3001 Background: SEZ6 is a transmembrane protein expressed in small cell lung cancer (SCLC) and other neuroendocrine neoplasms (NENs), and central nervous system (CNS) tumors. These malignancies have a high unmet need for novel effective therapies. ABBV-706 is an ADC targeting SEZ6 conjugated to a topoisomerase 1 inhibitor payload at a drug-to-antibody ratio of 6, and is highly efficacious in preclinical models of SCLC, NENs, and CNS tumors. Here, results from ABBV-706 monotherapy dose escalation (DE) are presented. Methods: Phase 1, open-label, multicenter, DE and dose-expansion study (NCT05599984) of ABBV-706 as monotherapy or in combination with budigalimab (a programmed cell death 1 inhibitor), carboplatin, or cisplatin. Primary objectives are to determine the safety, PK, preliminary efficacy, and recommended phase 2 dose of ABBV-706. Exploratory objectives are to assess SEZ6 expression retrospectively and its association with safety, PK, and efficacy. DE enrolled adults (≥18 yr) with relapsed/refractory SCLC, high-grade CNS tumors, and high-grade NENs, following the Bayesian optimal interval design. ABBV-706 was administered IV at 1.3–3.5 mg/kg doses Q3W in 21-d cycles. Results: As of data cutoff on Nov 15, 2023, 49 pts (SCLC: n=22 [45%]; CNS tumors: n=5 [10%]; NEN: n=22 [45%]) were enrolled and treated with ABBV-706 in DE and backfill cohorts. Median age was 64 yr (range 32–81) and median prior lines of therapy was 2.5 (range 1–6). 2 pts had a dose-limiting toxicity: 1 G4 leukopenia and neutropenia lasting >7 d at 3.0 mg/kg and 1 G4 thrombocytopenia at 3.5 mg/kg. TEAEs occurred in 45 (92%) pts, the most frequent being anemia (51%), fatigue (41%), neutropenia (31%), and leukopenia (31%). G≥3 TEAEs occurred in 28 (57%) pts and were mainly hematologic: neutropenia (29%), anemia (27%), and leukopenia (25%). No pneumonitis/interstitial lung disease was observed. Gastrointestinal TEAEs (all G1/2) were seen in 55% of pts, with the most common being nausea (27%) and vomiting (18%). There were no ABBV-706–related deaths. The maximum tolerated dose was 3 mg/kg IV Q3W. ABBV-706 ADC showed an approximate dose-proportional increase in exposure with an elimination half-life of approximately 7 d across doses. For 33 RECIST-evaluable pts, the confirmed (c) objective response rate was overall 21% (7 partial responses [PRs]); 40% (6/15) for SCLC and 6% (1/18) for NEN. The overall response (c and unconfirmed [u]) rate without confirmation was 45% (7 cPRs/8 uPRs); 73% (6 cPRs/5 uPRs) for SCLC, and 22% (1 cPR/3 uPRs) for NEN. 8 uPRs are pending confirmation and will be reported in the final presentation. The clinical benefit rate was 91% (7 PR, 23 stable disease). No activity was observed in 3/3 pts with high-grade gliomas. Conclusions: ABBV-706 demonstrated a manageable safety profile with promising efficacy in SCLC and NENs. Further evaluation of ABBV-706 is ongoing. Clinical trial information: NCT05599984 .