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SEZ6-targeting antibody-drug conjugate ABBV-706 in advanced small cell lung cancer and solid tumors: a phase 1 trial
Journal article   Open access   Peer reviewed

SEZ6-targeting antibody-drug conjugate ABBV-706 in advanced small cell lung cancer and solid tumors: a phase 1 trial

Lauren Averett Byers, Byoung Chul Cho, Alissa J Cooper, Anne C Chiang, Ji-Youn Han, Muhammad Furqan, Afshin Dowlati, Daniel Morgensztern, Kyriakos P Papadopoulos, Noura J Choudhury, …
Nature medicine
06/01/2026
DOI: 10.1038/s41591-026-04452-0
PMID: 42225988
url
https://doi.org/10.1038/s41591-026-04452-0View
Published (Version of record) Open Access

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Abstract

Seizure-related homolog 6 (SEZ6) is expressed in small cell lung cancer (SCLC) and neuroendocrine neoplasms. In an open label, phase 1 trial, ABBV-706, an antibody-drug conjugate with a SEZ6-directed antibody linked to topoisomerase-1 inhibitor (Top1i), was administered intravenously every 3 weeks (Q3W) to 288 patients with advanced solid tumors; 240 received monotherapy, including 124 with relapsed/refractory (R/R) SCLC. Primary objectives of dose escalation (part 1, advanced solid tumors), dose optimization and expansion (part 2, R/R SCLC only) and dose expansion (part 4, central nervous system tumors and high-grade neuroendocrine neoplasms only) were to evaluate the safety, tolerability, pharmacokinetics (PK), immunogenicity and antitumor activity of ABBV-706 monotherapy and, from parts 1 and 2, to determine the recommended phase 2 dose (RP2D) of ABBV-706 in R/R SCLC. In the monotherapy cohort (N = 240), the most common treatment-related adverse events (TRAEs) at any grade were anemia (61%) and fatigue (38%). Grade 3 or higher TRAEs occurred in 61% of patients and were dose dependent (39% at 1.8 mg kg and 70% at 2.5 mg kg ). In the R/R SCLC monotherapy cohort (n = 124), any-grade and grade 3 or higher TRAEs occurred in 93% and 61% of patients, respectively. ABBV-706 demonstrated promising preliminary efficacy in patients with R/R SCLC, with an objective response rate (ORR) of 52% (65/124). In patients with R/R SCLC receiving monotherapy in dose optimization and expansion part 2, ORR was similar between 1.8 mg kg and 2.5 mg kg doses (56% (23/41) and 59% (23/39), respectively), with a duration of response that was highest at the 1.8 mg kg dose and with most patients achieving rapid and durable tumor reduction. Although exploratory, long-term efficacy measures were an important consideration in the RP2D determination, and in R/R SCLC monotherapy, overall survival (OS) was highest at the 1.8 mg kg dose, with a median OS of 12.4 months. Based on the totality of available data, including, but not limited to, safety, preliminary efficacy measures and PK, 1.8 mg kg Q3W was confirmed as the optimal RP2D for patients with R/R SCLC. ClinicalTrials.gov: NCT05599984 .

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