Background: Endocrine blockade (EB) is standard of care for patients (pts) with HR+ LABC/MBC. RET over-expression (RET+) occurs in up to 75% of HR+ breast cancers and is a postulated mechanism of endocrine resistance. Preclinical studies show cross talk between RET and estrogen receptor, and at least additive treatment (Tx) effect of Len+EB. Methods: We performed a phase Ib trial (3+3 dose escalation) to study safety, tolerability, pharmacodynamics and efficacy of Len+Let. Both drugs were given as continuous daily dosing with 2 weeks (wks) of Len alone, followed by Len+Let for 12 wks then surgery (LABC), or till disease progression (PD) (MBC). Serial tumor biopsies (n = 15) were done at baseline, after Len alone, 4 wks post Len+Let, and at surgery [LABC] / upon PD [MBC]. Results: 16 pts were treated (4 LABC, 12 MBC); Among MBC pts, median lines of prior Tx was 3 (range 0-10); 84.6%, 66.7%, and 58.3% had prior EB, EB+CDK4/6 inhibitor (i), and chemotherapy (CT) respectively. At dose level (DL) 1, 2/4 pts had dose-limiting toxicities (DLT). There was no DLT at DL-1, but 6/6 pts needed dose reductions (DR), with 4/6 DR within 6 wks of Len+Let (3 G3 hypertension [HTN], 1 G3 wound pain), deeming DL-1 intolerable. At DL-2, 0/6 pts had DLT; this was declared recommended phase 2 dose (RP2D). Most frequent G3 toxicities (tox) were HTN (6/16), proteinuria (2/16) and palmar-plantar erythrodysesthesia (PPE) (2/16), with no G4/5 tox. Len+Let was active with 93.8% overall disease control rate (DCR) (50.0% partial response [PR], 43.8% stable disease [SD]). Among MBCts (8/12 had prior EB+CDK4/6i), DCR ≥12 wks was 91.7%; 1 pt had sustained PR for 48 wks and 1 ongoing PR at 40 wks. 9/16 pts had RET+ tumors on immunohistochemistry at baseline, and 66.7% showed down-regulation with Tx (RECIST: 4 PR, 2 SD). Conclusions: Len+Let showed significant anti-tumor activity, even in pts who failed prior CT or EB+CDK4/6i. RP2D of 14mg Len and 2.5mg Let is tolerated with efficacy; dose expansion is currently underway. Clinical trial information: NCT02562118