There has been tremendous progress with rapid development and approvals of targeted therapies in non-small-cell lung carcinoma (NSCLC) in the past few decades. Since the isolation of the “tooth-lid factor” by Stanley Cohen from the submaxillary glands of mice, the discovery of the epidermal growth factor (EGF) and EGF receptor (EGFR) has revolutionized lung cancer treatment. EGFR gene mutations in NSCLC can be common, including deletion of exon 19 (del19) and exon 21 L858R mutation, or uncommon/atypical. The prescription of EGFR tyrosine kinase inhibitors (TKIs) has come a long way since the first human dosing of gefitinib in 1998, with various drugs now being used either alone or in combination with other medications. Through this review, we describe the structure and molecular biology of the EGFR gene and receptor, molecular detection methods, and the therapeutic strategies for common EGFR mutations in NSCLC.
This is a narrative review; we have not performed a systematic analysis or meta-analysis. No specific inclusion or exclusion criteria were applied to select the articles for this review. We identified relevant articles by searching OncoKB, NCBI: PubMed, Embase, Scopus, and MyCancerGenome using the keywords “EGFR”, “NSCLC”, “Osimertinib”, and “Gefitinib”. A total of 132 articles were finally incorporated to write this review.
MOLECULAR BIOLOGY OF EGFR
Human EGFR (also known as ErbB1/HER1 after the viral erythroblastoma gene) is a receptor tyrosine kinase which is part of a family that comprises EGFR, ErbB2 ⁄ HER2, ErbB3 ⁄ HER3, and ErbB4 ⁄ HER4. EGF was the founder member of this family to be discovered. EGFR is located on chromosome 7p12-13. Exons 18–24 code for the tyrosine kinase domain. Most mutations are found in exons 18–21, which code for the N lobe and part of the C lobe [Figure 1].
STRUCTURE OF EGFR AND LIGAND BINDING
The EGFR protein has four functional domains. The ligands of EGFR include high-affinity targets such as EGF, transforming growth factor-alpha (TGFA), heparin-binding EGF-like growth factor (HBEGF), betacellulin (BTC), and low-affinity ligands such as amphiregulin (ARG), epiregulin (EPR), and epigen (EGN).
The various components of EGFR are a) extracellular region, b) extracellular juxtamembrane region (eJM), c) transmembrane domain d) intracellular juxtamembrane domain (iJM), e) tyrosine kinase domain, and f) carboxy terminal tail [Figure 1].
- The extracellular component: This consists of four domains. Domains I and III are responsible for ligand binding, and domain II is responsible for dimerization. In the inactive form, domain II is folded upon domain IV by disulfide bonds. This gives rise to a tethered configuration which automatically inhibits dimerization. Ligand binding leads to exposure of the dimerization arm of domain II (the tethered configuration changes to an extended configuration). The dimerization at domain II leads to rearrangement in the transmembrane, intracellular juxtamembrane, and kinase domains.
- The transmembrane domain: This is made of 23 amino acids and is responsible for anchoring the receptor to the cell membrane. It has been hypothesized to play a role during dimerization and may also play a role in the alignment of intracellular domains during rotational twisting.
- The intracellular domain: This contains 542 amino acids and includes a juxtamembrane segment, a tyrosine kinase domain, and a C-terminal tail. The kinase domain comprises N and C lobes separated by an adenosine triphosphate (ATP) binding cleft. The activation loop (A-loop) is borne by the alpha-helical C lobe. In the inactive state, the outward rotation of the alpha C helix is stabilized by the helical turn of the A-loop. This in turn prevents the interaction between K745 and E762, which are both located in the N-lobe and are responsible for binding and orientation of ATP by forming bonds with the alpha and beta phosphates. The C-terminal tail contains tyrosine residues. The phosphorylation of these residues allows attachment of various intracellular proteins to the receptor which allows for signal transduction.
SIGNALING PATHWAYS AFTER EGFR ACTIVATION
The important downstream signaling pathways of EGFR are
- RAS–RAF–MEK–ERK–MAPK pathway: When activated by EGF, EGFR signaling leads to progression through the G1/S phase of the cell cycle. The phosphorylated C-terminal domain recruits growth factor receptor binding protein 2 (GRB-2) and Src homology and collagen (SHC). They, in turn, bind to SOS1 (Son of Sevenless 1), which acts as a guanine nucleotide exchange factor for RAS GTPase. It acts by activating RAS. RAS interacts with the RAF1 RAS GTP-binding domain (RBD). RAF1 phosphorylates specific serine residues of MEK-1/2 (mitogen-activated protein kinase, MAPKK), which activates ERK1/2 that then induces various biological response pathways.
