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 Anti-Cancer Agents & Biologic Therapy
Ovarian Cancer
Breast Cancer
Lung and other Thoracic Tumours
Translational Research
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.