Novel SEZ6-Directed ADC Shows Robust Activity in Relapsed/Refractory SCLC

ABBV-706, a first-in-class antibody-drug conjugate (ADC) targeting seizure-related homolog protein 6 (SEZ6), demonstrated robust antitumor activity in patients with relapsed/refractory small cell lung cancer (SCLC), with accompanying biomarker analyses showing that SEZ6 is highly and stably expressed across the disease, according to data from an ongoing first-in-human phase 1 study (NCT05599984) presented at the 2026 European Society for Medical Oncology (ESMO) Congress.

What was the antitumor activity?

Among 41 patients with relapsed/refractory SCLC treated with ABBV-706 at the recommended phase 2 dose of 1.8 mg/kg once every 3 weeks in the second-line or later setting, the ORR was 56% (n = 23), as previously reported. The median progression-free survival (PFS) was 6.4 months (95% CI, 4.0-8.1), and the median overall survival (OS) was 12.4 months (95% CI, 8.2-17.3). Patients in this cohort had received a median of 2 prior lines of therapy (range, 1-6), 39% had brain metastases at baseline, and 61% had a chemotherapy-free interval of less than 90 days, reflecting a heavily pretreated, aggressive population.

What did the SEZ6 biomarker analysis show?

SEZ6, a neuroendocrine lineage marker, was highly expressed in SCLC. Among 108 tumors assessed by immunohistochemistry at screening, 93% were above a 1% positivity cutoff, with a median H-score of 145. Expression was stable regardless of prior treatment, with no significant difference between treatment-naive tumors and those from patients who had received at least 1 prior line of therapy (P = .163), or between primary and metastatic tumor tissue (P = .180).

Among 35 evaluable samples, SEZ6 expression did not correlate with the development of any-grade anemia or neutropenia, and expression was comparable between responders and nonresponders, findings the investigators said support a biomarker-unselected treatment approach. Preclinically, SEZ6 showed minimal expression in normal lung alveolar epithelial cells, translating to limited antibody binding and internalization relative to other SCLC ADC targets, which the investigators proposed as a rationale for a low risk of interstitial lung disease (ILD).

How did ctDNA and proGRP dynamics relate to outcomes?

ABBV-706 monotherapy triggered rapid declines in circulating tumor DNA (ctDNA) and pro-gastrin-releasing peptide (proGRP) as early as cycle 2, day 1, with greater decreases in responders than nonresponders. By cycle 3, day 1, ctDNA was reduced by at least 50% in 77% of patients (n = 24/31) and by at least 95% in 52% (n = 16/31), with complete ctDNA clearance in 29%. Deeper molecular responses tracked with improved outcomes; among patients with complete ctDNA clearance (n = 9), the median PFS was 13.6 months (95% CI, 8.4-not reached [NR]), and the median OS was NR, compared with a median PFS of 6.2 months (95% CI, 4.0-9.5) and a median OS of 10.1 months among molecular responders with a 50% to less than 100% reduction (n = 15), and a median PFS of 3.6 months (95% CI, 2.6-NR) and a median OS of 6.7 months (n = 3.6-NR) among those with less than a 50% reduction (n = 7).

What was the safety profile?

Treatment-related adverse events (TRAEs) of any grade occurred in 88% of patients (n = 36) treated at the 1.8-mg/kg dose. The most common grade 3 or higher TRAEs were hematologic, including anemia (42%; n = 17) and neutropenia (20%; n = 8), consistent with the previously reported manageable safety profile of the agent. The biomarker data were drawn from the total monotherapy population of 124 patients treated across doses of 1.3 mg/kg to 3.5 mg/kg in the first-in-human study.

“SEZ6 is highly expressed in SCLC, stable across [lines of therapy], and not correlated with response rates or hematological [AEs] following ABBV-706 monotherapy,” presenting study investigator Anne Chiang MD, PhD, an associate professor of Medical Oncology and Thoracic Oncology, as well as the Associate Cancer Center Director of Clinical Initiatives at Yale School of Medicine, concluded with coinvestigators. “ABBV-706 monotherapy has demonstrated promising clinical benefit, with biomarker and preclinical data supporting SEZ6 as a therapeutic target in SCLC; the phase 3 SEZanne-02 study [NCT07155174] in patients with [relapsed/refractory] SCLC previously treated with tarlatamab [Imdelltra] is ongoing.”

What is the trial design, and what comes next?

ABBV-706 is a first-in-class ADC composed of a SEZ6-targeting monoclonal antibody joined by a stable linker to a potent topoisomerase 1 inhibitor payload, adizutecan. The ongoing open-label first-in-human phase 1 study enrolled patients with relapsed/refractory extensive-stage SCLC who had received prior platinum/etoposide chemotherapy and/or immuno-oncology regimens; patients with treated or untreated stable brain metastases were eligible, while those with ILD or pneumonitis requiring treatment were excluded. The trial’s key end points included safety, ORR, PFS, OS, and SEZ per immunohistochemistry.

Based in part on the immunomodulatory effects of the adizutecan payload, ABBV-706 is being combined with anti–PD-L1 therapy in the ongoing phase 2 first-line SCLC SEZanne study (NCT07155174), and the phase 3 SEZanne-02 study in patients with relapsed/refractory SCLC previously treated with tarlatamab is ongoing.

Reference

Chiang AC, Jahchan N, Faivre E, et al. ABBV-706: a first-in-class SEZ6-targeted topoisomerase 1 inhibitor antibody-drug conjugate with robust antitumor activity in relapsed/refractory small cell lung cancer. Presented at: European Society for Medical Oncology (ESMO) Congress 2026; October 23-27, 2026; Madrid, Spain. Abstract 3837RO.