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].