Activation of the EGFR pathway influences several oncogenic processes, including cell proliferation, resistance to apoptosis, migration, invasion, and angiogenesis. The EGFR protein is expressed in approximately 85 % of NSCLC, and its gene has become an interesting target for lung cancer therapy as a result of the development of the small tyrosine kinase inhibitors (TKIs) gefitinib, erlotinib, and afatinib. Gefitinib and erlotinib are reversible inhibitors that specifically target the EGFR protein, while afatinib is an irreversible inhibitor that binds covalently to EGFR and the other members of the ERBB family, including HER2, ERBB3, and ERBB4. Investigation has shown that the presence of a mutation in the exons coding for the tyrosine kinase domain provides with a protein that functions as a cancer driver that is sensitive to TKI activity. More than 40 different mutation sites have been identified in the EGFR gene, the most common being a deletion in exon 19 (Del19) and the point mutation in exon 21 (L585R); both of these account for more than 85 % of all detected mutations [27]. EGFR mutations can be found in approximately 17 % of Caucasian and 40 % of East-Asian patients with lung ADC and are more common in nonsmokers. PCR-based EGFR mutation testing is routinely performed in the diagnostic develop of non-squamous NSCLC [26]. The clinical activity of EGFR-TKI in patients harboring an EGFR mutation has been determined in a number of clinical trials in which more than 1800 patients with advanced EGFR mutation-positive lung cancer have been randomly assigned to receive either EGFR-TKI (erlotinib [28, 29], gefitinib [30–32] or afatinib [33]) or conventional platinum-based chemotherapy. All studies have presented considerable advantages for TKIs in terms of PFS compared with chemotherapy alone. The median PFS was 9.2–13.6 versus 4.6–6.9 months for TKIs compared to chemotherapy alone, respectively. Conclusively, in terms of OS, all trials have presented similar results for TKIs and chemotherapy alone, probably due to the large number of patient intersecting to TKIs after progression on chemotherapy. Nevertheless, it is notable that a combined analysis of the two trials comparing afatinib to chemotherapy has presented little but significant difference of 3 months in median OS favoring afatinib in the subgroup of patients (89 %) harboring the most common EGFR mutations, Del19 and L858R [34]. To improve the activity of TKIs in the first-line chemotherapy, combination strategies have also been investigated. In a recent study, erlotinib was managed alone or combined with the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab as first-line chemotherapy in patients with EGFR-mutated lung ADC [35]. Median PFS was almost doubled by the addition of bevacizumab to erlotinib (16.0 vs. 9.7 months with erlotinib alone). OS data were not established at the time of publication. Further trials investigating the potential of this regimen are ongoing. Despite the high level of activity demonstrated by EGFR-TKI, patients’ tumor eventually progressed after a median period of nearly 10 months. Considerable research is currently focused on understanding the mechanism underlying the development of resistance to EGFR-TKI. The major mechanism is the acquirement of another mutation in exon 20 (T790M), which moderates the ATP-binding domain and significantly reduces the inhibition capabilities of TKIs. A T790M mutation is detected in more than 50 % of patients progressing on TKI. Other potential molecular changes with TKI resistance are MET amplification, HER2 amplification, PIK3CA mutations, and histological transformation into small-cell lung cancer.

Recently, third-generation EGFR inhibitors AZD9291, rociletinib, and HM61713 have produced extremely suggesting results. These drugs are specifically designed to target the T790M mutation but are also effective toward the other more common essential EGFR mutations. Expansion programs as well as randomized trials for this chemical substance are currently ongoing [36].

The discovery of ALK rearrangements represents another major breakthrough in the area of targeted therapies for NSCLC. Although this molecular change is detected in only 3–5 % of patients with lung ADC, considerable research has been dedicated to the clinical development of potent and specific ALK inhibitors, resulting in a time distance of only 4 years between the first account of ALK in lung cancer (in 2007) and approval by the Food and Drug Administration (FDA) of the first inhibitor, crizotinib (in 2011). The ALK gene is expressed as a result of fusion with another gene, the most common being EML4 in lung cancer. This fusion generates the expression of a kinase with high oncogenic potential that is mainly involved in cell proliferation (Fig. 18.1). The gold standard and FDA-approved method to detect ALK alterations in lung cancer is a break-apart fluorescence in situ hybridization (FISH) assay. However, FISH is relatively expensive and requires highly trained pathologists, since it may be difficult to identify and properly interpret the presence of split signals within the same chromosome, as often occurring with the ALK gene. Recently, an IHC assay targeting the effector protein has been developed and validated on a large scale and is likely to replace FISH as the standard diagnostic method for ALK expression in lung cancer [37]. In terms of clinical activity, crizotinib provides a better RR and PFS compared to chemotherapy in both the first-line (10.9 vs. 7.0 months with chemotherapy alone) and second-line setting (7.7 vs. 3.0 months with chemotherapy alone) [38, 39]. Again no differences in OS were observed between the crizotinib and chemotherapy arms, probably due to the frequent crossover to crizotinib at progression for patients assigned to receive chemotherapy.

As described with EGFR mutations, resistance to first-generation inhibitors in patients harboring ALK rearrangements is a matter of concern. The most common resistance mechanisms are the development of additional ALK mutations, ALK amplification, activation of EGFR signaling, and KIT amplification [40]. Furthermore, because penetration of crizotinib to the central nervous system (CNS) is poor, it is common to observe isolated CNS progression while other tumor localizations are still in reduction. Second-generation inhibitors, such as ceritinib, alectinib, and AP26113, have shown substantial activity against multiple ALK mutations and clinical effect in patients progressing on crizotinib. Thus far, ceritinib is the only approved ALK inhibitor besides crizotinib [41]. Several clinical trials comparing second-generation inhibitors to chemotherapy as well as adjacent association between the ALK inhibitors are ongoing to assess the best sequence of systemic therapy for ALK-positive lung cancer patients.

Approximately 1 % of lung ADC cases harbor a rearrangement in another fusion gene, ROS1. ALK and ROS1 share 70 % homology to crizotinib with similar response profiles [42]. It is very probable that the development of the other ALK inhibitors will lead to considerable benefit for the management of ROS1-positive lung cancer patients.