Safety of unconventional antibody-drug conjugate L-DOS47 in a Phase I/II monotherapy study targeting advanced NSCLC

Rodryg Ramlau¹Dariusz Kowalski²Aleksandra Szczęsna³Cezary Szczylik⁴Young Ou⁵Martin Köbel⁵Gabrielle M Siegers⁶Kim J Gaspar⁶Brenda Lee^6*Kazimierz Roszkowski-Sliz⁷

• ¹Med-Polonia Sp. z o.o. Poland, Poznań, Poland
• ²Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Masovian, Poland
• ³Mazowieckie Centrum Leczenia Chorób Płuc i Gruźlicy, Otwock, Poland
• ⁴Europejskie Centrum Zdrowia Otwock, Otwock, Poland
• ⁵Department of Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
• ⁶Helix BioPharma Corporation, Toronto, Ontario, Canada
• ⁷National Institute of Tuberculosis and Lung Diseases (Poland), Warsaw, Masovian, Poland

Introduction: Tumor acidity is emerging as a hallmark of cancer and carcinoembryonic antigenrelated cell adhesion molecule 6 (CEACAM6) expression is frequently increased in acidic tumors. L-DOS47, a novel antibody-drug conjugate (ADC), consists of jack bean urease crosslinked to anti-CEACAM6 nanobodies. L-DOS47 is thus both targeted to CEACAM6-expressing tumors and designed to improve tumor control by neutralizing the acidic tumor microenvironment (TME) through ammonia and bicarbonate production from local urea.Methods: This open-label, non-randomized study evaluated safety and tolerability of L-DOS47 in Stage IIIB/IV non-small cell lung cancer (NSCLC) patients. The Phase I 3+3 dose escalation aimed to determine the maximum tolerated dose (MTD) of L-DOS47 administered once/week over 14 days followed by seven days rest. Phase II explored twice-weekly dosing.Results: 55/90 patients enrolled in Phase I received L-DOS47 up to 13.55 μg/kg. Although one dose-limiting toxicity (DLT) occurred in a patient at 5.76 μg/kg, MTD was not reached.Common treatment-emergent adverse events (TEAEs), reported by 38% of patients, were respiratory/thoracic/mediastinal disorders including dyspnea. No complete (CR) or partial responses (PR) were observed in Phase I or Phase II, despite the latter's intensified dosing regimen; however, Phase I post-hoc exploratory analyses found that progression-free survival (PFS) was significantly extended at doses ≥5.76 μg/kg (P=0.0203). Anti-L-DOS47 antibody (ADA) titers were not associated with AE or shorter PFS. Immunohistochemistry (IHC) screening of an unrelated cohort revealed high CEACAM6 expression in 45.2% NSCLC cases.Conclusions: L-DOS47 monotherapy was well tolerated at doses up to 13.55 μg/kg. No CRs or PRs were observed but extended PFS was associated with higher doses. Pre-sScreening for L-DOS47 Safety in Advanced NSCLC CEACAM6 expression may select patients with CEACAM6 positive tumors may who are more likely to derive benefit from improve L-DOS47 efficacy.