Daniel W Bowles1, Mark Kochenderfer2, Allen Cohn3, Lucas Sideris4, Nghia Nguyen5, Vivian Cline-Burkhardt6, Ian Schnadig7, Minsig Choi8, Lisle Nabell9, Arvind Chaudhry10, Robert Ruxer11, Antonio Ucar12, Diana Hausman13, Luke Walker13, Alexander Spira14, Antonio Jimeno15. 1. Denver Veterans Affairs Medical Center, Denver, CO; Division of Medical Oncology, University of Colorado School of Medicine, Aurora, CO. Electronic address: daniel.bowles@ucdenver.edu. 2. Oncology and Hematology Associates of SW Virginia, Roanoke, VA. 3. Rocky Mountain Cancer Centers, Denver, CO. 4. Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada. 5. Centre de Sante et de Services Sociaux Champlin-Charles-LeMoyne, Longueuil, Quebec, Canada. 6. Texas Oncology, Austin, TX. 7. Northwest Cancer Specialists, Vancouver, WA. 8. Karmanos Cancer Institute, Detroit, MI. 9. University of Alabama-Birmingham, Birmingham, AL. 10. Medical Oncology Associates, Spokane, WA. 11. Texas Oncology-Ft. Worth, Ft. Worth, TX. 12. Advanced Medical Specialties, Miami, FL. 13. Oncothryeron, Inc, Seattle, WA. 14. Virginia Cancer Specialists, Fairfax, VA. 15. Division of Medical Oncology, University of Colorado School of Medicine, Aurora, CO.
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 II study evaluated cetuximab with or without PX-866 in patients with metastatic, anti-epidermal growth factor receptor-naive, KRAS codon 12 and 13 wild-type CRC. PATIENTS AND METHODS: Patients with metastatic CRC who had received bothoxaliplatin and irinotecan were randomized (1:1) to cetuximab (400 mg/m2 loading then 250 mg/m2 weekly) with or without PX-866 (8 mg orally daily; arms A and B, respectively). The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate, overall survival (OS), toxicity, and correlation of relevant biomarkers with efficacy outcomes. RESULTS: A total of 85 patients were enrolled. The median PFS was 59 days versus 104 days for arms A (cetuximab + PX-866) and B (cetuximab alone), respectively (P = .77). OS between the 2 arms (266 vs. 333 days for arm A vs. B) were similar (P = .83). Overall toxicity, including treatment-related toxicity, was higher in arm A compared with 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, objective response rate, or OS in patients with metastatic CRC. The combination arm had greater toxicity and may have been harmful in this study. Published by Elsevier Inc.
RCT Entities:
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 II study evaluated cetuximab with or without PX-866 in patients with metastatic, anti-epidermal growth factor receptor-naive, KRAS codon 12 and 13 wild-type CRC. PATIENTS AND METHODS: Patients with metastatic CRC who had received both oxaliplatin and irinotecan were randomized (1:1) to cetuximab (400 mg/m2 loading then 250 mg/m2 weekly) with or without PX-866 (8 mg orally daily; arms A and B, respectively). The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate, overall survival (OS), toxicity, and correlation of relevant biomarkers with efficacy outcomes. RESULTS: A total of 85 patients were enrolled. The median PFS was 59 days versus 104 days for arms A (cetuximab + PX-866) and B (cetuximab alone), respectively (P = .77). OS between the 2 arms (266 vs. 333 days for arm A vs. B) were similar (P = .83). Overall toxicity, including treatment-related toxicity, was higher in arm A compared with 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, objective response rate, or OS in patients with metastatic CRC. The combination arm had greater toxicity and may have been harmful in this study. Published by Elsevier Inc.
Authors: Julia Thierauf; Nisha Ramamurthy; Vickie Y Jo; Hayley Robinson; Ryan P Frazier; Jonathan Gonzalez; Maciej Pacula; Enrique Dominguez Meneses; Vania Nose; Valentina Nardi; Dora Dias-Santagata; Long P Le; Derrick T Lin; William C Faquin; Lori J Wirth; Jochen Hess; A John Iafrate; Jochen K Lennerz Journal: Oncologist Date: 2019-03-29