2041 Background: Patients (pts) with primary high-grade CNS tumors, especially those with glioblastoma (GBM), face poor clinical outcomes (GBM 5yr OS 5–10%). Seizure-related 6 homolog (SEZ6) is overexpressed in many tumor types, including primary CNS tumors. ABBV-706 is a SEZ6-targeting antibody-drug conjugate with topoisomerase 1-inhibitor payload that has shown a manageable safety profile in pts with small cell lung cancer. We present safety and efficacy data from a phase 1, FIH study evaluating ABBV-706 in pts with CNS tumors. Methods: This phase 1, FIH study (NCT05599984) enrolled pts ≥18 years with histologically/cytologically confirmed advanced relapsed/refractory GBM (IDH-wildtype, Grade G 4) or astrocytoma (IDH-mutant, G 3/4). Pts had ECOG performance score ≤1, and ≥1 measurable lesion per Response Assessment in Neuro-Oncology (RANO). Pts had prior surgical resection and progressed after receiving standard of care treatment. During dose escalation and expansion, pts received 1.3–3.5 mg/kg and 2.5 mg/kg ABBV-706, respectively. Treatment was every 3 weeks until disease progression or intolerable toxicity. Endpoints included safety and efficacy determined by RANO criteria. Results: As of Sep 27, 2025, 48 pts with primary CNS tumors (GBM, n=41; astrocytoma, n=6; missing indication, n=1) received ABBV-706 (1.3 mg/kg, n=1; 2.5 mg/kg, n=44; 3.0 mg/kg, n=1; 3.5 mg/kg, n=2). Among all pts, median age was 50 years (range 18–78), 58% were male, and the median number of prior lines of therapy was 2 (range 1–5). Median follow-up was 13.7 and 13.2 months for pts with GBM and astrocytoma, respectively. Treatment-related adverse events (TRAEs) were observed in 90% of pts. Most common toxicities were hematological (65%) and gastrointestinal (52%) events. G ≥3 TRAEs were observed in 60% of pts; most commonly anemia (40%). TRAEs led to treatment discontinuation, dose interruption, and dose reduction in 4%, 38%, and 27% of pts, respectively. No G 5 TRAEs were reported. One pt had pneumonitis (2.5 mg/kg, G 2). Among all pts, ORR was 8%, and 2 pts (4%) had a confirmed complete response. Efficacy data for GBM are shown in the Table. SEZ6 IHC expression was similar between GBM pts with (n=4) and without (n=31) an objective response. Conclusions: In pts with previously treated primary CNS tumors, ABBV-706 had a comparable safety profile to that observed in other tumors and showed encouraging antitumor activity. Clinical trial information: NCT05599984 . Efficacy of ABBV-706. a Pts with GBM2.5 mg/kg ABBV-706(n=41) BOR, n (%)CR b PR b SDPD b NE/not assessed 2 (5)4 (10)21 (51)9 (22)5 (12) ORR c , n (%), 95% CI 4 (10), 3–23 CBR, n (%), 95% CI>5 weeks>6 months 26 (63), 47–785 (12), 4–26 Median PFS, months (95% CI)Probability at 9 months, % (95% CI) 2.7 (2.3-5.4)10 (3-24) Median OS, months (95% CI)Probability at 12 months, % (95% CI) 6.4 (5.4–8.3)17 (6–33) a By investigator per RANO. b Including confirmed + preliminary. c Confirmed.
Vieito et al. (2026) studied this question.