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has higher efficacy against the exon 19 deletion [35,36] . The exon 20 insertion also leads to innate resistance
against afatinib.

Moving to clinical implications of EGFR inhibition, two seminal studies firstly described responsiveness
to gefitinib in EGFR-mutated NSCLC [37,38] , opening a new landscape for the treatment of oncogene-
addicted lung cancer. Phase III trials have further explored the efficacy of first- and second-generation
TKIs in this setting: a significant clinical benefit was observed for all the compounds in comparison with
chemotherapy, in terms of progression-free survival (PFS), response rates and disease control rates. Indeed,
the median PFS of first- and second-generation TKIs ranged from 8.0-13.1 months, which was consistent if
compared to 4.6-6.9 months achieved by standard chemotherapy. Moreover, the benefit was independent
of the line of treatment for which TKIs were administered, and no difference in efficacy was observed
between first- and second-generation inhibitors in available comparative studies, except for the second-
[4]
generation irreversible TKI dacomitinib . These results allowed first- and second-generation EGFR-TKIs
to become the new standard of care for frontline treatment of patients with EGFR-driven NSCLC.

Third-generation EGFR-TKIs
Virtually all patients treated with first- and second-generation TKIs will acquire resistance to this
targeted treatment within about one year. The onset of EGFR T790M secondary mutation is responsible
[39]
for 50% of patients progression . A more detailed description of all resistance mechanism is provided
in the paragraphs below. Before the advent of third-generation EGFR-TKIs, patients who harbored
T790M mutations had limited treatment options, which usually consisted of standard platinum-based
chemotherapy. Even if afatinib demonstrated preclinical activity in T790M positive EGFR-mutated
[40]
[41]
NSCLC , it showed no clinical benefit when given to patients who progressed after gefitinib or erlotinib .
Development of compounds that can overcome T790M mutation was addressed by the introduction of
third-generation EGFR-TKIs.

Osimertinib and rociletinib belong to the category of third-generation EGFR-TKIs. While osimertinib
has been approved by the FDA and EMA, further development of rociletinib has been terminated .
[42]
[43]
Osimertinib has a mono-anilino-pyrimidine core and its binding is irreversible to the EGFR receptor
via the C797 residue. It is active in the nanomolar range against both the sensitizing EGFR mutations and
the T790M mutation. Like all the other inhibitors, it is not active against exon 20 insertions. Since both the
insulin growth factor receptor 1 (IGF-1R) and the insulin receptor (IR) contain a gatekeeper, methionine,
osimertinib is specifically designed not to inhibit both receptors, to prevent hyperglycemia in treated
patients. This is in contrast to rociletinib, where the drug was intended to inhibit the IGF-1R and failed
[43]
partially because of hyperglycemia . Osimertinib is able to cross the BBB and shows activity against
metastases in the central nervous system [44,45] .

Since osimertinib was shown to have clinical activity in T790M mutated NSCLC after failure of previous
TKIs in multiple studies [46-48] , a study of T790M status is mandatory after progression to first- or second-
generation inhibitors and it could consist of both blood and tumor tissue sampling analysis [49-51] . Indeed,
after progression to gefitinib, erlotinib or afatinib, patients treated with osimertinib obtained a PFS of 10.4
months compared to 4.4 months achieved with the platinum plus pemetrexed doublet (HR 0.30, P < 0.001);
[49]
the objective response rate (ORR) was 71% vs. 31% in the two arms, respectively . Remarkably, osimertinib
was superior to both erlotinib and gefitinib also when administered frontline: PFS was 18.9 months vs.
10.2 months (HR 0.46; P < 0.001) for osimertinib and erlotinib/gefitinib, respectively, and the benefit
was independent of T790M mutation . Following these striking results, osimertinib has recently been
[48]
approved by both the FDA and EMA for the first-line treatment of NSCLC with activating EGFR mutations,
irrespective of T790M status .
[52]