Lilly announces new clinical data from Verzenio and oral SERD programs at the American Society of Clinical Oncology annual meeting

• New exploratory analysis of a pre-specified subgroup of patients with HR+, HER2- high risk early breast cancer who received neoadjuvant chemotherapy in the monarchE trial showed Verzenio plus endocrine therapy resulted in a 6.6% absolute difference in invasive disease-free survival versus endocrine therapy alone
• First results from investigational oral selective estrogen receptor degrader (SERD) LY3484356 demonstrate pharmacokinetics, safety, and efficacy consistent with preclinical design
• Two Phase 3 trials to be initiated in 2021: Verzenio eMonarcHER trial in HR+, HER2+ high risk early breast cancer and oral SERD EMBER-3 trial in ER+, HER2- advanced breast cancer

TORONTO, June 14, 2021 /CNW/ - Eli Lilly and Company announced new data for the investigational use of Verzenio® (abemaciclib) in high-risk early breast cancer, and for its oral selective estrogen receptor degrader (SERD) LY3484356 at the 57th Annual Meeting of the American Society of Clinical Oncology (ASCO). Lilly presented an exploratory analysis from the positive Phase 3 monarchE trial evaluating Verzenio, a CDK4/6 inhibitor, in a subgroup of patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) high risk early breast cancer (EBC) who had received neoadjuvant chemotherapy. Physicians often treat patients with HR+, HER2- breast cancer that they believe to be at the highest risk of recurrence with neoadjuvant chemotherapy prior to curative intent surgery.

In addition, Loxo Oncology at Lilly presented interim clinical data from the ongoing Phase 1a trial evaluating the safety and efficacy of the oral SERD LY3484356 in patients with estrogen receptor-positive (ER+) advanced breast cancer and endometrial endometrioid cancer.

New Verzenio data from monarchE trial
In an exploratory analysis of a pre-specified subgroup of patients who received neoadjuvant chemotherapy (n=2,056), the addition of Verzenio to endocrine therapy (ET) resulted in a numerically greater effect size when compared to the intent-to-treat (ITT) population (n=5,637).

This subgroup of patients, made up more than 36 per cent of the total trial population, had larger tumors at initial diagnosis and were more commonly premenopausal, representing one of the highest risk subgroups of patients in monarchE. Treatment with Verzenio in combination with standard adjuvant ET decreased the risk of breast cancer recurrence in these patients by 38.6% compared to ET alone (HR: 0.614; 95% CI: 0.473, 0.797). This corresponds to a 6.6% difference in the two-year rate of invasive disease-free survival (IDFS) between arms (87.2% in the Verzenio plus ET arm compared to 80.6% in the ET only control arm). The addition of Verzenio to ET also reduced the risk of developing metastatic disease by 39% (HR: 0.609; 95% CI: 0.459, 0.809). This corresponds to a 6.7% difference in two-year distant relapse-free survival (DRFS) rates – or time to developing breast cancer that has spread to other parts of the body – between the arms (89.5% in the Verzenio plus ET arm compared to 82.8% in the ET only control arm). This subgroup analysis was exploratory and not alpha-controlled for testing statistical significance. Safety data from the monarchE trial were consistent with the known safety profile of Verzenio and no new safety signals were observed.

"It was crucial to examine a patient population who received neoadjuvant chemotherapy in the monarchE trial, as this is a subgroup of patients associated with an increased risk of recurrence," says Dr. Doron Sagman, vice president, R&D and Medical Affairs, Eli Lilly Canada Inc. "We are encouraged by these results and Verzenio's ability to make a measurable difference in the lives of people living with early breast cancer."   

"The risk of developing metastatic diseases dropped by 38.6% in patients taking Verzenio in combination with endocrine therapy, a significant measure. We continue to see encouraging results from monarchE and I am looking forward to the findings of eMonarcHER," says Dr. Asselah Jamil, Medical Oncologist, McGill Hospital.

