Phase I dose-escalation results of 177 Lu-NYM032 in patients with progressive metastatic castration-resistant prostate cancer (mCRPC).

5049 Background: 177 Lu-NYM032 is a novel prostate-specific membrane antigen (PSMA)-targeted radioconjugate with optimized properties. Phase I dose-escalation study evaluated its safety, tolerability, pharmacokinetics, radiation dosimetry and preliminary antitumor activity in patients with mCRPC. Methods: Eligible patients had PSMA-positive mCRPC confirmed by 68 Ga-NYM032 PET/CT, no discordant lesions on 18 F-FDG PET/CT, progression after ≥1 AR-targeted therapy and 1–2 prior taxane regimens (or unsuitability/refusal), ECOG 0–2, and no prior radioisotope therapy. A modified 3+3 dose-escalation design was used ( 177 Lu-NYM032: 1.9–7.4 GBq). Pharmacokinetics and dosimetry were evaluated using sequential blood samples and SPECT/CT imaging post-administration (Cycle 1: 2h, 24h, 48h, 7d, 14d; Cycles 2–4: 48h). Primary objectives were safety and maximum tolerated dose (MTD); secondary objectives included pharmacokinetics, dosimetry, and antitumor activity. Results: Eleven patients were enrolled across four dose levels: 1.9 GBq (n = 1), 3.7 GBq (n = 4), 5.55 GBq (n = 3), and 7.4 GBq (n = 3). Ten patients completed the study and one patient (3.7GBq) withdrew consent and discontinued the study prior to DLT evaluation. Ten Patients received 2–6 treatment cycles（at 6-week intervals）of 177 Lu-NYM032. Four patients were administered up to 6 cycles at 7.4 GBq per cycle, reaching a total cumulative activity of 44 GBq. Treatment was well tolerated; with most treatment-emergent adverse events being grade 1-2. Grade≥3 TEAEs related to 177 Lu-NYM032 were limited to anemia, decreased lymphocyte count, and hypokalemia. No dose-limiting toxicities were observed. Clearance of 177 Lu-NYM032 from the kidney occurs rapidly (half-life: 18.37-38.66 hours). Physiological distribution of the radiopharmaceutical was observed including in the salivary glands, lacrimal glands, liver, spleen, kidneys, and intestines–consistent with known PSMA expression patterns. While the mean tumor absorption dose (7.73 Gy/GBq in cycle 1) decreased over time, mean absorbed doses per cycle to kidneys and salivary glands remained relatively stable across the administered dose range (1.9-7.4 GBq): kidney doses were 0.47-0.64 Gy/GBq in cycle 1 and 0.42-0.63 Gy/GBq in cycles 2–4; salivary gland doses were 0.42-1.34 Gy/GBq in cycle 1 and 0.43-0.83 Gy/GBq in cycles 2-4. Among 10 evaluable patients, objective response rate was 20% and disease control rate was 80%. Of 3 RECIST v1.1 measurable, 2 (66.7%) partial responded, 1 (33.3%) stable. PSA50 and PSA90 responses were observed in 60.0% and 20.0% of patients, respectively. Median rPFS was 6.5 months; median overall survival was not reached. Conclusions: 177 Lu-NYM032 demonstrated a favorable safety profile and promising antitumor activity in patients with mCRPC, supporting further evaluation in Phase II studies. Clinical trial information: NCT06383052 .