- PI3K-AKT-mTOR pathway: Phosphatidyl inositol 3 kinase comprises three classes (I, II, and III) based on its substrates, structure of sub-units, and regulatory mechanisms. Out of the three classes, Class I is a downstream effector of EGFR. PI3K phosphorylates the hydroxyl groups of membrane phosphatidyl inositol 4,5 biphosphate (PIP2) to generate phosphatidyl inositol 3,4,5 triphosphate (PIP3), which causes translocation of the AKT (protein kinase B) to the cell membrane. AKT is a potent stimulator of the mammalian target of rapamycin (mTOR). mTOR increases the synthesis of cyclin D1, hypoxia inducible factor 1 (HIF 1), and vascular endothelial growth factor (VEGF), and its components (especially TORC1) not only stimulate anabolic cellular pathways such as synthesis of ribosomes, nucleotides, and lipids but also suppress catabolism.
- PLC-gamma 1–PKC pathway: Phospholipase C (PLC) gamma 1 can bind directly to activated EGFR or be recruited to the cell membrane by the activity of phosphatidyl inositol 3,4,5 triphosphate (PIP3). Once recruited, it hydrolyzes PIP3 to free intracellular triphosphate (IP3) and diacylglycerol (DAG) as secondary messengers. IP3 then binds to the endoplasmic reticulum (ER) to release calcium. Both DAG and calcium are activators of protein kinase C (PKC). PLC gamma 1 is a downstream component of VEGF, EGF, and platelet derived growth factor (PDGF) pathways and plays an important role in cell proliferation, calcium influx, and cell differentiation.
Nuclear activation by EGFR: In the nucleus, EGFR acts as a transcription co-regulator. It helps in the transcription of various cell cycle mediators such as cyclin D1 and cMYC, which mediates the vital role that EGFR signal transduction plays in cancer pathogenesis. Along with EGF stimulation, H2O2, ultraviolet stimulation, and ionizing radiation can result in the translocation of EGFR to the nucleus. Nuclear EGFR has been proven to be associated with the promoter region of Cyclin D1, thus playing a role in cell proliferation.
ROLE OF EGFR MUTATIONS IN THE PATHOGENESIS OF NSCLC
The Ras/MAPK and PI3K/AKT pathways are involved in the uncontrolled growth and metastasis of lung tumors. The PI3K/AKT pathway is a suppressor of apoptosis and aids in cellular multiplication. It enhances metastasis through breakdown of the extracellular matrix and promotes angiogenesis by the augmented expression of VEGF, PDGF, and interleukin-8.
COMMON EGFR MUTATIONS
EGFR mutations can occur in various parts of the gene. In NSCLC, the mutations occur almost exclusively in the exons encoding the kinase domain (exons 18 to 21). They most commonly include the in-frame deletion of exon 19 (del19) and L858R mutation in exon 21. Del19 constitutes 44–51%, and exon 21 L858R mutation constitutes 38–40%. Together, they comprise ~90% of the total EGFR mutations in NSCLC. These mutations destabilize the inactive conformation of EGFR and place it in a state of constant activity. L858R mutation causes the loss of hydrophobic interactions between the activation loop and the residues in the N-loop which stabilize the inactive conformation of EGFR. Del19 destabilizes the inactive form of the EGFR β3-αC loop that prevents the αC helix from rotating outward. It has more than 30 variants starting from position 746 that delete the LREA amino acids. The most frequent of these is delE746_A750 (73%) resulting from the deletion of 9 to 24 bases. This is followed by variants which begin at E747 (25%). The remaining 2% include rarer variants that are classified as non-LREA and may also be associated with insertions. X-ray crystallography has shown that del19 and L858R substitution differ in their conformation, patterns of EGFR amplification, and EGFR autophosphorylation.
UNCOMMON EGFR MUTATIONS
In 7–23% of NSCLC cases, uncommon/atypical mutations are noted, which have almost 600 variants with variable responses to EGFR TKIs. The most important ones are exon 20 insertions (6% of EGFR mutations) and other single-nucleotide variants which include G719X, L861Q, S768I, and exon 19 insertions. About 25% of these uncommon mutations may exist along with other concomitant EGFR mutations which are termed compound mutations. A detailed description of these uncommon EGFR mutations is currently beyond the scope of this review.
