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Oncologist. 2019 Aug;24(8):1095-1102. doi: 10.1634/theoncologist.2018-0695. Epub 2019 Apr 11.

Randomized Phase II Trial of Seribantumab in Combination with Erlotinib in Patients with EGFR Wild-Type Non-Small Cell Lung Cancer.

Author information

1
Massachusetts General Hospital, Boston, Massachusetts, USA LVSEQUIST@PARTNERS.ORG.
2
H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.
3
Horizon Oncology Center, Lafayette, Indiana, USA.
4
Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon, USA.
5
University of Colorado Cancer Center, Aurora, Colorado, USA.
6
Arizona Clinical Research Center, Tucson, Arizona, USA.
7
Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
8
Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA.
9
Department of Hematology and Oncology, Institute of Clinical Research at Krankenhaus Nordwest, UCT-University Cancer Center, Frankfurt, Germany.
10
Vall d'Hebron University Hospital, Barcelona, Spain.
11
Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain.
12
Hospital Regional Universitario Málaga, Instituto de Investigación Biomédica de Málaga, Málaga, Spain.
13
Merrimack Pharmaceuticals, Inc., Cambridge, Massachusetts, USA.
14
Yonsei University College of Medicine, Seoul, South Korea.
15
Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
16
Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada.

Abstract

BACKGROUND:

Seribantumab (MM-121) is a fully human IgG2 monoclonal antibody that binds to human epidermal growth factor receptor 3 (HER3/ErbB3) to block heregulin (HRG/NRG)-mediated ErbB3 signaling and induce receptor downregulation. This open-label, randomized phase 1/2 study evaluated safety and efficacy of seribantumab plus erlotinib in advanced non-small cell lung cancer (NSCLC). Here, we report the activity of seribantumab plus erlotinib, versus erlotinib alone, in patients with EGFR wild-type tumors and describe the potential predictive power of HRG.

MATERIALS AND METHODS:

Patients with EGFR wild-type NSCLC were assigned randomly to receive seribantumab + erlotinib or erlotinib alone. Patients underwent pretreatment core needle biopsy and archived tumor samples were collected to support prespecified biomarker analyses.

RESULTS:

One hundred twenty-nine patients received seribantumab + erlotinib (n = 85) or erlotinib alone (n = 44). Median estimated progression-free survival (PFS) in the unselected intent-to-treat (ITT) population was 8.1 and 7.7 weeks in the experimental and control arm, respectively (hazard ratio [HR], 0.822; 95% confidence interval [CI], 0.37-1.828; p = 0.63), and median estimated overall survival was 27.3 and 40.3 weeks in the experimental and control arm, respectively (HR, 1.395; 95% CI, 0.846 to 2.301; p = .1898) In patients whose tumors had detectable HRG mRNA expression, treatment benefit was observed in the seribantumab + erlotinib combination (HR, 0.35; 95% CI, 0.16-0.76; p = .008). In contrast, in patients whose tumors were HRG negative, the HR was 2.15 (95% CI, 0.97-4.76; p = .059, HRG-by-treatment interaction, p value = .0016).

CONCLUSION:

The addition of seribantumab to erlotinib did not result in improved PFS in unselected patients. However, predefined retrospective exploratory analyses suggest that detectable HRG mRNA levels identified patients who might benefit from seribantumab. An ongoing clinical trial of seribantumab, in combination with docetaxel, is underway in patients with advanced NSCLC and high HRG mRNA expression (NCT02387216).

IMPLICATIONS FOR PRACTICE:

The poor prognosis of patients with non-small cell lung cancer (NSCLC) underscores the need for more effective treatment options, highlighting the unmet medical need in this patient population. The results of this study show that a novel biomarker, heregulin, may help to identify patients with advanced NSCLC who could benefit from treatment with seribantumab. On the basis of the observed safety profile and promising clinical efficacy, a prospective, randomized, open-label, international, multicenter phase II trial (SHERLOC, NCT02387216) is under way to investigate the efficacy and safety of seribantumab in combination with docetaxel in patients with heregulin-positive advanced adenocarcinoma.

KEYWORDS:

Antibody; Biomarkers; HER3/ErbB3; Heregulin; Seribantumab; Targeted therapy; Translational

PMID:
30975923
PMCID:
PMC6693700
[Available on 2020-08-01]
DOI:
10.1634/theoncologist.2018-0695

Conflict of interest statement

Disclosures of potential conflicts of interest may be found at the end of this article.

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