Pharmacodynamic separation of gemcitabine and erlotinib in locally advanced or metastatic pancreatic cancer: therapeutic and biomarker results

Thomas Semrad, Afsaneh Barzi, Heinz Josef Lenz, Irene M. Hutchins, Edward Kim, I. Yeh Gong, Michael Tanaka, Laurel A Beckett, William Holland, Rebekah A. Burich, Leslie Snyder-Solis, Philip Mack, Primo N Lara

Research output: Contribution to journalArticle

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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 languageEnglish (US)
Pages (from-to)518-524
Number of pages7
JournalInternational Journal of Clinical Oncology
Volume20
Issue number3
DOIs
StatePublished - Aug 5 2014

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gemcitabine
Tumor Biomarkers
Pancreatic Neoplasms
Kirsten murine sarcoma virus
Parvovirus
Disease-Free Survival
Epidermal Growth Factor Receptor
Survival
Therapeutics
Safety
Mutation
Lymphopenia
Neutropenia
Intravenous Infusions
Protein-Tyrosine Kinases
Fatigue
Erlotinib Hydrochloride
Drug Therapy
DNA

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 journalArticle

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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/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.",
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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

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