Multi-drug inhibition of the HER pathway in metastatic colorectal cancer: Results of a phase I study of pertuzumab plus cetuximab in cetuximab-refractory patients

Abstract

Purpose Resistance to cetuximab, a monoclonal antibody against the epithelial growth factor receptor (EGFR), in colorectal cancer (CRC) may result from compensatory signaling through ErbB receptors, ErbB2/neu/HER2 (HER2) and ErbB3/HER3 (HER3). Pertuzumab is a monoclonal antibody that blocks HER2 hetero-dimerization; thus the combination of pertuzumab and cetuximab could possibly overcome cetuximab resistance. Patients and methods This single-arm, open-label, multicenter phase I/II study was designed to assess the safety and efficacy of pertuzumab and cetuximab in patients with cetuximab-resistant KRAS wild type metastatic CRC. Thirteen patients were enrolled and received cetuximab in combination with pertuzumab at several dose levels in a 3+3 design. Patients were assessed for dose-limiting toxicity (DLT) during the first cycle. A phase II portion was planned, but not initiated due to toxicity. Results Six of the thirteen patients (46%) experienced DLTs, therefore the study was terminated early. Grade 3 or higher DLTs included dermatitis with desquamation and/or acneiform rash (n=6), mucositis or stomatitis (n=5), and diarrhea (n=2). There was one Grade 5 event (myocardial infarction) attributed to underlying disease. Among the 13 patients, seven (54%) were evaluable for response. The objective response rate was 14%: one patient had a partial response lasting 6 months. Two patients had stable disease (29%), and four had progressive disease (57%). Median progression free survival was 2.1 months (95% CI, 1.5–4.9) and median overall survival was 3.7 months (95% CI, 1.6–7.9). Conclusion Combination pertuzumab and cetuximab in refractory CRC was associated with potential antitumor activity; however, the combination was not tolerable due to overlapping toxicities.

Targeting HER2 in colorectal cancer: The landscape of amplification and short variant mutations in ERBB2 and ERBB3

“…Two basic strategies for targeting HER2 in mCRC have been taken: 1) targeting HER2 as the primary driver of the disease when appropriate; and 2) attempting to overcome the resistance to other targeted therapies mediated by ERBB2 genomic alterations . Initial studies targeting ERBB2 in mCRC focused exclusively on ERBB2‐ amplified cases detected by either FISH or direct sequencing methods . Figure provides an example of an ERBB2‐ amplified mCRC vigorously responding to anti‐HER2 targeted therapy .…”

Current and Future Approaches to Target the Epidermal Growth Factor Receptor and Its Downstream Signaling in Metastatic Colorectal Cancer

“…Seven patients were evaluable, and 1 (14%) had a partial response that lasted 6 months. 84 Ultimately, the activity of lapatinib combinations observed in unselected CRC models might be mediated mainly through the improved inhibition of EGFR rather than the effect of inhibition of HER2. 85 Because of the rarity of HER2 amplification, early clinical trials that attempted to select patients with an inclusion criterion of HER2 overexpression failed to accrue, 86,87 and subsequent studies did not limit enrollment to HER2-overexpressing tumors only.…”

Cell-type specific and non-redundant anti-proliferative effects of shRNA-mediated Galpha12- and Galpha13 knockdown in lung cancer cell lines

“…It should also be noted that, unlike seen in other oncogene families (see e.g. [24] for HER receptor), the double targeting of both Gα 12 and Gα 13 did not lead to synergistic anti-proliferative effects. In tumor cells insensitive to a single knockdown of Gα 12 or Gα 13 (see A549 experiments), the double targeting of both G proteins had no anti-proliferative effect either.…”