Lasofoxifene/Abemaciclib Combination Aims to Fill Need in ESR1-Mutant, ER+/HER2- Breast Cancer

Ciara O'Sullivan, MB, BCh

Finding effective treatments beyond the first line for patients with locally advanced or metastatic estrogen receptor (ER)-positive, HER2-negative breast cancer and an ESR1 mutation remains a challenge following development of resistance to agents. Investigators are seeking an efficacious combination regimen to join the paradigm.

Following progression on first-line treatment with endocrine therapy and CDK4/6 inhibitors, fulvestrant (Faslodex) monotherapy provides an average progression-free survival (PFS) of 2 to 3 months; up to 40% of patients with ER-positive, HER2-negative breast cancer will acquire an ESR1 mutation as the disease advances, highlighting the need for further therapies and combinations in the second line to improve efficacy in addition to tolerability.^1,2

In an interview with OncologyLive, Ciara O’Sullivan, MB, BCh, explained that acquired ESR1 mutations can emerge after treatment with aromatase inhibitors, which can constitutively activate the ER, leading to endocrine resistance as well as a worse prognosis. “Treatment options for patients with ER-positive metastatic breast cancer and an ESR1 mutation are limited,” said O’Sullivan, an oncologist at Mayo Clinic in Rochester, Minnesota. “However, there are data that suggest patients could derive clinical benefit from abemaciclib [Verzenio] after progression or on prior CDK4/6 inhibitors. Further, lasofoxifene [Fablyn], the third-generation SERM [selective estrogen receptor modulator], as monotherapy or combined with CDK4/6 inhibitors was shown to have superior efficacy over fulvestrant in preclinical breast cancer models expressing ESR1mutations. Based on those results, that [paved] the way for the phase 2 clinical trial of lasofoxifene combined [with] abemaciclib in patients with metastatic breast cancer and ESR1 mutations.”

The phase 2 ELAINE-2 trial (NCT04432454) evaluating lasofoxifene plus abemaciclib in a single-arm study and the phase 2 ELAINE-1 (NCT03781063) study examining lasofoxifene vs fulvestrant set the stage for the currently enrolling phase 3 ELAINE-3 (NCT05696626) trial evaluating lasofoxifene plus abemaciclib vs fulvestrant and abemaciclib.^3-5

“ELAINE-1 [data] did not meet statistical significance [in the] overall [population], but lasofoxifene is numerically superior to fulvestrant in most of the metrics,” Senthil Damodaran, MD, PhD, an associate professor at The University of Texas MD Anderson Cancer Center in Houston, said in an interview with OncologyLive. “We know lasofoxifene was active from ELAINE-1 as a single agent—now preclinical studies as well as ELAINE-2 confirm that its activity is enhanced when it’s combined with a CDK4/6 inhibitor. We chose abemaciclib [as an agent in the ELAINE-3 trial], because it seems like this might be a CDK4/6 inhibitor that could still have activity if somebody has previously progressed on a CDK4/6 [inhibitor].”

ELAINE-3 seeks to build upon its predecessor trials, enrolling a larger group of patients with ESR1 mutated, ER-positive, HER2-negative disease—approximately 400 patients will partake in the study compared with 103 patients enrolled in ELAINE-1 and 29 patients in ELAINE-2.^3-5 PFS will serve as the primary end point in the trial, which is enrolling at sites across the United States, Europe, Canada, Japan, and Israel.⁵

According to O’Sullivan, the current standard of care “beyond progression [in the first line] is fulvestrant possibly in combination with alpelisib [Piqray] if patients have PIK3CA mutations. We also use exemestane [Aromasin] [plus] everolimus [Afinitor] for some patients whom we feel to be endocrine resistant—oral chemotherapy, or antibody-drug conjugates are also used. The standard of care is quite all over the map in the second line right now, but we do use these targeted mutations. The role of the oral SERDs [selective estrogen receptor degraders] and the recent FDA approval of elacestrant [Orserdu] also influenced the treatment paradigm, but there’s a lot of variability in the treatment paradigm at this time.”

