On December 19, 2022 Sermonix Pharmaceuticals Inc., a privately held biopharmaceutical company developing innovative targeted therapeutics to specifically treat ESR1-mutated metastatic breast and gynecological cancers, reported two poster presentations initially released at the 2022 San Antonio Breast Cancer Symposium (SABCS) (Press release, Sermonix Pharmaceuticals, DEC 19, 2022, View Source [SID1234625451]). The presentations discussed exploratory analyses evaluating mutant allele frequencies (MAF) of ESR1 (mutESR1) in circulating tumor DNA (ctDNA) from patients who participated in each of Sermonix’s Evaluation of Lasofoxifene in ESR1 Mutations (ELAINE) Phase 2 studies.

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Using the Sysmex Inostics OncoBeam or SafeSeq assays, ELAINE 1 assessed the efficacy and safety of Sermonix’s lead development candidate, oral lasofoxifene, versus the current standard of care, intramuscular fulvestrant, in postmenopausal women with locally advanced or metastatic ER+/HER2- breast cancer (mBC) and an ESR1 mutation. ELAINE 2, which used the SafeSeq assay, evaluated lasofoxifene in combination with the CDK 4 and 6 inhibitor abemaciclib in a heavily pre-treated ESR1 mutation positive patient population.

"The ELAINE studies are biomarker driven, with patients selected for treatment utilizing liquid biopsy detection of ESR1 mutations," said Dr. David Portman, Sermonix chief executive officer. "The results confirm robust target engagement with decrease and clearance of ctDNA seen with lasofoxifene as both monotherapy and when combined with abemaciclib, and associated with improved progression-free survival (PFS) and clinical benefit. Future studies may help clarify the role of molecular response in optimizing clinical outcomes and we look forward to exploring this further in our upcoming Phase 3 program."

ELAINE 1 data demonstrated that targeted lasofoxifene more effectively decreased or cleared mutESR1 than fulvestrant. Further, mutESR1 MAF decreases on lasofoxifene were associated with prolonged progression-free survival of 8 months, whereas fulvestrant patients with a decrease in MAF achieved a median PFS of 4.5 months. These data indicate lasofoxifene results in robust mutESR1 target engagement. Taken together, the data suggest mutESR1 as a potential biomarker for predicting response to lasofoxifene in mutESR1, endocrine-resistant mBC patients.

In ELAINE 2, 81% of patients had decreased/cleared mutESR1 after 4 weeks of lasofoxifene plus abemaciclib, which correlated with clinical benefit. All mutESR1 variants detected appear targeted with this therapy. High sensitivity and favorable positive predictive value were observed in patients with undetectable MAF at 4 weeks, indicating that ESR1 liquid biopsy evaluation may be a potential molecular biomarker for monitoring patients on this treatment if confirmed in a larger randomized study.

ELAINE 1 RESULTS:

Among 103 patients, with 52 receiving lasofoxifene and 51 fulvestrant, median PFS was 6.04 mos. (95% CI, 2.82–8.04) for lasofoxifene vs. 4.04 mos. (95% CI, 2.93–6.04) for fulvestrant, P=0.138 (HR, 0.699 [95% CI, 0.445–1.125]).
The most common baseline ESR1 variants detected were D538G (56%), Y537S (39%), Y537N (29%), E380Q (22%); 56 (54%) pts were polyclonal.
Of the 61 participants with evaluable baseline and Week 8 ctDNA, lasofoxifene decreased ESR1 mutant allele fraction (MAF) in 29 of 35 pts (83%) while fulvestrant decreased ESR1 MAF in 16/26 pts (61.5%).
Median change from baseline in MAF across all mESR1 variants was −87.1% for lasofoxifene compared with −14.7% for fulvestrant.
Decreases in most commonly observed mESR1 variants (D538G, Y537S, Y537N, E380Q, Y537C) occurred more frequently for lasofoxifene than fulvestrant.
Among patients with the ESR1 Y537S variant, Y537S MAF decreased in most patients receiving lasofoxifene (87% [13/15]; in marked contrast, Y537S MAF increased in most patients receiving fulvestrant (61% [11/18]).
Median change from baseline to week 8 in Y537S MAF was −89.1% with lasofoxifene vs. +82.3% with fulvestrant.
Complete clearance of Y537S was observed in 5/15 (33%) and 1/18 (6%) patients receiving lasofoxifene and fulvestrant, respectively.
"The use of ctDNA is dramatically improving our understanding about the molecular evolution of breast cancer, particularly with regards to endocrine resistance," said Dr. Massimo Cristofanilli, a chief of breast oncology in New York and past president of the International Society of Liquid Biopsy. "The information allows us to evaluate the targeted endocrine agents and monitor not only the clinical response, but also the impact of such therapies on the molecular patient journey, especially in light of variants of the ESR1 mutation that are known to confer the worst outcomes."

ELAINE 2 RESULTS:

In an open-label, single-arm study of lasofoxifene in combination with abemaciclib in 29 heavily pre-treated post-CDK4/6i patients, the median PFS was 55.7 weeks (over 13 months), (95% CI, 32.0-NE).
Among patients with measurable target lesions (n=18), 10 had a confirmed partial response (PR), resulting in an ORR of 56% (95% CI, 29.0 – 71.0).

There was baseline mutESR1 of Y537S (66%), D538G (45%), Y537N (28%), and other less frequently detected mutations; 14 (48.3%) patients were polyclonal.
In 26 of 29 patients with evaluable baseline and Week 4 ctDNA: 21 patients had decreasing mutant ESR1 MAF (81%), 14 had undetectable MAF (54%), 3 (12%) had increased, and 2 (8%) had equivocal MAF changes.
Clinical benefit at 24 weeks was seen in 17 patients with a decrease, 2 with an increase, and 1 with equivocal MAF change.

A sensitivity of 89.5% and specificity of 20% were calculated for predicting clinical benefit based on direction of ESR1 MAF change. The positive predictive value (PPV) for clinical benefit with decreased MAF was 81% and the negative predictive value (NPV) for an increased MAF was 33%.
Of the 14 (54%) patients with total clearance of ESR1 MAF, 13 had clinical benefit resulting in 87% sensitivity, 50% specificity, 93% PPV, and 33% NPV.

About Lasofoxifene

Lasofoxifene is an investigational targeted endocrine treatment and next-generation nonsteroidal selective estrogen receptor modulator (SERM), which Sermonix licensed globally from Ligand Pharmaceuticals Inc. (NASDAQ: LGND) and has been studied in previous comprehensive Phase 1-3 non-oncology clinical trials in more than 15,000 postmenopausal women worldwide. Lasofoxifene’s bioavailability and activity in mutations of the estrogen receptor could potentially hold promise for patients who have acquired endocrine resistance due to ESR1 mutations, a common finding in the metastatic setting and an area of high unmet medical need. Lasofoxifene’s novel activity in ESR1 mutations was discovered at Duke University and Sermonix has exclusive rights to develop and commercialize the product in this area. Lasofoxifene, a potent, oral SERM could, if approved, play a critical role in the targeted precision medicine treatment of advanced ER+ breast cancer.