Abstract Purpose: BI 905711, a TRAILR2/cadherin-17 (CDH17) bispecific antibody, demonstrated preclinical apoptotic pathway activation and antitumor activity. Two phase Ia/Ib studies tested BI 905711 monotherapy (NCT04137289) or combination therapy (NCT05087992) in advanced, refractory gastrointestinal (GI) cancers. Patients and Methods: Both studies aimed to determine the maximum tolerated dose (MTD; phase Ia) and recommended phase II dose (RP2D)/recommended dose for expansion (RDE; phase Ib). In phase Ia, patients received BI 905711 monotherapy (0.02–4.8 mg/kg) or 0.6 to 1.2 mg/kg plus biweekly folinic acid (leucovorin), 5-fluorouracil, and irinotecan (FOLFIRI) and bevacizumab. Phase Ib assessed selected doses and regimens given biweekly or weekly (3 weeks on and 1 week off). Safety, efficacy, and pharmacokinetics/pharmacodynamics were evaluated. Results: In NCT04137289, 110 patients [median age 61 years; 80% with colorectal cancer; median of three prior therapies (range, 1–6)] received monotherapy. No dose-limiting toxicities (DLT) occurred, MTD was not reached, RP2D was not determined, and 48.2% of patients had treatment-related adverse events (TRAE), most commonly nausea (16.4%). In 104 response-evaluable patients, 22.1% achieved stable disease (SD). In NCT05087992, 12 patients with colorectal cancer (median age 54.5 years) received combination treatment. Two patients reported DLTs, MTD was not reached, and the selected RDE was 0.6 mg/kg plus biweekly FOLFIRI and bevacizumab. Most patients (91.7%) had TRAEs, including decreased appetite (33.3%), alanine transaminase increased, aspartate transaminase increased, and diarrhea (25% each). Eleven patients (91.7%) achieved SD. Pharmacokinetic/pharmacodynamic data indicated linear dose exposure and ≥2-fold activation of plasma caspase 3/7. Conclusions: In heavily pretreated patients with GI tumors, BI 905711 monotherapy or with FOLFIRI plus bevacizumab displayed a manageable safety profile and limited clinical activity. Significance: Translating preclinical activity of TRAILR2 agonists into the clinic has been hampered by severe hepatotoxicity. BI 905711, a bispecific antibody against TRAILR2 and CDH17, was developed to enhance efficacy and reduce hepatotoxicity. Two phase 1 studies (NCT04137289 and NCT05087992) demonstrated tolerability and minimal hepatotoxicity, dose-proportional pharmacokinetics, and increased markers of target engagement. Antitumor activity was limited. These data show that BI 905711 has reduced TRAIL-related hepatotoxicity in the clinic.
PURPOSE:Circulating tumor DNA (ctDNA) has emerged as an important biomarker for early recurrence detection and disease status monitoring during treatment in patients with cancer, including melanoma. We evaluate the prognostic value and impact of postoperative ctDNA detection in patients with stage I to IIIB melanoma using a clinically validated ctDNA assay. EXPERIMENTAL DESIGN:We conducted a retrospective analysis of real-world data of patients with stage I to IIIB melanoma, including ctDNA results using a personalized, tumor-informed, 16-plex multiplex PCR-next-generation sequencing assay. Adjuvant treatment decisions and postsurgical plasma sample collection timepoints were at the physician's discretion. ctDNA results were correlated with clinical outcomes. RESULTS:Across 190 patients and a total of 1,578 samples, a median of 7 ctDNA tests (range: 1-33) per patient were performed over a median period of 24.6 months (range: 3.7-74.7). ctDNA positivity at any postoperative timepoint was significantly associated with shorter recurrence-free survival [RFS; hazard ratio (HR): 40.63; 95% confidence interval (CI), 19.9-82.96; P < 0.0001). This finding was also observed in patients specifically with regional or distant recurrence (HR: 39.55; 95% CI, 18.08-86.51; P < 0.0001). In multivariate analysis, ctDNA positivity was the most significant prognostic factor associated with RFS when compared with other clinicopathologic factors, including stage, sex, and mitotic rate (HR: 25.36; 95% CI, 9.16-70.3; P < 0.001). CONCLUSIONS:Our findings highlight the prognostic value of postsurgical, personalized ctDNA detection of recurrence and longitudinal disease surveillance in stage I to IIIB melanoma. The impact of ctDNA on real-world clinical decision-making highlights the need to assess outcomes when cancer management is influenced by ctDNA dynamics.
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.
