TY - JOUR
T1 - 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
AU - Bowles, Daniel W.
AU - Kochenderfer, Mark
AU - Cohn, Allen
AU - Sideris, Lucas
AU - Nguyen, Nghia
AU - Cline-Burkhardt, Vivian
AU - Schnadig, Ian
AU - Choi, Minsig
AU - Nabell, Lisle
AU - Chaudhry, Arvind
AU - Ruxer, Robert
AU - Ucar, Antonio
AU - Hausman, Diana
AU - Walker, Luke
AU - Spira, Alexander
AU - Jimeno, Antonio
N1 - Funding Information:
This clinical trial was sponsored by Oncothyreon Inc. No funding was received from the National Institutes of Health, Wellcome Trust, or Howard Hughes Medical Institute.
Publisher Copyright:
© 2016
PY - 2016/12/1
Y1 - 2016/12/1
N2 - The phosphotidyinositol-3 kinase (PI3K) pathway in frequently activated on metastatic colorectal carcinoma (CRC). We combined a novel PI3K inhibitor, PX-866, with cetuximab for patients with KRAS codon 12 wide type metastatic CRC. Patients receiving PX-866 plus cetuximab did not improvement in response rate, progression-free survival, or overall survival compared to cetuximab alone. Toxicity, especially gastrointestinal, was higher in the combination arm. 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.
AB - The phosphotidyinositol-3 kinase (PI3K) pathway in frequently activated on metastatic colorectal carcinoma (CRC). We combined a novel PI3K inhibitor, PX-866, with cetuximab for patients with KRAS codon 12 wide type metastatic CRC. Patients receiving PX-866 plus cetuximab did not improvement in response rate, progression-free survival, or overall survival compared to cetuximab alone. Toxicity, especially gastrointestinal, was higher in the combination arm. 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.
KW - Combination therapy
KW - EGFR
KW - KRAS
KW - PI3K
KW - PIK3CA
UR - http://www.scopus.com/inward/record.url?scp=84964671208&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84964671208&partnerID=8YFLogxK
U2 - 10.1016/j.clcc.2016.03.004
DO - 10.1016/j.clcc.2016.03.004
M3 - Article
C2 - 27118441
AN - SCOPUS:84964671208
SN - 1533-0028
VL - 15
SP - 337-344.e2
JO - Clinical colorectal cancer
JF - Clinical colorectal cancer
IS - 4
ER -