ABBV-706 Yields Durable Responses and Is Deemed Tolerable in R/R SCLC

The seizure-related homolog protein 6 (SEZ6)–targeting antibody-drug conjugate (ADC) ABBV-706 produced durable clinical benefit with a manageable safety profile in patients with relapsed/refractory small cell lung cancer (SCLC), according to updated findings from the dose-optimization portion of a first-in-human phase 1 trial (NCT05599984), which were presented at the International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer.¹

In the total population (n = 80), the confirmed overall response rate (cORR) was 58%. Responses were seen across key patient subgroups, as well as patients with platinum-refractory/resistant disease and those with brain metastases. Among patients who had received 2 prior lines of therapy (n = 30) or at least 3 prior lines of therapy (n = 50), the cORRs were 77% and 46%, respectively. Among patients with prior chemotherapy-free intervals of 90 days or longer (n = 30), less than 90 days (n = 41), and less than 30 days (n = 19), the cORRs were 57%, 59%, and 53%, respectively. Among patients with (n = 28) and without (n = 36) brain metastases at baseline, the cORRs were 57% and 69%, respectively. Notably, SEZ6 expression levels were similar between responders and nonresponders.

Among patients treated at the 1.8-mg/kg dose (n = 41), the cORR was 56%. Of patients who had received 2 prior lines of therapy (n = 16) or at least 3 prior lines of therapy (n = 25), the cORRs were 81% and 40%, respectively. Among patients with prior chemotherapy-free intervals of 90 days or longer (n = 12), less than 90 days (n = 24), and less than 30 days (n = 11), the cORRs were 58%, 54%, and 46%, respectively. Among patients with (n = 16) and without (n = 16) brain metastases at baseline, the cORRs were both 63%.

Among patients treated at the 2.5-mg/kg dose (n = 39), the cORR was 59%. Of patients who had received 2 prior lines of therapy (n = 14) or at least 3 prior lines of therapy (n = 25), the cORRs were 71% and 52%, respectively. Among patients with prior chemotherapy-free intervals of 90 days or longer (n = 18), less than 90 days (n = 17), and less than 30 days (n = 8), the cORRs were 56%, 65%, and 63%, respectively. Among patients with (n = 12) and without (n = 20) brain metastases at baseline, the cORRs were 50% and 75%, respectively.

“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,” lead study author Lauren A. Byers, MD, emphasized in the presentation.

Byers is a professor in the Department of Thoracic/Head and Neck Medical Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston.

What Data Have Been Previously Shown With ABBV-706 in SCLC?

SEZ6 is a type I transmembrane protein and neuroendocrine lineage marker that is highly expressed in SCLC. It has a proprietary topoisomerase 1 payload, a stable linker attachment, and a drug-to-antibody ratio of 6.

Previously, data from the phase 1 study (NCT05599984) showed that ABBV-706 monotherapy elicited a median DOR of 6.37 months (95% CI, 4.4-9.46) and a median PFS of 7.62 months (95% CI, 5.52-8.31) in patients with SCLC and neuroendocrine carcinomas (n = 65).^2,3 The present analysis expanded on these findings in patients with SCLC.¹

What Is the Design of the Phase 1 Trial Investigating ABBV-706 in Relapsed/Refractory SCLC?

This phase 1 trial enrolled patients at least 18 years of age with histologically or cytologically documented extensive-stage SCLC (ES-SCLC) who had received at least 1 prior line of therapy with at least 1 platinum-based chemotherapy regimen. Patients also needed to have an ECOG performance status of 0 or 1 and at least 1 measurable lesion per RECIST 1.1 criteria. Patients with prior untreated or treated stable brain metastases were permitted to enroll. Patients were excluded if they had received prior therapy with SEZ6-targeted ADCs or ADCs with a topoisomerase 1 payload.

During the dose-escalation portion, patients with ES-SCLC, high-grade neuroendocrine neoplasms, or central nervous system tumors received ABBV-706 at doses ranging from 1.3 mg/kg to 3.5 mg/kg (n = 60). Following dose escalation, in the dose-optimization portion, patients with SCLC were randomly assigned 1:1 to receive ABBV-706 at 1.8 mg/kg or 2.5 mg/kg IV every 3 weeks in 21-day cycles until disease progression or unacceptable toxicity.

