PMID- 32694157 OWN - NLM STAT- MEDLINE DCOM- 20211126 LR - 20230207 IS - 1557-3265 (Electronic) IS - 1078-0432 (Print) IS - 1078-0432 (Linking) VI - 26 IP - 21 DP - 2020 Nov 1 TI - A Phase I Study of DLYE5953A, an Anti-LY6E Antibody Covalently Linked to Monomethyl Auristatin E, in Patients with Refractory Solid Tumors. PG - 5588-5597 LID - 10.1158/1078-0432.CCR-20-1067 [doi] AB - PURPOSE: DLYE5953A is an antibody-drug conjugate consisting of an anti-LY6E antibody covalently linked to the cytotoxic agent monomethyl auristatin E. This study characterized the safety, pharmacokinetics, immunogenicity, potential biomarkers, and antitumor activity of DLYE5953A in patients with metastatic solid tumors. PATIENTS AND METHODS: This was a phase I, open-label, 3+3 dose-escalation, and dose-expansion study of DLYE5953A administered intravenously every 21 days (Q3W) in patients with locally advanced or metastatic solid malignancies. RESULTS: Sixty-eight patients received DLYE5953A (median, four cycles; range, 1-27). No dose-limiting toxicities were identified during dose escalation (0.2-2.4 mg/kg; n = 20). The recommended phase II dose (RP2D) of 2.4 mg/kg Q3W was based on overall safety and tolerability. Dose-expansion cohorts for HER2-negative metastatic breast cancer (HER2-negative MBC; n = 23) and non-small cell lung cancer (NSCLC; n = 25) patients were enrolled at the RP2D. Among patients receiving DLYE5953A 2.4 mg/kg (n = 55), the most common (>/=30%) related adverse events (AEs) included alopecia, fatigue, nausea, and peripheral neuropathy. Grade >/=3 related AEs occurred in 14 of 55 (26%) patients, with neutropenia being the most common (13%). DLYE5953A demonstrated linear total antibody pharmacokinetics at doses of >/=0.8 mg/kg with low unconjugated monomethyl auristatin E levels in blood. Partial response was confirmed in eight of 68 (12%) patients, including three of 29 patients with MBC (10%) and five of 25 patients with NSCLC (20%) at the RP2D. Stable disease was the best response for 37 of 68 (54%) patients. CONCLUSIONS: DLYE5953A administered at 2.4 mg/kg has acceptable safety. Preliminary evidence of antitumor activity in patients with HER2-negative MBC and NSCLC supports further investigation of LY6E as a therapeutic target. CI - (c)2020 American Association for Cancer Research. FAU - Tolaney, Sara M AU - Tolaney SM AD - Dana-Farber Cancer Institute, Boston, Massachusetts. FAU - Do, Khanh T AU - Do KT AD - Dana-Farber Cancer Institute, Boston, Massachusetts. FAU - Eder, Joseph P AU - Eder JP AD - Smilow Cancer Center, Yale University, New Haven, Connecticut. FAU - LoRusso, Patricia M AU - LoRusso PM AD - Smilow Cancer Center, Yale University, New Haven, Connecticut. FAU - Weekes, Colin D AU - Weekes CD AD - Massachusetts General Hospital, Boston, Massachusetts. FAU - Chandarlapaty, Sarat AU - Chandarlapaty S AD - Memorial Sloan Kettering Cancer Center, New York, New York. FAU - Chang, Ching-Wei AU - Chang CW AD - Genentech, Inc., South San Francisco, California. FAU - Chen, Shang-Chiung AU - Chen SC AD - Genentech, Inc., South San Francisco, California. FAU - Nazzal, Denise AU - Nazzal D AD - Genentech, Inc., South San Francisco, California. FAU - Schuth, Eva AU - Schuth E AD - Genentech, Inc., South San Francisco, California. FAU - Brunstein, Flavia AU - Brunstein F AD - Genentech, Inc., South San Francisco, California. FAU - Carrasco-Triguero, Montserrat AU - Carrasco-Triguero M AUID- ORCID: 0000-0002-2805-1008 AD - Genentech, Inc., South San Francisco, California. FAU - Darbonne, Walter C AU - Darbonne WC AUID- ORCID: 0000-0002-4386-1826 AD - Genentech, Inc., South San Francisco, California. FAU - Giltnane, Jennifer M AU - Giltnane JM AD - Genentech, Inc., South San Francisco, California. FAU - Flanagan, William M AU - Flanagan WM AD - Genentech, Inc., South San Francisco, California. FAU - Commerford, S Renee AU - Commerford SR AUID- ORCID: 0000-0001-9916-8572 AD - Genentech, Inc., South San Francisco, California. FAU - Ungewickell, Alexander AU - Ungewickell A AD - Genentech, Inc., South San Francisco, California. FAU - Shapiro, Geoffrey I AU - Shapiro GI AD - Dana-Farber Cancer Institute, Boston, Massachusetts. geoffrey_shapiro@dfci.harvard.edu. FAU - Modi, Shanu AU - Modi S AUID- ORCID: 0000-0001-6427-7373 AD - Memorial Sloan Kettering Cancer Center, New York, New York. LA - eng GR - P30 CA006516/CA/NCI NIH HHS/United States GR - P30 CA008748/CA/NCI NIH HHS/United States PT - Clinical Trial, Phase I PT - Journal Article PT - Multicenter Study PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20200721 PL - United States TA - Clin Cancer Res JT - Clinical cancer research : an official journal of the American Association for Cancer Research JID - 9502500 RN - 0 (Antigens, Surface) RN - 0 (GPI-Linked Proteins) RN - 0 (Immunoconjugates) RN - 0 (LY6E protein, human) SB - IM MH - Adult MH - Aged MH - Aged, 80 and over MH - Antigens, Surface/*genetics/immunology MH - Breast Neoplasms/*drug therapy/genetics/immunology/pathology MH - Carcinoma, Non-Small-Cell Lung/*drug therapy/genetics/immunology/pathology MH - Drug-Related Side Effects and Adverse Reactions/classification/epidemiology/pathology MH - Female MH - GPI-Linked Proteins/antagonists & inhibitors/genetics/immunology MH - Humans MH - Immunoconjugates/*administration & dosage/adverse effects MH - Male MH - Middle Aged MH - Neoplasm Metastasis PMC - PMC9899652 MID - NIHMS1613872 EDAT- 2020/07/23 06:00 MHDA- 2021/11/27 06:00 PMCR- 2023/02/06 CRDT- 2020/07/23 06:00 PHST- 2020/03/31 00:00 [received] PHST- 2020/06/03 00:00 [revised] PHST- 2020/07/15 00:00 [accepted] PHST- 2020/07/23 06:00 [pubmed] PHST- 2021/11/27 06:00 [medline] PHST- 2020/07/23 06:00 [entrez] PHST- 2023/02/06 00:00 [pmc-release] AID - 1078-0432.CCR-20-1067 [pii] AID - 10.1158/1078-0432.CCR-20-1067 [doi] PST - ppublish SO - Clin Cancer Res. 2020 Nov 1;26(21):5588-5597. doi: 10.1158/1078-0432.CCR-20-1067. Epub 2020 Jul 21.