Clinical Cancer Research November 15, 2024

A Phase I First-in-Human Study of ABBV-011, a Seizure-Related Homolog Protein 6-Targeting Antibody-Drug Conjugate, in Patients with Small Cell Lung Cancer

Daniel Morgensztern, Neal Ready, Melissa L. Johnson, Afshin Dowlati, Noura Choudhury, David P. Carbone, Eric Schaefer, Susanne M. Arnold, Sonam Puri, Zofia Piotrowska, et al.

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Bottom Line

In a first-in-human phase 1 trial, the SEZ6-targeting antibody-drug conjugate ABBV-011 demonstrated a manageable safety profile and encouraging preliminary antitumor activity, yielding a 25% objective response rate in heavily pretreated patients with SEZ6-positive small cell lung cancer.

Key Findings

1. In the overall monotherapy cohort of 99 patients with relapsed/refractory SCLC, ABBV-011 pharmacokinetics were dose-proportional across the 0.3 to 2.0 mg/kg dose range.

2. The maximum tolerated dose (MTD) was not reached through 2.0 mg/kg; however, delayed-onset hepatotoxicity limited continuous long-term dosing at doses greater than 1.2 mg/kg, establishing 1.0 mg/kg every 3 weeks as the recommended dose for expansion.

3. In the 40-patient dose-expansion cohort (selected for SEZ6-positive tumors and treated at 1.0 mg/kg), the confirmed objective response rate (ORR) was 25% (95% CI, 13% to 41%).

4. The clinical benefit rate (CBR) was 65% (95% CI, 48% to 79%) in the 1.0 mg/kg expansion cohort, with 43% of these patients experiencing a clinical benefit lasting longer than 12 weeks.

5. Median progression-free survival (PFS) in the 1.0 mg/kg expansion cohort was 3.5 months (95% CI, 1.5 to 4.2), extending to 5.4 months in the subset of patients receiving it as a second-line therapy.

6. The median duration of response (DOR) for patients in the 1.0 mg/kg expansion cohort was 4.2 months (95% CI, 2.6 to 6.7).

7. The most common treatment-emergent adverse events across all treated patients were fatigue (50%), nausea (42%), and thrombocytopenia (41%).

Study Design

Design

Phase 1 Trial

Open-Label

Sample

Patients

Duration

Data cutoff August 2022

Median

Setting

Multicenter, multinational

Population Adult patients (median age 63 years) with relapsed or refractory small cell lung cancer who had received 1 to 3 prior lines of systemic therapy. Patients in the dose-expansion cohort were prospectively selected for SEZ6-positive tumors.

Intervention ABBV-011 (a SEZ6-targeting antibody conjugated to a calicheamicin payload) administered intravenously once every 3 weeks. Doses ranged from 0.3 to 2.0 mg/kg in escalation, with 1.0 mg/kg utilized in the expansion cohort.

Comparator None (single-arm study)

Outcome Safety, tolerability, pharmacokinetics, and determination of the maximum tolerated dose (MTD) and recommended phase 2 dose.

Study Limitations

• The small sample size inherent to a Phase 1 dose-escalation and expansion design limits the statistical precision of the efficacy estimates.

• The single-arm, non-randomized design precludes direct efficacy and safety comparisons with standard-of-care second-line chemotherapies, such as topotecan or lurbinectedin.

• Efficacy was a secondary and exploratory endpoint; the primary focus on safety and maximum tolerated dose necessitates that antineoplastic activity be validated in larger, powered Phase 2/3 trials.

• Delayed-onset hepatotoxicity (including veno-occlusive disease) observed at higher doses narrows the therapeutic index and necessitates careful ongoing liver function monitoring.

• The requirement for biomarker preselection (SEZ6 positivity via immunohistochemistry) in the expansion cohort may restrict the generalizability of the response rates to an unselected SCLC population.

Clinical Significance

This trial provides pivotal clinical proof-of-concept that targeting SEZ6 is a viable and highly active therapeutic strategy in small cell lung cancer (SCLC). By demonstrating a 25% objective response rate and a 65% clinical benefit rate in a heavily pretreated population, ABBV-011 exhibited single-agent activity that is highly competitive with historical salvage chemotherapy options. Furthermore, establishing the 1.0 mg/kg dose mitigated the calicheamicin-associated hepatotoxicity seen at higher levels, paving the way for targeted payload delivery in neuroendocrine tumors and accelerating the development of next-generation SEZ6-directed therapies.

Historical Context

Small cell lung cancer is a highly aggressive neuroendocrine malignancy characterized by initial responsiveness to platinum-etoposide but nearly universal, rapid, and fatal relapse. For decades, second-line options were largely limited to topotecan—a drug hampered by modest efficacy and severe myelosuppression—highlighting a desperate need for novel targets. Seizure-related homolog protein 6 (SEZ6) was recently discovered through patient-derived xenograft screening to be robustly expressed on the surface of SCLC cells while remaining minimally expressed in healthy tissues. ABBV-011 was developed as a first-in-class antibody-drug conjugate to exploit this differential expression, utilizing an anti-SEZ6 antibody to deliver a potent DNA-damaging calicheamicin payload directly into the tumor. This study forms the vanguard of a modern paradigm shift in SCLC, joining agents targeting DLL3 and B7-H3 in the pursuit of surface-antigen directed precision oncology for recalcitrant neuroendocrine tumors.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the mechanism of action of an antibody-drug conjugate (ADC) like ABBV-011, and why is SEZ6 considered a strong theoretical therapeutic target for small cell lung cancer (SCLC)?

