1379P - A phase Ib study of a single priming dose of 177Lu-PSMA-617 coupled with pembrolizumab in metastatic castration resistant prostate cancer (mCRPC)

Background

We sought to determine whether a single dose of ¹⁷⁷Lu-PSMA-617 (Lu) can induce an immunogenic priming effect to improve outcomes of men with mCRPC treated with pembrolizumab (P).

Methods

This was a phase 1b trial of mCRPC patients (pts) with progression (PD) on at least one prior androgen receptor (AR) signaling inhibitor (NCT03805594). Pts were required to have ≥ 3 PSMA-avid lesions on ⁶⁸Ga-PSMA-11 PET. No genomic selection was undertaken. Pts were enrolled on one of 3 schedules: A) Single dose of Lu (7.4 GBq) followed by initiation of P (200 mg IV q 3 weeks); B) Lu x 1 dose given with first P administration; C) Lu x 1 dose given after initiation of P. The primary endpoint was safety; secondary and correlative endpoints included objective response rate (ORR) by RECIST 1.1 criteria, PSA50 response rate, and whole blood immune profiling by CyTOF.

Results

A total of 43 pts were enrolled (Schedule A: n = 31; Schedule B: n = 6; Schedule C: n = 6). Median age was 71 (range 51 – 91), 11 pts (26%) had visceral metastases, and 43/43 (100%) were microsatellite stable with low TMB (< 10 mut/MB) on somatic genomic profiling. Thirteen (33%), 8 (19%), and 22 (52%) pts had PD on abiraterone, AR antagonist, or both, respectively. There were no dose-limiting toxicities and one pt (2%) with a Grade ≥ 3 treatment-related adverse event (AE) (inflammatory arthritis, schedule B). The ORR was 48% (20/42 evaluable pts); median duration of response was 9.9 months (range: 2.5 – 18.3+). Seven pts remain on study treatment for 3.5+ – 20.5+ months with durable responses. Median radiographic progression-free survival was 6.5 months (95% CI: 2.5 – 9.8). PSA50 and PSA90 response rates were 44% and 16%, respectively. Schedule A was the recommended phase 2 schedule based on aggregate safety and efficacy data. Serial profiling of immune cell subsets distinguished clinical responders from non-responders.

Conclusions

¹⁷⁷Lu-PSMA-617 as a single priming dose followed by pembrolizumab demonstrates a favorable safety profile and encouraging anti-tumor activity, with durable responses observed in mCRPC without genomic selection for microsatellite instability or high mutational burden. Further investigation of the combination is warranted.

Clinical trial identification

NCT03805594.

Editorial acknowledgement

Legal entity responsible for the study

University of California San Francisco.

Funding

Merck, Novartis.

Disclosure

R. Aggarwal: Financial Interests, Institutional, Research Grant: Merck, Zenith Epigenetics, Janssen; Financial Interests, Personal, Advisory Board: Novartis, Pfizer. F. Feng: Financial Interests, Personal, Advisory Board: Astellas, Bayer, Foundation Medicine, BMS, Janssen, Myovant, Novartis, Roivant, Bluestar Genomics, Artera, Serimmune. L. Fong: Financial Interests, Institutional, Research Grant: Merck. All other authors have declared no conflicts of interest.