imlunestrant (LY3484356)

Imlunestrant, as monotherapy and combined with abemaciclib, has a manageable safety profile with preliminary evidence of antitumor activity in patients with ER+ EEC.

EMBER-2 combined with existing phase 1 data has identified 400mg as the optimal imlunestrant dose.

Oral SERDs constitute an exciting new drug class. Ongoing and future research will further refine the role of these drugs next to standard endocrine treatments and targeted therapies.

Imlunestrant, as monotherapy or in combination with targeted therapy, had a manageable safety profile with evidence of preliminary antitumor activity in ER+/HER2- ABC.

P1, N=193, Active, not recruiting, Eli Lilly and Company | Recruiting --> Active, not recruiting | N=400 --> 193

P1, N=17, Active, not recruiting, Eli Lilly and Company | Trial completion date: Apr 2025 --> Dec 2025

P3, N=866, Active, not recruiting, Eli Lilly and Company | Recruiting --> Active, not recruiting

P1, N=500, Active, not recruiting, Eli Lilly and Company | Trial completion date: Dec 2024 --> Dec 2027

Prior fulvestrant or aromatase inhibitor therapy was not allowed. Imlunestrant, as monotherapy or with abemaciclib, appears safe and tolerable with preliminary evidence of efficacy in pts with metastatic ER+ EEC.

P1, N=28, Completed, Eli Lilly and Company | Recruiting --> Completed | N=42 --> 28

P1, N=500, Active, not recruiting, Eli Lilly and Company | Phase classification: P1a/1b --> P1

Median number of prior therapies for aBC was 2 (range, 0-8), including: prior CDK4/6 inhibitor (93%), fulvestrant (52%), or chemotherapy (25%). Table: 51P CBR (%, 95 CI) p D ND ctDNA 39/98 (40, 30-50) 7/11 (64, 31-89) 0.20 AKT1 2/5 (40, 5-85) 44/104 (42, 33-52) 1.00 ARID1A 2/7 (29, 4-71) 44/102 (43, 33-53) 0.70 ATM 0/5 (0, 0-52) 46/104 (44, 34-54) 0.07 BRCA2 0/4 (0, 0-60) 46/105 (44, 34-54) 0.14 ESR1 25/53 (47, 33-61) 21/56 (38, 25-51) 0.34 GATA3 8/14 (57, 29-82) 38/95 (40, 30-51) 0.26 KRAS 2/7 (29, 4-71) 44/102 (43, 33-53) 0.70 PIK3CA 14/40 (35, 21-52) 32/69 (46, 34-59) 0.32 PTEN 0/5 (0, 0-52) 46/104 (44, 34-54) 0.07 RB1 0/4 (0, 0-60) 46/105 (44, 34-54) 0.14 SMAD4 1/4 (25, 1-81) 45/105 (43, 33-53) 0.64 TP53 7/26 (27, 12-48) 39/83 (47, 36-58) 0.11 ESR1 & PIK3CA 10/22 (45, 24-68) 36/87 (41, 31-52) 0.81 PIK3CA or AKT1 or PTEN 16/47 (34, 21-49) 30/62 (48, 35-61) 0.17 Conclusions Exploratory ctDNA analyses of ER+, HER2- aBC pts treated with imlunestrant in the EMBER trial demonstrated no significant impact on clinical benefit in pts harboring common genomic alterations. These findings will be further explored in the ongoing phase III EMBER-3 trial.

Fulvestrant is the first approved SERD with proven efficacy and good tolerability in clinical practice...Elacestrant is an orally bioavailable SERD that has been recently approved by the FDA for postmenopausal women with ER+, human epidermal growth factor receptor 2-negative (HER2-), estrogen receptor 1 (ESR1)-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy. Other molecules of the same class currently tested in clinical trials are amcenestrant, giredestrant, camizestrant, and imlunestrant. The current review article offers a detailed pharmacological perspective of this emerging drug class, which may help with their possible future clinical applications.

P1, N=17, Active, not recruiting, Eli Lilly and Company | Recruiting --> Active, not recruiting

With longer follow-up, imlunestrant alone or in combination with abemaciclib ± AI continues to demonstrate a tolerable safety profile along with favorable preliminary efficacy in patients with ER+, HER2- aBC. Further data will be presented at the meeting. The Phase 3, EMBER-3 study is ongoing; evaluating imlunestrant, investigator's choice ET, and imlunestrant plus abemaciclib in ET pre-treated ER+, HER2- aBC patients (NCT04975308).

In the first-in-human phase 1a/b EMBER study, imlunestrant demonstrated favorable safety, pharmacokinetics (PK), and clinical benefit rate when administered as monotherapy (Jhaveri ASCO 2022) or with abemaciclib (Jhaveri SABCS 2022)...Median number of prior aBC therapies in combination cohorts was: 1 (range 1-2); including prior ET (100%), CDK4/6i (100%), fulvestrant (35%) and chemo (17%)...Conclusions Imlunestrant alone or in combination with everolimus or alpelisib demonstrated robust efficacy in pts with pre-treated ER+, HER-2 aBC. Toxicities were consistent with the known safety profile of both alpelisib and everolimus.

In early phase trials, imlunestrant monotherapy showed favorable safety with pharmacokinetic (PK) exposures exceeding fulvestrant and preliminary efficacy in ER+, HER2− advanced breast cancer patients (EMBER) and robust biological/pharmacodynamic activity and tolerability in EBC (EMBER-2). EMBER-4 is a randomized, open-label, global phase 3 study comparing imlunestrant and physicians’ choice of ET, in patients at increased risk of recurrence ~6,000 patients will be randomized 1:1 to imlunestrant (400mg daily) or physicians’ choice of adjuvant ET (tamoxifen or an aromatase inhibitor [AI], dosed per label) for 5 years. Key secondary endpoints include distant relapse-free survival, overall survival, IDFS including second non-breast primary invasive cancers, safety, PK, patient-reported outcomes. Recruitment for EMBER-4 begins globally in Q4 2022.Presented: SABCS2022.

