Seizure-related homolog 6 (SEZ6) expression and ctDNA methylation profiles in patients with high-grade neuroendocrine carcinomas (NECs)/neuroendocrine tumors (NETs) from a phase 1 study of ABBV-706 in advanced solid tumors.

3085 Background: SEZ6 is a transmembrane protein with overexpression in small cell lung cancer (SCLC) and other neuroendocrine neoplasms (NENs) and minimal expression in normal tissues, making it a promising therapeutic target for these NENs that have a significant unmet need for treatments. ABBV-706 is a novel SEZ6-targeting antibody-drug conjugate with a potent topoisomerase 1 inhibitor payload and is being evaluated in a phase 1 study (NCT05599984) in patients (pts) with advanced solid tumors. Preliminary data from ABBV-706 monotherapy dose escalation demonstrated a manageable safety profile and promising efficacy in pts with SCLC and NECs/NETs ( JCO 2024;42[suppl 16]: abs 3001). Herein, we describe SEZ6 expression at the protein and mRNA levels in tumor tissues of pts with NENs outside of SCLC, as well as detection of high-grade NEN cancer signal of origin (CSO) among these pts by investigating ctDNA methylation prior to ABBV-706 treatment. Methods: This phase 1, open-label study enrolled pts (≥18 yr) with relapsed/refractory high-grade NECs/NETs (well-differentiated grade 3 NETs and poorly differentiated NECs), atypical lung carcinoid, and medullary thyroid cancer (MTC) in dose-escalation and -expansion cohorts. Pts received ABBV-706 monotherapy IV at 1.3–3.5 mg/kg Q3W. FFPE tumor tissues of these pts, when available, were subjected to a proprietary IHC assay for SEZ6 and RNAseq analysis. ctDNA samples collected prior to ABBV-706 treatment were subjected to the Cancer Research Solution (RUO; GRAIL, Inc.). ctDNA abundance and CSO were assessed by examining cancer-specific methylation patterns of ctDNA. Results: As of Aug 27, 2024, in the NEC/NET cohort of 64 pts, median age was 63 yr (range 33–86) and the median number of prior therapies was 3 (range 1–8). High prevalence of moderate to strong SEZ6 expression (SEZ6 cytomembrane IHC H-score ≥100) was observed across NEC/NET histologies: 78% of extrapulmonary small cell NEC of diverse anatomic sites (n = 9); 80% of neuroendocrine prostate carcinoma (n = 5); 43% of large cell NEC of diverse anatomic sites (n = 14); 50% of MTC (n = 4); 40% of gastroenteropancreatic NENs (n = 10); 50% of atypical lung carcinoid (n = 6). SEZ6 mRNA levels were highly correlative with SEZ6 IHC scores. ctDNA positivity rate was 95% from baseline plasma samples of the NEC/NET cohort (n = 60); 67% of ctDNA-positive samples (n = 57) were predicted to have high-grade NEN as their primary CSO. Conclusions: Robust SEZ6 expression was observed with some heterogeneity across histologies of the NEC/NET monotherapy cohort. High ctDNA detection rate at baseline indicates the feasibility of monitoring molecular response longitudinally without an invasive procedure and identifying predictive biomarker(s) for ABBV-706. Clinical trial information: NCT05599984 .