A Jimeno1, K Shirai2, M Choi3, J Laskin4, M Kochenderfer5, A Spira6, V Cline-Burkhardt7, E Winquist8, D Hausman9, L Walker9, R B Cohen10. 1. Division of Medical Oncology, University of Colorado School of Medicine, Aurora antonio.jimeno@ucdenver.edu roger.cohen@uphs.upenn.edu. 2. Medical University of South Carolina, Charleston. 3. Karmanos Cancer Institute, Detroit, USA. 4. Department of Medical Oncology, British Columbia Cancer Agency, Vancouver, Canada. 5. Oncology and Hematology Associates of South West Virginia, Roanoke. 6. Department of Medical Oncology, Virginia Cancer Specialists, Fairfax US Oncology Research, The Woodlands. 7. Texas Oncology, Round Rock, USA. 8. London Health Sciences Centre, London, Canada. 9. Oncothyreon, Inc., Seattle. 10. Abramson Cancer Center of the University of Pennsylvania, Philadelphia, USA antonio.jimeno@ucdenver.edu roger.cohen@uphs.upenn.edu.
Abstract
BACKGROUND: 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 I trial demonstrated tolerability of this combination. This randomized phase II 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 (8 mg p.o. daily; arms A and B, respectively). The primary end point was progression-free survival (PFS). Secondary end points included objective response rate (ORR), overall survival (OS), toxicity, and correlation of key biomarkers with efficacy outcomes. RESULTS:Eighty-three patients were enrolled. There was a similar response rate between arms (10% versus 7%). Of patients for whom tissue was assessable, 57% were human papillomavirus (HPV) positive. Median PFS was 80 days in both arms and there was no difference in OS between the two arms (211 versus 256 days). Overall toxicity was higher in arm A compared with arm B, especially in terms of nausea (53% versus 23%), vomiting (45% versus 15%), fatigue (43% versus 23%), diarrhea (40% versus 21%), and hypokalemia (25% versus 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 preselection. 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.
RCT Entities:
BACKGROUND: 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 I trial demonstrated tolerability of this combination. This randomized phase II 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 (8 mg p.o. daily; arms A and B, respectively). The primary end point was progression-free survival (PFS). Secondary end points included objective response rate (ORR), overall survival (OS), toxicity, and correlation of key biomarkers with efficacy outcomes. RESULTS: Eighty-three patients were enrolled. There was a similar response rate between arms (10% versus 7%). Of patients for whom tissue was assessable, 57% were human papillomavirus (HPV) positive. Median PFS was 80 days in both arms and there was no difference in OS between the two arms (211 versus 256 days). Overall toxicity was higher in arm A compared with arm B, especially in terms of nausea (53% versus 23%), vomiting (45% versus 15%), fatigue (43% versus 23%), diarrhea (40% versus 21%), and hypokalemia (25% versus 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 preselection. 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.
Authors: Adam D Swick; Prashanth J Prabakaran; Margot C Miller; Amal M Javaid; Michael M Fisher; Emmanuel Sampene; Irene M Ong; Rong Hu; Mari Iida; Kwangok P Nickel; Justine Y Bruce; Deric L Wheeler; Randall J Kimple Journal: Mol Cancer Ther Date: 2017-04-26 Impact factor: 6.261
Authors: Dejan Juric; Johann S de Bono; Patricia M LoRusso; John Nemunaitis; Elisabeth I Heath; Eunice L Kwak; Teresa Macarulla Mercadé; Elena Geuna; Maria Jose de Miguel-Luken; Chirag Patel; Keisuke Kuida; Serap Sankoh; Eric H Westin; Fabian Zohren; Yaping Shou; Josep Tabernero Journal: Clin Cancer Res Date: 2017-05-10 Impact factor: 12.531