TY - JOUR
T1 - Phase I/II Study of AXL-Specific Antibody-Drug Conjugate Enapotamab Vedotin in Patients With Advanced Solid Tumors
AU - Rohrberg, Kristoffer Staal
AU - Lopez, Juanita S
AU - Milhem, Mohammed M
AU - Blank, Christian U
AU - Reijers, Irene
AU - Thistlethwaite, Fiona
AU - Plummer, Ruth
AU - Piha-Paul, Sarina A
AU - Janne, Pasi A
AU - Shum, Elaine
AU - Shaw, Heather M
AU - Debruyne, Philip R
AU - Lao, Christopher
AU - Baurain, Jean-Francois
AU - Choe, Jennifer H
AU - Gort, Eelke
AU - Zhao, Yujie
AU - Jerusalem, Guy
AU - Schöffski, Patrick
AU - Chen, Andrew William
AU - Cohen, Eric A
AU - Mankowski, Walter C
AU - Roshkovan, Leonid
AU - Katz, Sharyn I
AU - Kontos, Despina
AU - Brady, Lauren K
AU - Qutaish, Mohammed
AU - Castro, Patricia Garrido
AU - Pencheva, Nora
AU - Bajaj, Gaurav
AU - Fu, Yali
AU - Windfeld, Kristian
AU - Reiter, Panagiota
AU - Jure-Kunkel, Maria
AU - Higgs, Brandon W
AU - Amiri, Katayoun I
AU - Ahmadi, Tahamtan
AU - Forssmann, Ulf
AU - Ramalingam, Suresh S
AU - Vergote, Ignace
N1 - Publisher Copyright:
© (2025), This open access article is distributed under the Creative Commons Attribution 4.0 International (CC BY 4.0) license.
PY - 2025/11
Y1 - 2025/11
N2 - 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.
AB - 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.
U2 - 10.1158/2767-9764.CRC-25-0359
DO - 10.1158/2767-9764.CRC-25-0359
M3 - Article
C2 - 41166388
SN - 2767-9764
VL - 5
SP - 2066
EP - 2078
JO - Cancer Research Communications
JF - Cancer Research Communications
IS - 11
ER -