The Anti-FRα Antibody–Drug Conjugate Luveltamab Tazevibulin Demonstrates Efficacy in Non–Small Cell Lung Cancer Preclinical Models and Induces Immunogenic Cell Death

Luveltamab tazevibulin is a folate receptor α (FRα)-targeting antibody-drug conjugate currently being evaluated in phase I and II/III clinical trials in endometrial and ovarian cancers (NCT03748186 and NCT05870748), respectively. In this study, we report non-small cell lung cancer (NSCLC) as an additional cancer subtype enriched for FRα expression. In patient-derived xenograft models of NSCLC, FRα-expressing tumors demonstrated robust tumor growth inhibition following luveltamab tazevibulin treatment, demonstrating its potential use for NSCLC treatment. Luveltamab tazevibulin was additionally identified as a potent inducer of immunogenic cell death (ICD). In in vitro cell killing assays, luveltamab tazevibulin induced all three hallmarks of ICD-high mobility group box 1 release, ATP release, and surface exposure of calreticulin. Furthermore, in in vivo vaccination studies, injection of luveltamab tazevibulin-treated tumor cells established protective immunity against subsequent tumor challenge. Consistent with ICD induction, luveltamab tazevibulin treatment in tumor-bearing mice also altered tumor immune cell infiltrate and activation, demonstrating its ability to modulate the tumor immune microenvironment. Given the success of immune checkpoint therapy in NSCLC and luveltamab tazevibulin's ability to potentiate the immune response, we evaluated the combination therapy of luveltamab tazevibulin with immune checkpoint blockade in syngeneic mouse models and demonstrated that combination treatment results in enhanced efficacy compared with either monotherapy alone. This improved activity with combination therapy was associated with increased tumoral infiltration of CD8+ T cells. In conclusion, the work presented here provides rationale for evaluating luveltamab tazevibulin in NSCLC either as monotherapy or in combination with immune checkpoint blockade.