These data build on the results from the Phase 3 monarchE trial, which met its primary endpoint at the second interim efficacy analysis by showing a statistically significant improvement in IDFS. Verzenio, given in combination with ET, decreased the risk of breast cancer recurrence by 28.7 per cent compared to ET alone (HR: 0.713; 95% CI: 0.583, 0.871; p=0.0009) with a 3 per cent absolute difference in the two-year IDFS and DRFS rates in the ITT population. The monarchE trial is ongoing and patients will continue to be followed to assess safety, overall survival and patient reported outcomes, as well as other endpoints.

New Verzenio Phase 3 Trial
Lilly recently initiated a new Phase 3 trial, eMonarcHER, which will evaluate the safety and efficacy of Verzenio in combination with standard adjuvant ET in patients with HR+, HER2+, node-positive, high risk early breast cancer receiving adjuvant ET after completing surgery and neoadjuvant and/or adjuvant HER2 targeted therapy. Despite several advancements for the neoadjuvant and adjuvant treatment of HER2+ breast cancer, research has primarily involved HER2 targeting agents; however, not all HER2+ breast cancers are successfully treated with HER2 targeted therapy. This new Phase 3 study introduces the novel strategy of CDK4/6 inhibition to improve outcomes with adjuvant hormonal therapy in patients with HR+/HER2+ breast cancer at high risk of recurrence after completion of HER2 targeted therapy. Lilly shared the trial design of eMonarcHER at ASCO.

Oral SERD (LY3484356) phase 1a data
The first clinical data from the ongoing Phase 1 EMBER trial of LY3484356 were also presented at ASCO. As of April 7, 2021, 65 patients were enrolled in the trial, including 58 with ER+ advanced breast cancer and seven with ER+ endometrial endometrioid cancer (EEC). All patients received LY3484356 monotherapy. Advanced breast cancer patients had received a median of two prior lines of therapy with 60 per cent having received prior fulvestrant, 83 per cent a CDK4/6 inhibitor, and 26 per cent chemotherapy. Of 54 patients with available circulating tumor DNA (ctDNA) data, ESR1 mutations were detected in 37 per cent.

Pharmacokinetic analyses during the dose escalation phase demonstrated dose-proportional increases in LY3484356 exposure across all evaluated doses (200 mg once daily [QD] to 1200 mg QD). At all doses, steady state LY3484356 plasma concentrations in patients exceeded the EC80 range associated with efficacy in preclinical studies, as well as steady state fulvestrant peak serum concentration.

No dose-limiting toxicities were observed and no maximum tolerated dose was established. Most treatment-emergent adverse events were grade 1 or 2 in severity. The treatment-related adverse events observed most commonly were nausea (19 [29%]), diarrhea (11 [17%]), and fatigue (8 [12%]). Grade 3 treatment-emergent adverse events occurred in six (9%) patients, which were treatment-related in two (3%) patients (diarrhea [n=1] and decreased neutrophil count [n=1]). Serious adverse events occurred in three (5%) patients, only one of which (grade 3 diarrhea) was treatment-related. No cardiac safety signal was seen. Dose reductions due to adverse events occurred in two (3%) patients, one of which was the treatment-related grade 3 diarrhea. No patient discontinued due to an adverse event and 400 mg QD has been selected as the recommended Phase 2 dose.

The efficacy data presented were based on investigator assessment. Patients were considered efficacy-evaluable for objective response rate (ORR) if they had RECIST measurable disease at baseline and at least one post-baseline tumor assessment or discontinued treatment prior to their first post-baseline assessment. Patients were considered efficacy-evaluable for clinical benefit rate (CBR) if they were enrolled at least 24 weeks prior to the data cut-off date. In advanced breast cancer, two confirmed partial responses were observed in 35 efficacy-evaluable patients, both occurring after 24 weeks of therapy at the 400 mg dose and in patients who had received at least three prior regimens for metastatic disease. One of the observed partial responses was seen in a patient with fulvestrant, CDK4/6, and chemotherapy-refractory disease. The other partial response occurred in a patient with three lines of prior endocrine therapy, including an mTOR inhibitor. The CBR across all dose levels was 48 per cent (13/27). In EEC, no objective responses were observed among the six efficacy-evaluable patients and the CBR was 50 per cent (2/4). In patients with available serial ctDNA data, 86 per cent (18/21) had early (cycle 2 day 1) declines in overall ctDNA and the degree of decline was generally deeper in patients who experienced clinical benefit versus those who did not. As of the data cut-off, 35 patients remained on treatment, including both patients with partial responses, and 79 per cent (31/39) of those with stable disease or partial responses.

