Exceptional responses in patients with metastatic colorectal cancer enrolled in first-in-man studies from 2002 through 2012.

Abstract

687 Background: Understanding exceptional responses to therapy at the molecular level may open new venues for the treatment of patients with metastatic colorectal cancer (mCRC). Responses in first-in-man (FIM) studies with targeted therapies are rare and may indicate that actionable genetic aberrations are present in these patients. Methods: We utilized Scopus using the search term “phase 1 and solid tumors” to collect all FIM studies published between 2002 and 2012. We identified patients with mCRC who attained an exceptional response to therapy defined as a complete response (CR) or a partial response (PR) lasting > 6 months (m). Results: We identified 118 FIM studies enrolling 5,369 patients with advanced malignancies. mCRC was the most common tumor type, totaling 1,055 (19.6%) patients. Of these, two patients enrolled in protocols with MDX-1106 (anti PD-1) and RG7180 (mAb EGFR) attained a complete response (CR). Five patients had PR lasting > 6 m. These patients were treated with RG7180 (time on study 7.8 m), Apatinib, a VEGFR tyrosine kinase inhibitor (8.5 and 7.1 m), PV701, a replication-competent oncolytic virus (10 m) and RO4929097, a gamma-secretase inhibitor (7 m). In addition two patients had PR lasting < 6 m with regorafenib (5.3 m) and RG7180 (5.6 m). This database of exceptional responders to therapy will be publicly available at Huntsman Cancer Institute website. Currently, regorafenib and EGFR mAbs (cetuximab and panitumumab) are approved for use in mCRC. EGFR mAbs have shown improvement in survival in RAS wild-type mCRC. Clinical trials are underway evaluating apatinib. Anti-PD1s have shown limited activity as single agents in mCRC and are currently undergoing testing in combination with chemotherapy. Conclusions: We identified exceptional responses among patients with mCRC enrolled in FIM in the last decade. Ongoing efforts are directed to conduct next generation sequencing (NGS) in archived tissue from these patients. Ultimately, this initiative may facilitate the identification of biomarkers of response to be tested in clinical trials with these or novel drugs sharing similar mechanisms of action.