ASCO 2021: Immunogenic Priming with 177Lu-PSMA-617 Plus Pembrolizumab in Metastatic Castration-Resistant Prostate Cancer: A phase 1b study

( There has been a proliferation in treatment options for patients with metastatic castration resistant prostate cancer (mCRPC) in the last 10 years. While the most commonly utilized approaches in prostate cancer are cytotoxic chemotherapy or target the androgen-axis, immune checkpoint inhibitors have revolutionized care of many solid organ malignancies. To data, immune checkpoint inhibitors have demonstrated relatively limited activity in patients with mCRPC who don’t have evidence of microsatellite instability. Recently, theranostic treatment with the PSMA-targeting radioligand therapy 177Lu-PSMA-617 (Lu) has demonstrated promising single agent activity among pre-treated individuals with mCRPC. In the Prostate, Testicular, Penile Poster session at the 2021 American Society of Clinical Oncology (ASCO) 2021 Annual Meeting held on Friday June 4th, 2021, Dr. Aggarwal presented data assessing whether a single dose of Lu can induce an immunogenic priming effect to improve outcomes of men with mCRPC subsequently treated with the immune checkpoint inhibitor pembrolizumab.

To do so, the authors performed a phase 1b, single arm trial among chemotherapy-naïve patients with mCRPC who had progression on at least one prior androgen signaling inhibitor (NCT03805594). To be eligible, patients were required to have at least three PSMA-avid lesions on 68Ga-PSMA-11 PET and measurable disease by RECIST 1.1 criteria. No genomic selection was undertaken. 

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Three different treatment schedules were employed, sequentially:

A) Single dose of Lu (7.4 GBq) followed by initiation of pembrolizumab (200 mg IV q 3 weeks) 28 days later; 
B) Lu x 1 dose given concomitantly with first pembrolizumab administration; 
C) Lu x 1 dose given on cycle 2, day 1 following initiation of pembrolizumab. 

Patients continued on pembrolizumab until confirmed radiographic or clinical disease progression. The primary endpoint was safety with key secondary endpoints including efficacy outcomes including PSA response, objective response rate by RECIST 1.1 criteria (ORR), median duration of response (DOR), and radiographic progression-free survival (rPFS).

The authors enrolled 18 patients in total, with 6 per schedule. The median age was 64 years (range 51 – 80) and 44% of patients had visceral metastases. Based on 68Ga-PSMA-11 PET staging, the median baseline number of PSMA-avid metastatic lesions was 20 (range 6 – 50+). In terms of prior treatment, 6 patients (33%) had progressed on prior abiraterone, 4 (22%) had progressed on prior enzalutamide, and 8 (44%) had progressed on both. 

In the experimental treatment regime, there were no dose-limiting toxicities and one Grade ≥ 3 treatment-related adverse event (AE) (inflammatory arthritis, schedule B). Further, there were no grade ≥ 3 hematologic AEs. 

Assessing the oncologic, secondary endpoints, the ORR was 8/18 (44%) and median DOR has not been reached (range 1.9+ – 15.9+ months). 

Five patients had an objective response which lasted 8 months or longer. All of these patients had microsatellite stable disease with homologous repair deficiency wild type. 
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The median rPFS was 6.5 months (95% CI: 2.5 – 9.8). In terms of PSA-based outcomes, PSA30, PSA50, and PSA90 response rates were 44%, 28%, and 17%, respectively. 

Fourteen patients (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). 

The authors concluded that a single priming dose 177Lu-PSMA-617 followed by pembrolizumab was well tolerated and leads to durable responses in a subset of mCRPC without high mutational burden or microsatellite instability. These data formed the basis for an ongoing phase 2 study (NCT03805594). Further, the effect of 177Lu-PSMA-617 on circulating and intra-tumoral T cells using single cell RNA-seq is ongoing.

Presented by: Rahul R. Aggarwal, MD, Medical Oncologist within the Division of Hematology/Oncology at the University of California San Francisco

Written by: Christopher J.D. Wallis, Urologic Oncology Fellow, Vanderbilt University Medical Center, Contact: @WallisCJD on Twitter at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Virtual Annual Meeting #ASCO21, June, 4-8, 2021

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