Senthil Damodaran, MD, PhD, on How Lasofoxifene Combo May Fulfill Unmet Needs in ESR1+ Breast Cancer After CDK4/6

A combination of lasofoxifene (Fablyn) and abemaciclib (Verzenio) may help to fulfill an unmet need in the post-CDK4/6 inhibitor setting for patients with locally advanced or metastatic ESR1-mutant, estrogen receptor–positive, HER2-negative breast cancer, according to Senthil Damodaran, MD, PhD.

The combination was assessed as part of the phase 2 ELAINEII study (NCT04432454), which read out at the 2022 American Society for Clinical Oncology Annual Meeting. Findings from the study indicated that patients treated with the combination experienced a censored median progression-free survival (PFS) of 13.9 months (95% CI, 8.0-not estimable). Moreover, the overall response rate (ORR) was 33.3% (95% CI, 16.3%-56.3%), including 6 partial responses. The clinical benefit rate was 62.1% (95% CI, 44.0%-56.3%). Damodaran indicated that although previous treatments have fallen short for this patient population, the lasofoxifene and abemaciclib regimen could potentially fulfill an unmet.

“Obviously, everybody understands that in the post-CDK4/6 progression space, we don't have good regimens that have been ironed out,” Damodaran said. “The post CDK4/6 [inhibitor setting presents] an unmet need in terms of how we should [be treating patients]. Everybody is looking for a treatment paradigm that will help our patients. Hopefully this could be one such option going forward.”

In an interview with CancerNetwork^®, Damodaran, an assistant professor of the Department of Breast Medical Oncology, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, highlighted key safety data from ELAINEII study and the rationale for conducting the research.

Why was this combination thought to be a good fit for this patient population?

Targeting ESR1 is an unmet need. We know at least 30% to 40% of patients in the metastatic setting will have these ESR1 mutations but right now, there’s no approved therapy. We and others have been looking at agents that will target these mutations. Lasofoxifene is a SERM [selective estrogen receptor modulator] as opposed to most of the other drugs which are SERDs [selective estrogen receptor degraders]. It had shown excellent preclinical activity against ESR1 mutations. That is 1 of the reasons to focus on lasofoxifene in this population.

We understood that single-agent activity is going to be limited [based on] other studies in the post-CDK4/6 progression space. We wanted to combine that with other targeted therapy with the hope that it will give patients a longer clinical benefit. Preclinical work done by our group and other labs have shown that abemaciclib can still be active after prior progression on palbociclib [Ibrance] and ribociclib [Kisqali]. The favorable toxicity profile and clinical efficacy [served as the rationale to combine both therapies].

Were there any surprises regarding safety?

In terms of toxicity, it’s very well tolerated. We know this drug from years ago because it was studied in women’s health for osteoporosis. This drug had shown reductions in breast cancer [in addition to] helping promote bone health in general. We know the drug as a whole is well tolerated and that abemaciclib is fairly well tolerated. We are aware of some expected [adverse] effects [AEs] like diarrhea, but they’re easily manageable. The combination itself was well tolerated; most of the AEs can be attributed more to abemaciclib than lasofoxifene itself.

What were the efficacy findings of this combination?

What was impressive was the efficacy data from this study. This was intended as a safety combination study and we know it is safe and well tolerated. But in terms of efficacy, we’ve so far observed a median PFS of about 13 months. Of the 29 patients who had been enrolled, 12 patients are still on the study. The ORR was about 50%. This has to be put in context being that of the patients who have progressed on prior CDK4/6, 80% of them have received prior fulvestrant and 50% have already received chemotherapy. Considering all of that, the PFS and response rate that we see with this combination in this population is impressive. I can’t say that we’ve seen such clinical metrics for any other targeted therapy combination in this setting.

Reference

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