Elacestrant Shows Tolerability in Combination With CDK4/6, PI3K Inhibitors in Advanced ER+ Breast Cancer

Elacestrant (Orserdu) demonstrated tolerability when used in combination with multiple targeted agents, including abemaciclib (Verzenio), everolimus (Afinitor), and ribociclib (Kisqali), among others, for patients with estrogen receptor (ER)–positive, HER2-negative advanced breast cancer, according to an analysis from the phase 1b/2 ELEVATE trial (NCT05563220) presented at the 2024 San Antonio Breast Cancer Symposium.1

Elacestrant was tested as part of the following regimens:

• Elacestrant at 345 mg plus abemaciclib at 150 mg twice daily
• Elacestrant at 345 mg plus everolimus at 7.5 mg
• Elacestrant at 345 mg plus palbociclib (Ibrance) at 125 mg
• Elacestrant at 172 mg plus ribociclib at 600 mg
• Elacestrant at 258 mg plus capivasertib (Truqap) at 320 mg
• Elacestrant at 258 mg plus alpelisib (Piqray) at 200 mg

“At current tested doses, the exposure-safety data support the selection of elacestrant as a potential endocrine therapy backbone due to the absence of drug-drug interactions,” lead study author Hope S. Rugo, MD, FASCO, Winterhof Family Endowed Professorship in Breast Cancer, professor in the Department of Medicine (Hematology/Oncology), director of Breast Oncology and Clinical Trials Education and medical director of Cancer Infusion Services, all within University of California San Francisco Helen Diller Family Comprehensive Cancer Center,and coinvestigators, wrote in the poster presented during the meeting. “The safety profiles support the combinability of elacestrant with abemaciclib, ribociclib, palbociclib, everolimus, alpelisib, and capivasertib given that the co-administration of elacestrant does not increase the risk of associated adverse events.”

Endocrine therapy (ET) plus CDK4/6 inhibitors is a standard first-line treatment for patients with ER-positive/HER2-negative metastatic breast cancer; however, patients’ tumors do acquire resistance mechanisms, such as intrinsic alterations in the cell cycle or PI3K/AKT/mTOR pathway or acquired ESR1 mutations, ultimately leading to disease progression.

In January 2023, the FDA approved elacestrant for the treatment of postmenopausal women or adult men with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least 1 line of ET.2

Investigators rationalized that combining elacestrant with either PI3K/AKT/mTOR or CDK4/6 inhibitors could overcome different resistance mechanisms and provide an all-oral regimen for patients. Previous combination data of elacestrant with abemaciclib showed a median progression-free survival (PFS) of 8.7 months, an objective response rate (ORR) of 26%, and a clinical benefit rate (CBR) of 70%.3 When explored in combination with everolimus, the ORR was 22% and the CBR was 72%.4

In the analysis presented at the 2024 SABCS, investigators presented updated safety data for the multiple agents that elacestrant was combined with, which included: abemaciclib, everolimus, palbociclib, ribociclib, capivasertib, and alpelisib from the ongoing ELEVATE trial.1

To be eligible for enrollment, patients with confirmed ER-positive, HER2-negative breast cancer needed to be at least 18 years old, have at least 1 measurable lesion as per RECIST v1.1 criteria, and an ECOG performance status of 0 or 1. Female patients could be post-, pre-, or perimenopausal.

They must have had 1 to 2 prior lines of ET, one of which needed to be with alpelisib, everolimus, palbociclib, ribociclib, or abemaciclib. If there was prior receipt of an alpelisib combination, patients must have had PIK3CA-mutated disease; if previously given a capivasertib combination, patients must have had a PIK3CA/AKT1/PTEN alteration and must have received 1 to 2 prior hormonal treatments in the advanced or metastatic setting or had radiological evidence of breast cancer recurrence or progression within 12 months from the end of adjuvant ET.

Those with active or newly diagnosed central nervous system metastases, including meningeal carcinomatosis; advanced, symptomatic visceral spread with risk of life-threatening complications in short term; prior chemotherapy in the advanced or metastatic setting; and prior therapy with elacestrant or other investigational compounds in the advanced or metastatic setting, were excluded, although fulvestrant (Faslodex) was permitted. Other exclusion criteria were reported based on the various combination regimens.

The phase 1b portion (n = 90) of ELEVATE comprised 3 cohorts:

• Cohort 1 (n = 33): Elacestrant at 258 mg was combined with alpelisib at 150 to 250 mg, ev
  erolimus at 5 mg, palbociclib at 100 mg, ribociclib at 400 mg, or capivasertib at 320 mg;
• Cohort 2 (n = 24): Elacestrant at 345 mg was combined with alpelisib at 250 mg, everolimus at 5 mg, palbociclib at 100 mg, ribociclib at 400 mg, or capivasertib at 320 mg;
• Cohort 3+ (n = 35): Elacestrant at 345 mg was combined with alpelisib at 300 mg, everolimu
  s at 7.5 to 10 mg, palbociclib at 125 mg, ribociclib at 400 to 600 mg, or capivasertib at 400 mg.