P3, N=6000, Recruiting, Eli Lilly and Company | Trial primary completion date: Oct 2026 --> Oct 2027

P3, N=6000, Recruiting, Eli Lilly and Company | Trial primary completion date: Oct 2027 --> Oct 2026

P1, N=24, Recruiting, Eli Lilly and Company | Trial completion date: Mar 2024 --> Jan 2025 | Trial primary completion date: Jun 2023 --> Jan 2024

P1a/1b, N=500, Active, not recruiting, Eli Lilly and Company | Trial completion date: Dec 2023 --> Dec 2024

P1, N=86, Completed, Eli Lilly and Company | Active, not recruiting --> Completed

P1a/1b, N=500, Active, not recruiting, Eli Lilly and Company | Recruiting --> Active, not recruiting

P1, N=400, Recruiting, Eli Lilly and Company | N=300 --> 400

Methods ER+ breast cancer cell lines and mouse models with ESR1 wild-type or mutant tumors were treated with imlunestrant alone or with abemaciclib, alpelisib or everolimus...In a brain orthotopic tumor model, imlunestrant prolonged survival compared to either vehicle or fulvestrant (60%, 0% and 10% alive at 68 days, respectively)...Drs. Cecilia Mur and Matthew VandeKopple have equally contributed to the study.

P3, N=860, Recruiting, Eli Lilly and Company | Trial completion date: Sep 2026 --> Aug 2027 | Trial primary completion date: Jun 2023 --> Apr 2024

P1, N=90, Active, not recruiting, Eli Lilly and Company | Recruiting --> Active, not recruiting

P1, N=24, Recruiting, Eli Lilly and Company | Not yet recruiting --> Recruiting

P3, N=6000, Recruiting, Eli Lilly and Company | Not yet recruiting --> Recruiting

Imlunestrant in combination with abemaciclib ± AI showed acceptable safety and tolerability, comparable to the MONARCH 2 trial of fulvestrant + abemaciclib, along with evidence of clinical activity in ER+, HER2- aBC patients. These data suggest no additive toxicity of imlunestrant when administered in combination with abemaciclib, along with comparable clinical benefit to that observed in MONARCH 2. Further data will be presented at the meeting.

Results Combining LOXO-783 with either fulvestrant (FUL; CI at 50% inhibition = 0.28) or imlunestrant (CI at 50% inhibition = 0.43) showed increased efficacy in cell proliferation assays using the HR+, HER2-, PI3Kα H1047R- mutant T47D model...Similar results were observed in a T47D model engineered to express ESR1 D538G, as well as in an HR+, HER2- PI3Kα double in-cis mutant model (H1047R/D350G) also harboring ESR1 D538G and derived from a patient who had progressed on prior letrozole plus taselisib...Extending these studies to additional treatment settings, LOXO-783 was similarly efficacious as a single agent in abemaciclib-resistant and abemaciclib/FUL double-resistant models, and was additive in combination with paclitaxel in a triple negative breast cancer model in vitro and in vivo...LOXO-783 is also efficacious in ESR1 mutant as well as in abemaciclib and abemaciclib/FUL double-resistant models. A phase 1 trial of LOXO-783 alone or in combination with anticancer therapies is ongoing (PIKASSO-01; NCT05307705).

In early phase trials, imlunestrant monotherapy showed favorable safety with pharmacokinetic (PK) exposures exceeding fulvestrant and preliminary efficacy in ER+, HER2- advanced breast cancer patients (EMBER, Jhaveri 2022) along with robust biological/pharmacodynamic activity and tolerability in EBC (EMBER-2, Neven)...Approximately 6,000 patients will be randomized 1:1 to receive imlunestrant (400 mg daily) for 5 years or physicians’ choice of adjuvant ET (tamoxifen or an aromatase inhibitor, AI, dosed per label)...Key secondary endpoints include distant relapse-free survival, overall survival, IDFS including second non-breast primary invasive cancers, safety, PK and patient reported outcomes. Recruitment for EMBER-4 begins globally in Q4 2022.

The L391F mutation resulted in an increased binding affinity for Lasofoxifene (LAS) (dAff -0.34), Giredestrant (GIR) (dAff -0.18), Elacestrant (ELA) (dAff -0.08) and Amcenestrant (AMC) (dAff -0.41), while a decreased binding affinity was observed for 4OH-Tamoxifen (TAM) (dAff 0.01), Imlunestrant (IML) (dAff 0.15), Fulvestrant (FUL) (dAff 0.43), and Camizestrant (CAM) (dAff 0.02). The study suggests that genomic variability in drug targets detectable through ctDNA may modulate therapeutic response. Preclinical models are under development to investigate the combined endocrine resistance mechanism suggested by the significant co- occurrence between ESR1 mutations in SERDs/SERMs docking sites and ESR1 hotspot mutations and provide valuable additional insights for drug development and future treatment algorithms.

P1, N=24, Not yet recruiting, Eli Lilly and Company | Trial primary completion date: Mar 2023 --> Jun 2023

P3, N=6000, Not yet recruiting, Eli Lilly and Company

P1, N=24, Not yet recruiting, Eli Lilly and Company

P1a/1b, N=500, Recruiting, Eli Lilly and Company | Trial completion date: Apr 2023 --> Dec 2023

P1, N=260, Recruiting, Eli Lilly and Company | Not yet recruiting --> Recruiting