177Lu-PSMA-617 may prime prostate tumors for immunotherapy

A single dose of ¹⁷⁷Lu-PSMA-617 (LuPSMA) primed prostate tumors to respond to the immune checkpoint inhibitor pembrolizumab (Keytruda), according to phase 1b study findings shared during the 2021 ASCO Annual Meeting.¹

Single-agent immune checkpoint inhibitors have not shown strong activity in patients with prostate cancer, particularly patients with microsatellite stable metastatic castration-resistant prostate cancer (mCRPC). Researchers suggest this may be the result of an immunologically “cold” tumor microenvironment. The hypothesis of the phase 1b study was that a dose of ¹⁷⁷Lu-PSMA-617 might make the prostate tumor microenvironment immunologically “hot” and primed for pembrolizumab therapy.

Among 18 patients with mCRPC in the phase 1b study, 44% (n = 8) achieved a response. Five of these patients—all of whom were microsatellite stable, homologous recombination deficiency (HRD) wild-type—reached a response greater than 8 months.

“¹⁷⁷Lu-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,” the authors wrote in their conclusion.

The study included 18 patients ­with mCRPC and ≥3 PSMA-avid metastases on 68Ga-PSMA-11 imaging. All patients had progressed on at least 1 second-generation androgen receptor inhibitor (eg, enzalutamide [Xtandi], abiraterone acetate [Zytiga]). Patients had not received chemotherapy in the CRPC setting. Prior treatment with radium-223 (Xofigo) or another radio-isotope was not allowed.

The median patient age was 64 (range 51-80). Prior systemic therapy therapies included abiraterone (n = 6), enzalutamide (n = 4), or both (n = 8). At study entry, 7 patients had visceral metastases, 16 patients had lymph node metastases, 3 patients had soft tissue metastases, and 14 patients had bone metastases. The median baseline PSA level was 24.5 ng/mL (range 0.5-723).

Regarding HRD mutation status, (germline or somatic), 15 patients were wild-type, 1 patient had a pathogenic mutation, and 2 patients had unknown status. Microsatellite status was stable for 15 patients and unknown for 3 patients.

There were 3 treatment schedules with 6 patients assigned to each schedule. Schedule A was a single dose of the targeted radioligand therapy ­­LuPSMA (7.4 GBq), followed by pembrolizumab (200 mg IV every 3 weeks) initiation 28 days later. Schedule B involved 1 dose of LuPSMA administered concomitantly with the first administration of pembrolizumab. Patients assigned to schedule C received their first cycle of pembrolizumab followed by a single dose of LuPSMA administered concomitantly with pembrolizumab on day 1 of cycle 2.

According to the study design, patients could receive up to 35 cycles of pembrolizumab (21-day cycles; about 2 years), unless they experienced disease progression or unacceptable toxicity. Further, patients achieving stable disease or better are eligible to receive an additional 17 cycles (about 1 year) of pembrolizumab. Safety was the primary end point. Secondary end points included PSA response, objective response rate, median duration of response, and radiographic progression-free survival (rPFS)

The median duration of response had not been reached (range, 1.9+ – 15.9+ months). The median rPFS was 6.5 months. Forty-four percent of patients had a PSA decline of ≥30%. An additional 28% and 17% had PSA declines of ≥50% and ≥90%, respectively.

Somatic genomic data were available for 14 patients, including all durable responders. Of these patients, 1 had a DNA repair mutation (BRCA1, non-responder), all had a low mutational burden (≤ 5 mutations/MB), and none were microsatellite instability–high.

The researchers reported that the combination was well tolerated. No dose-limiting toxicities occurred and there were no grade ≥3 hematologic adverse events (AEs). There was only 1 grade ≥3 treatment-related AE, which was inflammatory arthritis in a patient receiving treatment schedule B.

Pembrolizumab does not have a specific approval for patients with prostate cancer; however, the immune checkpoint inhibitor does have a tumor-agnostic FDA approval for the treatment of patients with microsatellite instability–high or mismatch repair deficient cancer.

LuPSMA is also not approved by the FDA for prostate cancer. Results from the phase 3 VISION trial presented at the 2021 ASCO Annual Meeting showed that adding LuPSMA to standard of care (SOC) led to a nearly 40% reduction in the risk of death versus SOC alone in patients with progressive PSMA-positive mCRPC. Novartis, the manufacturer of LuPSMA, plans to file for FDA approval of the radioligand therapy based on these positive findings.

Reference

1. Aggarwal RR, Sam SL, Koshkin VS, et al. Immunogenic priming with 177Lu-PSMA-617 plus pembrolizumab in metastatic castration resistant prostate cancer (mCRPC): A phase 1b study. ­­ J Clin Oncol 39, 2021 (suppl 15; abstr 5053). doi: 10.1200/JCO.2021.39.15_suppl.5053