246P - A meta-analysis of biomarkers in three randomized, phase 2 studies of MM-121, a ligand-blocking anti-ErbB3 antibody, in patients with ovarian, lung...

Date 28 September 2014
Event ESMO 2014
Session Poster Display session
Topics Anticancer agents
Ovarian Cancer
Breast Cancer
Thoracic malignancies
Translational Research
Basic Principles in the Management and Treatment (of cancer)
Therapy
Biological therapy
Presenter Gavin MacBeath
Citation Annals of Oncology (2014) 25 (suppl_4): iv58-iv84. 10.1093/annonc/mdu326
Authors G. MacBeath1, B. Adiwijaya1, J. Liu2, L.V. Sequist3, E. Pujade-Lauraine4, M. Higgins3, I. Tabah-Fisch5, J. Pearlberg6, V. Moyo7, W. Kubasek1, R. Nering8, A. Czibere8
  • 1Translational Research And Discovery, Merrimack Pharmaceuticals, 02139 - Cambridge/US
  • 2Gynecologic Oncology Program, Dana Farber Cancer Institute, 02155 - Boston/US
  • 3Hematology/oncology, Massachusetts General Hospital, 02114 - Boston/US
  • 4Chu Paris Centre - Hôpital Hôtel-dieu, CHU Paris Centre - Hôpital Hôtel-Dieu, Paris/FR
  • 5Sanofi Oncology, Sanofi, Paris/FR
  • 6Sanofi Oncology, Sanofi, Cambridge/US
  • 7Discovery, Merrimack Pharmaceuticals, 02139 - Cambridge/US
  • 8Clinical Development, Merrimack Pharmaceuticals, Cambridge/US

Abstract

Aim

Heregulin (HRG)-driven ErbB3 signaling mediates resistance to standard-of-care (SOC) cancer therapy in a variety of preclinical models. MM-121, a HRG-blocking anti-ErbB3 antibody, underwent clinical evaluation to determine if patients with advanced malignancies would derive benefit from the addition of MM-121 to their standard therapy. Potential predictive biomarkers were identified from a pre-specified set of mechanistic markers.

Study BM+ n/N* BM+ Prevalence PFS HR in study PFS HR in measured BM PFS HR in BM+ PFS HR in BM-
Ovarian 69/150 46% 1.03 [0.74-1.42] 1.10 [0.74-1.63] 0.40 [0.21-0.76] 2.02 [1.17-3.50]
Lung 36/67 54% 0.82 [0.55-1.21] 0.91 [0.51-1.61] 0.39 [0.18-0.82] 2.43 [1.07-5.55]
Breast 21/57 37% 0.75 [0.48-1.15] 0.68 [0.38-1.23] 0.35 [0.13-0.94] 0.99 [0.47-2.08]

*n = BM + , N = patients with measured biomarkers

Methods

Randomized Phase 2 studies were conducted in: i) platinum-resistant ovarian cancer, ii) EGFR wt NSCLC, and iii) ER/PR + , HER2- mBC. Patients were randomized to SOC therapy, with or without MM-121. Safety and clinical activity data from these studies have previously been presented. Tumor tissue was acquired from each patient and five pre-specified biomarkers were measured and correlated with clinical benefit: HRG, betacellulin, EGFR, HER2, and ErbB3. Protein levels were determined by quantitative IHC (qIHC) and mRNA levels by RT-PCR and RNA in-situ hybridization (RNA-ISH).

Results

Among 464 patients (220 ovarian, 115 breast, 129 lung), RNA-ISH data were available from 224 patients (157 ovarian, 67 lung), qIHC from 252 (174 ovarian, 78 lung), and RT-PCR from 175 (105 ovarian, 57 breast, 13 lung). Of the five biomarkers, the most predictive of response was HRG mRNA: patients with detectable HRG in pre-treatment biopsies or high HRG in archived tissue blocks responded poorly to SOC therapy and benefited most from MM-121. In addition, benefit was largely restricted to patients with low ErbB2. Hazard ratios for PFS were calculated, defining biomarker positive (BM+) patients: Ovarian cancer, detectable HRG and low ErbB2; Lung cancer, detectable HRG; and, Breast cancer, high HRG. PFS hazard ratios with 95% CI and prevalence of the BM+ and BM- subpopulations are provided below.

Conclusions

Heregulin is a potential biomarker for poor response to SOC therapy and a potential predictor of clinical benefit from MM-121 in late-stage ovarian, lung, and breast cancers.

Disclosure

G. MacBeath is an employee of Merrimack Pharmaceuticals and holds stock in the company; B. Adiwijaya is an employee of Merrimack Pharmaceuticals, the sponsor of this clinical research, and holds stock in the company; J. Liu is an unpaid advisor for Merrimack Pharmaceuticals and was a Principal Investigator for one of the clinical studies included in this analysis; L.V. Sequist is an upaid advisor for Merrimack Pharmaceuticals and was a Principal Investigator of one of the clinical studies included in this analysis; E. Pujade-Lauraine serves as an upaid advisor to Merrimack Pharmaceuticals and Sanofi. He was also a lead investigator for one of the clinical studies included in this analysis; M. Higgins is an unpaid advisor to Merrimack Pharmaceuticals and Sanofi. She was a Principal Investigator of one of the clinical studies included in this analysis; I. Tabah-Fisch is an employee of Sanofi, a sponsor of the clinical studies summarized in this abstract, and holds stock in the company; J. Pearlberg is an employee of Sanofi, a sponsor of this clinical research, and holds stock in the company; V. Moyo, W. Kubasek, R. Nering and A. Czibere: Is an employee of Merrimack Pharmaceuticals, a sponsor of the clinical research, and holds stock in the company.