Phase 3 EMBER-3 Trial of LY3484356
Lilly is preparing to initiate a randomized, open-label, Phase 3 study of LY3484356 in patients with ER+, HER2- locally advanced or metastatic breast cancer previously treated with endocrine therapy. Patients will be randomized to receive LY3484356 monotherapy or investigator's choice of monotherapy endocrine therapy (fulvestrant or exemestane). The trial, EMBER-3, is expected to begin enrollment in the third quarter of 2021.

Please refer to Lilly's press release from May 19, 2021 for a full list of presentations at the meeting.

About the monarchE Trial
monarchE is a Phase 3, multicenter, randomized, open-label trial that enrolled 5,637 patients with HR+, HER2-, node-positive, high risk early breast cancer. Patients were randomized 1:1 to Verzenio (150 mg twice daily) plus standard adjuvant ET or standard adjuvant ET alone. Patients were treated for two years (treatment period) or until meeting criteria for discontinuation. Patients in both arms will receive 5-10 years of ET as clinically indicated (2 years on study followed by a further 3-8 years in long-term follow-up). The primary objective is invasive disease-free survival (IDFS) defined according to the Standard Definitions for Efficacy Endpoints (STEEP) criteria. In adjuvant breast cancer trials, this includes the length of time before any cancer comes back, a new cancer develops or death. Secondary objectives include distant relapse-free survival, overall survival, safety, pharmacokinetics and health outcomes.
High risk was specifically defined as women (any menopausal status) and men with resected HR+, HER2- invasive early breast cancer with either ≥4 pathologically positive axillary lymph nodes (ALNs) or 1 to 3 positive ALNs and at least one of the following high-risk features: primary invasive tumor size ≥5 cm, histological grade 3 tumor, or central Ki-67 index ≥20%. If applicable, patients must have also completed adjuvant chemotherapy and radiotherapy prior to enrolling and have recovered from all acute side effects.

About Verzenio®
Verzenio (abemaciclib) is an inhibitor of cyclin-dependent kinases (CDK)4 & 6, which are activated by binding to D-cyclins. In estrogen receptor-positive (ER+) breast cancer cell lines, cyclin D1 and CDK4 & 6 promote phosphorylation of the retinoblastoma protein (Rb), cell cycle progression, and cell proliferation.

In vitro, continuous exposure to Verzenio inhibited Rb phosphorylation and blocked progression from G1 to S phase of the cell cycle, resulting in senescence and apoptosis (cell death). Preclinically, Verzenio dosed daily without interruption resulted in reduction of tumor size. Inhibiting CDK4 & 6 in healthy cells can result in side effects, some of which may be serious. Clinical evidence also suggests that Verzenio crosses the blood-brain barrier. In patients with advanced cancer, including breast cancer, concentrations of Verzenio and its active metabolites (M2 and M20) in cerebrospinal fluid are comparable to unbound plasma concentrations.

Verzenio is Lilly's first solid oral dosage form to be made using a faster, more efficient process known as continuous manufacturing. Continuous manufacturing is a new and advanced type of manufacturing within the pharmaceutical industry, and Lilly is one of the first companies to use this technology.

Indication
In Canada, Verzenio® (abemaciclib) is indicated for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer:

• in combination with an aromatase inhibitor in postmenopausal women as initial endocrine based therapy.
• in combination with fulvestrant in women with disease progression following endocrine therapy. Pre- or perimenopausal women must also be treated with a gonadotropin-releasing hormone (GnRH) agonist.
• as a single agent in women with disease progression following endocrine therapy and at least 2 prior chemotherapy regimens. At least one chemotherapy regimen should have been administered in the metastatic setting, and at least one should have contained a taxane.

Please consult the Verzenio Product Monograph for important information on contraindications, warnings, precautions, adverse reactions, interactions and dosing. The product monograph is also available by calling us at 1-888-545-5972.