EGFR MUTATION DIAGNOSTIC MODALITIES
The National Comprehensive Cancer Network (NCCN) and Indian guidelines recommend testing for EGFR mutation in stages IB to IV non-squamous NSCLC, NSCLC NOS (not otherwise specified), adenosquamous carcinoma, and selected cases of squamous cell carcinoma lung. Smoking history, race, ethnicity, age, and grade should not be incorporated as selection criteria to select patients for EGFR testing.
Diagnostic samples may include formalin-fixed paraffin-embedded tissue (FFPET), cytological samples (smear preparations, cell blocks), and cfDNA (cell-free DNA in liquid biopsies on blood or other body fluids). The various methodologies for testing EGFR mutations are broadly classified into non-targeted assays, targeted single-gene assays, and broad-based gene panel testing.
Sanger sequencing (non-targeted assay) presently plays a limited role in testing in view of the low sensitivity (15–20%) and high 50% tumor cellularity requirement for testing. Single-gene targeted testing modalities include real-time polymerase chain reaction (qPCR), which relies on target amplification and the use of fluorescent probes to identify a known DNA sequence. There are various United States Food and Drug Administration (US FDA)-approved companion diagnostic tests (CDx) that show good concordance with Sanger sequencing. These include Roche cobas® EGFR Mutation Test v2 (companion for erlotinib and osimertinib) and the Qiagen therascreenEGFR rotor-gene Q (RGQ) PCR Kit (companion for gefitinib and afatinib), competitive allele-specific TaqMan PCR (Cast-PCR), and the fully automated RT-PCR system IdyllaTM (Biocartis). qPCR combines the advantage of the need for a small amount of tissue and a rapid turnaround time. Droplet digital PCR (ddPCR) is a variant of PCR where individual PCRs occur within suspended aqueous droplets in oil. The droplets are analyzed by flow cytometry using systems such as Bio-Rad (Hercules, California) where probe-specific fluorescent signals are detected, and the variant allele fraction is quantified. Its role has been validated in tissue samples as well as liquid biopsies in NSCLC. The sensitivity of ddPCR in cfDNA ranges from 63 to 82%.
Next-generation sequencing (NGS) simultaneously tests for several concomitant mutations as well as acquired resistance mechanisms in patients on EGFR TKIs. It works especially well with scarce tissue, but the high cost and long turnaround time are the major limitations. Table 1 compares these diagnostic modalities.
Chougule et al. reported a high concordance between the detection of del19 and exon 21 L858R mutations in FFPE tumor blocks and bodily fluids. Batra et al. tested the concordance between plasma genotyping platforms and the gold standard tissue sample and reported the sensitivity of cobas to be 97.1% and that of ddPCR to be 71%. The NCCN states that the plasma circulating tumor DNA can be used in place of FFPET for molecular testing, especially when the tissue is scarce.
TREATMENT OF EGFR MUTANT NSCLC
With the advent of EGFR TKIs either alone or in combination with other agents, the treatment paradigm of metastatic NSCLC has been completely revolutionized. Several generations of EGFR TKIs are presently available.
First- and second-generation EGFR TKIs
- Gefitinib or ZD1839 is a reversible first-generation EGFR TKI. This was the first TKI to be tested for the treatment of advanced NSCLC before the discovery of EGFR mutations and their clinical significance. The Iressa Pan-Asia Study (IPASS) was a phase III study that compared gefitinib to carboplatin/paclitaxel in the Asian population. IPASS proved that gefitinib was superior to chemotherapy in patients with EGFR-mutant NSCLC [median progression-free survival (PFS) of 9.5 vs 6.3 months; HR = 0.48; 95% CI = 0.36–0.64; P < 0.001], but there was no statistically significant difference in the overall survival (OS). The West Japan Oncology Group 172 and the North-East Japan Study Group 002 studies were conducted exclusively in patients with advanced EGFR- mutant NSCLC and showed statistically significant improvements in PFS, OS, and objective response rates (ORRs) in the gefitinib-treated patients as compared to chemotherapy in the first-line setting. These studies led to the approval of gefitinib in this setting by the European Medicines Agency (EMA) and the US FDA. Gefitinib is dosed at 250 mg once daily (with or without food). Common side effects include hepatoxicity, mucositis, diarrhea, and bullous and exfoliative skin disorders. The risk of interstitial lung disease is approximately 1.3%. The hepatic metabolism of gefitinib gives rise to significant drug interactions with cytochrome 3A4 inhibitors and inducers.
