Perspective Adds Keytruda to Phase 1/2a Trial of FAP-Targeted Alpha Therapy Through Merck Collaboration

Perspective Therapeutics is expanding clinical development of its targeted alpha-particle therapy [212Pb]PSV359 by evaluating it in combination with Merck’s anti-PD-1 therapy Keytruda (pembrolizumab) in patients with FAP-α-positive advanced solid tumors. The clinical trial collaboration will test whether targeted radiation can complement immune checkpoint blockade in tumors characterized by a dense, immunosuppressive microenvironment.

Combination Strategy Targets FAP-α-Positive Tumors

Under the collaboration, Perspective will sponsor an amendment to its ongoing Phase 1/2a study (NCT06710756), while Merck will provide pembrolizumab at no cost. The combination will initially be evaluated in certain advanced non-small cell lung cancer (NSCLC) and colorectal cancer patients whose tumors express fibroblast activation protein alpha (FAP-α).

The study has completed enrollment in its first three monotherapy dose cohorts. The addition of pembrolizumab will extend the program into combination dosing, with safety and tolerability remaining central to the early-stage evaluation.

FAP-α is highly expressed on cancer-associated fibroblasts (CAFs), which form part of the stromal compartment of many epithelial tumors. This tumor stroma can restrict drug penetration and contribute to immune suppression or exclusion, creating barriers to effective treatment.

FAP-α is also expressed directly on certain cancer cells, including some sarcomas and mesotheliomas. Higher FAP-α expression has been associated with poorer prognosis across several solid tumors, while expression in healthy tissues is generally low.

Targeted Alpha Radiation Provides the Therapeutic Component

[212Pb]PSV359 uses a proprietary targeting ligand to deliver lead-212 (212Pb) to FAP-α-expressing tumor sites. Lead-212 serves as a source of alpha-particle radiation, which deposits high-energy radiation over a short range and can produce extensive DNA damage within targeted tissue.

The approach also incorporates a theranostic component. The targeting moiety can be radiolabeled with lead-203 (203Pb) or gallium-68 (68Ga), with the latter referred to as PSV377, to enable imaging of FAP-α expression and help identify patients whose tumors contain the target.

Perspective has reported preclinical and human imaging findings suggesting tumor target engagement and uptake with reduced retention in healthy tissues. These findings provide the rationale for further clinical testing of the therapeutic candidate.

Trial Will Establish the Therapeutic Window

NCT06710756 is a multicenter, open-label, dose-finding and dose-expansion study evaluating [212Pb]PSV359 in patients with advanced solid tumors expressing FAP-α, as determined through imaging with [203Pb]PSV359.

The primary objective of the dose-finding phase is to assess safety and tolerability across dose levels and establish the recommended Phase 2 dose. During dose expansion, antitumor activity may become an additional primary outcome measure.

The combination with pembrolizumab is based on a complementary biological rationale. Targeted radiation can produce substantial tumor-cell damage and may alter the local tumor environment, while PD-1 blockade can restore antitumor T-cell activity. The trial will determine whether these mechanisms can work together in FAP-α-positive tumors.

Combination Data Will Shape Further Development

Markus Puhlmann, Perspective’s chief medical officer, said the company expects the combination of targeted radiopharmaceutical therapy and immune checkpoint inhibition to test whether the tumor environment can be reshaped to improve treatment response.

The immediate focus is establishing the safety and tolerability of [212Pb]PSV359 with pembrolizumab. Subsequent dose-expansion data will provide an early assessment of antitumor activity and help determine whether the combination supports broader development across FAP-α-positive solid tumors.

For Perspective, the collaboration also extends PSV359 beyond a monotherapy radiopharmaceutical strategy toward a combination approach that could potentially address both tumor cells and the stromal and immune barriers surrounding them.

Reference

Perspective Therapeutics Announces Clinical Collaboration and Supply Agreement with Merck to Evaluate [212Pb]PSV359 in Combination with Keytruda® (Pembrolizumab) in FAP-α Positive Solid Tumors, Perspective Therapeutics, 14 September 2026

Lead-212 PSV359 Therapy for Patients With Solid Tumors, ClinicalTrials.gov ID NCT06710756