Abstract P3-10-21: Phase Ib dose-finding study of [177Lu]Lu-NeoB + ribociclib + fulvestrant in patients w/ ER+/HER2- advanced breast cancer (ABC) w/ GRPR expression w/ early relapse from (neo)adjuvant endocrine therapy (ET) or progression on ET + CDK

Abstract Background: Ribociclib (RIB) + ET has shown significant progression-free survival and overall survival benefit in patients (pts) with HR+/HER2− ABC. However, there is still an unmet need for novel therapies for pts with disease progression on or after ET +/− a CDK4/6 inhibitor (CDK4/6i). Radioligand therapies (RLTs) have shown improvements in survival vs standard of care in castration-resistant metastatic prostate cancer and gastroenteropancreatic neuroendocrine tumors. Given their known benefit in other disease settings, RLTs are now being evaluated in ABC. We describe the CAAA603B12101 study, evaluating the addition of [177Lu-NeoB](177Lu-NeoB), a first-in-class RLT that selectively binds to GRPR, which is overexpressed in ER+ breast cancer cells, to the currently approved and recommended combination of ET + CDK4/6i for pts with ER+/HER2− ABC with GRPR expression who experienced early recurrence from (neo)adjuvant ET +/− a CDK4/6i or progression on ET + a CDK4/6i for ABC. Methods: The purpose of this Phase Ib, single-arm, multicenter, open-label, dose-finding study is to estimate the recommended dose (RD) of 177Lu-NeoB in combination with RIB and fulvestrant (FUL). Eligible pts include adult women (regardless of menopausal status) and men with ER+/HER2− ABC with GRPR expression who meet one of the following criteria: (i) experienced recurrence ≤12 mo from completion of (neo)adjuvant ET (+/− CDK4/6i) with no treatment for ABC, (ii) experienced recurrence >12 mo from completion of (neo)adjuvant ET and then subsequent progression after one line of ET (except FUL) + a CDK4/6i for ABC, or (iii) had ABC at diagnosis that progressed after one line of ET (except FUL) in combination with a CDK4/6i. Pts are required to have one target lesion (measurable per RECIST 1.1) in the baseline stand-alone CT or MRI. All pts are required to have diagnostic screening with a target lesion showing uptake of [68Ga]Ga-NeoB. This study comprises a dose-escalation part and a concurrent backfill part. In the dose-escalation part, four provisional dose levels are planned to be tested: 100 mCi (initial dose), 150 mCi, 200 mCi and 250 mCi in cohorts of three to six pts. The initial dose of 177Lu-NeoB will be 100 mCi (every 28d for six cycles) in combination with RIB (600 mg/d; 3 wk on/1wk off) and FUL (500 mg on d1 of a 28-d cycle with an additional single dose on d15 of cycle 1). Pre/perimenopausal pts will also receive goserelin (3.6 mg on d1 of a 28-d cycle). After inclusion of pts in each cohort, the incidence rate of dose-limiting toxicities (DLTs) will be compared with the predefined toxicity rate boundaries to decide whether the next cohort will receive a lower, higher, or same dose or whether the trial will be terminated. The backfill part will allow enrollment to a previously cleared dose level (during escalation part) to obtain additional safety, tolerability, and preliminary efficacy data. During the backfill part, the cumulative incidence rate of DLTs will also be compared with the predefined toxicity rate boundaries to determine if escalation should be restarted from a lower dose level. Primary outcomes include incidence and nature of DLTs, incidence and severity of adverse events (AEs) and serious AEs, and incidence of dose interruptions, discontinuations, and dose reductions. Secondary outcomes include preliminary antitumor activity and pharmacokinetic and biodistribution (dosimetry) data. The RD will be determined considering all available data from the escalation and backfill parts. Planned enrollment is approximately 48 pts. Pt enrollment is currently open. Clinical trial ID: NCT05870579. Citation Format: Debasish Tripathy, Dejan Juric, Sonia Pernas, Francois-Clement Bidard, Ana Sofia Ferreira, Kevin Perraud, Louise Emmett. Phase Ib dose-finding study of [177Lu]Lu-NeoB + ribociclib + fulvestrant in patients w/ ER+/HER2- advanced breast cancer (ABC) w/ GRPR expression w/ early relapse from (neo)adjuvant endocrine therapy (ET) or progression on ET + CDK4/6i for ABC [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P3-10-21.