PI3K INHIBITOR FOR HEAD-NECK CANCER

Ann Oncol. 2014 Dec 18. pii: mdu574. [Epub ahead of print]

A randomized, phase 2 trial of cetuximab with or without PX-866, an irreversible oral phosphatidylinositol 3-kinase Inhibitor, in patients with relapsed or metastatic head and neck squamous cell cancer.

Jimeno A1, Shirai K2, Choi M3, Laskin J4, Kochenderfer M5, Spira A6, Cline-Burkhardt V7, Winquist E8, Hausman D9, Walker L9, Cohen RB10.

Author information

Abstract

INTRODUCTION: 

The phosphotidylinositol-3 kinase (PI3K)/serine-threonine kinase/mammalian target of rapamycin signaling pathway is frequently altered in head and neck squamous cell cancer (HNSCC). PX-866 is an oral, irreversible, pan-isoform inhibitor of PI3K. A phase 1 trial demonstrated tolerability of this combination. This randomized phase 2 study evaluated PX-866 combined with cetuximab in patients with advanced, refractory HNSCC.

METHODS: 

Patients with recurrent or metastatic HNSCC who had received at least one and no more than two prior systemic treatment regimens were randomized (1:1) to cetuximab 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 key biomarkers with efficacy outcomes.

RESULTS: 

83 patients were enrolled. There was a similar response rate between arms (10% vs. 7%). Of patients for whom tissue was assessable, 57% were HPV positive. Median PFS was 80 days in both arms and there was no difference in OS between the two arms (211 vs. 256 days). Overall toxicity was higher in arm A compared to arm B, especially in terms of nausea (53% vs. 23%), vomiting (45% vs. 15%), fatigue (43% vs. 23%), diarrhea (40% vs. 21%), and hypokalemia (25% vs. 10%). Grade 3 or higher adverse events were infrequent, but more common in the combination arm although without a specific pattern. PIK3CA mutations were observed in 17% of the cases assessed, and PTEN loss was infrequently observed.

CONCLUSION: 

The addition of PX-866 to cetuximab did not improve PFS, RR, or OS in patients with advanced, refractory HNSCC enrolled without molecular pre-selection. In this contemporary cohort, HPV positive patients comprised the majority, and neither HPV positive nor HPV negative patients derived clinical benefit for the addition of cetuximab plus PX-866.