The primary end points included safety and tolerability, pharmacokinetics, and identification of the recommended phase 2 dose (RP2D). Antitumor activity end points included investigator-assessed ORR, duration of response (DOR), and progression-free survival (PFS); overall survival (OS); and clinical benefit. Exploratory end points included SEZ6 expression by immunohistochemistry, as well as the identification of pharmacodynamic and predictive biomarkers.

What Were the Baseline Characteristics of the Dose-Optimization SCLC Population in the Phase 1 Trial Investigating ABBV-706?

In the total SCLC patient population, at baseline, the median age was 65 years (range, 48-85), 55% of patients were male, 80% of patients had an ECOG performance status of 1, and 35% of patients had brain metastases. Patients had received a median of 2 prior lines of systemic therapy (range, 1-6), and 63% of patients had received at least 2 prior lines of systemic therapy. Chemotherapy-free intervals lasted at least 90 days, less than 90 days, and less than 30 days in 38%, 51%, and 24% of patients, respectively; this information was missing for 11% of patients. A total of 29% and 4% of patients had previously received prior topoisomerase 1–directed chemotherapy and tarlatamab-dlle (Imdelltra), respectively. Additionally, 75% of patients had received prior anti-PD-(L)1–directed therapy.

At a data cutoff date of January 3, 2025, 12 and 10 patients were ongoing treatment in the 1.8 mg/kg and 2.5 mg/kg arms, respectively. Fifty-eight patients discontinued treatment due to progressive disease (1.8 mg/kg arm, n = 20; 2.5 mg/kg arm, n = 22), treatment-emergent adverse effects (TEAEs; n = 6; n = 5), death (n = 9; n = 9), and withdrawal of consent (n = 3; n = 0). The median treatment durations in these respective arms were 6.21 months (range, 0.7-10.9) and 5.52 months (range, 0.7-11.3). The median follow-ups were 9.0 months and 8.3 months, respectively.

What Additional Efficacy Data Were Seen in the Dose-Optimization Phase?

In the total population, the median DOR was 5.6 months (95% CI, 4.2-6.9). Among patients who received ABBV-706 as their second line of therapy and those with a chemotherapy-free interval of less than 30 days, the median DORs were 6.9 months (95% CI, 3.2-7.1) and 5.7 months (95% CI, 2.8-7.5), respectively. Overall, among patients who received the agent in the second-line setting or later, only 1 did not respond to ABBV-706 on the first scan.

Treatment with ABBV-706 led to rapid responses at both tested dose levels. In the 1.8 mg/kg cohort, the median DOR was 6.2 months (95% CI, 4.2-not evaluable [NE]) overall, 6.9 months (95% CI, 3.0 months-NE) among patients treated in the second-line setting, and 6.2 months (95% CI, 2.8-NE) among patients with a chemotherapy-free interval of less than 30 days.In the 2.5 mg/kg cohort, the median DORs in these respective populations were 4.4 months (95% CI, 3.5-6.9), 5.2 months (95% CI, 2.7 months-NE), and 5.0 months (95% CI, 3.2-7.0).

In the overall population, the median PFS was 5.7 months (95% CI, 4.9-7.0); the median PFS was 6.8 months (95% CI, 4.4-8.4) in the second-line population and 5.7 months (95% CI, 3.9-7.5) in the population of patients with a chemotherapy-free interval of less than 30 days. OS data were immature at the time of the presentation; however, the estimated 9-month OS rate was 0.6% (95% CI, 0.5%-0.7%).

The median PFS was longer in the 1.8 mg/kg cohort compared with the 2.5 mg/kg cohort, at 6.8 months (95% CI, 4.0-8.2) vs 5.6 months (95% CI, 4.4-7.0). The median PFS also trended toward further improvement in the second-line setting with the lower dose, at 7.5 months (95% CI, 4.0-8.4) vs 5.4 months (95% CI, 2.8-NE), respectively. Among patients with a chemotherapy-free interval of less than 30 days, these respective values were 7.0 months (95% CI, 2.0-NE) and 4.4 months (95% CI, 2.2-7.0). The estimated 9-month OS rates in these respective arms were 0.6% (95% CI, 0.4%-0.7%) and 0.6% (95% CI, 0.4%-0.7%).

