AZD5335

Overview

AZD5335 (nonproprietary name: torvutatug samrotecan) is an antibody–drug conjugate (ADC) that targets folate receptor alpha (FRα/FOLR1), which is frequently overexpressed in epithelial ovarian cancer and present in subsets of other solid tumors (for example, lung adenocarcinoma). It is being evaluated in the modular, first‑in‑human Phase 1/2a FONTANA trial as monotherapy and in combinations (e.g., with PARP inhibitors, bevacizumab, and carboplatin). Early clinical signals of activity and a manageable safety profile were reported in platinum‑resistant recurrent ovarian cancer (PRROC) at ESMO 2024, and preclinical combination data were presented at AACR 2025. (oncologypro.esmo.org)

Mechanism of action

• Target: FRα (FOLR1), a GPI‑anchored cell‑surface protein that internalizes folate; expression is enriched in ovarian cancer and some other solid tumors. (oncologypro.esmo.org)
• Construct: Human IgG1 anti‑FRα monoclonal antibody conjugated to a proprietary topoisomerase I inhibitor payload (samrotecan; internal code AZ14170132) via an ADC design with a homogeneous drug‑to‑antibody ratio of 8 (DAR8). The TOP1 inhibitor payload supports “bystander” killing of neighboring tumor cells. (aacrjournals.org)
• INN mapping: “Torvutatug samrotecan” is the INN for the FRα IgG1–samrotecan conjugate; AZD5335 is a listed other name. (eutct.ema.europa.eu)

Efficacy

Clinical (early, PRROC; FONTANA M1A, ESMO 2024) - In dose‑escalation (data cutoff March 30, 2024; n=28 treated), confirmed responses were observed at all dose levels. Among evaluable patients with high FRα expression (≥75% tumor cells at ≥2+ intensity; n=8), 5 had an objective radiologic response (1 pending confirmation). In those with high FRα given the top three dose levels (n=5), 4 had an objective response (1 pending confirmation). (oncologypro.esmo.org) - Additional summary data reported by a patient/scientific foundation (sourced to the Annals of Oncology ESMO 2024 abstract/poster 754P) indicate observed activity even in FRα‑low tumors: FRα‑low cohort ORR 35.7% (n=14); FRα‑low at doses ≥1.6 mg/kg ORR 41.7% (n=12). These figures should be considered preliminary from early phase cohorts. (clearityfoundation.org)

Preclinical - AZD5335 demonstrated robust antitumor activity in FRα‑expressing ovarian cancer models, including patient‑derived xenografts, and showed superior activity versus a microtubule‑inhibitor FRα‑ADC benchmark in low‑to‑medium FRα expression models. (aacrjournals.org) - In ovarian cancer xenograft models, combinations with bevacizumab, paclitaxel, and/or carboplatin yielded more durable tumor control than monotherapy, supporting ongoing clinical combination exploration. (aacrjournals.org)

Safety

ESMO 2024 (FONTANA M1A, n=28 treated; investigator‑attributed, any grade unless noted) - Most common treatment‑related adverse events (≥15%): nausea (61%; no grade 3–4), anemia (25%; grade 3–4 in 18%), decreased neutrophil count (21%; grade 3–4 in 7%), pyrexia (21%; no grade 3–4). No dose‑limiting toxicities or treatment‑related deaths were reported; maximum tolerated dose not reached at the time of analysis. Pharmacokinetics were linear over the evaluated dose range. (oncologypro.esmo.org) - A foundation summary of the same ESMO 2024 dataset reported overall grade 3–4 adverse events in 43.6%, with neutropenia 17.9% and anemia 15.4%; serious adverse events 15.4%. These are early, preliminary safety data. (clearityfoundation.org)

Ongoing clinical development

• FONTANA (NCT05797168): Modular Phase 1/2a, open‑label study assessing AZD5335 as monotherapy (ovarian cancer, lung adenocarcinoma) and in combinations (e.g., with PARP1‑selective inhibitors saruparib/AZD5305 or AZD9574, and with bevacizumab ± carboplatin). Status: recruiting across multiple centers; study start June 5, 2023; estimated primary completion January 2028. (astrazenecaclinicaltrials.com)

Further reading

• Initial clinical results (ESMO 2024 abstract 754P): Initial results from a first‑in‑human study of AZD5335 in PRROC. (oncologypro.esmo.org)
• Preclinical first disclosure (AACR 2023 LB025): AZD5335, a TOP1i‑ADC targeting low and high FRα‑expressing ovarian cancer. (aacrjournals.org)
• Preclinical combinations (AACR 2025): AZD5335 enhances ovarian cancer treatment with bevacizumab, paclitaxel and/or carboplatin (abstract). (aacrjournals.org)
• Trial registry/overview: FONTANA Phase 1/2a (AstraZeneca page; ClinicalTrials.gov‑linked details). (astrazenecaclinicaltrials.com)
• INN/identity: Human IgG1 anti‑FRα conjugated to samrotecan; other names include AZD5335; INN torvutatug samrotecan (EMA EUTCT). (eutct.ema.europa.eu)

Notes - Human efficacy and safety data are from early, small, dose‑escalation cohorts and remain preliminary; dose optimization and expansion are ongoing as of October 7, 2025. (oncologypro.esmo.org)

Last updated: Oct 2025