Molecular Markers and Targeted Therapies in the Management of Non-Small Cell Lung Cancer

EGFR MUTATIONS

CASE PRESENTATION 1

A 54-year-old Caucasian man who is a former smoker with a 10 pack-year history and past medical history of hypertension and dyslipidemia presents with progressive dyspnea for several weeks. A chest x-ray shows moderate pleural effusion on the left side with possible mass-like opacity on the left upper lung field. An ultrasound-guided thoracentesis is performed and cytology is positive for adenocarcinoma of likely pulmonary origin. Staging workup including positron emission tomography (PET)/computed tomography (CT) and magnetic resonance imaging of the brain with and without contrast is done. PET/CT shows a 5.5-cm mass in the left upper lobe of the lung with high fluorodeoxyglucose (FDG) uptake, several 1- to 2-cm mediastinal lymph nodes with moderate FDG uptake, and small pleural effusion on both sides with moderate FDG uptake. MRI-brain is negative for malignancy. The patient subsequently undergoes a CT-guided biopsy of the lung mass, which shows moderately differentiated adenocarcinoma. Comprehensive molecular profiling reveals EGFR L858R mutation only. The patient now presents for the initial consultation. Of note, his Eastern Cooperative Oncology Group performance status is 1.

• What is the next step in the management of this patient?

FIRST-LINE TKI FOR SENSITIZING EGFR MUTATIONS

The 2 most common EGFR mutations are deletions in exon 19 and substitution of arginine for leucine in exon 21 (L858R), found in approximately 45% and 40% of patients with EGFR mutations, respectively.³⁶ Both mutations are sensitive to EGFR TKIs. The benefit may be greater in patients with exon 19 deletions as compared to exon 21 L858R substitution,^37,38 but this has not been demonstrated consistently in clinical trials.^39-43 In the United States, EGFR mutations are found in approximately 10% of patients with NSCLC, while the incidence can be as high as 50% in Asia.⁴⁴ Even though the cobas EGFR mutation test is the companion diagnostic approved by the US FDA, a positive test result from any laboratory with the Clinical Laboratory Improvement Amendments (CLIA) certificate should prompt the use of an EGFR TKI as the initial treatment.

Three EGFR TKIs that have been approved as first-line therapy in the United States are available: erlotinib, afatinib, and gefitinib.⁵ Both erlotinib and gefitinib are considered first-generation TKIs. They have higher binding affinity for the 2 common EGFR mutations than wild-type EGFR. In addition, they reversibly bind to the intracellular tyrosine kinase domain, resulting in inhibition of autophosphorylation of the tyrosine residues. Afatinib, a second-generation and irreversible TKI, targets EGFR (HER1) as well as HER2 and HER4.⁴⁵

The superior efficacy of the EGFR TKIs over platinum doublet chemotherapy in treatment-naïve patients with EGFR mutations has been demonstrated in 7 randomized trials to date (Table).⁴⁶ Erlotinib was the TKI arm for the OPTIMAL,⁴¹ EURTAC,⁴² and ENSURE trials;³⁸ afatinib was the TKI arm for LUX-LUNG 3³⁷ and 6;⁴³ gefitinib was the TKI arm for NEJ002^39,47 and WJTOG3405.⁴⁰ A meta-analysis of these 7 trials by Lee et al showed that progression-free survival (PFS) was significantly prolonged by EGFR TKIs (hazard ratio [HR] 0.37 [95% confidence interval {CI} 0.32 to 0.42]).⁴⁶ For instance, in the EURTAC trial, median PFS was 9.7 months for patients treated with erlotinib as compared to 5.2 months for patients treated with platinum/gemcitabine or platinum/docetaxel.⁴² In this meta-analysis, prespecified subgroups included age, sex, ethnicity, smoking status, performance status, tumor histology, and EGFR mutation subtype. The superior outcome with TKIs was observed in all subgroups. Furthermore, patients with exon 19 deletions, nonsmokers, and women had even better outcomes.⁴⁶

Erlotinib is the most commonly used TKI in the United States largely because gefitinib was off the market for some time until it was re-approved by the FDA in 2015. Interestingly, this “re-approval” was not based on either 1 of the 2 prospective trials (NEJ002^39,47 and WJTOG3405⁴⁰), but rather was based on an exploratory analysis of the IPASS trial^48,49 as well as a prospective phase 4, single-arm trial in Europe (IFUM).⁵⁰ The superior efficacy of gefitinib over carboplatin/paclitaxel among patients with EGFR mutations in the IPASS trial was confirmed by blind independent central review, with longer PFS (HR 0.54 [95% CI 0.38 to 0.79] P = 0.0012) and higher objective response rate (ORR; odds ratio 3 [95% CI 1.63 to 5.54], P = 0.0004).⁴⁹