A phase I first-in-human study of telisotuzumab adizutecan (Temab-A, ABBV-400) — a novel c-Met–targeting antibody-drug conjugate (ADC) — has reported encouraging efficacy and a manageable safety profile in heavily pretreated patients with metastatic colorectal cancer (mCRC). Published in the Journal of Clinical Oncology, these findings position Temab-A as a potential future option in the third-line mCRC setting, where treatment choices remain limited and prognosis is poor.

Clinical Takeaway

Temab-A monotherapy at 2.4 mg/kg once every 3 weeks (Q3W) demonstrated a tolerable safety profile and promising antitumor activity in patients with late-line mCRC, with overall response rates (ORR) enriched in those with increased c-Met protein expression. These data support 2.4 mg/kg Q3W as the recommended phase II dose (RP2D) and validate c-Met protein as a clinically meaningful therapeutic target in mCRC.

Drug Profile & Mechanism

  • Agent: Telisotuzumab adizutecan (Temab-A; ABBV-400) — an ADC comprising the c-Met–targeting antibody telisotuzumab (ABT-700) conjugated to adizutecan, a novel potent topoisomerase 1 (Top1) inhibitor payload, with a drug-antibody ratio (DAR) of 6
  • Target: c-Met (MET) protein, which is overexpressed in approximately 50%–70% of mCRC cases and is associated with tumor cell proliferation, angiogenesis, invasion, metastasis, and reduced survival
  • Mechanism: Temab-A selectively delivers the Top1 inhibitor payload to c-Met–expressing tumor cells, minimizing off-target toxicity; c-Met expression on healthy cells is generally below the threshold required for ADC-induced cytotoxicity
  • Administration: Intravenous infusion once every 3 weeks (Q3W)
  • Pharmacokinetics (at 3.0 mg/kg Q3W): Half-life of Temab-A conjugate 4.7 days; half-life of adizutecan payload 9.3 days; Temab-A conjugate and total antibody concentrations were highly correlated

Target Population

  • Patients with confirmed mCRC that is BRAF V600E wild-type and microsatellite stable (MSS)/mismatch repair-proficient (pMMR)
  • Disease progression after fluoropyrimidine, oxaliplatin, and irinotecan; prior anti-EGFR and/or anti-VEGF therapy if applicable
  • Patients with prior trifluridine/tipiracil or regorafenib exposure were also eligible
  • Heavily pretreated population: Median number of prior lines of systemic therapy was 4.0 (range, 1–12); 95% had received a prior Top1 inhibitor (e.g., irinotecan); 92% had received prior bevacizumab
  • ECOG performance status ≤1; age ≥18 years; measurable disease per RECIST v1.1

Study Design

  • Trial: Phase I, open-label, multicenter, first-in-human study (NCT05029882)
  • Structure:
    • Part 1 – Dose escalation: 57 patients with advanced solid tumors received escalating IV doses of Temab-A (1.6, 2.4, 3.0, 3.5, 4.0, and 6.0 mg/kg Q3W); dose escalation guided by the Bayesian Optimal Interval (BOIN) design with a target toxicity rate of 30%
    • Part 4 – mCRC dose expansion: 93 patients with mCRC randomly assigned to 1.6 mg/kg, 2.4 mg/kg, or 3.0 mg/kg Q3W; randomization adjusted to a 1:1:5 ratio after addition of the 1.6 mg/kg cohort
  • Total mCRC population analyzed: N = 122 (dose escalation, n = 29; dose expansion, n = 93)
  • Maximum tolerated dose (MTD): 3.0 mg/kg Q3W, established when DLT rates exceeded the BOIN de-escalation boundary at all doses ≥3.0 mg/kg Q3W; all DLTs occurred in cohorts ≥3.0 mg/kg Q3W
  • Data cutoff: August 23, 2024
  • A risk mitigation plan for interstitial lung disease (ILD) was implemented midway through the study, including exclusion of patients with clinically significant lung illnesses and establishment of an independent ILD adjudication committee

Endpoints

  • Primary endpoints: Safety, tolerability, pharmacokinetics, RP2D of Temab-A monotherapy, and Temab-A efficacy in patients with mCRC
  • Primary efficacy endpoint: Confirmed overall response rate (ORR) — complete response (CR) or partial response (PR) per RECIST v1.1 as assessed by the investigator
  • Secondary efficacy endpoints: Duration of response (DOR), progression-free survival (PFS), and overall survival (OS)
  • Exploratory endpoint: Correlation between c-Met protein expression by immunohistochemistry (IHC) and clinical response; c-Met positivity defined as ≥10% tumor cells with IHC 3+ staining intensity (≥10%|3+)

Efficacy Outcomes

  • Overall mCRC population (all doses, N = 122):
    • ORR: 15.6% (95% CI, 9.6–23.2); all 19 confirmed responses were partial responses (PRs); no complete responses were observed
    • Disease control rate (DCR): 74.6% (95% CI, 65.9–82.0)
    • Median DOR: 5.9 months (95% CI, 4.1–10.5)
    • Median PFS: 4.6 months (95% CI, 4.0–5.4)
    • Median OS: 10.4 months (95% CI, 8.9–13.1)
  • Efficacy by dose level:
    • 1.6 mg/kg Q3W (n = 32): ORR 3.1% (95% CI, 0.1–16.2); 1 confirmed PR
    • 2.4 mg/kg Q3W (n = 40): ORR 17.5% (95% CI, 7.3–32.8); mPFS 5.3 months; mOS 10.7 months
    • 3.0 mg/kg Q3W (n = 41): ORR 24.4% (95% CI, 12.4–40.3)
    • Responses were more frequent at doses of 2.4 and 3.0 mg/kg Q3W compared with 1.6 mg/kg Q3W
  • Biomarker-enriched response (patients dosed at ≥2.4 mg/kg Q3W):
    • ORR in patients with increased c-Met protein expression (≥10%|3+): 36.0% (9/25)
    • ORR in overall ≥2.4 mg/kg Q3W population: 20.0% (18/90)
    • ORR in patients with lower c-Met expression (<10%|3+): 12.0% (6/50), indicating activity even below the positivity threshold
  • Context vs. current third-line SOC: Trifluridine/tipiracil + bevacizumab has demonstrated mPFS of 5.6 months and mOS of 10.8 months; fruquintinib monotherapy has demonstrated mPFS of 3.7 months and mOS of 7.4 months — placing Temab-A results within a clinically competitive range at 2.4 mg/kg Q3W

