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

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^-1 and 70% at 2.5 mg kg^-1). 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^-1 and 2.5 mg kg^-1 doses (56% (23/41) and 59% (23/39), respectively), with a duration of response that was highest at the 1.8 mg kg^-1 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^-1 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^-1 Q3W was confirmed as the optimal RP2D for patients with R/R SCLC. ClinicalTrials.gov: NCT05599984 .