status and clinical benefit (CR/PR or SD ≥24 weeks)

Figure 3. Tumor response in patients with measurable disease

Table 3. ORR and CBR in evaluable patients

– – Fulvestrant CmaxEC80

aTreatment related SAE (G3 diarrhea) led to dose reduction, patient remains on study 13+ months. UTI: Urinary tract infection.

a12 patients enrolled prior to protocol amendment had received ≥4 prior therapies. bIn patients with available cfDNA data (n=54).