Lasofoxifene versus fulvestrant for ER+/HER2- metastatic breast cancer with an ESR1 mutation: Results from the randomized, phase II ELAINE 1 trial

BACKGROUND: Acquired estrogen receptor alpha (ER/ESR1) mutations commonly cause endocrine resistance in ER+ metastatic breast cancer (mBC). Lasofoxifene, a novel selective ER modulator, stabilizes an antagonist conformation of wild-type and ESR1-mutated ER-ligand binding domains, and has antitumor activity in ESR1-mutated xenografts. PATIENTS AND METHODS: In this open-label, randomized, phase II, multicenter, ELAINE 1 study (NCT03781063), we randomized women with ESR1-mutated, ER+/human epidermal growth factor receptor 2 negative (HER2-) mBC that had progressed on an aromatase inhibitor (AI) plus a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) to oral lasofoxifene 5 mg daily or IM fulvestrant 500 mg (days 1, 15, and 29, and then every 4 weeks) until disease progression/toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints were safety/tolerability. RESULTS: A total of 103 patients received lasofoxifene (n = 52) or fulvestrant (n = 51). The most current efficacy analysis showed that lasofoxifene did not significantly prolong median PFS compared with fulvestrant: 24.2 weeks (∼5.6 months) versus 16.2 weeks (∼3.7 months; P = 0.138); hazard ratio 0.699 (95% confidence interval 0.434-1.125). However, PFS and other clinical endpoints numerically favored lasofoxifene: clinical benefit rate (36.5% versus 21.6%; P = 0.117), objective response rate [13.2% (including a complete response in one lasofoxifene-treated patient) versus 2.9%; P = 0.124], and 6-month (53.4% versus 37.9%) and 12-month (30.7% versus 14.1%) PFS rates. Most common treatment-emergent adverse events with lasofoxifene were nausea, fatigue, arthralgia, and hot flushes. One death occurred in the fulvestrant arm. Circulating tumor DNA ESR1 mutant allele fraction (MAF) decreased from baseline to week 8 in 82.9% of evaluable lasofoxifene-treated versus 61.5% of fulvestrant-treated patients. CONCLUSIONS: Lasofoxifene demonstrated encouraging antitumor activity versus fulvestrant and was well tolerated in patients with ESR1-mutated, endocrine-resistant mBC following progression on AI plus CDK4/6i. Consistent with target engagement, lasofoxifene reduced ESR1 MAF, and to a greater extent than fulvestrant. Lasofoxifene may be a promising targeted treatment for patients with ESR1-mutated mBC and warrants further investigation

Risk of Early & Late Obstetric Complications in Women with IVF- Conceived Pregnancies and Polycystic Ovary Syndrome (PCOS)

There is conflicting evidence on the association between PCOS and early and late obstetric complications. It is unclear if the reported risks are independent of BMI, preexisting hypertension and diabetes. We performed a retrospective chart review to examine the risk of early and late obstetrical complications after IVF in women with PCOS (n=130) compared to controls (n=130). The miscarriage rate was 17.7% in PCOS women and 15.4% in controls. PCOS was not associated with miscarriage independent of age and BMI. The prevalence of gestational DM (GDM) was similar in both groups (12% PCOS versus 11% controls). BMI was independently associated with GDM (p=0.01). Risk of both preeclampsia and PIH was 10% in PCOS and 5% in controls, but not statistically significant. Preexisting HTN showed a significant association with preeclampsia (

Risk of Early & Late Obstetric Complications in Women with IVF- Conceived Pregnancies and Polycystic Ovary Syndrome (PCOS)

There is conflicting evidence on the association between PCOS and early and late obstetric complications. It is unclear if the reported risks are independent of BMI, preexisting hypertension and diabetes. We performed a retrospective chart review to examine the risk of early and late obstetrical complications after IVF in women with PCOS (n=130) compared to controls (n=130). The miscarriage rate was 17.7% in PCOS women and 15.4% in controls. PCOS was not associated with miscarriage independent of age and BMI. The prevalence of gestational DM (GDM) was similar in both groups (12% PCOS versus 11% controls). BMI was independently associated with GDM (p=0.01). Risk of both preeclampsia and PIH was 10% in PCOS and 5% in controls, but not statistically significant. Preexisting HTN showed a significant association with preeclampsia (

Phase 1b trial of anti-VEGF/PDGFR vorolanib combined with immune checkpoint inhibitors in patients with advanced solid tumors

PURPOSE: Vorolanib is a multi-target tyrosine kinase inhibitor with anti-angiogenic properties. This study aimed to evaluate the tolerability, safety and efficacy of vorolanib when added to checkpoint inhibitors (CPIs) in patients with advanced solid tumors. METHODS: We conducted a phase 1b study of vorolanib (300 or 400 mg orally once daily) plus pembrolizumab or nivolumab using a standard 3 + 3 design to determine the dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). The endpoints included safety, toxicity and objective response rate, according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1). RESULTS: Sixteen patients (9 in pembrolizumab arm, 7 in nivolumab arm) with gastrointestinal or lung cancers were enrolled. All patients had at least 1 treatment-related adverse event (TRAE). The most common TRAEs across all cohorts were lymphopenia (n = 7), leukopenia (n = 5), fatigue (n = 5), and alanine aminotransferase elevation (n = 5); most toxicities were grade (G) 1-2. DLTs were reported in 3 patients at vorolanib 400 mg dose level, with G3 aspartate aminotransferase elevation, G3 rectal hemorrhage, and G3 rash. Of 13 total response-evaluable patients, 2 patients had confirmed partial responses (1 rectal squamous cell cancer and 1 small cell lung cancer). Two patients achieved prolonged stable disease. Vorolanib 300 mg daily was determined to be the RP2D for either pembrolizumab or nivolumab. CONCLUSION: Combination vorolanib 300 mg orally once daily plus CPI appears to be a feasible regimen with manageable toxicity and promising efficacy in select tumor types. NCT03511222. Date of Registration: April 18, 2018

Cellular stressors contribute to the expansion of hematopoietic clones of varying leukemic potential

Cellular stressors can impact clonal hematopoiesis. Here, the authors explore the impact of cytotoxic therapy and hematopoietic transplantation on clonal expansion, suggesting different stressors can promote expansion of distinct long-lived clones