Phase 1/2 study of tusamitamab ravtansine in patients with advanced solid tumors: Pooled safety analysis of corneal adverse events.

person Anas Gazzah Drug Development Department, Gustave Roussy, Villejuif, France info_outline Anas Gazzah, Josep Tabernero, Antoine Italiano, Sophie Cousin, Fabrice Barlesi, Herve Lena, Philippe L. Bedard, Min-Hee Ryu, Kyung Rim Sung, Byoung Chul Cho, Emiliano Calvo, Semra Yoruk, Mustapha Chadjaa, Nina Masson, Nathalie Fagniez, Oscar Balaguer, Helena Brosa, Eric E. Gabison

Authors person Anas Gazzah Drug Development Department, Gustave Roussy, Villejuif, France info_outline Anas Gazzah, Josep Tabernero, Antoine Italiano, Sophie Cousin, Fabrice Barlesi, Herve Lena, Philippe L. Bedard, Min-Hee Ryu, Kyung Rim Sung, Byoung Chul Cho, Emiliano Calvo, Semra Yoruk, Mustapha Chadjaa, Nina Masson, Nathalie Fagniez, Oscar Balaguer, Helena Brosa, Eric E. Gabison Organizations Drug Development Department, Gustave Roussy, Villejuif, France, Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain, Early Phase Trials Unit, Institut Bergonié, Bordeaux, France, Department of Medicine, Institut Bergonié, Bordeaux, France, Aix Marseille University, INSERM, CNRS, CRCM, APHM, CEPCM CLIP2; Medical Oncology Department, Gustave Roussy; Université Paris Saclay, Marseille; Villejuif; Paris, France, Centre Hospitalier Universitaire de Rennes, Rennes, France, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada, Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Seoul, Korea, Republic of (South), Department of Ophthalmology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea, Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea, Republic of (South), START Madrid-CIOCC, Centro Integral Oncológico Clara Campal, Madrid, Spain, R&D Oncology Development, Sanofi, Inc., Istanbul, Turkey, Clinical Development, Sanofi, Vitry-Sur-Seine, France, IT&M STATS on behalf of Sanofi, Neuilly-Sur-Seine, France, Pharmacokinetics, Dynamics and Metabolism, Sanofi, Chilly-Mazarin, France, Ophthalmology Department, Vall d’Hebron Hospital, Barcelona, Spain, Hôpital Fondation Rothschild, Paris, France Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Sanofi, Inc. Background: Tusamitamab ravtansine (tusa rav) is a novel antibody-drug conjugate (ADC) targeted to carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) and delivering DM4, a cytotoxic maytansinoid. CEACAM5 is highly expressed in several tumor types, including nonsquamous non-small cell lung cancer (NSQ NSCLC). An open-label, Phase 1/2, dose-escalation/expansion study (NCT02187848) in patients with advanced solid tumors found the maximum tolerated dose of tusa rav to be 100 mg/m 2 every 2 weeks (Q2W) with a dose-limiting toxicity of microcystic keratopathy. Tusa rav had a favorable safety profile and, in patients with NSQ NSCLC with high CEACAM5 expression, promising antitumor activity. Methods: Here we evaluate pooled corneal safety results in patients (n = 186) who received tusa rav 100 mg/m 2 Q2W, including cohorts of patients with NSQ NSCLC, colorectal, gastric, or small cell lung cancers. Patients who had history of corneal disorders, contraindications to ocular prophylactic drops, or were unable to stop contact lens use for the study were ineligible. Artificial tear use was encouraged during the study. Results: In patients treated with tusa rav 100 mg/m² (median treatment duration 8.7 weeks [range 2–154]), corneal treatment-emergent adverse events (TEAEs) were reported in 56/186 (30.1%), with the worst grade being Grade 1 as asymptomatic (n = 7), Grade 2 (n = 33), and Grade 3 (n = 16). No patients had Grade 4 (perforation or blindness) or serious corneal adverse events. The most frequent corneal TEAEs were keratitis and keratopathy in 22% and 11.8% (Grade 3 in 6.5% and 2.7%) of 186 patients, respectively. Occurrence of Grade ≥2 corneal events was significantly associated with tusa rav exposure in Q2W dosing (including dose-escalation ≤150 mg/m 2 ). Most patients with corneal TEAEs had first occurrence within the first 4 cycles (45/56), including 16 in Cycle 2 and none in Cycle 1. At analysis cut-off, corneal TEAEs had resolved in 40/56 (71.4%) patients. The median recovery time was 20.5 days (range, 8–264). Of the 186 patients, corneal TEAEs led to cycle delay in 15.6%, cycle delay with dose reduction in 7.0%, and no treatment discontinuations. Corneal TEAEs recurred in 19/56 (33.9%) patients with a median time to recurrence of 16 days. Primary prophylaxis (ophthalmic vasoconstrictor, corticosteroid gel, and/or cold masks at infusion) in only the right eye in 107 patients did not show benefit (98% of the 55 events were bilateral), supporting use of secondary prophylaxis only as needed in subsequent patients. Conclusions: Corneal TEAEs observed in the study were nonserious and typically reversible; management with dose modification allowed continuation of treatment. These results support the ongoing clinical development of tusa rav. Further investigation of the mechanisms of corneal TEAEs with ADCs and their management is necessary. Clinical trial information: NCT02187848.

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