Benjamin Levy1, Alexander Spira2, Daniel Becker3, Tracey Evans4, Ian Schnadig5, D Ross Camidge6, Julie E Bauman7, Diana Hausman8, Luke Walker8, John Nemunaitis9, Charles M Rudin10, Balazs Halmos11, Daniel W Bowles12. 1. Beth Israel Hospital, St. Luke's Hospital, Mount Sinai Health System, New York, New York. Electronic address: belevy@chpnet.org. 2. Virginia Cancer Specialists, Fairfax, Virginia; US Oncology Research, The Woodlands, Texas. 3. Beth Israel Hospital, St. Luke's Hospital, Mount Sinai Health System, New York, New York. 4. Abramson Cancer Center of the University of Pennsylvania, Philadelphia, Pennsylvania. 5. US Oncology Research, The Woodlands, Texas; Northwest Cancer Specialists, Portland, Oregon. 6. Division of Medical Oncology, University of Colorado School of Medicine, Aurora, Colorado. 7. University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. 8. Oncothyreon Inc., Seattle, Washington. 9. Mary Crowley Cancer Research Centers, Dallas, Texas. 10. Johns Hopkins University, Baltimore, Maryland; Memorial Sloan Kettering Cancer Center, New York, New York. 11. New York-Presbyterian Hospital, Columbia University Medical Center, New York, New York. 12. Division of Medical Oncology, University of Colorado School of Medicine, Aurora, Colorado; Section of Hematology/Oncology, Denver Veterans Affairs Medical Center, Denver, Colorado.
Abstract
INTRODUCTION: The phosphotidylinositol-3 kinase/serine-threonine kinase (AKT)/mammalian target of rapamycin signaling pathway is frequently altered in non-small-cell lung cancer (NSCLC). PX-866 is an oral, irreversible, pan-isoform inhibitor of phosphotidylinositol-3 kinase. Preclinical models revealed synergy with docetaxel and a phase 1 trial demonstrated tolerability of this combination. This randomized phase 2 study evaluated PX-866 combined with docetaxel in patients with advanced, refractory NSCLC. METHODS:Patients with locally advanced, recurrent, or metastatic NSCLC who had received at least one and no more than two prior systemic treatment regimens were randomized (1:1) to a combination of docetaxel (75 mg/m intravenous every 21 days) with or without PX-866 (8 mg orally daily; arms A and B, respectively). The primary end point was progression-free survival (PFS). Secondary end points included objective response rate, overall survival (OS), toxicity, and correlation of biomarker analyses with efficacy outcomes. RESULTS: A total of 95 patients were enrolled. Median PFS was 2 months in arm A and 2.9 months in arm B (p = 0.65). Objective response rates were 6% and 0% in arms A and B, respectively (p = 0.4). There was no difference in OS between the two arms (7.0 versus 9.2 months; p = 0.9). Grade 3 or higher adverse events were infrequent, but more common in the combination arm with respect to diarrhea (7% versus 2%), nausea (4% versus 0%), and vomiting (7% versus 0%). PIK3CA mutations or PTEN loss were infrequently observed. CONCLUSION: The addition of PX-866 to docetaxel did not improve PFS, response rate, or OS in patients with advanced, refractory NSCLC without molecular preselection.
RCT Entities:
INTRODUCTION: The phosphotidylinositol-3 kinase/serine-threonine kinase (AKT)/mammalian target of rapamycin signaling pathway is frequently altered in non-small-cell lung cancer (NSCLC). PX-866 is an oral, irreversible, pan-isoform inhibitor of phosphotidylinositol-3 kinase. Preclinical models revealed synergy with docetaxel and a phase 1 trial demonstrated tolerability of this combination. This randomized phase 2 study evaluated PX-866 combined with docetaxel in patients with advanced, refractory NSCLC. METHODS:Patients with locally advanced, recurrent, or metastatic NSCLC who had received at least one and no more than two prior systemic treatment regimens were randomized (1:1) to a combination of docetaxel (75 mg/m intravenous every 21 days) with or without PX-866 (8 mg orally daily; arms A and B, respectively). The primary end point was progression-free survival (PFS). Secondary end points included objective response rate, overall survival (OS), toxicity, and correlation of biomarker analyses with efficacy outcomes. RESULTS: A total of 95 patients were enrolled. Median PFS was 2 months in arm A and 2.9 months in arm B (p = 0.65). Objective response rates were 6% and 0% in arms A and B, respectively (p = 0.4). There was no difference in OS between the two arms (7.0 versus 9.2 months; p = 0.9). Grade 3 or higher adverse events were infrequent, but more common in the combination arm with respect to diarrhea (7% versus 2%), nausea (4% versus 0%), and vomiting (7% versus 0%). PIK3CA mutations or PTEN loss were infrequently observed. CONCLUSION: The addition of PX-866 to docetaxel did not improve PFS, response rate, or OS in patients with advanced, refractory NSCLC without molecular preselection.
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