ABBV-400

Overview

ABBV-400 (telisotuzumab adizutecan; sometimes “Temab-A”) is an investigational, c‑Met–targeting antibody–drug conjugate (ADC) being developed for multiple solid tumors. Human trials are ongoing, including a first‑in‑human phase 1 study (NCT05029882) and subsequent signal‑seeking and randomized studies across tumor types. Early clinical activity has been reported in metastatic colorectal cancer (mCRC) and in non‑small cell lung cancer (NSCLC). (ascopubs.org)

Mechanism of action

• Target: c‑Met (MET receptor tyrosine kinase). The antibody component is telisotuzumab.
• Payload: a novel topoisomerase‑1 inhibitor (adizutecan) linked via a cleavable valine–alanine linker; the conjugation uses a bromoacetamide attachment designed to minimize systemic payload release.
• Rationale: leverages c‑Met expression to deliver a potent Topo‑1 inhibitor to tumor cells, aiming for activity even at lower c‑Met expression levels and in settings where MMAE‑based c‑Met ADCs have had limitations. (aacrjournals.org)

Efficacy

Metastatic colorectal cancer (monotherapy, phase 1; NCT05029882) - As of the October 2023 data cut, among 122 treated patients (dose escalation plus CRC‑specific expansion), objective response rates (ORR) by dose cohort were: - 1.6 mg/kg Q3W: 0% (n=32) - 2.4 mg/kg Q3W: 15% (6/40) - 3.0 mg/kg Q3W: 20% (8/41) - Median duration of response: 4.1 months at 2.4 mg/kg and 5.5 months at 3.0 mg/kg (data immature).
- Median PFS: 5.3 months (2.4 mg/kg) and 4.5 months (3.0 mg/kg) (data immature).
- Responses were enriched at higher c‑Met expression (reported >30% ORR at efficacious doses ≥2.4 mg/kg), with some activity at lower expression levels (approximately 10–15% ORR). (ascopubs.org)

ctDNA‑based translational readouts in mCRC (phase 1; NCT05029882) - In 113 evaluable patients, confirmed ORR was 18%. Molecular response in ctDNA (≥50% decrease in circulating tumor fraction by Guardant panels) correlated with higher ORR (about 35% with molecular response vs 0–8% without) and longer PFS. (ascopubs.org)

NSCLC (phase 1; NCT05029882) - Preliminary antitumor activity has been reported in previously treated EGFR‑wild‑type, non‑squamous NSCLC, presented at ESMO 2024. (dailyreporter.esmo.org)

Planned/ongoing studies - A multicohort phase 1b “signal‑seeking” trial (NCT06084481) is enrolling across additional solid tumors (e.g., HCC, PDAC, BTC, ESCC, breast, HNSCC). (ascopubs.org) - A randomized phase 3 trial in refractory, c‑Met–overexpressing mCRC compares ABBV‑400 monotherapy to trifluridine/tipiracil plus bevacizumab (NCT06614192). A separate, large phase 2 master protocol in mCRC is evaluating combinations with FOLFOX/bevacizumab or 5‑FU/leucovorin/panitumumab (e.g., NCT06820463). (jhoonline.biomedcentral.com)

Safety

Phase 1 (mCRC cohorts; cut as of October 2023; N=122) - Any grade ≥3 treatment‑emergent adverse event (TEAE): 64%; serious TEAEs: 41%.
- Common hematologic TEAEs: anemia 52% (grade ≥3: 30%), neutropenia 37% (≥3: 25%), leukopenia 25% (≥3: 12%), thrombocytopenia 23% (≥3: 12%).
- Common non‑hematologic TEAEs: nausea 57% (≥3: 3%), fatigue 43% (≥3: 2%), vomiting 39% (≥3: 4%).
- Diarrhea grade ≥3: <1%.
- Unadjudicated interstitial lung disease/pneumonitis: 7% (grade ≥3: 2%).
- Treatment‑related discontinuations: 9%.
Dose levels of 2.4–3.0 mg/kg Q3W showed “tolerable and manageable” profiles, with better long‑term tolerability noted at 2.4 mg/kg. The maximum tolerated dose reported for subsequent evaluations was 3.0 mg/kg Q3W. (ascopubs.org)

Preclinical/targeted toxicology - Non‑clinical studies indicated expected Topo‑1–class toxicities (bone marrow and gastrointestinal) in cynomolgus monkeys. (aacrjournals.org)

Key details and development status

• Modality: c‑Met–directed IgG1 ADC carrying a novel Topo‑1 inhibitor payload (adizutecan). (aacrjournals.org)
• Dosing under study: Q3W intravenous dosing; evaluated 1.6–6.0 mg/kg in phase 1; dose expansion commonly at 2.4 or 3.0 mg/kg Q3W; MTD 3.0 mg/kg Q3W. (ascopubs.org)
• Indications under active study: mCRC (monotherapy and combinations), NSCLC (various molecular subsets), and multiple additional solid tumors in signal‑seeking cohorts. (ascopubs.org)

Further reading

• First‑in‑human phase 1 (CRC cohorts; efficacy and safety details, including ORR by dose): Journal of Clinical Oncology ASCO 2024 abstract 3515. (ascopubs.org)
• Dose optimization/exposure–response analyses in mCRC: Journal of Clinical Oncology ASCO 2024 abstract 3030. (ascopubs.org)
• ctDNA molecular response analyses in mCRC (ASCO GI 2025): Journal of Clinical Oncology abstract 258. (ascopubs.org)
• PK/PD ctDNA analyses in mCRC (ASCO GI 2025): Journal of Clinical Oncology abstract 233. (ascopubs.org)
• Preclinical mechanism/linker–payload description: AACR Cancer Research abstract (Abstract 6311). (aacrjournals.org)
• NSCLC EGFR‑WT cohort meeting coverage (ESMO 2024): ESMO Daily Reporter. (dailyreporter.esmo.org)
• Ongoing phase 1b signal‑seeking study design (NCT06084481): Journal of Clinical Oncology ASCO 2024 TPS abstract. (ascopubs.org)
• Phase 3 in refractory, c‑Met–overexpressing mCRC (NCT06614192) and overview of ongoing status: Journal of Hematology & Oncology ADC review; registries/sites listing the trial. (jhoonline.biomedcentral.com)

Note: ABBV‑400 remains investigational; efficacy and safety findings are preliminary and derived from early‑phase studies and meeting abstracts. Results may evolve with ongoing and future randomized trials. (ascopubs.org)

Last updated: Oct 2025