Abemaciclib holds approvals in the hormone receptor–positive, HER2-negative space.⁶ Damodaran notes that it also may serve as an option for those who have progressed following treatment with other CDK4/6 inhibitors such as palbociclib (Ibrance) and ribociclib (Kisqali).

Implications of ELAINE-2

“Investigators hypothesized that patients with ER-positive, HER2-negative metastatic breast cancer with an ESR1 mutation may derive more benefit from combination regimens as opposed to monotherapies,” O’Sullivan said. “Preclinical studies in treatment-resistant breast cancer tumors show that this appears to be the case as it related to combinations of lasofoxifene and palbociclib and fulvestrant plus palbociclib.”

Results from ELAINE-2 presented at the 2023 American Society of Clinical Oncology Annual Meeting demonstrated that as of April 2023, patients (n = 29) who received abemaciclib plus lasofoxifene experienced a clinical benefit rate of 65.5% (95% CI, 47.3%-80.1%). The median PFS was 56.0 weeks (95% CI, 31.9-not estimable) and as of January 2023, the 6-, 12-, and 18-month PFS rates were 76.1% (54.4%-88.5%), 56.1% (39.4%-72.8%), and 38.8% (20.0%-57.3%), respectively, for patients treated with the doublet.⁷ The data also revealed that ESR1-mutant allele fractions, which were analyzed in circulating tumor DNA, had decreased in80.8% of 26 patients at week 4 from baseline, suggesting there was target engagement.⁷

“[In ELAINE-2] we observed a PFS of approximately 13 months, which is not usual in patients who had progressed on CDK4/6 inhibitors,” Damodaran explained. “The clinical data [were] very impressive; the caveat is it’s a small study so that needs to be confirmed in a larger phase 3 study, which is what led up to ELAINE-3.”

Managing Adverse Events

Previous safety data showed that the abemaciclib/lasofoxifene combination was well tolerated among patients, with thrombotic events being an adverse event (AE) warranting close attention. In ELAINE-2, thrombotic events occurred in 3 patients (10.3%) and included a symptomatic spontaneous event with a confirmed grade 3 pulmonary embolism, deep vein thrombosis as well as a pulmonary embolism, and an asymptomatic pulmonary embolism as well as an asymptomatic popliteal deep vein thrombosis.⁷

“There were several thrombotic events, which are well established and known as associated with abemaciclib and SERMs,” O’Sullivan said, referring to ELAINE-2. “Of note, all of these AEs occurred in patients who received clinical benefit from the combination.” She said an interim efficacy futility analysis will serve as one way of monitoring these AEs as well as overall safety in ELAINE-3.

Damodaran echoed the importance of monitoring deep vein thrombosis, adding that anticoagulation allowed most patients to continue ELAINE-2 as well. He shared that although most patients in that trial tolerated the combination well, expected AEs such as diarrhea were more attributed to abemaciclib. Diarrhea was the most common any-grade treatment-emergent AE in ELAINE-2, occuring in 82.8% of patients.⁷

Additionally, Damodaran noted that because lasofoxifene was initially evaluated in women with osteoporosis, an advantage lies with the agent’s ability to have some positive estrogenic activity. “Unlike some of the complete estrogen [agents], the hope is this will be better for our patients from a symptomatic standpoint,” he explained. “But, of course, the combination needs to be clinically active.… One of the things that is exciting is lasofoxifene’s nature because it probably has some benefits that are beyond breast cancer, which could be a big advantage for patients with breast cancer. Some of the SERDs have other AEs such as muscle aches and elacestrant, [which] is approved for ESR1[-mutated breast cancer] as a single agent, does have some gastrointestinal toxicity—lasofoxifene so far has been well tolerated.”

A New Way to Screen for ESR1 Mutations

The Guardant360 CDx liquid biopsy next-generation sequencing–based test, which was newly approved in January 2023 as a companion diagnostic with elacestrant in this patient population,⁸ will be used to screen for ESR1 mutations, marking a different platform used than the first 2 ELAINE studies.⁵ Damodaran noted that Guardant360 CDx is a broader panel than those used in the previous ELAINE studies, encompassing approximately 74 genes.