- Erlotinib is a reversible first-generation EGFR TKI. Initial trials tested the drug in the metastatic setting. The OPTIMAL trial compared erlotinib to gemcitabine plus carboplatin and demonstrated the PFS to be significantly superior (13.1 versus 4.6 months; HR = 0.16; 95% CI = 0.10–0.26; P < 0.0001) with ORR of 83 vs 36% and OS of 22.8 vs 27.2 months; HR = 1.19; 95% CI = 0.83–1.71; P = 0.2663. The EURTAC trial compared erlotinib to a platinum-based chemotherapy combination and found the PFS to be increased with erlotinib (9.7 vs 5.2 months; HR = 0.37; 95% CI = 0.25–0.54; P < 0.0001) with no significant improvement in the OS (22.9 vs 19.6 months; HR = 0.92; 95% CI = 0.63–1.35; P = 0.68). The ENSURE trial compared erlotinib to the combination of gemcitabine and cisplatin. The PFS was significantly improved with erlotinib (11.0 vs 5.5 months; HR = 0.34; 95% CI = 0.22–0.51; P < 0.0001) without a significant difference in the OS (26.3 vs 25.5 months; HR = 0.91; 95% CI = 0.63–1.31; P = 0.607). The lack of OS benefit in all these trials may be ascribed to the cross-over to the EGFR-directed oral TKI in the patients who progressed on chemotherapy. Erlotinib is prescribed at a dose of 150 mg daily on an empty stomach and should not be combined with proton pump inhibitors. Notable adverse effects include bullous and exfoliative skin disorders, diarrhea, and hepatotoxicity. Interstitial lung disease was seen in 1.1% of the patients across various clinical trials.
- Afatinib is a second-generation EGFR TKI and an irreversible inhibitor of all members of the ErbB family (EGFR/HER1, HER2, HER4). LUX-Lung 3, a phase III trial, compared afatinib to pemetrexed plus cisplatin in patients with EGFR-mutant advanced NSCLC. There was a significant prolongation in the median PFS [11.1 (afatinib) versus 6.9 (chemotherapy) months; HR = 0.58; 95% CI = 0.43–0.78; P = 0.001], 12-month PFS (51% versus 21%; HR= 0.58), and the ORR (56% vs 23%). There was no overall OS benefit [28.2 (afatinib) vs 28.2 (chemotherapy) months; HR = 0.88; 95% CI = 0.66–1.17; P = 0.39], but in a pre-planned subset analysis, the del19-positive patients were noted to benefit significantly in terms of OS, 33.3 (afatinib) vs 21.1 (chemotherapy) months, HR = 0.54, 95% CI = 0.0.36–0.79, P = 0.0015, with no observed benefit in the patients with the L858R mutation: 27.6 (afatinib) vs 40.3 (chemotherapy) months (HR = 1.3; 95% CI = 0.80–2.11; P = 0.29). LUX-Lung 6 was a phase III trial conducted in Asian patients that compared the efficacy of afatinib to that of gemcitabine plus cisplatin and found a statistically significant PFS benefit of 11.0 months (afatinib) over 5.6 months (chemotherapy) (HR = 0.28; P < 0.001), without a significant OS benefit [23.1 (afatinib) vs 23.5 (chemotherapy) months; HR = 0.93; 95% CI = 0.72–1.22; P = 0.61]. Among patients with del19, the median OS was 31.4 (afatinib) vs 18.4 (chemotherapy) months, HR = 0.64, 95% CI = 0.44–0.94, P = 0.023, and in those with L858R mutation, the median OS was 19.6 (afatinib) versus 24.3 (chemotherapy) months, HR = 1.22, 95% CI = 0.81–1.83, P = 0.34. A pooled analysis of these two trials showed a statistically significant PFS benefit, with an OS advantage limited to del19 EGFR mutant tumors only. LUX-Lung 7 was a phase IIb trial that compared afatinib to gefitinib as first-line therapy in EGFR-mutant NSCLC and found a statistically significant PFS and ORR advantage but no statistically significant difference in OS. Afatinib is also approved for use in uncommon EGFR mutations (S768I, L861Q, and G719X). Afatinib is administered at a dose of 40 mg once a day on an empty stomach. Notable side effects include diarrhea (95%), rash (89%), stomatitis (72%), paronychia (57%), and dry skin (29%). The incidence of interstitial lung disease is approximately 1% and mandates the permanent discontinuation of treatment.
