Guideline: Patients with advanced NSCLC harbouring an activating EGFR mutation should receive an EGFR TKI in the first line setting.
Level of Evidence: I
Ten to 15% of all NSCLC have a somatic mutation within the EGFR gene at exons 18-21. 90% of those mutations are either a deletion in exon 19 or a point mutation in exon 21. Most pathology labs including the BCCA lab test for these 2 common activating mutations. When these mutations are present, the EGFR, also known as EbrB1/HER1 in the 4 member ErbB family, is abnormally activated. This abnormal activation results in an enzymatic cell-signalling cascade kicked off by the phosphorylation of the intracellular component of the transmembrane EGFR by the EGFR tyrosine kinase. EGFR tyrosine kinase inhibitors (EGFR TKIs) interfere with the activation and down-stream signalling of EGFR and have anti-tumour activity in EGFR mutated (EGFRm+) NSCLC.2Adenocarcinoma histology, Asian background, female gender and non-smoker status increase the likelihood of a patient with NSCLC harbouring an EGFR mutation but clinical profiling is not considered an appropriate replacement for mutation testing.2-3
Gefitinib and erlotinib are known as first-generation, reversible, EGFR TKIs. They have both shown activity in advanced NSCLC harbouring activating EGFR mutations. Among the two summarized below, several phase III clinical trials have demonstrated that these EGFR TKIs are superior to chemotherapy in the first-line treatment of EGFRm+ NSCLC.
The Iressa Pan Asian Study (IPASS) randomized Asian non-smokers or former light smokers with adenocarcinoma to either gefitinib or carboplatin and paclitaxel. Of the 1200 patients involved in this study 437 had tumour specimens suitable for EGFR mutation testing and 59.7% of these were EGFR mutation positive. In those patients the RR for gefitinib was 71.2% versus 47.2% for the chemotherapy. Median PFS (mPFS) also favoured the gefitinib (9.5 versus 6.3 months, HR 0.48). Median OS (mOS) was not significantly different between the 2 arms (22 months for both). This was likely because of significant crossover (almost 40% in each arm). Quality of life (QOL) data significantly favoured the gefitinib arm. 4-5
The European Tarceva versus Chemotherapy (EURTAC) trial randomized 174 non-Asian EGFRm+ patients with advanced NSCLC to either first line erlotinib or chemotherapy (either cisplatin/gemcitabine or cisplatin/docetaxel). This study was halted at the first interim analysis. Like IPASS the RR was better in the erlotinib arm than the chemotherapy arm (58% versus 15%) as was the mPFS (9.7 versus 5.2 months, HR 0.37, 95% CI 0.25-0.54). Also like IPASS there was no significant difference in mOS (19.3 months for erlotinib and 19.5 months for chemotherapy). Unfortunately there was poor compliance with symptom questionnaires and QOL data was not captured.6
Not all patients with EGFRm+ cancers respond to first generation EGFR TKIs (primary resistance) and the majority of those who do will ultimately develop secondary resistance. Primary resistance can occur through a mutation of the T790 domain of exon 20 which encodes the tyrosine kinase part of the EGFR. Other gene mutations likely account for the other mechanisms of resistance to first-generation EGFR TKIs.
Afatinib is a second-generation, irreversible, inhibiter of EGFR (ErbB1) as well as other members of the ErbB family. Preclinical data and non-randomized clinical studies suggest that afatinib may be able to overcome and even prevent the resistance of EGFRm+ NSCLC to the first-generation EGFR TKIs. For example Afatinib has been shown to block mutations inT790 of exon 20.7 Afatinib has also been compared favourably to first-line chemotherapy in randomized trials.
The LUX-Lung 3 trial randomized 345 EGFRm+ patients in a 2:1 fashion to afatinib or the chemotherapy regimen many would consider optimal in these adenocarcinoma patients: cisplatin and pemetrexed. RR was higher in the afatinib group (56.1% versus 22.6%) as was mPFS (11.1 months versus 6.9 months; HR 0.58). With a predefined analysis in those with the common exon 19 and 21 mutations the mPFS advantage of afatinib over chemotherapy was even more pronounced (13.6 months versus 6.9 months; HR 0.47; p<0.0001). HRQol as well as improvements in dyspnea and fatigue were greater with afatinib.8-9 The LUX-Lung 6 trial reinforced the findings of LUX-Lung 3 in a randomized comparison of afatinib with cisplatin and gemcitabine.10
These and other randomized studies as well as a meta-analysis of data from 13 phase III clinical trials confirm the relative value of EGFR TKIs over chemotherapy in the setting of first-line systemic therapy for EGFRm+ NSCLC with respect to RR and PFS.11 While there are no completed randomized trials that compare the different EGFR TKIs with each other there is an ongoing randomized study of the comparative efficacy and toxicity of afatinib and gefitinib. Gefitinib, erlotinib and Afatinib are all Health Canada approved for EGFRm+ patients.
EGFR TKIs are generally better tolerated than chemotherapy. Typical side-effects of EGFR TKIs are dry skin, acneiform rash, stomatitis, diarrhea and paronychia. Rare but clinically important pulmonary and hepatic toxicity may also occur. It is felt that afatinib, because of it’s affinity for multiple targets within the ErbB family, has higher toxicity compared to the first-generation EGFR TKIs but without direct randomized comparisons this is unconfirmed.
Treatment with first-line EGFR TKI usually continues until there is disease progression or intolerable toxicity. Second-line therapy in this circumstance involves the same platin-doublet chemotherapy regimens used in the first-line setting for those with EFGR wild type (EGFRwt) NSCLC. Refer to the section Systemic Therapy for Advanced NSCLC Without Actionable Driver Mutations. It is usually advised that chemotherapy begin, if possible, soon after withdrawal of EGFR TKIs, particularly in those with prolonged benefit, as rapid disease progression has been observed in this setting.
A phase II study (LUX-Lung 1) of afatinib in a small group of patients with acquired resistance to gefitinib or erlotinib showed an encouraging rate of disease control but further, larger, trials will be needed to support the use of this second-generation EGFR TKI in this particular setting.12
Lastly, several large randomized studies in patients not tested for EGFR mutations showed no benefit to the addition of a first-generation EFGR TKIs to platin-doublet chemotherapy. Whether patients with EGFRm+ NSCLC benefit from the addition of EGFR TKIs to chemotherapy remains an area of research interest.