Two groundbreaking clinical trials are investigating [177Lu]Lu-NeoB, a first-in-class radioligand therapy that selectively binds to gastrin-releasing peptide receptor (GRPR), for patients with estrogen receptor-positive (ER+)/HER2-negative advanced breast cancer who have experienced disease progression despite standard treatments.
Addressing Treatment Resistance in Advanced Breast Cancer
While CDK4/6 inhibitors combined with endocrine therapy have become standard of care in first-line ER+/HER2-negative advanced breast cancer and have shown significant progression-free survival and overall survival benefits, patients will eventually experience disease progression. The optimal treatment sequence following progression on CDK4/6 inhibitor plus endocrine therapy has not yet been established, creating a significant unmet medical need for novel targeted treatments in patients with endocrine therapy-resistant advanced breast cancer.
Triple Combination Approach: CAAA603B12101 Study
The phase 1b CAAA603B12101 study is evaluating [177Lu]Lu-NeoB in combination with ribociclib plus fulvestrant in a single-arm, multicenter, open-label, dose-finding design. This trial targets patients with ER+/HER2-negative advanced breast cancer plus GRPR expression who fall into specific categories: those who experienced recurrence within 12 months from completion of neoadjuvant or adjuvant endocrine therapy, those with recurrence more than 12 months after adjuvant therapy followed by progression after one line of endocrine therapy plus CDK4/6 inhibitor, or those diagnosed with advanced breast cancer that progressed after one line of endocrine therapy plus CDK4/6 inhibitor.
The dose escalation phase plans four provisional dose levels in cohorts of 3 to 6 patients, with an initial dose of 100 mCi of [177Lu]Lu-NeoB combined with ribociclib at 600 mg daily plus fulvestrant. The study will use dose-limiting toxicity incidence rates compared with predefined toxicity rate boundaries to guide dose escalation decisions.
Radiosensitizer Strategy: CAAA603D12101 Study
The phase 1/2 CAAA603D12101 study, also known as NeoB D1, is evaluating [177Lu]Lu-NeoB plus capecitabine, leveraging capecitabine's properties as a known radiosensitizer. This open-label, multicenter study includes both dose-escalation and dose-optimization phases for patients with ER+/HER2-negative advanced breast cancer with GRPR expression after progression on prior endocrine therapy plus CDK4/6 inhibitor.
Eligible patients can have received 1 to 3 prior lines of endocrine therapy for advanced breast cancer, with one line required to include a CDK4/6 inhibitor. The study accommodates patients with BRCA1/2 mutations who have received prior PARP inhibitor treatment and those with HER2-low disease who have been treated with trastuzumab deruxtecan.
Treatment Protocols and Dosing Strategies
In the phase 1 portion of the CAAA603D12101 study, patients receive [177Lu]Lu-NeoB at 150 millicurie every 6 weeks plus capecitabine at 1000 mg/m² orally for 14 days, followed by 7 days off. If dose escalation is supported, patients will be randomized to two higher dose levels: 200 mCi every 6 weeks or 100 mCi every 3 weeks. The treatment duration is planned for 6 administrations for the every-6-weeks regimen and 12 administrations for the every-3-weeks regimen.
Study Objectives and Enrollment
Both trials have comprehensive primary objectives focusing on safety and efficacy. The CAAA603B12101 study's primary outcomes include incidence and nature of dose-limiting toxicities, incidence and severity of adverse events, and incidence of dose interruptions, discontinuations, or reductions. Secondary outcomes encompass preliminary antitumor activity, pharmacokinetics, and biodistribution.
The CAAA603D12101 study's dose-escalation phase primarily evaluates incidence and severity of dose-limiting toxicities and adverse effects, while the dose-optimization phase focuses on objective response rate, clinical benefit rate, time to response, duration of response, progression-free survival, and overall survival.
The CAAA603B12101 study plans to enroll approximately 48 patients, while the CAAA603D12101 study targets about 58 patients. Both trials are currently enrolling participants, representing important steps in developing radioligand therapies for advanced breast cancer treatment.
