Merrimack, Cambridge, MA
Biljana Bazdar-Vinovrski , Marisa Wainszelbaum , Gavin MacBeath
Background: The Epidermal Growth Factor Receptor (EGFR) is a key driver of tumor growth in colorectal cancer (CRC), squamous cell carcinoma of the head and neck (SCCHN), and non-small cell lung cancer (NSCLC). Although EGFR inhibitors prolong overall survival in many patients, resistance inevitably develops. Resistance usually arises through alterations in the EGFR pathway itself or through upregulation of alternative signaling pathways. In CRC in particular, mutations in KRAS and NRAS are strong predictors of resistance to EGFR inhibitors. Such resistance may potentially be overcome by combining MM-151, a potent EGFR inhibitor, with trametinib, a MEK inhibitor. In KRAS/NRAS wild-type tumors, resistance may arise through activation of parallel signaling pathways. Emerging data suggest that heregulin (HRG)-driven signaling through ErbB3 and insulin-like growth factor-1 (IGF-1)-driven signaling through IGF-1R may confer resistance to EGFR inhibitors by activating pro-survival signaling through the PI3K/Akt pathway. If HRG-mediated signaling is active, resistance may potentially be overcome through the combined administration of MM-151 and the ErbB3-targeting antibody MM-121. Similarly, if IGF-1-mediated signaling is active, resistance may be overcome by combining MM-151 with the IGF-1R-targeting antibody MM-141. The rationale underlying this trial is that mechanisms of resistance may be identified through biomarker analyses, allowing patients to be prospectively assigned to an appropriate investigational regimen. Methods: This is a Phase 1, biomarker-directed open-label study evaluating the safety, pharmacology and preliminary activity of MM-151 in combination with trametinib, MM-121, or MM-141. Patients are evaluated for KRAS/NRAS status and tumoral expression of HRG and IGF-1 and are then assigned to the study arm matching their biomarker profile. A modified “3 + 3” design is used to establish a recommended Phase 2 dose. Expansion cohorts in CRC and SCCHN will then be opened to further evaluate safety and preliminary signs of efficacy. Key exploratory analyses include evaluations of PK, PD, and biomarkers of additional resistance pathways. Clinical trial information: NCT02538627
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