SAN FRANCISCO—The promising outcomes from studies of the radioligand lutetium Lu 177 vipivotide tetraxetan (Lu177-PSMA) as a second-line therapy for metastatic castration-resistant prostate cancer (mCRPC) has encouraged researchers to explore its effectiveness when moved earlier in treatment and in combination with other cancer therapies.
At the 2024 Society of Nuclear Medicine and Molecular Imaging annual meeting in June, Thomas Hope, MD, chief of nuclear medicine at the San Francisco VAMC and vice chair of clinical operations and strategy in the department of radiology at the University of California-San Francisco (UCSF), discussed studies undertaken by UCSF and the San Francisco VAMC that combined the immune checkpoint inhibitor (ICI) pembrolizumab with Lu177-PSMA, also known as 177Lu-PSMA-617.
The first study, an open-label, dose-expansion, phase I trial published in The Lancet Oncology, evaluated whether a single priming dose of Lu177-PSMA combined with pembrolizumab would benefit patients with mCPRC. The researchers found that the combination generated significant anti-tumor activity while minimizing toxicity.1
“Targeted radioligand therapy can enhance the effectiveness of immune checkpoint inhibition by improving priming of an immune response or by resetting the immunosuppressive tumor microenvironment to enhance anti-tumor response,” said Hope. “We thought that, if 177Lu-PSMA-617 induced anti-tumor immunity, the immune effector cells recruited to the sites of metastasis would increase with repeated doses given on a fixed schedule.”
The study enrolled 43 patients with mCRPC who had progressed during treatment with at least one androgen-signaling inhibitor. All patients had microsatellite instability, 14% had received docetaxel prior to the study, and 30% had visceral metastases.
Eighteen patients participated in the first part of the study, which determined whether Lu177-PSMA should be given before starting pembrolizumab, concurrent with its start, or after starting the ICI.
Researchers settled on providing Lu177-PSMA 28 days before initiating pembrolizumab, which was administered intravenously every three weeks. The remaining 25 participants were followed for a median of 16.5 months.
More than half (56%) of the participants had a positive response, with three experiencing durable, complete response. In addition, 47% had a confirmed partial response, and 28% had stable disease on the therapy. Twenty-one percent experienced disease progression.
The median radiographic progression-free survival was 6.9 months.
“This phase 1 trial represents the first clinical study to our knowledge to evaluate a single priming dose of targeted radioligand therapy coupled with immune checkpoint inhibition in patients with metastatic prostate cancer,” said study first author Rahul Aggarwal, MD, a genitourinary medical oncologist and UCSF professor of medicine. “We observed lasting responses in a subset of patients, in whom there was an increase in circulating T-cells and decreased activity of immunosuppressive cells following the priming dose of 177Lu-PSMA-617.”
The combination therapy showed comparatively low toxicity levels, with only two patients experiencing treatment-related adverse events of grade 3 or worse (inflammatory arthritis and pneumonitis). No grade 4 or 5 events occurred.
While the trial included patients with lower PSMA uptakes in the liver to enroll, Hope said that baseline uptake on PSMA PET correlated with response to the combination therapy. The study also included seven patients with at least one PSMA-negative soft tissue lesions, who would have been excluded in previous trials.
“Radiation therapy is an established treatment, but we are still learning how best to combine immunotherapy and radiation therapy,” said study co-senior author, Lawrence Fong, MD, leader of UCSF’s Cancer Immunotherapy Program. “Our study shows using just a single dose of radioligand therapy, rather than the usual six planned doses, can be combined with immunotherapy and have durable responses.”
The team began enrolling patients in a phase II trial earlier this year. It will explore the possible benefit of “as-needed” boosts of Lu177-PSMA. Participants will receive six cycles of Lu177-PSMA at dosing intervals based on their individual PSA response, with subsequent doses given at the point PSA rises 24% or 2 ng/dL.
- Aggarwal R, Starzinski S, de Kouchkovsky I, Koshkin V, Single-dose 177Lu-PSMA-617 followed by maintenance pembrolizumab in patients with metastatic castration-resistant prostate cancer: an open-label, dose-expansion, phase 1 trial. Lancet Oncol. 2023 Nov;24(11):1266-1276. doi: 10.1016/S1470-2045(23)00451-5. PMID: 37922930; PMCID: PMC10667020.
