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Phase I/II Study of AXL-Specific Antibody-Drug Conjugate Enapotamab Vedotin in Patients with Advanced Solid Tumors
Kristoffer Staal Rohrberg1, Juanita S Lopez2, Mohammed M Milhem3
1Department of Oncology, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark.
Purpose:
AXL, a receptor tyrosine kinase related to oncogenic processes, is aberrantly expressed in various cancers and associated with treatment resistance. Enapotamab vedotin (EnaV), a novel anti-AXL human IgG1 and monomethyl auristatin E antibody-drug conjugate, demonstrated antitumor activity in preclinical models, including non-small cell lung cancer (NSCLC). This phase 1/2 study assessed the safety and preliminary efficacy of EnaV in solid tumors.
Patients And Methods:
This study comprised dose-escalation and dose-expansion phases; both phases investigated EnaV once every 3 weeks (Q3W) and EnaV on days 1, 8, and 15 of a 28-day cycle (3Q4W). Primary objectives determined the maximum tolerated dose (dose escalation) and safety (dose expansion). Pharmacokinetic profile, antitumor activity, and AXL expression were also assessed.
Results:
During dose escalation, 32 patients received EnaV Q3W; 15 received EnaV 3Q4W. The maximum tolerated dose and recommended phase 2 dose were 2.2 mg/kg in Q3W and 1.0 mg/kg in 3Q4W schedules. In dose expansion, 189 patients received EnaV Q3W; 70 received EnaV 3Q4W. Common adverse events in dose expansion included fatigue, constipation, nausea, decreased appetite, and diarrhea. Overall response rates ranged from 4.5% to 12.5% with Q3W dose schedule and from 9.1% to 11.5% with 3Q4W dose schedule. Disease control rates for NSCLC cohorts were 40.9% to 50.0%. NSCLC subset analysis demonstrated correlation between radiomics signature and disease control. The relationship between clinical activity and AXL expression was not apparent.
Conclusions:
EnaV had an acceptable safety profile; however, because the evaluation of antitumor activity did not show clinically meaningful responses, clinical development of EnaV was discontinued.
Significance:
EnaV, an anti-AXL human IgG1 and monomethyl auristatin E antibody-drug conjugate, showed single-agent antitumor activity in preclinical models. This phase 1/2 study of EnaV demonstrated a manageable safety profile and antitumor activity in selected tumor types. Further studies exploring alternative targeting modalities, patient selection, and/or combinations are needed.
Insights
Enapotamab vedotin (EnaV) showed a manageable safety profile in solid tumors but did not demonstrate clinically meaningful antitumor activity. Further research into alternative strategies is recommended.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- AXL receptor tyrosine kinase is implicated in cancer oncogenesis and treatment resistance.
- Enapotamab vedotin (EnaV) is a novel antibody-drug conjugate targeting AXL.
Purpose of the Study:
- To assess the safety and preliminary efficacy of Enapotamab vedotin (EnaV) in patients with solid tumors.
- Determine the maximum tolerated dose and recommended phase 2 dose for EnaV.
Main Methods:
- Phase 1/2 study with dose-escalation and dose-expansion phases.
- Administered EnaV every 3 weeks (Q3W) or on a 3-week schedule (3Q4W).
- Evaluated safety, pharmacokinetics, antitumor activity, and AXL expression.
Main Results:
- Recommended doses: 2.2 mg/kg (Q3W) and 1.0 mg/kg (3Q4W).
- Common adverse events included fatigue, constipation, nausea, decreased appetite, and diarrhea.
- Overall response rates ranged from 4.5% to 12.5%; disease control rates in NSCLC were 40.9% to 50.0%.
Conclusions:
- Enapotamab vedotin (EnaV) exhibited an acceptable safety profile.
- Antitumor activity was not clinically meaningful, leading to discontinuation of development.
- Further investigation into alternative targeting, patient selection, or combinations is warranted.
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