A randomized, phase 2 trial of cetuximab with or without PX-866, an irreversible oral phosphatidylinositol 3-kinase inhibitor, in patients with metastatic colorectal carcinoma

Abstract Background The phosphotidylinositol-3 kinase (PI3K)/serine-threonine kinase/mammalian target of rapamycin signaling pathway is frequently altered in colorectal cancer (CRC). PX-866 is an oral, irreversible, pan-isoform inhibitor of PI3K. This randomized phase 2 study evaluated cetuximab with or without PX-866 in patients with metastatic, anti-EGFR naïve, KRAS codon 12 and 13 wildtype CRC. Methods Patients with metastatic CRC who had received both oxaliplatin and irinotecan were randomized (1:1) to cetuximab (400mg/m2 loading then 250mg/m2 weekly) with or without PX-866 (8mg PO daily; arms A and B, respectively). The primary endpoint was progression free survival (PFS). Secondary endpoints included objective response rate (ORR), overall survival (OS), toxicity, and correlation of relevant biomarkers with efficacy outcomes. Results 85 patients were enrolled. Median PFS was 59 days versus 104 days for arms A (cetuximab + PX-866) and B (cetuximab alone), respectively (p=0.77). OS between the two arms (266 vs. 333 days for arm A vs. B) were similar (p=0.83). Overall toxicity, including treatment-related toxicity, was higher in arm A compared to arm B, especially in terms of all grade nausea (66% vs. 37%), vomiting (50% vs. 29%), diarrhea (64% vs. 18%), and rash (66% vs 37%). Grade 3 diarrhea occurred in 19% of patients in Arm A and 0% in Arm B. PIK3CA mutations and PTEN loss by immunohistochemistry were infrequently seen. Conclusion The addition of PX-866 to cetuximab did not improve PFS, RR, or OS in patients with metastatic CRC. The combination arm had greater toxicity and may have been harmful in this study.