Abstract
Purpose: Erlotinib marginally improves survival when administered continuously with gemcitabine to patients with advanced pancreatic cancer; however, preclinical data suggest that there is antagonism between chemotherapy and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors when these are delivered concurrently. We tested a pharmacodynamic separation approach for erlotinib plus gemcitabine and interrogated EGFR signaling intermediates as potential surrogates for the efficacy of this strategy. Methods: Patients with measurable, previously untreated locally advanced unresectable or metastatic pancreatic cancer were treated with gemcitabine 1000 mg/m<sup>2</sup> as an intravenous infusion over 30-min on days 1, 8, 15 and erlotinib 150 mg/day on days 2–5, 9–12, 16–26 of each 28-day cycle. The primary endpoint was progression-free survival (PFS); secondary endpoints included RECIST objective response rate (ORR) and safety. The study was terminated after thirty patients due to funding considerations. Results: The median PFS was 2.07 months (95 % CI; 1.87–5.50 months) and the ORR was 11 %. No unexpected safety signals were seen: the most common grade 3 or higher adverse events were neutropenia (23 %), lymphopenia (23 %), and fatigue (13 %). Patients with mutant plasma Kirsten rat sarcoma virus (KRAS) had significantly lower median PFS (1.8 vs. 4.6 months, p = 0.014) and overall survival (3.0 vs. 10.5 months, p = 0.003) than those without detected plasma KRAS mutations. Conclusions: Although pharmacodynamically separated erlotinib and gemcitabine were feasible and tolerable in patients with advanced pancreatic cancer, no signal for increased efficacy was seen in this molecularly unselected cohort. Detection of a KRAS mutation in circulating cell-free DNA was a strong predictor of survival.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 518-524 |
| Number of pages | 7 |
| Journal | International Journal of Clinical Oncology |
| Volume | 20 |
| Issue number | 3 |
| DOIs | |
| State | Published - Aug 5 2014 |
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Keywords
- Erlotinib
- Gemcitabine
- KRAS mutation
- Pancreatic cancer
- Pharmacodynamic separation
ASJC Scopus subject areas
- Oncology
- Surgery
- Hematology
Cite this
Pharmacodynamic separation of gemcitabine and erlotinib in locally advanced or metastatic pancreatic cancer : therapeutic and biomarker results. / Semrad, Thomas; Barzi, Afsaneh; Lenz, Heinz Josef; Hutchins, Irene M.; Kim, Edward; Gong, I. Yeh; Tanaka, Michael; Beckett, Laurel A; Holland, William; Burich, Rebekah A.; Snyder-Solis, Leslie; Mack, Philip; Lara, Primo N.
In: International Journal of Clinical Oncology, Vol. 20, No. 3, 05.08.2014, p. 518-524.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Pharmacodynamic separation of gemcitabine and erlotinib in locally advanced or metastatic pancreatic cancer
T2 - therapeutic and biomarker results
AU - Semrad, Thomas
AU - Barzi, Afsaneh
AU - Lenz, Heinz Josef
AU - Hutchins, Irene M.
AU - Kim, Edward
AU - Gong, I. Yeh
AU - Tanaka, Michael
AU - Beckett, Laurel A
AU - Holland, William
AU - Burich, Rebekah A.
AU - Snyder-Solis, Leslie
AU - Mack, Philip
AU - Lara, Primo N
PY - 2014/8/5
Y1 - 2014/8/5
N2 - Purpose: Erlotinib marginally improves survival when administered continuously with gemcitabine to patients with advanced pancreatic cancer; however, preclinical data suggest that there is antagonism between chemotherapy and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors when these are delivered concurrently. We tested a pharmacodynamic separation approach for erlotinib plus gemcitabine and interrogated EGFR signaling intermediates as potential surrogates for the efficacy of this strategy. Methods: Patients with measurable, previously untreated locally advanced unresectable or metastatic pancreatic cancer were treated with gemcitabine 1000 mg/m2 as an intravenous infusion over 30-min on days 1, 8, 15 and erlotinib 150 mg/day on days 2–5, 9–12, 16–26 of each 28-day cycle. The primary endpoint was progression-free survival (PFS); secondary endpoints included RECIST objective response rate (ORR) and safety. The study was terminated after thirty patients due to funding considerations. Results: The median PFS was 2.07 months (95 % CI; 1.87–5.50 months) and the ORR was 11 %. No unexpected safety signals were seen: the most common grade 3 or higher adverse events were neutropenia (23 %), lymphopenia (23 %), and fatigue (13 %). Patients with mutant plasma Kirsten rat sarcoma virus (KRAS) had significantly lower median PFS (1.8 vs. 4.6 months, p = 0.014) and overall survival (3.0 vs. 10.5 months, p = 0.003) than those without detected plasma KRAS mutations. Conclusions: Although pharmacodynamically separated erlotinib and gemcitabine were feasible and tolerable in patients with advanced pancreatic cancer, no signal for increased efficacy was seen in this molecularly unselected cohort. Detection of a KRAS mutation in circulating cell-free DNA was a strong predictor of survival.
AB - Purpose: Erlotinib marginally improves survival when administered continuously with gemcitabine to patients with advanced pancreatic cancer; however, preclinical data suggest that there is antagonism between chemotherapy and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors when these are delivered concurrently. We tested a pharmacodynamic separation approach for erlotinib plus gemcitabine and interrogated EGFR signaling intermediates as potential surrogates for the efficacy of this strategy. Methods: Patients with measurable, previously untreated locally advanced unresectable or metastatic pancreatic cancer were treated with gemcitabine 1000 mg/m2 as an intravenous infusion over 30-min on days 1, 8, 15 and erlotinib 150 mg/day on days 2–5, 9–12, 16–26 of each 28-day cycle. The primary endpoint was progression-free survival (PFS); secondary endpoints included RECIST objective response rate (ORR) and safety. The study was terminated after thirty patients due to funding considerations. Results: The median PFS was 2.07 months (95 % CI; 1.87–5.50 months) and the ORR was 11 %. No unexpected safety signals were seen: the most common grade 3 or higher adverse events were neutropenia (23 %), lymphopenia (23 %), and fatigue (13 %). Patients with mutant plasma Kirsten rat sarcoma virus (KRAS) had significantly lower median PFS (1.8 vs. 4.6 months, p = 0.014) and overall survival (3.0 vs. 10.5 months, p = 0.003) than those without detected plasma KRAS mutations. Conclusions: Although pharmacodynamically separated erlotinib and gemcitabine were feasible and tolerable in patients with advanced pancreatic cancer, no signal for increased efficacy was seen in this molecularly unselected cohort. Detection of a KRAS mutation in circulating cell-free DNA was a strong predictor of survival.
KW - Erlotinib
KW - Gemcitabine
KW - KRAS mutation
KW - Pancreatic cancer
KW - Pharmacodynamic separation
UR - http://www.scopus.com/inward/record.url?scp=84930570411&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84930570411&partnerID=8YFLogxK
U2 - 10.1007/s10147-014-0730-2
DO - 10.1007/s10147-014-0730-2
M3 - Article
C2 - 25091263
AN - SCOPUS:84930570411
VL - 20
SP - 518
EP - 524
JO - International Journal of Clinical Oncology
JF - International Journal of Clinical Oncology
SN - 1341-9625
IS - 3
ER -