A phase I study evaluating DLYE5953A, an antibody-drug conjugate targeting the tumor-associated antigen lymphocyte antigen 6 complex locus E (Ly6E), in patients (Pts) with solid tumors

Abstract

Background: Ly6E is over‐expressed in breast, lung, and pancreatic cancers. DLYE5953A is a humanized IgG1 anti‐Ly6E monoclonal antibody conjugated to the potent anti‐mitotic agent monomethyl auristatin E (MMAE), linked through the protease‐labile linker MC‐vc‐PAB. DLYE5953A has the potential to selectively target Ly6E‐expressing cancers. Methods: This open‐label, 3 + 3 dose‐escalation study assessed safety, tolerability, pharmacokinetics (PK), and preliminary anti‐tumor activity (RECIST v1.1) of DLYE5953A administered intravenously every 21 days (q3w) in pts with locally advanced or metastatic solid malignancies that had progressed on standard therapy. Tumor Ly6E expression was assessed by IHC and qRT‐PCR. Results: As of 31 December 2015, 57 pts, median age 57 (range 33‐82), received a median of 4 cycles of DLYE5953A (range 1‐14). Escalating doses of DLYE5953A (0.2‐2.4 mg/kg) were tested in 20 pts. No dose limiting toxicities were identified. The maximum administered dose of 2.4 mg/kg was tested further in 20 HER2‐negative metastatic breast cancer (HER2‐ MBC) and 17 non‐small cell lung cancer (NSCLC) pts. Primarily Grade 1‐2 DLYE5953A‐related adverse events (AEs) observed in 14/57 (>25%) of patients included: alopecia (53%), fatigue (49%), nausea (39%), anorexia (30%), and chills (28%). Grade >3 related AEs occurred in 14/57 (25%) of pts; neutropenia (7/57, 12%) was most frequent. Four pts discontinued DLYE5953A for AEs, and 4/44 pts (9%) underwent a dose reduction from 2.4 mg/kg for AEs. DLYE5953A demonstrated linear PK at > 0.8 mg/kg by total antibody with low unconjugated MMAE levels in blood. Among pts who received >1 dose of 2.4 mg/kg DLYE5953A, partial responses (PR) were seen in 5 HER2‐ MBC (3 confirmed PRs; n = 26) and 4 NSCLC (1 confirmed PR, 2 PRs pending confirmation; n = 17) pts, with 8 pts remaining on treatment and enrollment ongoing. Conclusions: DLYE5953A administered at 2.4 mg/kg has acceptable tolerability with manageable AEs and promising preliminary anti‐tumor activity in NSCLC and MBC pts. Updated results including tumor LY6E expression analysis will be presented.