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Clinical Trial
. 2025 Sep 1;5(9):1664-1673.
doi: 10.1158/2767-9764.CRC-25-0019.

Phase 2 Study of Zilovertamab Vedotin in Participants with Metastatic Solid Tumors

Funda Meric-Bernstam  1 , Martin Gutierrez  2 , Enrique Sanz-Garcia  3 , Diego Villa  4 , Jun Zhang  5   6 , Jennifer Friedmann  7 , Fengting Yan  8 , Mark A Socinski  9 , John Sarantopoulos  10 , Luis E Raez  11 , Quincy S Chu  12 , Maxime Chénard-Poirier  13 , Manash S Chatterjee  14 , Hong Ren  14 , Qi Liu  14 , Douglas A Levine  14 , Komal L Jhaveri  15   16
Affiliations
Clinical Trial

Phase 2 Study of Zilovertamab Vedotin in Participants with Metastatic Solid Tumors

Funda Meric-Bernstam et al. Cancer Res Commun. .

Abstract

Purpose: Zilovertamab vedotin, an antibody-drug conjugate targeting receptor tyrosine kinase-like orphan receptor 1 (ROR1), had manageable safety and promising antitumor activity in participants with relapsed or refractory non-Hodgkin lymphomas. We evaluated zilovertamab vedotin in participants with previously treated metastatic solid tumors.

Patients and methods: This phase 2, open-label, nonrandomized study (NCT04504916) enrolled participants with metastatic triple-negative breast cancer, hormone receptor-positive breast cancer, nonsquamous non-small-cell lung cancer, platinum-resistant ovarian cancer, or pancreatic cancer. Participants received zilovertamab vedotin ≤2.5 mg/kg once every 3 weeks (Q1/3W) or <1.75 mg/kg twice every 3 weeks (Q2/3W). The primary endpoint was objective response rate per RECIST version 1.1 by blinded independent central review. ROR1 protein expression was correlated with clinical outcomes.

Results: A total of 102 participants were enrolled (Q1/3W, n = 70; Q2/3W, n = 32). The objective response rate was 1% [95% confidence interval (CI), 0%-8%] with Q1/3W dosing (one partial response, hormone receptor-positive/HER2-negative breast cancer cohort) and 0% with Q2/3W dosing. The median progression-free survival (95% CI) was 2.3 (2.0-4.1) and 1.9 (1.7-2.1) months, respectively; the median overall survival (95% CI) was 8.3 (5.2-10.3) and 5.5 (4.4-11.0) months, respectively. Across dosing regimens, treatment-related adverse events were reported in 85 participants (83%), most commonly fatigue (29%) and nausea (28%). Treatment-related peripheral neuropathy occurred in 8%. Treatment-related adverse events led to dose interruption/reduction in 32 participants (31%) and permanent treatment discontinuation in 7 (7%). Tissue for ROR1 IHC was available on 17 participants, with only 3 (all nonresponders) showing ROR1 expression.

Conclusions: Zilovertamab vedotin had minimal antitumor activity, with only a single responder, and manageable safety in participants with previously treated metastatic solid tumors.

Significance: Zilovertamab vedotin had minimal antitumor activity and manageable safety in participants with previously treated metastatic solid tumors of various histologic subtypes. The results suggest that further development of zilovertamab vedotin in these solid tumors is not warranted.

