New data from Phase III monarchE trial for Verzenio in high risk early breast cancer and Phase Ia data for LY 3484356.- Eli Lilly

Lilly is presenting an exploratory analysis from the positive Phase III 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 who they believe to be at the highest risk of recurrence with neoadjuvant chemotherapy prior to curative intent surgery. In addition, Loxo Oncology at Lilly is presenting 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 percent 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 percent compared to ET alone (HR: 0.614; 95% CI: 0.473, 0.797) . This corresponds to a 6.6 percent difference in the two-year rate of invasive disease-free survival (IDFS) between arms (87.2 percent in the Verzenio plus ET arm compared to 80.6 percent in the ET only control arm). The addition of Verzenio to ET also reduced the risk of developing metastatic disease by 39 percent (HR: 0.609; 95% CI: 0.459, 0.809) . This corresponds to a 6.7 percent 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 percent in the Verzenio plus ET arm compared to 82.8 percent 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. "People who receive neoadjuvant chemotherapy typically represent a patient population with a substantial risk of breast cancer recurrence. The data from monarchE further confirm this higher risk based on the number of events that occurred in the control arm for this subset of patients," said Maura Dickler, M.D., distinguished medical fellow, Lilly Oncology. "Given the need for new treatments for high risk early breast cancer, especially in this neoadjuvant population, it's encouraging to see these impressive results with a 38 percent reduction in the risk of recurrence with the addition of Verzenio to standard endocrine therapy." These data build on the results from the Phase III 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 percent compared to ET alone (HR: 0.713; 95% CI: 0.583, 0.871; p=0.0009) with a 3 percent 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 III Trial ; Lilly recently initiated a new Phase III 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 III 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 percent receiving prior fulvestrant, 83 percent a CDK4/6 inhibitor, and 26 percent chemotherapy. Of 54 patients with available circulating tumor DNA (ctDNA) data, ESR1 mutations were detected in 37 percent. 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 II 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 and 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 percent (13/27). In EEC, no objective responses were observed among the six efficacy-evaluable patients and the CBR was 50 percent (2/4). In patients with available serial ctDNA data, 86 percent (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 percent (31/39) of those with stable disease or partial responses. "When we began clinical development of our oral SERD, we hoped to see pharmacokinetic exposures that exceeded fulvestrant, a safety profile amenable to chronic use and combination, and evidence of single agent efficacy. To date, LY3484356 has delivered on these objectives," said David Hyman, M.D., chief medical officer, oncology at Lilly. "We look forward to continuing to explore the profile of LY3484356 in the ongoing dose expansion portion of the EMBER study and through the Phase III EMBER-3 trial in metastatic ER+, HER2- breast cancer, set to begin later this year." Phase III EMBER-3 Trial of LY3484356 : Lilly is preparing to initiate a randomized, open-label, Phase III 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.