29 ELEVATE: A Phase 1b/2, Open-Label, Umbrella Study Evaluating Elacestrant in Various Combinations in Patients (pts) With Estrogen Receptor–Positive (ER+), HER2-Negative (HER2–) Locally Advanced or Metastatic Breast Cancer (mBC)
29 ELEVATE: A Phase 1b/2, Open-Label, Umbrella Study Evaluating Elacestrant in Various Combinations in Patients (pts) With Estrogen Receptor–Positive (ER+), HER2-Negative (HER2–) Locally Advanced or Metastatic Breast Cancer (mBC)
Background
Endocrine therapy (ET) plus CDK4/6 inhibitor is the mainstay for the management of estrogen receptor-positive (ER+)/HER2- negative (HER2–) metastatic breast cancer (mBC) as first-line therapy; however, tumors eventually develop resistance to ET. After progression on first-line ET plus CDK4/6 inhibitors, both ET monotherapy and combination therapies are available. Disease progression is a result of resistance mechanisms due to alterations in PI3K/ATK/mTOR or the cell cycle pathways but can also be due to the development of an ESR1 mutation during therapy with an aromatase inhibitor, a type of acquired resistance. In the phase 3 EMERALD trial (NCT03778931), single-agent elacestrant was associated with significantly prolonged progression-free survival (PFS) and a manageable safety profile vs standard-of-care (SOC) ET in patients with ER+/HER2–, ESR1-mutated advanced mBC, leading to the first oral selective estrogen receptor degrader approved. Patients receiving elacestrant demonstrated a median PFS of 3.8 months vs 1.9 months with SOC ET (Bidard, 2022). Patients who had received 12 or more months of prior CDK4/6 inhibitors experienced a median PFS of 8.6 months with elacestrant vs 1.9 months with SOC ET (SABCS, 2022). The rationale for the phase 1b/2 ELEVATE study (NCT05563220) is to combine elacestrant with inhibitors of the PI3K/AKT/mTOR pathway or CDK4/6 inhibitors to overcome different resistance mechanisms to enable oral-oral combination options. This analysis reports all combination data from cohort 1 of phase 1b.
Methods
Eligible patients must have confirmed ER+/HER2– advanced metastatic breast cancer and more than 1 measurable lesion as per RECIST v1.1. The objective for phase 1b is to determine the recommended phase 2 dose of elacestrant combined with other targeted agents. The recommended phase 2 dose of elacestrant and abemaciclib will be determined in the ELECTRA trial. Phase 2 will evaluate the PFS of elacestrant with the various combinations.
Results
As of October 2023, 26 patients were enrolled in cohort 1: elacestrant plus everolimus (n = 6); elacestrant plus alpelisib (n = 8); elacestrant plus palbociclib (n = 6); elacestrant plus ribociclib (n = 6). No dose-limiting toxicities were observed with elacestrant in combination with everolimus, palbociclib, or ribociclib. The most common adverse effects (AEs) were grade 1/2 nausea, fatigue, and rash. No AEs led to the discontinuation of elacestrant or combination drugs. Grade 3 rash with alpelisib led to ongoing exploration of a lower alpelisib dose.
Conclusion
In cohort 1, elacestrant combined with everolimus, palbociclib, or ribociclib is well tolerated with predictable safety profiles. Additional cohorts are currently under evaluation to assess pharmacokinetics and determine the recommended phase 2 dose for each combination. The phase 2 portion of the study will further characterize the safety and efficacy of the elacestrant combinations.