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Conflict of interest statement

F. Meric-Bernstam reports personal fees from AstraZeneca, Becton Dickinson, Biocartis NV, Calibr, Daiichi Sankyo, Dava Oncology, Debiopharm, EcoR1 Capital, eFFECTOR Therapeutics, Elevation Oncology, Exelixis, GT Aperion, Incyte, Jazz Pharmaceuticals, LigaChem Biosciences, Lengo Therapeutics, Menarini Group, Molecular Templates, Protai Bio, Ribometrix, SystImmune, Tallac Therapeutics, Tempus, Vir Biotechnology, and Zymeworks; advisory committee participation for Cybrexa, go Therapeutics, Guardant Health, Harbinger Health, Illumen Therapeutics, Kivu Biosciences, Loxo Oncology, Mersana Therapeutics, OnCusp Therapeutics, Sanofi Pharmaceuticals, Seagen, Theratechnologies, and Zentalis Pharmaceuticals; research funding (to institution) from Aileron Therapeutics, AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences, Curis Inc., CytomX Therapeutics, Daiichi Sankyo, Debiopharm International, eFFECTOR Therapeutics, Genentech, Guardant Health, Jazz Pharmaceuticals, Klus Pharma, Takeda Pharmaceutical, Novartis, Puma Biotechnology, Taiho Pharmaceutical, and Zymeworks; honoraria from Dava Oncology; and travel support from European Organisation for Research and Treatment of Cancer (EORTC), European Society for Medical Oncology (ESMO), Cholangiocarcinoma Foundation and Dava Oncology. E. Sanz-Garcia reports other support from Merck during the conduct of the study, as well as personal fees and other support from GSK and other support from Rgenta Therapeutics outside the submitted work. D. Villa reports personal fees from Merck during the conduct of the study and personal fees from Roche, Janssen, AstraZeneca, BeOne, Kite/Gilead, AbbVie, Bristol Myers Squibb/Celgene, Incyte, and Kyowa Kirin outside the submitted work. J. Zhang reports grants and personal fees from Janssen, Regeneron, AstraZeneca, AbbVie, and BridgeBio, personal fees from MJH Life Sciences, Novocure, Sanofi, Dava Oncology, and Fosun, and grants from Kahr Medical, Lilly, Mirati, BeiGene, Genentech, InnoCare Pharma, Nilogen, and Fontier Medicines outside the submitted work. F. Yan reports research support from Pfizer, Genentech, Agendia, Gilead, and MSD and consultant/speaking role for AstraZeneca, DSI, Eli Lilly, Gilead, Grail, MSD, Seagen, and Stemline. M.A. Socinski reports personal fees from Jazz, Janssen, Merck, Bristol Myers Squibb, AstraZeneca, Lilly, Guardant, Regeneron, and Genetech and grants from Genentech, AstraZeneca, Spectrum, BeiGene, Enliven, and Lilly during the conduct of the study. L.E. Raez reports grants from Bristol Myers Squibb, AstraZeneca, Merck, Genentech, Lilly Oncology, Loxo Pharmaceuticals, Natera, and Guardant Health during the conduct of the study. Q.S. Chu reports personal fees from AbbVie, Amgen, AnHeart, Astellas, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Genprex, Janssen, Merck, Merck KgaA, Novartis, Pfizer, Roche, and Takeda, grants and personal fees from AstraZeneca, and personal fees and other support from GSK outside the submitted work. M. Chénard-Poirier reports personal fees from Pfizer, Merck, Amgen, Bristol Myers Squibb, and Incyte outside the submitted work. M.S. Chatterjee reports other support from Merck outside the submitted work. Q. Liu reports personal fees from Merck during the conduct of the study and outside the submitted work. D.A. Levine reports personal fees from Merck & Co., Inc. during the conduct of the study. K.L. Jhaveri reports other support from Merck during the conduct of the study, as well as personal fees from Novartis, Pfizer, AstraZeneca, Genentech, Bicycle Therapeutics, Blueprint Medicines, Eisai, Daiichi Sankyo, Menarini, Gilead, Scorpion Therapeutics, Olema Pharmaceuticals, Lilly, Merck, Halda Therapeutics, Zymeworks, Arvinas, and RayzeBio and other support from RayzeBio, Arvinas, Zymeworks, Merck, Lilly, Pfizer Novartis, AstraZeneca, Scorpion, Gilead, Eisai, Blueprint Medicines, and Genentech outside the submitted work. No other disclosures were reported by the other authors.

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