Targeting EGFR/ERBB2 With Neratinib in Hormone Receptor (HR)-Positive/HER2-negative HER2-enriched Advanced/Metastatic Breast Cancer

Summary

HR+/HER2-negative BC represent ∼70% of all newly diagnosed breast tumours and are responsible for most recurrences and deaths due to this disease, and despite available standard therapies, ∼15-20% of hormone tumours recur at distant sites. As BC is a clinically and biologically heterogeneous disease, intrincsic subtype may play an important role in classifying patients. In this case, HER2-E subtype is present in approximately 6.6-11.0% of HR+/HER2-negative tumors and might express either HER2, estrogen receptor (ER) or progesterone receptor (PR), we also know that HER2-E is present twice as much in metastatic tumors compared to primary tumors and that HER2-E patients may benefit in terms of PFS form an anti-HER2 drug as was showed using retrospective sample in EGF30008 trial. Therefore, incorporation of novel drugs in combination with endocrine therapy (ET) can improve patient outcomes in HR+/HER2-negative BC advanced disease specially in those with HER2-E subtype.

Methods NEREA is an open-label, single arm, multicenter phase II study evaluating treatment with neratinib in combination with ET in pre and post-menopausal women and men with locally advanced or metastatic HER2-enriched (HER2-E), HR+/HER2-negative breast cancer who had recurrence or progression while receiving previous ET (either aromatase inhibitors, tamoxifen or fulvestrant) in the adjuvant setting or to treat advanced disease or both. The study will follow a Simon's 2-stage design with one interim and one final efficacy analysis. The primary objective will is assess the efficacy of neratinib in combination with ET is this group of patients, efficacy will be measured as Progression-Free Survival at 6 months (PFS6) defined as the proportion of patients alive and without progression, locally assessed by the investigator through the use of RECIST v.1.1 at 24 weeks after first treatment administration, imaging evaluation will be performed every 8 weeks for the first 12 months following treatment start, and every 12 weeks thereafter. Secondary endpoints include Clinical Benefit Rate at 6 months , Overall Response rate, Duration of response, Time to response and Incidence, duration and severity of Adverse Events. The interim analysis will be conducted when 33 patients are evaluable for the primary endpoint having the potential for at least 3 'on treatment' disease assessment scans. If less than 15 patients achieved a PFS6, the trial will be terminated for futility in favor of the null hypothesis. If more than 28 patients achieved a PFS6, the trial will be stopped in favor of the alternative hypothesis demonstrating activity. If none of the two above-mentioned conditions are attain, up to a further 23 patients may be evaluated, for at least a total of 56 evaluable patients. Therefore, if a total of 28 or more patients achieved a PFS6 at the end of the second stage, then the null will be rejected in favor of the alternative.

Eligible patients will receive neratinib 240 mg every day in combination with ET, with either exemestane, fulvestrant or tamoxifen: exemestane 25 mg every day orally, tamoxifen 20mg every day orally or fulvestrant 500 mg administered in two intramuscular injections of 250 mg each at C1D15 and at D1 of each subsequent 28-day cycle at investigator discretion. LHRH agonist will be used in men and premenopausal women if no oophorectomy has been performed previously. All patients will take prophylactic loperamide with a stablished doses scheme during the firs cycle and on demand in subsequent cycles

Conditions

• Breast Cancer

Interventions

DRUG

Neratinib + endocrine therapy

Neratinib plus Fulvestrant, Exemestane or Tamoxifen

Sponsors & Collaborators

• SOLTI Breast Cancer Research Group

  lead OTHER

Study Design

Allocation

NA

Purpose

TREATMENT

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2020-07-23

Primary Completion

2021-11-29

Completion

2021-11-29

Countries

• Portugal
• Spain

Study Locations