989PD - Phase 1b study of MEHD7945A (MEHD) plus cisplatin/fluorouracil (cis/5FU) or carboplatin/paclitaxel (carbo/pac) for 1st-line treatment of recurrent/...

Date 28 September 2014
Event ESMO 2014
Session Head and neck cancer
Topics Anticancer agents
Immunotherapy
Head and Neck Cancers
Therapy
Biological Therapy
Presenter Paul Clement
Citation Annals of Oncology (2014) 25 (suppl_4): iv340-iv356. 10.1093/annonc/mdu340
Authors P.M. Clement1, J. Machiels2, L.J. Wirth3, P. Specenier4, T. Seiwert5, F. Mardjuadi2, X. Wang6, A. Kapp6, S. Royer-Joo7, E. Penuel6, B. McCall8, A. Pirzkall7, A. Jimeno9
  • 1General Medical Oncology, UZ Leuven University Hospital, 3000 - Leuven/BE
  • 2Oncology, Cancer Center, Service d’Oncologie Médicale, Cliniques Universitaires Saint-Luc and Institut de Recherche Clinique et Expérimentale (Pole MIRO), Université Catholique de Louvain, 1200 - Brussels/BE
  • 3Department Of Medicine, Massachusetts General Hospital, 02114 - Boston/US
  • 4Oncology, Universitair Ziekenhuis Antwerpen, Edegem/BE
  • 5Medicine, University of Chicago, Chicago/US
  • 6Research And Early Development, Genentech, Inc., South San Francisco/US
  • 7Oncology Early Clinical Development, Genentech, Inc., South San Francisco/US
  • 8Product Development, Oncology, Genentech, Inc., 94080 - South San Francisco/US
  • 9Medicine/oncology And Otolaryngology, University of Colorado School of Medicine, 80045 - Aurora/US

Abstract

Aim

MEHD, a novel dual-action humanized IgG1 antibody that blocks ligand binding to HER3 and EGFR, inhibits signaling from ligand-dependent HER dimers. MEHD is active in multiple tumor models, including models resistant to anti-EGFR or anti-HER3, and enhances activity of chemotherapeutic agents. Single-agent activity in Phase 1a included confirmed PR in 2 RMSCCHN patients (pts) who had high levels of the HER3 ligand NRG1.

Methods

This open-label, multicenter, Phase 1b study with a modified 3 + 3 + 3 design assesses safety, PK and preliminary anti-tumor activity (RECIST v1.1) of MEHD plus platinum-based chemotherapy in 1st-line RMSCCHN pts. MEHD 1650 mg IV every 3 wks is combined with cis 100 mg/m2 / 5FU 1000 mg/m2/d on Days 1-4 (Arm A) or carbo (AUC 6 mg/mL·min) / pac 200 mg/m2 (Arm B) on Day 1 of 21-d cycles (up to 6), followed by MEHD maintenance until disease progression / intolerable toxicity. Mandatory tumor samples are assayed by qRT-PCR for biomarkers related to mechanism of action and SCCHN.

Results

As of 28MAR14, 18 pts were treated and remain active: 6 ARM A pts have received 2-7 cycles (median 5.5) of MEHD; 13 Arm B pts have received 1-8 cycles (median 3.5). DLTs occurred in 2 pts in Arm A (1 G3 diarrhea, 1 G3 acute renal failure & G3 febrile neutropenia) and 1 pt in Arm B (G3 dehydration, anorexia). G ≥ 3 treatment-related AEs in ≥2 pts were hypokalemia (3), neutropenia (3), dehydration (3), fatigue (2), and hyponatremia (2) in Arm A and neutropenia (6), febrile neutropenia (3), and hyponatremia (2) in Arm B. Chemo dose was reduced in 9/18 pts. Preliminary MEHD PK in both arms was similar to single-agent MEHD profile. In 12 pts with on-treatment tumor assessments, best responses were 9 (75%) PR (4 confirmed) [Arm A: 4; Arm B: 5; HPV: 2 + , 5-, 2 unknown], and 3 (25%) stable disease [Arm A: 1; Arm B: 2]; after data cutoff 2 pts were reported with CR. Further biomarker data are pending.

Conclusions

MEHD plus cis/5FU or carbo/pac has been reasonably well tolerated with no new safety signals. G ≥ 3 AEs were manageable and less frequent post-Cycle 1. Both combinations had promising anti-tumor activity. Updated results will be presented.

Disclosure

T. Seiwert: Research funding; X. Wang, A. Kapp, S. Royer-Joo, E. Penuel, B. McCall and A. Pirzkall: Genentech employee. All other authors have declared no conflicts of interest.