A Randomized, Phase II Trial of Cetuximab With or Without PX-866, an Irreversible Oral Phosphatidylinositol 3-Kinase Inhibitor, in Patients With Metastatic Colorectal Carcinoma.
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 with metastatic CRC who had received both oxaliplatin and irinotecan were randomized (1:1) to cetuximab (400 mg/m2loading then 250 mg/m2weekly) 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.



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.



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.
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.
Daniel W
DW
Bowles
Oncology and Hematology Associates of SW Virginia, Roanoke, VA.
Mark
M
Kochenderfer
Rocky Mountain Cancer Centers, Denver, CO.
Allen
A
Cohn
Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada.
Lucas
L
Sideris
Centre de Sante et de Services Sociaux Champlin-Charles-LeMoyne, Longueuil, Quebec, Canada.
Nghia
N
Nguyen
Texas Oncology, Austin, TX.
Vivian
V
Cline-Burkhardt
Northwest Cancer Specialists, Vancouver, WA.
Ian
I
Schnadig
Karmanos Cancer Institute, Detroit, MI.
Minsig
M
Choi
University of Alabama-Birmingham, Birmingham, AL.
Lisle
L
Nabell
Medical Oncology Associates, Spokane, WA.
Arvind
A
Chaudhry
Texas Oncology-Ft. Worth, Ft. Worth, TX.
Robert
R
Ruxer
Advanced Medical Specialties, Miami, FL.
Antonio
A
Ucar
Oncothryeron, Inc, Seattle, WA.
Diana
D
Hausman
Oncothryeron, Inc, Seattle, WA.
Luke
L
Walker
Virginia Cancer Specialists, Fairfax, VA.
Alexander
A
Spira
Division of Medical Oncology, University of Colorado School of Medicine, Aurora, CO.
Antonio
A
Jimeno
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D000068818:Cetuximab / Q000008:administration & dosage* / Q000009:adverse effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality; D018572:Disease-Free Survival; D005260:Female; D006067:Gonanes / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged
D006067:Gonanes; C496788:PX-866; D000068818:Cetuximab
Combination therapy; EGFR; KRAS; PI3K; PIK3CA