357O - A phase I study evaluating DLYE5953A, an antibody-drug conjugate targeting the tumor-associated antigen lymphocyte antigen 6 complex locus E (Ly6E)...

Date 08 October 2016
Event ESMO 2016 Congress
Session Developmental therapeutics
Topics Clinical research
Basic Scientific Principles
Presenter Shanu Modi
Citation Annals of Oncology (2016) 27 (6): 114-135. 10.1093/annonc/mdw368
Authors S. Modi1, J.P. Eder2, P. Lorusso2, C. Weekes3, S. Chandarlapaty4, S.M. Tolaney5, J. McLaughlin2, D.R. Camidge6, C. Chang7, D. Nazzal7, S. Chen7, E. Schuth7, F. Brunstein7, W. Darbonne7, W. Flanagan7, A. Ungewickell7, G. Shapiro8
  • 1Medicine, Memorial Sloan Kettering Cancer Center, 10065 - New York/US
  • 2Yale School Of Medicine, Yale Cancer Center, New Haven/US
  • 3Department Of Medicine, University of Colorado Cancer Center Anschutz Cancer Pavilion, Aurora/US
  • 4Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York/US
  • 5Breast Oncology Center, Dana-Farber Cancer Institute, Boston/US
  • 6Cancer Center, University of Colorado, Aurora/US
  • 7Early Development, Genentech, Inc., 94080 - South San Francisco/US
  • 8Early Drug Development Centre, Dana-Farber Cancer Institute, Boston/US

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.

Clinical trial identification

NCT02092792

Legal entity responsible for the study

Study sponsored by Genentech, Inc.

Funding

Study sponsored by Genentech, Inc.

Disclosure

S. Modi: Research funding from Genentech, Novartis, and Seattle Genetics. P. Lorusso: Honoraria from Genentech. C. Weekes: Research support from Genentech. S. Chandarlapaty: Honoraria from AstraZeneca and Chugai, grant support from Novartis and Lilly. S.M. Tolaney: Research funding from Genentech/Roche, Exelixis, Pfizer, Merck, Lilly, Novartis. D.R. Camidge: Honoraria from Roche. C-W. Chang, D. Nazzal, S-C. Chen, E. Schuth, F. Brunstein, W. Darbonne, W. Flanagan, A. Ungewickell: Roche employee and shareholder. All other authors have declared no conflicts of interest.