Phase II 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.
The ELAINEII study evaluated lasofoxifene plus abemaciclib in ER+/HER2− metastatic breast cancer who had acquired ESR1 mutations on circulating tumor DNA (ctDNA) after progressing on 1 or 2 prior lines of therapy, 1 of which could have been chemotherapy. Lasofoxifene has been granted a Fast Track Designation by the FDA to treat women who have ER+ metastatic breast cancer with an ESR1 mutation.
The objective response rate (ORR) was 50% in a group of patients who had advanced on 1 or 2 prior lines of therapy, according to data given at the ASCO 2022 Annual Meeting, with a 24-week clinical benefit rate (CBR) of 69%. The median PFS after censoring was 55.7, or roughly 13 months.
Nine patients (50%) with detectable target lesions had partial responses (PRs). The median time to PR was 169 days, with a 164-day median response duration. Out of 4 patients who had previously progressed while receiving abemaciclib, 3 had significant clinical responses of PR in 1 and stable disease in 2. Clinical effect was seen in two out of three individuals who had previously been treated with fulvestrant + alpelisib (Piqray).
SafeSEQ next-generation sequencing technology was used to evaluate ESR1 mutant allele fractions by ctDNA at baseline and 4 weeks. At the start, 47 ESR1 mutant variants were discovered. After four weeks of treatment, 68% of these were undetectable, 23% were reduced, and just 9% increased.
“This clinically meaningful efficacy of [lasofoxifene plus abemaciclib] may offer a significant benefit than currently available therapies, with a differentiated profile from intra-muscular or oral SERDs [selective estrogen degraders], particularly in this patient population, and warrants further study. – Expert Opinion
Long-term endocrine therapy administration can lead to treatment resistance caused by acquired ESR1 mutations. In preclinical investigations, lasofoxifene showed an effect against ESR1 mutations alone or in conjunction with CDK4/6 inhibition vs. fulvestrant. Abemaciclib has also been demonstrated to be effective in patients with metastatic breast cancer who have progressed on previous CDK4/6 inhibitors. The results from the ELAINE 2 study have shown that the combination of lasofoxifene and abemaciclib (Verzenio) provided a meaningful progression-free survival (PFS) benefit and elicited encouraging responses with an acceptable toxicity profile in patients.
The company has also planned to start ELAINE 3 (lasofoxifene vs. Fulvestrant in monotherapy) and ELAINE 4 (lasofoxifene + CDK 4/6 Inhibitor in combination therapy) study in breast cancer that will be potentially registrational. In parallel, the company is assessing lasofoxifene as monotherapy compared to fulvestrant for the treatment of metastatic breast cancer with an ESR1 mutation post-CDK4/6i therapy in the ELAINE-1 study, which is fully enrolled, and the data will be presented in late Q3 of 2022.
Apart from lasofoxifene, the potential players that can mark a significant change in the ESR1 mutated breast cancer space are Radius Pharmaceuticals (Elacestrant), AstraZeneca (camizestrant [AZD9833]), Roche (giredestrant), H3 Biomedicine/Eisai (H3B-6545), and Eli Lilly (Imlunestrant) which are evaluating their lead candidates in different stages of clinical development, respectively.