Abstract 3299: Anti-FRα antibody-drug conjugate luveltamab tazevibulin for the treatment of FRα-expressing non-small cell lung cancer
Authors: Robert Yuan, Andrew McGeehan, Sihong Zhou, Mark Armanini, Jennifer Smith, Millicent Embry, Rhoneil Pena, Danielle K. Lewis, Krishna Bajjuri, Cuong Tran, Gang Yin, Xiaofan Li, Hanspeter Gerber, Alice Yam, Helena Kiefel, Genevive Hernandez
Journal: Cancer Research (2025)

Abstract Luveltamab tazevibulin (luvelta; STRO-002) is a novel antibody-drug conjugate (ADC) designed to target folate receptor alpha (FRα)-positive cancers across a broad range of expression levels. It is composed of an anti-FRα antibody conjugated to a tubulin-directed hemiasterlin payload via a protease-cleavable linker. The linker-payload is site-specifically conjugated via non-natural amino acids incorporated into the antibody sequence using Sutro’s Xpress CF+® system, yielding a homogenous ADC with a drug-antibody ratio of four (DAR4). Preliminary results from Phase 1 and 2/3 studies in endometrial and ovarian cancer, respectively, show robust clinical activity and enhanced tolerability of luvelta as a single agent and in combination with bevacizumab. Here, we report preclinical data to support therapeutic targeting of advanced non-small cell lung cancer (NSCLC), for which there remains an unmet medical need, with luvelta. IHC staining of NSCLC patient tumor microarrays shows a prevalence of 48% and 14% FRα-positive tumors in non-squamous and squamous NSCLC tumors, respectively, as defined by ≥1% tumor cells with FRα membrane staining at any intensity. In NSCLC patient-derived xenograft (PDX) models, luvelta treatment resulted in robust tumor growth inhibition, with best responses strongly correlating with FRα levels. The majority of PDX models evaluated were EGFR wild type, but responses were also observed in some EGFR mutant models. An existing standard-of-care option for NSCLC is immunotherapy. ADCs and chemotherapeutic drugs have been shown to promote an inflamed tumor environment by triggering immunogenic cell death (ICD), which can synergize with immune checkpoint blockade. We provide evidence that luvelta is a potent inducer of ICD. In in vitro assays, luvelta induced all three hallmarks of ICD: HMGB1 release, ATP release, and surface expression of calreticulin. Furthermore, in in vivo vaccination studies, injection of luvelta-treated tumor cells established protective immunity against subsequent tumor challenge. Consistent with ICD induction, luvelta treatment in combination with anti-PD-1 or anti-PD-L1 immune checkpoint inhibitors resulted in enhanced in vivo efficacy in syngeneic mouse tumor models. Luvelta treatment in tumor-bearing mice also altered tumor immune cell infiltration and activation, demonstrating its ability to modulate the tumor immune microenvironment. In conclusion, the work presented here provides support for luvelta as a promising targeted therapy for NSCLC, either as monotherapy or in combination with immune checkpoint blockade. Luvelta is now being evaluated in a Phase 2 study in patients with advanced or metastatic NSCLC (NCT06555263). Citation Format: Robert Yuan, Andrew McGeehan, Sihong Zhou, Mark Armanini, Jennifer Smith, Millicent Embry, Rhoneil Pena, Danielle K. Lewis, Krishna Bajjuri, Cuong Tran, Gang Yin, Xiaofan Li, Hanspeter Gerber, Alice Yam, Helena Kiefel, Genevive Hernandez. Anti-FRα antibody-drug conjugate luveltamab tazevibulin for the treatment of FRα-expressing non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3299.