Lasofoxifene Plus Abemaciclib Shows Encouraging Efficacy in Locally Advanced or Metastatic ESR1-Mutated, ER+ Breast Cancer

Lasofoxifene plus abemaciclib produced promising efficacy when administered to pre- and postmenopausal patients with locally advanced or metastatic, estrogen receptor–positive, HER2-negative breast cancer who harbored an ESR1 mutation.

The combination of lasofoxifene plus abemaciclib (Verzenio) produced promising efficacy and had a favorable risk-to-benefit ratio when administered to pre- and postmenopausal patients with locally advanced or metastatic, estrogen receptor (ER)–positive, HER2-negative breast cancer who harbored an ESR1 mutation and who had progressed on other therapies, according to data from the phase 2 ELAINE-2 trial (NCT04432454).

Among 29 patients, the censored median progression-free survival (PFS) was 13 months (55.7 weeks; 95% CI, 32.0–not evaluable). The clinical benefit rate (CBR) achieved with the agent was 69.0% (95% CI, 50.8%-82.7%). In 18 patients with measurable target lesions, the objective response rate (ORR) was 50% (95% CI, 29.0%-71.0%); this included 9 partial responses (PRs). Participants experienced a PR at a median of 169 days and the median duration of response (DOR) was 164 days.

Of 4 patients who previously experienced disease progression while receiving abemaciclib, 3 derived a significant clinical response from lasofoxifene plus abemaciclib. Specifically, 1 patient achieved a PR to treatment, and 2 patients had disease stability. Moreover, 2 of 3 patients who received prior fulvestrant (Faslodex)/alpelisib (Piqray) experienced clinical benefit from the lasofoxifene combination regimen.

“This is one of the first clinical trials to prospectively observe a meaningful PFS and CBR of endocrine therapy/CDK4/6 combination in CDK4/6 pretreated metastatic breast cancer population with acquired ESR1 mutations,” lead study author Senthil Damodaran, MD, assistant professor in the Department of Breast Medical Oncology, of the Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, and colleagues, wrote in a poster on the data presented at the 2022 ASCO Annual Meeting.

Endocrine therapy, particularly with aromatase inhibitors (AIs), has served as the mainstay treatment of patients with ER-positive breast cancer; however, long-term treatment with this approach is known to result in resistance caused by acquired ESR1 mutations.

A selective estrogen receptor modulator (SERM), lasofoxifene, either as a monotherapy or in combination with a CDK4/6 inhibitor, has been found to have strong activity in metastatic breast cancer xenograft models expressing ESR1 mutations. The agent alters the constitutive conformation of the mutated ERα to an antagonist conformation, thereby inactivating the receptor. Abemaciclib has demonstrated meaningful clinical activity following progressive disease on previous CDK4/6 inhibition in those with metastatic breast cancer.

Those with metastatic breast cancer whose tumors harbor ESR1 mutations have limited therapeutic options available to them, thus representing an unmet need—especially in those who have progressed on a CDK4/6 inhibitor.

The open-label, multicenter, single-arm ELAINE-2 trial enrolled women aged 18 years and older who had ER-positive/HER2-negative metastatic breast cancer and acquired ESR1 mutations identified in circulating tumor DNA (ctDNA). Patients were required to have progressed on 1 or 2 lines of endocrine treatment for metastatic disease; they were permitted to have received 1 line of chemotherapy.

Study participants received oral lasofoxifene at a daily dose of 5 mg plus abemaciclib at a twice-daily dose of 150 mg. Treatment was delivered until disease progression, death, toxicity, or withdrawal.

The primary end point of the trial was safety and tolerability, and secondary end points comprised PFS, CBR, ORR, DOR, and time to response.

A total of 29 patients were enrolled to the trial from October 2020 to June 2021 at 16 sites throughout the United States. The median age of participants was 60 years (range, 35-79). Most patients were White (86.2%) and had measurable (62.1%) and visceral (55.2%) disease; 34.5% of patients had bone-only disease.

Participants had received a median of 2 prior lines of treatment in the metastatic setting, and the median duration of previous CDK4/6 inhibition was 2 years. Regarding previous treatment, 86.2% had chemotherapy, 48.3% received chemotherapy in the metastatic setting, and 96.6% had CDK4/6 inhibitors, such as palbociclib (86.2%), abemaciclib (13.8%), ribociclib (Kisqali; 6.9%), or unknown (3.4%). All patients received endocrine therapy in the form of an AI (96.6%), fulvestrant (79.3%), or tamoxifen (41.4%). Additionally, 13.8% of patients received everolimus (Afinitor) and 10.3% received alpelisib.

Forty-eight percent of patients had polyclonal ESR1 mutations; 66% had Y537S mutations and 48% had D538G mutations. In those with evaluable ctDNA, 47 ESR1 mutant variants were identified at baseline. Following 4 weeks of treatment, 91% of these variants were undetectable or reduced and only 9% increased.

Of the 29 patients, 5 discontinued for reasons beyond progressive disease; 2 discontinued because of toxicities, 2 due to investigator decision, and 1 due to patient withdrawal.

The most common adverse effects (AEs) experienced with the regimen included diarrhea, nausea, fatigue, cough, decreased white blood cell count, vomiting, dyspnea, anemia, lymph decreased, muscle spasm, constipation, increased creatinine, myalgia, hyperglycemia, decreased albumin, decreased appetite, stomatitis, dehydration, dizziness, and hypokalemia.

The most common grade 3 AEs included lymph decreased (10.3%), hypokalemia (6.9%), fatigue (3.4%), vomiting (3.4%), and anemia (3.4%).

The most likely treatment-emergent toxicities because of lasofoxifene were muscle spasms and hot flashes. A total of 2 patients developed a deep vein thrombosis and pulmonary embolism; 1 of these cases was diagnosed following knee surgery. Both cases were successfully treated with anticoagulants and continued ELAINE-2.

Lasofoxifene was not reduced in accordance with study protocol. In 5 patients, abemaciclib was reduced to twice daily 100 mg; 4 of these reductions were due to toxicities and 1 was due to investigator discretion.

“The clinically meaningful efficacy of [the] lasofoxifene/abemaciclib combination may offer a significantly greater benefit than currently available therapies, with a differentiated profile from intramuscular and oral SERDs, particularly in this patient population, and warrants further study,” the authors concluded.


Damodaran S, Plourde PV, Moore HCF, et al. Open-label, phase 2, multicenter study of lasofoxifene (las) combined with abemaciclib (abema) for treating pre- and postmenopausal women with locally advanced or metastatic ER+/HER2- breast cancer and an ESR1 mutation after progression on prior therapies. J Clin Oncol. 2022;40(suppl 16):1022. doi:10.1200/JCO.2022.40.16_suppl.1022