Key Response

ADCs consist of a monoclonal antibody linked to a cytotoxic payload. The antibody binds a specific tumor surface antigen, the complex is internalized, and the payload is released intracellularly to cause cell death, sparing normal tissue. SEZ6 (Seizure-Related Homolog Protein 6) is highly and selectively expressed on neuroendocrine tumor cells like SCLC, but has minimal expression in normal adult tissues, making it an ideal target to minimize off-target toxicity.

Resident

Given the 25% objective response rate (ORR) observed with ABBV-011 in this heavily pretreated SCLC population, how does this preliminary efficacy compare to current standard-of-care options for relapsed SCLC?

Key Response

Second-line and beyond SCLC historically has dismal outcomes. Standard options like topotecan yield response rates around 15-20% with significant myelosuppression, and lurbinectedin shows roughly 35% ORR in the second-line but much lower in later lines. A 25% ORR in a heavily pretreated (often 3rd-line or later) population is clinically meaningful and highlights the critical unmet need for active novel agents in relapsed/refractory SCLC.

Fellow

ADCs often have specific toxicity profiles driven by both their payloads and targets. What specific adverse events should be anticipated with a calicheamicin-based payload like the one used in ABBV-011, and how might baseline SEZ6 expression levels impact patient selection?

Key Response

Payloads like calicheamicin (used in other ADCs like inotuzumab ozogamicin) are historically associated with veno-occlusive disease (VOD)/sinusoidal obstruction syndrome and profound myelosuppression (especially thrombocytopenia). Fellows must weigh cumulative payload toxicity against patient comorbidities. Furthermore, understanding the minimum threshold of SEZ6 positivity required for response is critical, as it dictates the stringency of biomarker-driven patient selection.

Attending

If ABBV-011 progresses to later-phase trials and eventual approval, how might the integration of this SEZ6-directed ADC shift the broader treatment paradigm for SCLC, particularly considering sequencing strategies and acquired resistance mechanisms?

Key Response

If approved, ABBV-011 would introduce biomarker-selected therapy to a disease conventionally treated empirically. Attendings must strategize sequencing it after platinum-etoposide and immunotherapy, managing cumulative bone marrow suppression from prior cytotoxic therapies, and anticipating resistance mechanisms (e.g., SEZ6 target downregulation versus payload efflux pumps), which will dictate subsequent therapeutic choices.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

In Phase 1 first-in-human ADC trials, uncoupling target-mediated efficacy from off-target payload toxicity is challenging. What advanced pharmacokinetic/pharmacodynamic (PK/PD) modeling approaches are optimal for determining the recommended Phase 2 dose (RP2D) of ABBV-011 compared to a traditional 3+3 design?

Key Response

The traditional 3+3 design is often suboptimal for ADCs because dose-limiting toxicities may be delayed and payload-driven, while efficacy often plateaus early due to target saturation. Utilizing advanced approaches like a continuous reassessment method (CRM) that integrates longitudinal PK data (intact ADC vs. free payload) and target receptor occupancy (SEZ6 saturation) provides a far more rigorous foundation for selecting an optimal biological dose over a maximum tolerated dose.

Journal Editor

As a peer reviewer analyzing this Phase 1 trial, what potential confounders in the patient selection criteria or prior therapy regimens might artificially influence the reported 25% ORR, and how robust is the assay used to establish the SEZ6 positivity threshold?

Key Response

Editors must scrutinize whether the 25% ORR is disproportionately driven by a biologically distinct subgroup, such as patients with platinum-sensitive relapse rather than refractory disease. Additionally, the immunohistochemistry (IHC) assay validation and the clinical cut-offs for defining 'SEZ6-positive' are critical; if the threshold is set too low or lacks independent validation, the biological rationale weakens, threatening the study's external validity and reproducibility in Phase 3.

Guideline Committee

While Phase 1 data is preliminary, how would the eventual confirmation of these findings in a Phase 3 trial prompt an update to NCCN or ASCO guidelines for extensive-stage SCLC, specifically regarding the integration of routine biomarker testing?

Key Response

Current NCCN guidelines for SCLC recommend platinum-based chemoimmunotherapy upfront, followed by agents like lurbinectedin or topotecan for relapse, but completely lack mandatory routine biomarker testing for targetable mutations or surface antigens (in stark contrast to NSCLC). Validation of ABBV-011 would require guideline committees to establish a Level 1 recommendation for mandatory SEZ6 IHC testing upon relapse, fundamentally transforming the SCLC algorithm into a targeted, at least partially, biomarker-driven paradigm.

Clinical Landscape

Noteworthy Related Trials

2018

IMpower133

n = 403 · NEJM

Tested

Atezolizumab + Carboplatin + Etoposide

Population

Treatment-naive extensive-stage SCLC patients

Comparator

Placebo + Carboplatin + Etoposide

Endpoint

Overall survival (OS) and progression-free survival (PFS)

Key result: Addition of atezolizumab to standard chemotherapy significantly improved both overall survival and progression-free survival in extensive-stage small-cell lung cancer.

2018

TRINITY Trial

n = 339 · Lancet Oncol

Tested

Rovalpituzumab tesirine (Rova-T)

Population

Patients with relapsed/refractory DLL3-expressing SCLC

Comparator

None (Single arm phase 2)

Endpoint

Objective response rate (ORR) and overall survival (OS)

Key result: The DLL3-targeted ADC Rova-T showed modest activity with a 12.4% ORR and 5.6 month OS, but suffered from prohibitive toxicities that eventually halted its clinical development.

2023

DeLLphi-301

n = 220 · NEJM

Tested

Tarlatamab (DLL3-targeted bispecific T-cell engager)

Population

Patients with previously treated SCLC

Comparator

Internal dose comparison (10mg vs 100mg)

Endpoint

Objective response rate (ORR)

Key result: Tarlatamab yielded a clinically meaningful ORR of 40% at the 10-mg dose with durable anti-tumor responses and a manageable safety profile in heavily pretreated SCLC.

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