“For ELAINE-1 and ELAINE-2, the investigators used [panels that] interrogated the ESR1 ligand binding domain and a few other genes [such as] AKT and PIK3CA,” O’Sullivan said. “But the Guardant360 CDx panel will not only identify patients with ESR1 point mutations for inclusion in the study but will also provide broader next-generation sequencing information, which could be informative from a translational standpoint in identifying genomic alterations associated with response or resistance. This could hopefully help inform further research.” Damodaran explained that correlative data from ELAINE-3 examining other genes presented along with ESR1 will shed some light on how they affect the response to the combination.

Enrollment criteria

ELAINE-3 is enrolling men and premenopausal and postmenopausal women with locally advanced or metastatic ER-positive, HER2-negative breast cancer who have experienced disease progression on an aromatase inhibitor in combination with either palbociclib or ribociclib as their first hormonal treatment for metastatic disease and who have an ESR1 mutation.⁵ Abemaciclib will be given orally at 150 mg twice daily with either 5 mg of lasofoxifene once daily or 500 mg of intramuscular fulvestrant on days 1, 15, and 29 and then once monthly.

In addition to the primary end point of PFS, secondary end points will include objective response rate, overall survival, clinical benefit rate, duration of response, time to response, time to cytotoxic chemotherapy, quality of life, and AEs/serious AEs. Patients with lymphangitic carcinomatosis involving the lung, visceral crisis that requires cytotoxic chemotherapy, brain metastases, and prior disease progression on a SERD or fulvestrant are not eligible for enrollment.

Beginning the Trial

At MD Anderson, Damodaran noted the study is anticipated to activate in 2023. At Mayo Clinic in Minnesota, O’Sullivan hopes to enroll 5 to 10 patients with the first expected later in 2023.

“As the only tissue-selective SERM being studied in this advanced space, lasofoxifene previously demonstrated benefits on ER-dependent, nonbreast tissue such as the vaginal tissues and bones. [It] could offer a novel endocrine therapy with unique quality-of-life benefits for our patients should the efficacy data be confirmed in the upcoming ELAINE study, so I’m excited about that for patients,” O’Sullivan said.

References

1. Corti C, De Angelis C, Bianchini G, et al. Novel endocrine therapies: what is next in estrogen receptor positive, HER2 negative breast cancer? Cancer Treat Rev. 2023;117:102569. doi:10.1016/j.ctrv.2023.102569
2. Poucher Harbin J. Duke researchers play key role in new breast cancer drug. Duke Health. March 7, 2023. Accessed July 28, 2023. https://physicians.dukehealth.org/articles/duke-researchers-play-key-role-new-breast-cancer-drug
3. Evaluation of lasofoxifene combined with abemaciclib in advanced or metastatic ER+/HER2- breast cancer with an ESR1 mutation (ELAINEII). ClinicalTrials.gov. Updated January 12, 2023. Accessed July 28, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT04432454
4. Evaluation of lasofoxifene versus fulvestrant in advanced or metastatic ER+/HER2- breast cancer with an ESR1 mutation. ClinicalTrials.gov. Updated April 11, 2023. Accessed July 28, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT03781063
5. Evaluation of lasofoxifene combined with abemaciclib compared with fulvestrant combined with abemaciclib in locally advanced or metastatic ER+/HER2- breast cancer with an ESR1 mutation (ELAINEIII). ClinicalTrials.gov. Updated August 1, 2023. Accessed August 3, 2023.https://classic.clinicaltrials.gov/ct2/show/NCT05696626?term=sermonix&draw=2&rank=2
6. Verzenio. Prescribing information. Eli Lilly and Co; 2023. Accessed July 28, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/208716s010s011lbl.pdf
7. Damodaran S, Moore HCF, Anderson IC, et al. Lasofoxifene (LAS) plus abemaciclib (Abema) for treating ESR1-mutated ER+/HER2- metastatic breast cancer (mBC) after progression on prior therapies: ELAINE 2 study update. J Clin Oncol. 2023;41(suppl 16):1057. doi:10.1200/JCO.2023.41.16_suppl.1057
8. FDA approves elacestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. FDA. January 27, 2023. Accessed July 28, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/