Clinical cancer research : an official journal of the American Association for Cancer Research · 2026
Correlative Biomarker Analysis of PSMA Expression on CTCs and PSMA Imaging in a Phase I Study of PSMA-Targeted Tubulysin Conjugate EC1169.
СтатьяКлиническое исследование I фазыНазвание и аннотация: Перевод в очереди
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Zaidi Samir, Kuo Phillip H, Paiva Prudente Tiago, Lacuna Kristine P, Babiker Hani M, Aparicio Renan, Schonhoft Joseph D, Fernandez Luisa, Messmann Richard, Groaning Michael, Tolcher Anthony W, Gordon Michael S, Yoo Don C, Vaishampayan Ulka, Picus Joel, Petrylak Daniel P, Sartor Oliver, Morris Michael J
Аннотация
PURPOSE: Prostate-specific membrane antigen (PSMA)-directed therapies provide meaningful clinical benefit in metastatic castration-resistant prostate cancer (mCRPC), yet responses remain limited, underscoring the need for additional biomarkers of PSMA expression heterogeneity. In this study, we explored the relationship between PSMA imaging and PSMA expression on circulating tumor cells (CTC) in our early-phase trial using a PSMA-targeted small molecule.
EXPERIMENTAL DESIGN: This phase I study investigated EC1169, a small molecule conjugated to a tubulysin analog warhead, and 99mTc-EC0652, a PSMA imaging agent. Part A (dose escalation) identified the recommended phase II dose. Part B (dose expansion) assessed radiographic progression-free survival (rPFS) as its primary endpoint. We enrolled and treated 103 patients with mCRPC. Most part B patients underwent 99mTc-EC0652 PSMA imaging. A CTC assay assessed PSMA-positive CTCs and their association with response and PSMA imaging.
RESULTS: 99mTc-EC0652 single-photon emission computed tomography (SPECT) imaging demonstrated increased sensitivity for detecting bone lesions compared with standard scans (computed tomography/bone scans). Using an optimized CTC assay, we observed that patients with a decrease in PSMA+ CTCs at baseline versus C3D1 displayed a longer rPFS (8 vs. 2.9 months; P = 0.04). Importantly, patients with predominantly PSMA-positive disease on 99mTc-EC0652 imaging also harbored PSMA-negative CTCs, with a subset displaying neuroendocrine prostate cancer-like morphology.
CONCLUSIONS: Although EC1169 showed limited activity, CTC and imaging analyses showed significant heterogeneity in PSMA expression on CTCs in patients with predominantly PSMA-positive lesions on SPECT. Our study highlights the importance of assessing both PSMA-based CTC and imaging assays in future validation trials.
EXPERIMENTAL DESIGN: This phase I study investigated EC1169, a small molecule conjugated to a tubulysin analog warhead, and 99mTc-EC0652, a PSMA imaging agent. Part A (dose escalation) identified the recommended phase II dose. Part B (dose expansion) assessed radiographic progression-free survival (rPFS) as its primary endpoint. We enrolled and treated 103 patients with mCRPC. Most part B patients underwent 99mTc-EC0652 PSMA imaging. A CTC assay assessed PSMA-positive CTCs and their association with response and PSMA imaging.
RESULTS: 99mTc-EC0652 single-photon emission computed tomography (SPECT) imaging demonstrated increased sensitivity for detecting bone lesions compared with standard scans (computed tomography/bone scans). Using an optimized CTC assay, we observed that patients with a decrease in PSMA+ CTCs at baseline versus C3D1 displayed a longer rPFS (8 vs. 2.9 months; P = 0.04). Importantly, patients with predominantly PSMA-positive disease on 99mTc-EC0652 imaging also harbored PSMA-negative CTCs, with a subset displaying neuroendocrine prostate cancer-like morphology.
CONCLUSIONS: Although EC1169 showed limited activity, CTC and imaging analyses showed significant heterogeneity in PSMA expression on CTCs in patients with predominantly PSMA-positive lesions on SPECT. Our study highlights the importance of assessing both PSMA-based CTC and imaging assays in future validation trials.