HER2-negative

Novel Drug Combo Offers Hope for Advanced HER2-Negative Breast Cancer

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woman lymph armpit examination. Node-Positive Breast Cancer

Researchers at the Johns Hopkins Kimmel Cancer Center have unveiled a promising new treatment approach for advanced HER2-negative breast cancer, using a three-drug combination that significantly improved responses in patients suffering from the disease.

The study, published in Nature Cancer, involved a combination of a histone deacetylase (HDAC) inhibitor, which halts tumor cell division by inducing chemical changes, along with two types of immunotherapy known as checkpoint inhibitors—working by unleashing the immune system’s power to target and destroy cancer cells.

Led by Evanthia Roussos Torres, PhD, the study enrolled 24 women with HER2-negative metastatic breast cancer, including both hormone receptor-positive and triple-negative cases. The results were striking, with an overall response rate (ORR) of 25 percent across all participants and an even more impressive ORR of 40 percent among those with triple-negative breast cancer.

Breast cancer is the most common cancer among American women, with approximately 300,000 new diagnoses each year in the United States. The majority of these cases are hormone receptor-positive and HER2-negative, underscoring the significance of developing effective treatments for this patient population.

Triple-negative breast cancer, accounting for 10–15 percent of cases, poses particular challenges due to its aggressive nature and limited treatment options.

Importantly, the study demonstrated the safety and tolerability of the combination therapy, with no patients needing to discontinue treatment due to adverse effects. The average progression-free survival (PFS) at six months was 50 percent, indicating that half of the participants experienced no disease progression during this period.

“Our results support the hypothesis that pre-treatment with the HDAC inhibitor entinostat, combined with dual immune checkpoint inhibitors, is a safe and promising strategy for metastatic breast cancer,” Torres said, emphasizing the significance of the findings.

She also underscored the need for further evaluation in larger phase II studies to assess the treatment’s efficacy more comprehensively.

“To our knowledge, this is the first published study that investigates treatment with an HDAC inhibitor in combination with dual immune checkpoint inhibitor therapy in patients with advanced breast cancer,” said Elizabeth Jaffee, PhD, a co-author of the study.

The researchers noted that while immune checkpoint inhibitors have revolutionized the treatment landscape for many solid tumors, their effectiveness in breast cancer has been limited. This novel combination therapy presents a potential solution to this challenge.

“Our study highlights the need for a deeper investigation of the breast cancer tumor microenvironment with a focus on changes in myeloid (immune) cell populations to determine their role in sensitization of the tumor microenvironment to treatment with immune checkpoint inhibitors,” Torres concluded in a press statement.

FDA approves elacestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer

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On January 27, 2023, the Food and Drug Administration (FDA) approved elacestrant (Orserdu, Stemline Therapeutics, Inc.) for postmenopausal women or adult men with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy.

FDA also approved the Guardant360 CDx assay as a companion diagnostic device to identify patients with breast cancer for treatment with elacestrant.

Efficacy was evaluated in EMERALD (NCT03778931), a randomized, open-label, active-controlled, multicenter trial that enrolled 478 postmenopausal women and men with ER-positive, HER2-negative advanced or metastatic breast cancer of which 228 patients had ESR1 mutations. Patients were required to have disease progression on one or two prior lines of endocrine therapy, including one line containing a CDK4/6 inhibitor. Eligible patients could have received up to one prior line of chemotherapy in the advanced or metastatic setting. Patients were randomized (1:1) to receive elacestrant 345 mg orally once daily (n=239) or investigator’s choice of endocrine therapy (n=239), which included fulvestrant (n=166) or an aromatase inhibitor (n=73). Randomization was stratified by ESR1 mutation status (detected vs. not detected), prior treatment with fulvestrant (yes vs. no), and visceral metastasis (yes vs. no). ESR1 mutational status was determined by blood circulating tumor deoxyribonucleic acid (ctDNA) using the Guardant360 CDx assay and was limited to ESR1 missense mutations in the ligand binding domain.

The major efficacy outcome measure was progression-free survival (PFS), assessed by a blinded imaging review committee. A statistically significant difference in PFS was observed in the intention to treat (ITT) population and in the subgroup of patients with ESR1 mutations.

In the 228 (48%) patients with ESR1 mutations, median PFS was 3.8 months (95% CI: 2.2, 7.3) in the elacestrant arm and 1.9 months (95% CI: 1.9, 2.1) in the fulvestrant or aromatase inhibitor arm (hazard ratio [HR] of 0.55 [95% CI: 0.39, 0.77], 2-sided p-value=0.0005).

An exploratory analysis of PFS in the 250 (52%) patients without ESR1 mutations showed a HR 0.86 (95% CI: 0.63, 1.19) indicating that the improvement in the ITT population was primarily attributed to the results seen in the ESR1 mutated population.

The most common adverse events (≥10%), including laboratory abnormalities, were musculoskeletal pain, nausea, increased cholesterol, increased AST, increased triglycerides, fatigue, decreased hemoglobin, vomiting, increased ALT, decreased sodium, increased creatinine, decreased appetite, diarrhea, headache, constipation, abdominal pain, hot flush, and dyspepsia.

The recommended elacestrant dose is 345 mg taken orally with food once daily until disease progression or unacceptable toxicity.