- Dacomitinib is a second-generation, irreversible, pan-HER oral TKI with efficacy against the common EGFR mutations. Its efficacy as a first-line TKI for EGFR-mutant advanced NSCLC was demonstrated in ARCHER 1050, a randomized, open-label, phase III trial comparing dacomitinib to gefitinib. At a median follow-up of 22 months, a significant PFS advantage was seen with dacomitinib (14.7 versus 9.2 months; HR = 0.59; 95% CI = 0.47–0.74; P < 0.0001), OS was 34 versus 27 months, HR = 0.76, 95% CI = 0.58–0.99, P = 0.044, at a median follow-up of 31 months. Grades 3 and 4 dermatitis and diarrhea were the notable toxicities. This trial excluded patients who had brain metastases; hence, the central nervous system (CNS) efficacy of the drug has not yet been determined. Dacomitinib is dosed at 45 mg daily, with or without food. Interstitial lung disease and pneumonitis can be seen in approximately 3% of patients and necessitate permanent discontinuation of treatment.
Third-generation EGFR TKIs
- Osimertinib (AZD9291) is a mono-anilino pyrimidine compound and an irreversible inhibitor of the C797 residue of the ATP-binding site of the kinase domain of EGFR. It is a third-generation EGFR TKI with manifold greater affinity in the presence of the canonical EGFR mutations and T790M mutations as compared to wild-type EGFR. Greater selectivity for the mutated EGFR leads to lesser dermatological and gastrointestinal adverse events. This drug is given at a dose of 80 mg daily, has no drug interactions with proton pump inhibitors, and does not need to be administered on an empty stomach.
- Lazertinib is a third-generation EGFR TKI, which, with a median PFS of 11.0 months (95% CI, 5.5–16.4) and an ORR of 55.3%, is approved for treatment of EGFR T790M-positive NSCLC in South Korea. MARIPOSA-2 (NCT04988295) is an ongoing open label, randomized phase III study that is assessing the efficacy of lazertinib in combination with platinum-based chemotherapy and amivantamab (a bispecific antibody against EGFR and MET tyrosine kinase receptors) versus platinum-based chemotherapy alone in EGFR-mutant metastatic or locally advanced NSCLC post osimertinib failure. Other new third-generation EGFR TKIs under evaluation are oritinib and furmonertinib.
Role of osimertinib in the metastatic setting
AURA3 was a randomized open-label, phase III trial that compared the efficacy of osimertinib to that of pemetrexed plus platinum-based combination chemotherapy in patients with metastatic EGFR-mutant NSCLC who had progressed on first-generation TKI therapy and had developed a T790M secondary resistance mutation. Osimertinib demonstrated a significant PFS benefit (10.1 vs 4.4 months; HR = 0.30; 95% CI = 0.23–0.41; P < 0.001). FLAURA was a double-blind trial that evaluated the efficacy of osimertinib versus erlotinib or gefitinib in the first-line setting for EGFR-mutant metastatic NSCLC. Osimertinib demonstrated a significant PFS advantage (18.9 vs 10.2 months; HR = 0.46; 95% CI = 0.37–0.57; P < 0.001) and OS benefit (38.6 vs. 31.8 months; HR = 0.80; 95.05% CI = 0.64–1.00; P = 0.046). These trials led to the approval of osimertinib in the first line for metastatic EGFR- mutant NSCLC as well as post first-generation TKI failure in EGFR T790M mutation-positive disease.
Role of osimertinib in EGFR-mutant NSCLC with brain metastases
Pre-clinical studies have shown that osimertinib significantly penetrates the blood brain barrier. In patients with brain metastases, in the FLAURA study, osimertinib resulted in an ORR of 91% versus 68% from first-generation EGFR TKIs. The assessment of CNS response in AURA3 showed a superior CNS ORR with osimertinib as compared to platinum and pemetrexed-based chemotherapy and a longer median CNS PFS of 11.7 versus 5.6 months (HR = 0.32; 95% CI = 0.15–0.69; P = 0.004).
