作者
Rahul Aggarwal,Srey Luch Sam,Vadim S. Koshkin,Eric J. Small,Felix Y. Feng,Ivan de Kouchkovsky,Daniel H. Kwon,Terence W. Friedlander,Hala T. Borno,Rohit Bose,Jonathan Chou,Arpita Desai,Tammy J. Rodvelt,Maya Aslam,Medini Rastogi,Lawrence Fong,Thomas A. Hope
摘要
5053 Background: Immune checkpoint inhibitors have limited single agent activity in microsatellite-stable mCRPC. 177 Lu-PSMA-617 (Lu) is a PSMA-targeting radioligand therapy that has demonstrated promising anti-tumor activity. We sought to determine whether a single dose of Lu can induce an immunogenic priming effect to improve outcomes of men with mCRPC subsequently treated with pembrolizumab (P). Methods: We undertook a phase 1b, single arm trial enrolling chemotherapy-naïve mCRPC patients (pts) with progression (PD) on at least one prior androgen signaling inhibitor (NCT03805594). Pts were required to have ≥ 3 PSMA-avid lesions on 68 Ga-PSMA-11 PET and measurable disease by RECIST 1.1 criteria. No genomic selection was undertaken. Pts were enrolled sequentially on one of three schedules: A) Single dose of Lu (7.4 GBq) followed by initiation of P (200 mg IV q 3 weeks) 28 days later; B) Lu x 1 dose given concomitantly with first P administration; C) Lu x 1 dose given on C2D1 following initiation of P on C1D1. Pts were treated with P until confirmed radiographic or clinical PD. The primary endpoint was safety; key secondary endpoints included PSA response, objective response rate by RECIST 1.1 criteria (ORR), median duration of response (DOR), and radiographic progression-free survival (rPFS). Results: 18 pts were enrolled, 6 per schedule. The median age was 64 (range 51 – 80) and 44% of pts had visceral metastases. The median baseline number of PSMA-avid metastatic lesions was 20 (range 6 – 50+). Six pts (33%) had progressed on prior abiraterone, 4 (22%) on enzalutamide, and 8 (44%) on both. There were no dose-limiting toxicities and one Grade ≥ 3 treatment-related adverse event (AE) (inflammatory arthritis, schedule B). There were no grade ≥ 3 hematologic AEs. The ORR was 8/18 (44%) and median DOR has not been reached (range 1.9+ – 15.9+ months). Four pts (2 on schedule A, 1 on schedule B, 1 on schedule C) with durable partial responses remain on study treatment for 5.4+, 8.9+, 9.2+, and 17.8+ months, respectively. The median rPFS was 6.5 months (95% CI: 2.5 – 9.8). PSA30, PSA50, and PSA90 response rates were 44%, 28%, and 17%, respectively. Fourteen pts (78%), including all durable responders, had somatic genomic data available. One (7%) harbored a DNA repair mutation ( BRCA1, non-responder), none were MSI-high, and all carried low tumor mutational burden (≤ 5 mutations/MB). Single cell sequencing of the immune microenvironment from paired metastatic tumor biopsies is underway. Conclusions: 177 Lu-PSMA-617 as a priming dose followed by pembrolizumab was well tolerated and leads to durable responses in a subset of mCRPC without high mutational burden or microsatellite instability, suggesting a possible immunogenic priming effect of radioligand therapy. Further evaluation of the combination is ongoing in a phase 2 study. Clinical trial information: NCT03805594.