After determining the recommended phase 2 dose (RP2D) of the various combinations, 310 patients then moved into the phase 2 portion of the research, which comprised 5 arms:

• Arm A (n = 50): elacestrant plus alpelisib
• Arm B (n = 50): elacestrant plus everolimus
• Arm C (n = 60): elacestrant plus abemaciclib and elacestrant plus ribociclib
• Arm D (n = 90): elacestrant plus palbociclib, elacestrant plus abemaciclib, and elacestrant plus ribociclib
• Arm E (n = 60): elacestrant plus capivasertib

In arms A through C, patients must have previously received a CDK4/6 inhibitor. In arm D, patients could not have previously received a CDK4/6 inhibitor; in arm E, prior exposure to CDK4/6 inhibition was permitted.

In the phase 1b portion, the primary end point was determining the RP2D of elacestrant in combination with each of the other agents. In the phase 2 portion, the primary end point was PFS with each regimen; secondary end points were efficacy and safety of each combination.

Baseline characteristics were similar across the 6 arms. The median age was 61.7 years (range, 29-85), most patients were female (99.2%), and 35.2% of patients had an ECOG performance status of 1. A total 86.7% of patients had visceral metastasis, 44% had ESR1 mutations, and 52.7% had PIK3CA mutations. Primary endocrine resistance was observed in 18.7% of patients. Moreover, the median number of prior therapies for advanced disease was 1 (range, 1-4). Most patients previously received a CDK4/6 inhibitor (94.2%) and had 1 prior line of ET for their advanced disease (75.3%). Regarding type of prior ET, patients either had fulvestrant (42.5%), aromatase inhibitor (69.5%), tamoxifen (7%), or tamoxifen plus an aromatase inhibitor (6.2%).

The data cutoff date was October 15, 2024. The most common TEAEs were reported with each combination.

For arm C of elacestrant and abemaciclib at the RP2D (n = 30), all-grade and grade 3/4 TEAEs consisted of diarrhea (80% and 7%, respectively), nausea (63%; 7%), fatigue (43%; 7%), vomiting (43%; 0%), constipation (30%; 0%), abdominal pain (23%; 0%), decreased appetite (23%; 0%), anemia (20%; 7%), dizziness (17%; 3%), neutropenia (17%; 13%), rash (17%; 0%) and deceased weight (17%; 3%).

Additionally, the phase 2 evaluation of elacestrant at 345 mg daily plus abemaciclib at 150 mg twice daily is ongoing. Investigators added that the median observational time for PFS was 4.6 months at the data cutoff, so it could not be evaluated.

The elacestrant and everolimus combinations were analyzed across cohorts 1 (n = 6), 2 (n = 6), 3 (n = 4), and cohort 4 plus arm B (n = 57).

• In cohort 1, all-grade TEAEs included nausea (67%), diarrhea (67%), stomatitis (50%), fatigue (50%), vomiting (33%), neutropenia (33%), decreased appetite (33%), dysgeusia (17%), rash (17%), mucosal inflammation (17%), and increased blood cholesterol (17%). Grade 3/4 TEAEs were neutropenia (33%), vomiting, and fatigue (17% each).
• In cohort 2, all-grade TEAEs included diarrhea (50%), fatigue (50%), nausea (33%), stomatitis (33%), rash (33%), dysgeusia (17%), vomiting (17%), decreased appetite (17%), increased blood cholesterol (17%), and hyperglycemia (17%). Grade 3/4 TEAEs were nausea, diarrhea, fatigue, and decreased appetite (17% each).
• In cohort 3, all-grade TEAEs included nausea (75%), and diarrhea, stomatitis, dysgeusia, fatigue, vomiting, rash, mucosal inflammation, neutropenia, decreased appetite, and increased blood cholesterol (17% each). Grade 3/4 TEAEs were diarrhea, mucosal inflammation, and neutropenia (25% each).
• In cohort 4 and arm B, all-grade TEAEs included nausea (51%), diarrhea (40%), stomatitis (33%), dysgeusia (25%), fatigue (23%), vomiting (21%), rash (19%), mucosal inflammation (19%), neutropenia (18%), decreased appetite (16%), increased blood cholesterol (16%), and hyperglycemia (16%). Grade 3/4 TEAEs were neutropenia (7%), diarrhea (5%), stomatitis (4%), fatigue (2%), nausea (2%), increased blood cholesterol (2%), and hyperglycemia (2%).

The cohort 4 and arm B dosing schedule of elacestrant at 345 mg and everolimus at 7.5 mg, deemed as the RP2D, is being tested in the phase 2 portion. Similarly, the median observational time for PFS in the phase 2 portion was 2.8 months at the time of data cutoff and could not be evaluated.

The elacestrant and palbociclib combinations were analyzed across cohorts 1 (n = 6), 2 (n = 6), and 3 (n = 7).

