Optimizing EGFR Targeted Therapy in Pancreatic Cancer

Review Article

Austin Pancreat Disord. 2017; 1(1): 1005.

Optimizing EGFR Targeted Therapy in Pancreatic Cancer

Baxevanos P¹ and Fountzilas C²*

¹Athens Naval Hospital and Veterans Medical Center, Greece

²Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, USA

*Corresponding author: Fountzilas C, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, USA

Received: May 15, 2017; Accepted: June 06, 2017; Published: June 13, 2017


Pancreatic cancer is one of the major causes of cancer related death in the western hemisphere. Despite years of research effort, advanced disease remains incurable with median survival of less than a year. Systemic therapy targeting the epidermal growth factor receptor (small molecule tyrosine kinase inhibitors and monoclonal antibodies) has promising preclinical activity but clinical efficacy has been proven to be modest at best. In this paper, we review relevant clinical trials and discuss potential solutions for anti-EGFR therapy.

Keywords: Pancreatic cancer; EGFR; Therapy optimization; Drug exposure; Biomarkers


EGF/EGFR: Epidermal Growth Factor/Epidermal Growth Factor Receptor; FcGR: Fc Gamma Receptors; FDA: Food and Drug Administration; FISH: Fluorescence In Situ Hybridization; HER2: Human Epidermal Growth Factor Receptor2; 5-FU: 5-Fluouracil; IGFR: Insulin-like Growth Factor Receptor; IHC: Immunohistochemistry; K-RAS: Kirsten Rat Sarcoma; nab: Nanoparticle Albumin Bound; mAb: Monoclonal Antibody; NCCN: National Comprehensive Cancer Network; NCIC-CTG: The National Cancer Institute of Canada Clinical Trials Group; OS: Overall Survival; PC: Pancreatic Cancer; PCR: Polymerase Chain Reaction; PFS: Progression-Free Survival; RET: Rearranged During Transfection; TKI: Tyrosine Kinase Inhibitor; VEGF/VEGFR: Vascular Endothelial Growth Factor/Vascular Endothelial Growth Receptor


Pancreatic cancer (PC) is the fourth most common cause of cancer-related death in the United States with an estimated 5-year survival rate of 8% [1]. Given the absence of early specific signs and symptoms and effective screening methods, PC is most frequently diagnosed at advanced stages (locally advanced or metastatic) [1]. In the late 1990s, gemcitabine was established as an active agent in advanced PC– mostly because of its palliative potential compared to 5-fluouracil (5-FU)– and became the standard of care and basis for further systemic therapy development [2]. The culmination of research for advanced PC over next two decades was the combination of oxaliplatin/irinotecan/5-FU (FOLFIRINOX) and gemcitabine plus nanoparticle albumin bound (nab)-paclitaxel as the most appropriate first-line options only in patients with good performance status [3,4]. Both approaches significantly prolonged overall survival (OS) compared to Gem alone but still most patients with advanced PC succumb to their disease after a median of 11 months [3]. The epidermal growth factor receptor (EGFR/HER1) is another potential target in PC as it is over expressed in up to 60% of cases [5] and EGFR inhibition was shown to have antitumor activity in preclinical PC models [6]. Erlotinib, a small molecule tyrosine kinase inhibitor (TKI) that can selectively target EGFR, has also resulted in a statistically significant prolongation of OS in combination with gemcitabine compared to gemcitabine as single agent [7]. This combination is approved by the National Comprehensive Cancer Network (NCCN) for the treatment of advanced PC but infrequently used by oncology providers given the modest prolongation of survival (less than 1 month) that was achieved [7,8].

Nevertheless, anti-EGFR targeted therapy with either TKIs or monoclonal antibodies remains a promising therapeutic approach, as long as we achieve better insight into the specific mechanisms that will help us use these agents in patients who are likely to benefit the most. In this manuscript, we will review major findings from phase 2 and 3 studies incorporating anti-EGFR therapy in advanced PC. Our purpose is to provide considerations regarding better patient selection and further development.

Summary of Clinical Findings

Erlotinib is a first generation EGFR TKI and presents the only Food and Drug Administration (FDA) approved targeted agent for advanced PC. The National Cancer Institute of Canada (NCIC) Clinical Trials Group (CTG) PA. 3 study was a randomized, placebocontrolled phase 3 trial (N=569) comparing the erlotinib/gemcitabine combination to gemcitabine alone [7]. Median OS and progressionfree survival (PFS) were superior in the active drug group (6.24 vs. 5.91 months, P=0.038; and 3.75 months v 3.55 months, P=0.004 respectively). There was an 18% relative decrease in the risk of death and 23% relative decrease in the risk of progression or death with erlotinib therapy. Individuals assigned to erlotinib therapy had more episodes of diarrhea and rash even though mild to moderate in severity; diarrhea secondary to erlotinib did appear to affect patients’ quality of life.

Gemcitabine with or without erlotinib has also been tested in patients with locally advanced disease. The LAP 07 study was a phase3 trial (N=449) randomizing patients with advanced, inoperable, non-metastatic PC to gemcitabine with or without erlotinib (first randomization); individuals who were progression-free after 4 months of therapy were randomized to continuation of the same regimen or concurrent chemo radiotherapy plus capecitabine [9]. This was a negative study for both the primary– the median OS from first randomization was 13.6 months for the gemcitabine/erlotinib combination vs. 11.9 months for gemcitabinemonotherapy, P=0.09– and secondary outcomes – OS from second randomization and PFS from first and second randomization were not different between groups. Moreover, EGFR TKIs have been tested in several phase II trials as a partner of variable chemotherapeutic drugs. A summary of the results of clinical trials with EGFR TKIs in advanced PC as firstline therapy is presented in (Table 1).

Citation: Baxevanos P and Fountzilas C. Optimizing EGFR Targeted Therapy in Pancreatic Cancer. Austin Pancreat Disord. 2017; 1(1): 1005.