木瓜直播

A novel drug combination led to clinically meaningful antitumor activity in metastatic ESR1-mutated, estrogen receptor-positive (ER+)/HER2-negative breast cancer that had progressed on CDK4/6 inhibition, a small prospective study showed.

Adding the selective estrogen receptor modulator (SERM) lasofoxifene to abemaciclib (Verzenio) resulted in a median progression-free survival (PFS) of 56 weeks, and a 24-week clinical benefit rate (CBR) of 65.5%. The combination was well tolerated with no new or unexpected toxicities and low rates of grade ≥3 toxicity.

The findings supported the initiation of a of the combination, reported Senthil Damodaran, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, and co-authors in .

"All patients in had baseline ESR1 mutations, which are associated with a less favorable prognosis," the authors pointed out during their discussion of the results. "Two of the four patients who developed rapid disease progression after 3-4 months on prior abemaciclib-based treatment experienced durable clinical benefit with lasofoxifene plus abemaciclib in ELAINE 2, suggesting that lasofoxifene contributes substantially to PFS outcomes and may synergistically interact with abemaciclib in modulating ER- and CDK-signaling cross-talk."

A reported in the same issue of the journal showed no statistically significant clinical benefits with lasofoxifene versus the selective estrogen receptor degrader (SERD) fulvestrant in metastatic ESR1-mutated, ER+/HER2- breast cancer, but all clinical endpoints favored lasofoxifene, reported Matthew Goetz, MD, of the Mayo Clinic in Rochester, Minnesota, and co-authors.

In both studies, investigators examined dynamic changes in ESR1 allelic fraction during lasofoxifene treatment, which revealed significant reductions in mutant allelic fraction for several variants, noted the author of an .

"Lasofoxifene demonstrated impressive target engagement across a wide spectrum of ESR1 variants," wrote Seth Wander, MD, Massachusetts General Hospital and Harvard 木瓜直播 School in Boston. "Emerging evidence supports the unsurprising notion that different ESR1 mutations convey distinct impacts on disease progression and therapeutic resistance."

Ongoing studies "will foster new opportunities and new questions," Wander continued. "Will there be a role for these agents as monotherapy, or will we continue to rely on combinations with other targeted agents? And which partner will provoke optimal benefit with these novel antiestrogens ... As we develop these therapeutic strategies, we must remain focused on expanding our understanding of the molecular pathways driving progression in each individual patient."

The open-label, multicenter, phase II ELAINE 2 trial reflected the evolving understanding of ESR1 mutations' effect on ER+ breast cancer, including endocrine resistance, metastasis, and poor outcomes, Damodaran and co-authors noted in their introduction. Current systemic options for ESR1-mutated, HR+/HER2- metastatic breast cancer post-CDK4/6 inhibition are limited, and no established standard has emerged.

Recent small studies have shown modest clinical benefit from combined treatment with a CDK4/6 inhibitor and a SERD for ESR1-mutated advanced HR+ breast cancer after progression on CDK4/6 inhibition, underscoring the need for new and novel approaches, the authors continued. Lasofoxifene reduced the incidence of invasive ER+ breast cancer in a . Additionally, lasofoxifene demonstrated superior antitumor activity versus fulvestrant in a of ESR1-mutated metastatic breast cancer, either alone or in combination with palbociclib (Ibrance).

Following the "encouraging antitumor activity" of lasofoxifene in the ELAINE 1 trial reported by Goetz and colleagues, ELAINE 2 was initiated to evaluate lasofoxifene's safety and efficacy in combination with abemaciclib in metastatic ER+/HER2- breast cancer associated with ESR1 mutations.

ELAINE 2 included 29 patients, all with metastatic HR+/HER2- breast cancer and acquired ESR1 mutations. All the patients had disease that had progressed on prior systemic therapy, including CDK4/6 inhibition in 28 of 29 cases. Treatment consisted of lasofoxifene plus abemaciclib (regardless of the prior CDK4/6 inhibitor, which included abemaciclib in four cases).

Treatment continued until disease progression or development of unacceptable toxicity. The primary endpoint was safety/tolerability of the combination, and PFS was a secondary endpoint. The most common all-grade treatment emergent adverse events (TEAEs) included diarrhea (82.8%), nausea (51.7%), fatigue (37.9%), vomiting (31.0%), anemia (27.6%), dyspnea (27.6%), decreased white blood cell count (27.6%), and increased blood creatinine (24.1%).

Two patients developed grade 4 neutropenia. The most common grade 3 TEAEs were anemia (10.3%), hypokalemia (10.3%), neutropenia (6.9%), and fall (6.9%). No patient died during the study. One patient discontinued because of grade 2 diarrhea.

In addition to the median PFS exceeding 1 year, 6-month PFS was 76.1%, 12-month PFS was 56.1%, and 18-month PFS was 38.8%. The objective response rate was 55.6% among 18 patients with measurable lesions. ESR1-mutant circulating tumor DNA allele fraction decreased in 21 of 26 evaluable patients from baseline to week 4.

The ELAINE 1 trial included 103 patients with metastatic ESR1-mutated metastatic HR+/HER2- breast cancer. The patients were randomized to lasofoxifene or fulvestrant, and the primary endpoint was PFS.

Patients assigned to lasofoxifene had a median PFS of 24.2 weeks versus 16.2 weeks for the fulvestrant arm (P=0.138). CBR (36.5% vs 21.6%), objective response (13.2% vs 2.9%), 6-month PFS (53.4% vs 37.9%), and 12-month PFS (30.7% vs 14.1%) all favored lasofoxifene, but none of the differences achieved statistical significance, Goetz and co-authors reported.