Epidermal growth factor receptor (EGFR) is a cell surface receptor that binds to epidermal growth factor. The EGFR signaling pathway is one of the most important for regulation of growth, proliferation, and differentiation in mammalian cells. Overexpression of EGFR and its ligands has been demonstrated in many types of tumors, such as glioblastoma, head and neck squamous cell carcinoma (HNSCC), and lung, breast, and colorectal cancers (CRCs). Molecular alterations that lead to constitutive activation of EGFR signaling have been identified in a variety of tumors.
EGFR mutations were first identified in brain tumors in 1985. EGFR mutations produce an in-frame deletion in the extracellular domain of the receptor, most frequently EGFRvIII. Other mutations in the tyrosine-kinase (TK) domain of the EGFR gene demonstrate increased sensitivity to EGFR-TK inhibitors (TKIs) in non–small cell lung cancer (NSCLC). The mutations stimulate constitutive EGFR signaling, acting as driver mutations in oncogenesis.
EGFR Signaling Pathway
EGFR is a 170-kd glycoprotein with an extracellular ligand binding domain, a transmembrane lipophilic segment, and an intracellular TK domain. The human EGFR or ERBB family consists of four receptor TKs: EGFR/ERBB1, ERBB2, ERBB3, and ERBB4. Ligand binding causes EGFR to form homo- or heterodimers, thus activating a complex signaling network that promotes tumor proliferation, migration, stromal invasion, neovascularization, and resistance to apoptosis. EGFR signaling modulates multiple intracellular pathways: MAPK, PI3K-AKT, and signal transducer and activator of transcription proteins.
Targeting the Pathway
Effective therapeutics that have been approved by the U.S. Food and Drug Administration (FDA) for treatment of several cancers include agents that target the pathway with monoclonal antibodies (mAbs) and small-molecule TKIs:
- Cetuximab, a chimeric IgG1mAb9, and panitumumab, a fully human IgG2 mAB, inhibit binding of both EGFR and transforming growth factor (TGF)-a to block tyrosine phosphorylation and tumor cell proliferation; these drugs activate antibody-dependent cell-mediated cytotoxicity.
- Erlotinib and gefitinib, two EGFR-TKIs, inhibit tumor growth and enhance apoptosis.
Clinical trials of these agents have led to treatment indications for HNSCC, CRC, pancreatic cancer, and NSCLC.
Head and Neck Squamous Cell Carcinoma
EGFR is overexpressed in approximately 80% to 90% of patients with HNSCC and is associated with decreased survival.1
- Combination cetuximab and radiotherapy (RT) has demonstrated improved locoregional control and overall survival (OS) compared with RT alone in a randomized phase III trial.2 Follow-up at 5 years showed median survival of 49.0 months with the combination compared with 29.3 months with RT alone.3
- Improved progression-free survival (PFS) and OS rates were reported in a trial with cetuximab as first-line therapy for recurrent or metastatic HNSCC in combination with a platinum agent and infusional fluorouracil. In the study, 442 patients were randomly assigned to chemotherapy with or without cetuximab. PFS was 10.1 months for those treated with cetuximab compared with 7.4 months for those treated with chemotherapy alone (p = 0.04).4
These trials changed therapy for HNSCC, but the addition of cetuximab therapy results in clinical benefit only for approximately 20% of those treated. The limited efficacy of EGFR therapy in HNSCC is attributed to the complex signaling pathways involved, including interaction with MET and AKT activation.5
Most patients with CRC demonstrate high expression of EGFR, and this correlates with poor prognosis.
- The BOND trial showed a time to progression with cetuximab combined with irinotecan of 4.1 months compared with 1.5 months with cetuximab alone.6
- Cetuximab was compared with best supportive care in patients with CRC who were previously treated and those who could not tolerate standard therapy. Cetuximab resulted in improved OS with maintenance of quality of life, establishing the agent as valid therapy for refractory CRC in combination with irinotecan or as monotherapy.7
- Cetuximab as first-line therapy in combination with irinotecan was evaluated in association with KRAS mutation status in the CRYSTAL trial. The addition of cetuximab resulted in a modest improvement in PFS without an increase in OS in an unselected population; both PFS and OS were enhanced in patients with wild-type KRAS tumors when cetuximab was added to chemotherapy.8
- Panitumumab as single-agent therapy showed improved response rates and PFS of 8.0 weeks compared with 7.3 weeks with best supportive care in patients with refractory metastatic CRC.9
- A randomized phase III trial compared the first-line therapy of panitumumab and infusional FOLFOX4 with chemotherapy alone, and KRAS status was analyzed prospectively. The combination improved PFS by 1.6 months in patients with wild-type KRAS (p = 0.02), with nonsignificant improvement in OS.10
- Panitumumab combined with FOLFIRI was compared with FOLFIRI alone as second-line therapy for metastatic CRC, and KRAS status was analyzed prospectively. PFS improved in the combination therapy arm for patients with KRAS-mutant tumors (5.9 months vs. 3.9 months, p = 0.004). No significant difference in OS was seen.11
- Two studies evaluated bevacizumab, an anti-VEGF therapy, plus cetuximab and panitumumab in combination with chemotherapy. No clinical benefit was demonstrated in either trial.12,13
Studies have shown that only patients with tumors that have KRAS wild-type status should receive anti-EGFR monoclonal antibody therapy. Approximately 30% to 40% of patients with CRC have a KRAS mutation.
