EGFR- mutant advanced NSCLC
The incidence of somatic EGFR mutation in advanced NSCLC is approximately 20% in Caucasian patients, but higher incidence rates of about 48% have been found among patients of East Asian ethnicity [24]. The incidence of mutation also correlates with histologic type of NSCLC, sex and age of patient and smoking history. [25]EGFR belongs to a receptor kinase family that also includes human HER2(ERBB3) and HER3 (ERBB4) [26]. The most commonly seen mutations are EGFR exon 19 deletion or missense point mutation on exon 21 (EGFR L858R),associated with increased sensitivity to EGFR tyrosine kinase inhibitors (TKI) [26].First-generation EGFR TKIs, including gefitinib and erlotinib, resulted inhigher objective response rates (ORRs) and progression-free survival (PFS) compared to cytotoxic therapy in previously untreated patients with EGFR mutations [27-31]. In a meta-analysis of randomized trials of the EGFR tyrosine kinase inhibitors gefitinib, erlotinib and afatinib, significant improvement was seen in ORR and PFS, as compared with first-line chemotherapy (PFS 9.6-13.1 months versus4.6-6.9 months; (HR)for progression or death, 0.37; 95% confidence interval (CI), 0.32 to 0.41; p<0.001) [32].
In contrast to the first-generation EGFR TKIs gefitinib and erlotinib, which are reversible competitive ATP inhibitors targeting only EGFR, second-generation inhibitors including afatinib and dacomitinib are irreversible inhibitors that also target HER2 and HER4. Second-generation TKIsafatinib and dacomitinibdemonstrated improved PFS when compared to first generation TKI gefitinib[33, 34]. Despite impressive initial responses to both first- and second-generation EGFR TKIs, most patients experience disease progression after 9-12 months of treatment, indicating the frequent emergence of resistance to these agents.
Many mechanisms of resistance have been known by which first and second generation TKIs become ineffective in patients taking it. The most common is a second mutation in exon 20, with a threonine-to-methionine substitution on codon 790 (T790M). [35] This eventually causes resistance either due to tyrosine kinase domain having increased affinity for ATP or from steric hindrance. [35 ] Other mechanisms of acquired resistance include SCLC transformation, mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit-alpha (PIK3CA) , MET or BRAF and  amplifications in HER 2. [36] Nearly 60% of patients develop resistance after first- or second-generation EGFR TKI due to T790M mutation and third generation EGFR TKI can specifically overcome it. [36]Therefore, it becomes important to repeat next generation sequencing at the time of disease progression. [36] Osimertinib, a third generation irreversible EGFR TKI targeting T790M mutation, binds covalently to cysteine on codon 797, overcoming the resistance.  [37, 38]Osimertinib has now been FDA approved as upfront treatment for advanced NSCLC patients with exon 19 deletion or L858R sensitizing mutation replacing first and second generation TKIs. [39]This is based on efficacy and safety data results of the FLAURA trial.  In this double-blind phase III randomized control study, 556 treatment naive EGFR mutation-positive advanced NSCLC patients were assigned to either receive osimertinib or standard EGFR-TKI (gefitinib or erlotinib) in 1:1 ratio. Osimertinib was found to have superior efficacy with median PFS 18.9 months vs 10.2 months ; p<0.001 and median OS 38.6 vs 31.8 months;p= 0.046 compared with erlotinib and gefitinib. Some other favorable outcomes with osimertinib were lower rates and grades of side-effects, fewer cases of central nervous system progression and improved post-progression outcomes.[40]
Unfortunately, patients eventually progress on osimertinib as well indicating resistance to the drug. One of the mechanisms suggested is acquisition of C797S mutation which along with L858R sensitizing mutation leads to resistance to third generation EGFR TKIs. [41] Patients with mutation in T790M, C797S and sensitizing mutations are called triple mutants and it causes resistance to all three generations of EGFR TKIs.[42] In order to overcome resistance caused by triple mutation, various strategies are being tried. Cetuximab, an anti-EGFR monoclonal antibody, is being used along with allosteric inhibitor EAI045 in patients with L858-R sensitizing mutation and an ALK inhibitor, brigatinib, known to have activity against EGFR mutations, in tumors with exon 19 deletion. [43,44]
Combinatorial approaches in the treatment of metastatic lung adenocarcinoma have shown promise. The combination of ramucirumab plus erlotinibwas approved by FDA for upfront treatment of patients with metastatic NSCLC whose tumors have EGFR exon 19 deletion or exon 21 (L858R) substitution mutation, based on a phase III multinational, randomized, double-blind, placebo-controlled trial, the RELAY trial[45]. A 1:1 randomization of 449 patients was done to receive oral erlotinib (150 mg/day) plus either intravenous ramucirumab (10 mg/kg) or matching placebo once every 2 weeks. Ramucirumab plus erlotinib group showed significantly longer PFS compared to erlotinib plus placebo (19.4 months; 95% CI, 15.4–21.6 versus 12.4 months;95% CI,11.0–13.5, respectively) with a HR of 0.59 (95% CI 0.46–0.76; p<0.0001) [45].