About the EMBER Trial
This global, first-in-human, open-label Phase 1a/b trial evaluates LY3484356 alone or in combination with other anticancer therapies in participants with ER+ advanced breast cancer or endometrioid endometrial cancer. The trial includes a Phase 1a dose escalation phase and a Phase 1b dose expansion phase. The Phase 1a dose escalation enrolls patients with ER+/HER2- advanced breast cancer who have received up to three prior treatment regimens and ER+ EEC who have progressed after prior platinum-based therapy. The dose escalation phase followed an i3+3 design with LY3484356 administered orally in 28-day cycles. As dose cohorts were cleared, additional patient enrollment to cleared dose levels was permitted. The primary objective of the Phase 1a portion is to determine the recommended Phase 2 dose. Secondary objectives include assessments of safety, pharmacokinetics, and anti-tumor activity (objective response rate (ORR) and clinical benefit rate (CBR), as assessed per Response Evaluation Criteria in Solid Tumors (RECIST v1.1).

About LY3484356
LY3484356 is an investigational, oral selective estrogen receptor degrader (SERD) with pure antagonistic properties. The estrogen receptor (ER) is the key therapeutic target for patients with ER+/HER2- breast cancer. Novel degraders of ER may overcome endocrine therapy resistance while providing consistent oral pharmacology and convenience of administration. LY3484356 was specifically designed to deliver continuous estrogen receptor target inhibition throughout the dosing period and regardless of ESR1 mutational status.

LY3484356 is currently being studied in the first-in-human, multi-center Phase 1a/1b EMBER trial in patients with estrogen receptor-positive locally advanced or metastatic breast cancer and other select non-breast cancers, and in the Phase 1 EMBER-2 trial in preoperative, postmenopausal women with stage I-III, ER+/HER2- breast cancer. For additional information about LY3484356 clinical trials, please refer to www.clinicaltrials.gov.

About Lilly Oncology
For more than 50 years, Lilly has been dedicated to delivering life-changing medicines and support to people living with cancer and those who care for them. Lilly is determined to build on this heritage and continue making life better for all those affected by cancer around the world.

About Loxo Oncology at Lilly
Loxo Oncology at Lilly was created in December 2019, combining the Lilly Research Laboratories oncology organization and Loxo Oncology, which was acquired by Lilly in early 2019. Loxo Oncology at Lilly brings together the focus and spirit of a biotech with the scale and resources of large pharma, with the goal of rapidly delivering impactful new medicines for people with cancer. Our approach centers on creating new oncology medicines that unequivocally work early in clinical development and will matter to patients.

About Lilly Canada
Eli Lilly and Company is a global healthcare leader that unites caring with discovery to make life better for people around the world. We were founded more than a century ago by Colonel Eli Lilly, who was committed to creating high quality medicines that meet people's needs, and today we remain true to that mission in all our work. Lilly employees work to discover and bring life-changing medicines to people who need them, improve the understanding and management of disease, and contribute to our communities through philanthropy and volunteerism.

Eli Lilly Canada was established in 1938, the result of a research collaboration with scientists at the University of Toronto which eventually produced the world's first commercially available insulin. Our work focuses on oncology, diabetes, autoimmunity, neurodegeneration, and pain. To learn more about Lilly Canada, please visit us at www.lilly.ca.

For our perspective on issues in healthcare and innovation, follow us on twitter @LillyPadCA.

Lilly Forward-Looking Statement
This press release contains forward-looking statements (as that term is defined in the Private Securities Litigation Reform Act of 1995) about Lilly's oncology portfolio and pipeline, including Verzenio (abemaciclib) and LY3484356 as treatments for patients with breast cancer and reflects Lilly's current beliefs and expectations. However, as with any pharmaceutical product, there are substantial risks and uncertainties in the process of research, development, regulatory approval, and commercialization. Among other things, there can be no guarantee that future studies will be completed as planned, that future study results will be consistent with the results to date, or that Verzenio or LY3484356 will receive (or receive additional) regulatory approvals or be commercially successful. For further discussion of these and other risks and uncertainties, see Lilly's most recent Form 10-K and Form 10-Q filings with the United States Securities and Exchange Commission. Except as required by law, Lilly undertakes no duty to update forward-looking statements to reflect events after the date of this release.

SOURCE Eli Lilly Canada Inc.