“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,” Byers and coauthors wrote in the presentation.

What Is the Safety Profile of ABBV-706?

In the total population, any-grade treatment-related AEs (TRAEs) were reported in 90% of patients. Grade 3 or higher TRAEs and serious AEs occurred in 63% and 14% of patients in the 1.8 mg/kg and 2.5 mg/kg groups, respectively. TRAEs led to dose interruption, reduction, and discontinuation in 44%, 28%, and 9% of patients in these respective patient populations. At a median follow-up of 8.4 months, the median treatment duration was 5.8 months (95% CI, 0.7-11.3), and the relative dose intensity was 92%.

Overall, Byers noted that the safety profile of ABBV-706 was more favorable at the 1.8-mg/kg dose vs the 2.5-mg/kg dose, including fewer grade 3 or higher TRAEs, dose interruptions, and dose reductions. In the 1.8 mg/kg arm, any-grade TRAEs, grade 3 or higher TRAEs, and serious AEs were reported in 85%, 49%, and 17% of patients, respectively, as opposed to 95%, 77%, and 10% of patients, respectively, in the 2.5 mg/kg arm. TRAEs led to dose interruption, reduction, and discontinuation in 24%, 20%, and 10% of patients, respectively, in the 1.8 mg/kg arm vs 64%, 36%, and 8% in the 2.5 mg/kg arm. The relative dose intensities in these respective arms were 99% vs 85%.

Hematological AEs were dose dependent. In the 1.8 mg/kg arm, the most common hematological TEAEs included anemia (any-grade, 54%; grade ≥ 3, 42%), neutropenia (27%; 20%), thrombocytopenia (22%; 20%), and leukopenia (17%; 5%). In the 2.5 mg/kg arm, TEAEs rates were as follows: anemia (any-grade, 74%; grade ≥ 3, 62%), neutropenia (44%; 31%), thrombocytopenia (41%; 23%), and leukopenia (26%; 21%).

The most common nonhematologic TEAEs in the 1.8 mg/kg arm were fatigue (any-grade, 42%; grade ≥ 3, 5%), nausea (37%; 0%), decreased appetite (20%; 2%), and dyspnea (29%; 2%). In the 2.5 mg/kg arm, the rates of these TEAEs were as follows: fatigue (any-grade, 44%; grade ≥ 3, 5%), nausea (36%; 2%), decreased appetite (46%; 2%), and dyspnea (23%; 8%).

Furthermore, any-grade adjudicated interstitial lung disease (ILD) was reported in 7 patients, including 4 in the 1.8 mg/kg arm and 3 in the 2.5 mg/kg arm. Two patients in each arm had grade 3 or higher ILD.

“ABBV-706 provides high response rates, quick tumor shrinkage, and rapid symptomatic relief,” Byers and study coauthors wrote in the concluding slide of the presentation.

Based on the benefit-risk profile of ABBV-706, 1.8 mg/kg every 3 weeks was determined to be the RP2D for the agent as monotherapy in patients with SCLC.

References

1. Byers LA, Cho BC, Cooper AJ, et al. Safety and efficacy of ABBV-706, a seizure-related homolog protein 6–targeting antibody-drug conjugate, in R/R SCLC. Presented at: International Association for the Study of Lung Cancer (IASLC) 2025 World Conference on Lung Cancer; September 6-9, 2025; Barcelona, Spain. Abstract OA06.04.
2. Chandana SR, Choudhury NJ, Dowlati A, et al. First-in-human study of ABBV-706, a seizure-related homolog protein 6 (SEZ6)–targeting antibody-drug conjugate (ADC), in patients (pts) with advanced solid tumors. J Clin Oncol. 2024;43(suppl 16):3001. doi:10.1200/JCO.2024.42.16_suppl.3001
3. Cooper A, Chandana S, Furqan M, et al. Safety and efficacy of ABBV-706, a seizure-related homolog protein 6 (SEZ6)–targeting antibody-drug conjugate, in high-grade neuroendocrine neoplasms. J Clin Oncol. 2025;43(suppl 16):105. doi:10.1200/JCO.2025.43.16_suppl.105