Non–Small Cell Lung Cancer
Elevated expression of EGFR is common in NSCLC. Early studies with EGFR-TKI therapy found an improved response in patients with adenocarcinoma, female sex, Asian ethnicity, and never-smoking status.
- The FDA gave accelerated review to gefitinib after promising phase II data; gefitinib was FDA approved for treatment of metastatic NSCLC with EGFR mutation in July 2015. Approval was based on a single-arm open-label study in 106 patients who were treatment naive and whose tumors had EGFR exon 19 deletions or exon 21 (L858R) substitution mutations. Objective response rate was 50%, and the median duration of response was 6 months.14
- A reversible EGFR-TKI agent, erlotinib, demonstrated OS of 6.7 months compared with 4.7 months with placebo (p < 0.01) and improved quality of life as a second- or third-line therapy for metastatic NSCLC.15 Multivariate analyses suggested that adenocarcinoma histology, never-smoking status, and EGFR expression correlated with response. Erlotinib was FDA approved for treatment of metastatic NSCLC with EGFR mutation in May 2013.16
- In a randomized open-label trial in patients with NSCLC with EGFR mutation, PFS was significantly prolonged in patients receiving afatinib compared with chemotherapy. In patients whose tumors had EGFR exon 19 deletions or exon 21 (L858R) substitution mutations, the median PFS was 13.6 months in the afatinib arm and 6.9 months in the chemotherapy arm.17,18 Afatinib was FDA approved for the treatment of metastatic NSCLC with EGFR mutation in July 2013.19
- A third-generation TKI inhibitor, osimertinib, was approved by the FDA in November 2015 for the treatment of patients with metastatic EGFR T790M mutation–positive NSCLC who have experienced progression during or after EGFR-TKI therapy.20
- Rociletinib has also shown activity in a phase I/II study of patients with EGFR-mutated NSCLC associated with the T790M resistance mutation.21
- A subsequent trial and subset analysis definitively identified mutation status as a predictive marker for EGFR-TKI therapy and supported molecular selection for patients with metastatic NSCLC.
- IPASS, a phase III trial, included chemotherapy-naive never-smokers, mostly of Asian ethnicity, with adenocarcinoma of the lung. The study demonstrated superior PFS with gefitinib therapy compared with carboplatin/paclitaxel chemotherapy. A subset analysis found that patients with EGFR mutations had superior PFS with gefitinib; patients with wild-type EGFR had superior PFS with chemotherapy.22
- Multiple trials have demonstrated increased response rates and PFS with first-line EGFR-TKI therapy in patients who have tumors with EGFR mutations. Analysis of OS has not shown significant differences in survival.23-28
Overcoming Mechanisms of Resistance
- Second- and third-generation EGFR-TKIs that irreversibly bind and inhibit multiple ERBB family members;
- Combination therapies using EGFR inhibition with MET, HSP90, AKT, SRC, and mTOR inhibitors; and
- The combination of cetuximab and afatinib, which has produced intriguing results, with a 36% response rate in EGFR-resistant tumors.29
The Future of EGFR-TKI Therapy
Further investigation of new agents and combinations will require additional biopsy specimens at the time of progression and resistance to EGFR-TKI therapy to better understand and overcome mechanisms of resistance. Molecular selection, either with KRAS in CRC or EGFR in NSCLC, can clearly identify specific populations that derive enhanced benefit and can provide insights about potential resistance. Further work is imperative to untangle the complex causes of primary and secondary resistance to EGFR therapy and make a dramatic impact on the lives of patients.
This ASCO Fact Sheet was condensed and updated from an editorial by Karen L. Reckamp, MD, published previously in the ASCO Daily News. Dr. Reckamp is an associate professor in the Department of Medical Oncology and Therapeutics Research and the co-director of the Lung Cancer and Thoracic Oncology Program at City of Hope Comprehensive Cancer Center.