The seizure-related homolog protein 6 (SEZ6)-targeting antibody-drug conjugate ABBV-706 demonstrated significant clinical activity in patients with relapsed/refractory small cell lung cancer (SCLC), achieving a 58% confirmed overall response rate in a phase I dose-optimization study presented at the International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer.
The study enrolled 80 patients with extensive-stage SCLC who had received at least one prior line of therapy including platinum-based chemotherapy. Patients were randomly assigned to receive ABBV-706 at either 1.8 mg/kg or 2.5 mg/kg intravenously every three weeks until disease progression or unacceptable toxicity.
Efficacy Across Patient Subgroups
Responses were observed across key patient populations, including those with challenging clinical characteristics. Among patients who had received two prior lines of therapy (n=30), the confirmed overall response rate reached 77%, while those with at least three prior lines of therapy (n=50) achieved a 46% response rate.
Notably, the therapy showed activity regardless of platinum sensitivity status. Patients with prior chemotherapy-free intervals of 90 days or longer, less than 90 days, and less than 30 days achieved response rates of 57%, 59%, and 53%, respectively. Among patients with brain metastases at baseline (n=28), the response rate was 57% compared to 69% in those without brain metastases (n=36).
"ABBV-706 has manageable safety and promising efficacy in heavily pretreated patients with relapsed/refractory SCLC, with most patients receiving durable clinical benefit, including those patients with platinum-refractory disease," emphasized lead study author Lauren A. Byers, MD, professor in the Department of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center.
Dose-Dependent Efficacy and Safety Profile
The study revealed important dose-dependent differences in both efficacy and tolerability. At the 1.8 mg/kg dose (n=41), the confirmed overall response rate was 56%, with particularly strong activity in second-line patients (81% response rate). The 2.5 mg/kg dose (n=39) achieved a 59% overall response rate, with a 71% response rate in second-line patients.
However, the lower dose demonstrated superior tolerability. Grade 3 or higher treatment-related adverse events occurred in 49% of patients receiving 1.8 mg/kg compared to 77% at the higher dose. Treatment-related adverse events led to dose interruptions in 24% versus 64% of patients, respectively.
Durable Clinical Benefit
The median duration of response in the total population was 5.6 months (95% CI, 4.2-6.9), with the median progression-free survival reaching 5.7 months (95% CI, 4.9-7.0). In the second-line setting, median progression-free survival extended to 6.8 months, while patients with chemotherapy-free intervals of less than 30 days achieved a median progression-free survival of 5.7 months.
Treatment with ABBV-706 led to rapid responses at both tested dose levels, with only one patient among those receiving the agent in the second-line setting or later failing to respond on the first scan.
Safety and Tolerability
In the total population, any-grade treatment-related adverse events were reported in 90% of patients. The most common hematological adverse events included anemia, neutropenia, and thrombocytopenia, with rates generally higher at the 2.5 mg/kg dose. Common non-hematologic adverse events included fatigue, nausea, decreased appetite, and dyspnea.
Adjudicated interstitial lung disease was reported in seven patients overall, with four cases in the 1.8 mg/kg arm and three in the 2.5 mg/kg arm. Two patients in each arm experienced grade 3 or higher interstitial lung disease.
Mechanism and Future Development
SEZ6 is a type I transmembrane protein and neuroendocrine lineage marker highly expressed in SCLC. ABBV-706 features a proprietary topoisomerase 1 payload with a stable linker attachment and a drug-to-antibody ratio of 6. Importantly, SEZ6 expression levels were similar between responders and non-responders, suggesting broad applicability across the SCLC patient population.
Based on the favorable benefit-risk profile, the 1.8 mg/kg dose administered every three weeks was selected as the recommended phase II dose for ABBV-706 monotherapy in patients with SCLC.
"The ABBV-706 efficacy profile in terms of ORR, DOR, and PFS is similar to that of the first-line standard of care (platinum-etoposide-checkpoint inhibitor) even if given in a later line of treatment," the researchers noted, highlighting the potential significance of this targeted therapy for patients with limited treatment options.