• In cohort 1, all-grade TEAEs included neutropenia, both of which were grade 3/4 events and related to palbociclib (33%) and decreased platelet count (17%).
• In cohort 2, the all-grade TEAEs were neutropenia (67%), with 3 cases related to palbociclib and 1 related to the combination, the latter of which was noted as grade 3/4; decreased platelet count (17%); and decreased white blood cell count (17%).
• In cohort 3, which was defined as the RP2D, all-grade TEAEs were neutropenia (57%), with 3 related to palbociclib alone and 1 related to in combination with elacestrant; decreased platelet count (29%); decreased white blood cell count (29%); and insomnia (29%). Grade 3/4 TEAEs included neutropenia (43%) and decreased white blood cell count (14%).

The elacestrant and ribociclib combinations were analyzed across cohorts 1 (n = 6), 2 (n = 6), 3 (n = 6), and 4 (n = 6).

• In cohort 1, all-grade TEAEs were neutropenia, all of which were related to ribociclib (50%); fatigue (33%); nausea (17%); vomiting (17%); and anemia (17%). Grade 3/4 TEAEs were 2 of the neutropenia cases.
• In cohort 2, all-grade TEAEs were neutropenia, all of which were related to ribociclib (67%); nausea (50%); anemia (50%); increased aspartate aminotransferase (AST; 50%); increased blood creatinine (50%); vomiting (33%); and fatigue (33%). Grade 3/4 TEAEs include 2 of the neutropenia cases related to ribociclib.
• In cohort 3, all-grade TEAEs included vomiting (33%); neutropenia, which was related to ribociclib (17%); nausea, fatigue, anemia, and increased AST (17% each). Grade 3/4 TEAEs were neutropenia and increased AST.
• In cohort 4, all-grade TEAEs included neutropenia (50%), 1 case of which was related to ribociclib and 2 related to ribociclib plus elacestrant; nausea (50%); vomiting (50%); fatigue (50%); anemia (17%); increased AST (17%); and increased blood creatinine (17%). Grade 3/4 TEAEs were neutropenia and increased AST (17% each).

The elacestrant and capivasertib combination was analyzed in cohort 1 (n = 7). Here, all-grade TEAEs included fatigue (57%), nausea (57%), vomiting (43%), and diarrhea (43%), none of which were grade 3/4.

Finally, the elacestrant and alpelisib combinations were analyzed across cohorts 1 (n = 3) and 2 (n = 6).

• In cohort 1, all-grade TEAEs were nausea (100%), vomiting (67%), fatigue (67%), and maculopapular rash (33%). Grade 3/4 events included 1 case each of nausea and maculopapular rash.
• In cohort 2, all-grade TEAEs were nausea (83%), maculopapular rash (50%), blurred vision (50%), stomatitis (50%), hyperglycemia (50%), dizziness (50%), vomiting (33%), and fatigue (17%). Grade 3/4 TEAEs were 1 case each of maculopapular rash and hyperglycemia.

Investigators concluded that the evaluation of the phase 1b combinations for elacestrant with alpelisib, capivasertib, and ribociclib is ongoing.

“Elacestrant has the potential to become the ET partner for multiple targeted agents, providing an all-oral treatment option in patients with ER-positive/HER2-negative metastatic breast cancer, delaying chemotherapy or ADC-based regimens,” the authors wrote.

Disclosures: No disclosures were published with this abstract.

References

1. Rugo HS, Tolaney SM, Chan N, et al. Elacestrant combinations in patients with estrogen receptor-positive (ER+), HER2-negative (HER2-) locally advanced or metastatic breast cancer (mBC): Update from ELEVATE, a phase 1b/2, open-label, umbrella study. Presented at: 2024 San Antonio Breast Cancer Symposium; December 10-13, 2024; San Antonio, TX. Abstract PS7-06.
2. FDA approves elacestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. News release. FDA. January 27, 2023. Accessed December 11, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-elacestrant-er-positive-her2-negative-esr1-mutated-advanced-or-metastatic-breast-cancer
3. Rugo HS, O’Shaughnessy J, Cortés J, et al. Elacestrant combinations in patients (pts) with estrogen receptor-positive (ER+), HER2-negative (HER2-) locally advanced or metastatic breast cancer (mBC): Preliminary data from ELEVATE, a phase Ib/II, open-label, umbrella study. Ann Oncol. 2024;35(suppl 2):S357-S405. doi:10.1016/annonc/annonc1579
4. Ciruelos EM, Hamilton EP, Kim S, et al. Elacestrant in combination with abemaciclib in patients (pts) with brain metastasis (mets) from estrogen receptor-positive (ER+), HER2-negative (HER2-) breast cancer: preliminary data from ELECTRA, an open-label, multicenter, phase Ib/II study. Ann Oncol. 2024;35(suppl 2):S357-S405. doi:10.1016/annonc/annonc1579