Safety

  • 100% of patients with mCRC experienced ≥1 treatment-emergent adverse event (TEAE); 74% experienced a grade ≥3 TEAE
  • Most frequent TEAEs:
    • Gastrointestinal (GI) toxicities: 78% — most common were nausea (57%), vomiting (41%), decreased appetite (29%), and diarrhea (21%); approximately 70% of GI events were low-grade
    • Hematologic toxicities: 71% — most common were anemia (58%), neutropenia (43%), leukopenia (28%), and thrombocytopenia (25%)
    • Other common TEAEs: fatigue (43%), myalgia (25%)
  • Grade ≥3 hematologic events: Anemia (38%) and neutropenia (28%) were most frequent; generally managed through dose reductions, interruptions, blood transfusions, and/or G-CSF; 76% of patients with neutropenia did not require G-CSF
  • ILD/pneumonitis: Any-grade adjudicated rate 6% (7/122); only 1 grade ≥3 event (0.8%); median time to first ILD event was 4.6 months (range, 1.3–10.5); events were observed across all dose levels and did not appear dose-dependent
  • Dose modifications:
    • TEAEs leading to dose interruption: 59% of patients
    • TEAEs leading to dose reduction: 34% of patients
    • Lower rates of dose interruptions and reductions at 2.4 mg/kg Q3W vs 3.0 mg/kg Q3W (60% vs 73% interruptions; 28% vs 49% reductions)
  • Treatment discontinuations due to treatment-related AEs: 10%
  • Treatment-related deaths: 3% (4 patients): febrile neutropenia (n = 1, >3.0 mg/kg Q3W); ILD (n = 1, 3.0 mg/kg Q3W); cardiorespiratory arrest (n = 1, 3.0 mg/kg Q3W); multiple organ dysfunction syndrome (n = 1, 3.0 mg/kg Q3W)
  • Relative dose intensity: Higher at 2.4 mg/kg Q3W (95.7%) vs 3.0 mg/kg Q3W (86.5%), supporting the selection of 2.4 mg/kg Q3W as the RP2D

Key Clinical Implications

✔ Temab-A (2.4 mg/kg Q3W) is established as the RP2D for further evaluation in mCRC, balancing meaningful antitumor activity with a more manageable safety profile compared with the MTD of 3.0 mg/kg Q3W.

✔ c-Met protein expression is a clinically relevant predictive biomarker in mCRC: ORR was markedly enriched at 36.0% in patients with high c-Met IHC expression (≥10%|3+) dosed at ≥2.4 mg/kg Q3W, underscoring the importance of IHC-based patient selection in future trials.

✔ Activity was also observed in patients with lower c-Met expression (<10%|3+; ORR 12.0%), suggesting a potential role for Temab-A beyond strictly biomarker-selected populations, though further investigation is warranted.

✔ The ADC approach overcomes limitations of prior c-Met–targeted strategies: unlike small-molecule MET tyrosine kinase inhibitors, which primarily benefit patients with MET amplification or exon 14 skipping mutations, Temab-A targets c-Met protein expression broadly and delivers cytotoxic payload directly to tumor cells, minimizing off-target toxicity.

✔ Survival outcomes at 2.4 mg/kg Q3W compare favorably with current third-line standard-of-care regimens, although cross-trial comparisons should be interpreted cautiously.

✔ Hematologic toxicities, while common, were generally manageable and rarely led to treatment discontinuation; proactive monitoring and use of supportive measures (dose modifications, transfusions, selective G-CSF prophylaxis) are important components of clinical management.

✔ Larger randomized trials are needed to confirm these findings, define the optimal biomarker-selected population, and establish Temab-A’s role relative to other emerging Top1-based ADCs in the mCRC treatment landscape.

Bottom Line

This phase I study of telisotuzumab adizutecan (Temab-A) provides the first clinical evidence supporting its use as a c-Met–targeted ADC in heavily pretreated mCRC. At the RP2D of 2.4 mg/kg Q3W, Temab-A demonstrated an ORR of 17.5%, a DCR of 74.6% across all doses, and survival outcomes broadly comparable to existing third-line therapies — with a manageable and tolerable safety profile. Responses were markedly enriched in patients with high c-Met IHC expression, reinforcing the precision medicine rationale for this agent. While these early results are promising, confirmatory randomized trials with biomarker-driven patient selection will be essential to define Temab-A’s place in the evolving mCRC treatment paradigm.

Sources:

  • Sharma MR, Powderly J, Kuboki Y, et al. Phase I Study of Telisotuzumab Adizutecan (Temab-A, ABBV-400), a Novel c-Met Antibody-Drug Conjugate, in Patients With Late-Line Colorectal Cancer and Advanced Solid Tumors. J Clin Oncol. 2026;44(20):1876-1888. doi:10.1200/JCO-25-01525
  • ClinicalTrials.gov. A Study of ABBV-400 Alone and in Combination With Other Anticancer Agents in Adult Participants With Advanced Solid Tumors (NCT05029882).