Clinical Summary:

• Design/Population: This phase 1 trial evaluated ABBV-706, a SEZG-targeted antibody drug conjugate, in patients with relapsed or refractory small cell lung cancer, including 41 treated at the recommended phase 3 dose of 1.8 mg/kg every 3 weeks in the second-line or later setting. 
• Key Outcomes: ABBV-706 demonstrated an objective response rate (ORR) of 56% and median overall survival (OS) of 12.4 months. Among patients receiving second-line treatment, the ORR was 82% and median OS was 14.3 months. Exploratory analyses associated complete ctDNA clearance with improved survival outcomes. 
• Clinical Relevance: These findings support further development of ABBV-706, with preliminary biomarker and preclinical data suggesting selective antitumor activity and potential opportunities for treatment monitoring. 

Updated results from a phase 1 trial demonstrated promising antitumor activity with ABBV-706, a SEZ6-targeted antibody-drug conjugate, in patients with relapsed or refractory small cell lung cancer (SCLC), with encouraging response and survival outcomes supported by exploratory biomarker and preclinical findings. 

These findings were presented by Anne Chiang, MD, PhD, Yale School of Medicine, New Haven, Connecticut, at the European Society for Medical Oncology (ESMO) Congress. 

In this trial, 124 patients received ABBV-706, an investigational antibody-drug conjugate designed to selectively deliver the topoisomerase I inhibitor payload adizutecan to SEZ6-expressing tumor cells.

This analysis included 41 patients with relapsed or refractory SCLC receiving second-line or later treatment at the recommended phase 3 dose of 1.8 mg/kg every 3 weeks during part 2a dose optimization. 

Investigators also evaluated potential biomarkers of response using archival tumor tissue collected at baseline for IHC and RNA sequencing, alongside longitudinal assessments of ctDNA and serum progastrin-releasing peptide (proGRP). 

Preclinical analyses examined SEZ6 binding and intracellular trafficking in normal pulmonary alveolar cells and SCLC cell lines, as well as the antitumor and immunomodulatory activity of adizutecan. 

At the data cutoff point, the objective response rate (ORR) was 56% in patients who received the recommended phase 3 dose, with a median overall survival (OS) of 12.4 months.

In a subgroup of 17 patients receiving ABBV-706 as second-line treatment, the ORR was 82%, and median OS was 14.3 months. 

The safety profile of ABBV-706 in the second-line or later population was reported to be consistent with previously observed findings.

Exploratory biomarker analyses demonstrated rapid reductions in ctDNA and serum proGRP as early as cycle 2, day 1. At cycle 3, day 1, complete ctDNA clearance was associated with improved progression-free survival (PFS) and OS. 

SEZ6 expression was detected in 93% of evaluable tumor samples using an IHC cutoff of at least 1% of cells with 1+ staining. Expression remained stable across treatment lines and was similar among who responded to ABBV-706 and those who did not. 

Preclinical analyses demonstrated minimal SEZ6 antibody binding and lysosomal trafficking in normal human pulmonary alveolar epithelial cells, while substantial trafficking was observed in SEZ6-expressing SCLC cells. 

Additionally, adizutecan demonstrated potent cytotoxic activity in SCLC cell lines, reducing cell viability and increasing expression of major histocompatibility complex class I, PD-L1, and key immune-related pathways.

These findings provide preliminary evidence supporting the selective delivery and antitumor activity of ABBV-706 in SEZ6-expressing SCLC cells, while suggesting that ctDNA clearance may serve as a potential marker of treatment response.

Investigators concluded that ABBV-706 monotherapy demonstrated promising clinical activity in heavily pretreated relapsed or refractory SCLC, with biomarker and preclinical findings supporting its selective antitumor profile and continued clinical development.

Source:

Chiang AC, Jahchan N, Faivre E, et al. ABBV-706: A first-in-class SEZ6-targeted topoisomerase 1 inhibitor (Top1i)-antibody-drug conjugate (ADC) with robust antitumour activity in relapsed/refractory small cell lung cancer (R/R SCLC). Presented at the ESMO Congress. October 23–27, 2026; Madrid, Spain. Abstract 3837RO.