A very small percentage of patients with NSCLC have leptomeningeal (LM) involvement at diagnosis, but it is intriguing to note that the incidence is higher in EGFR-mutant NSCLC as compared to the EGFR- wild type (9.4% vs 1.7%, respectively). Prior to osimertinib, pulse erlotinib (1200 mg on days 1 and 2, and 50 mg on days 3 to 7; repeated weekly) had been used in this setting with some success; the response rate in the brain metastases was 75%, and the median PFS was 10 months (95% CI = 7, not reached). In patients with EGFR T790M mutation with LM disease in the AURA study, osimertinib 80 mg once a day was found to be effective [LM ORR of 55% (95% CI, 32–76), median LM PFS of 11.1 months (95% CI = 4.6, not reached); median OS of 18.8 months (95% CI = 6.3, not reached)]. In the phase I BLOOM study, in patients who had progressed on previous EGFR-directed oral TKIs, osimertinib at a dose of 160 mg orally once a day was shown to have good activity against LM metastasis with an acceptable toxicity profile [LM ORR = 62% (95% CI = 45–78) as assessed by neuroradiologic blinded independent central review; the LM duration of response was 15.2 months (95% CI = 7.5-17.5)]. In a retrospective review conducted by Sharmaet al. in patients with EGFR mutant NSCLC with LM metastasis on osimertinib, the ORR in the first line was 83.3% and that in later lines was 60%. The median LM PFS for these patients was 7.9 months (95% CI = 3.2–8.3), and the median LM OS was 8.2 months (95% CI = 2.6–19.8).
Role of EGFR TKI in the adjuvant setting
The ADJUVANT-CTONG1104 trial was the only phase III study that demonstrated the disease-free survival (DFS) benefit of gefitinib for 2 years as compared to platinum-based chemotherapy (vinorelbine + cisplatin, every 3 weeks for 4 cycles) as adjuvant therapy in post-operative stages II-IIIA (N1-N2) EGFR-mutant NSCLC. There was no significant difference in OS [median OS, 75.5 (gefitinib) vs 62.8 (chemotherapy) months; HR = 0.92; 95% CI = 0.62–1.36; P = 0.674]; however, OS was not the primary end point of the study. The Kaplan–Meier survival curves were not indicative of long-term disease-free survivors in either arm. In view of these limitations, this study failed to change practice, despite showing a DFS advantage. EVAN was a randomized phase II study conducted in patients with EGFR- mutant, stage IIIA surgically resected NSCLC in which adjuvant erlotinib was found to confer a longer 2-year DFS (81.4%) as compared to adjuvant cisplatin plus vinorelbine (44.6%), relative risk = 1.82, 95% CI = 1.19–2.78, P = 0.0054. The long-term follow-up data from EVAN reported that the 5-year DFS in the erlotinib arm was 48.2% compared to 46.2% in the chemotherapy arm; the median OS in the erlotinib arm was 84.2 versus 61.1 months in the chemotherapy arm, HR = 0.318, 95% CI = 0.15–0.67. SELECT was another phase II study that showed that adjuvant erlotinib following standard chemotherapy conferred a 2-year DFS of 88%, a 5-year DFS of 56% (95% CI = 45–66), and a 5-year OS of 86% (95% CI = 77–92).
ADAURA was a phase III, randomized, double-blind, placebo-controlled trial that assessed the role of adjuvant osimertinib for 3 years in stages IB, II, or IIIA completely resected NSCLC harboring del19 or exon 21 L858R mutations; the decision regarding adjuvant chemotherapy was as per the treating physicians’ discretion. Osimertinib showed a significant DFS advantage; the 2-year DFS in patients with stage II and IIIA disease was 90% in the osimertinib arm versus 44% in the placebo arm, HR = 0.17, 99.96% CI = 0.11–0.26, P < 0.001). A significant DFS was noted in both patients who received adjuvant chemotherapy (DFS HR = 0.16, 95% CI = 0.10–0.26) and those who did not receive chemotherapy (HR = 0.23, 95% CI = 0.13–0.40). The use of osimertinib can also be considered in patients with microscopically (R1) or macroscopically (R2) positive resection margins. It is worth noting that patients with stage IB disease did not benefit to the same extent as those with stages II and IIIA [DFS HR = 0.39 (Ib) versus 0.17 (II), and 0.12 (IIIA)]. ADAURA-eligible patients with significant concerns regarding the tolerance of osimertinib should be started on the medication after due optimization while balancing the risk of adverse events against the DFS advantage to be gained with an unknown impact on OS. Among patients who recur after the completion of adjuvant osimertinib, based on data extrapolated from the first-generation TKI (SELECT) trials and in the face of inadequate data for osimertinib in this scenario, it is recommended to re-challenge with osimertinib. Patients who recur while on osimertinib may be planned for local ablative therapies or repeat biopsies to look for targetable resistance mechanism pathways.
EGFR TKI in combination with other agents: Anti-VEGF agents, chemotherapy, and radiation
The phase II JO25567 trial demonstrated a significant median PFS improvement with erlotinib plus bevacizumab (16 months) versus erlotinib alone (9.7 months) in the first line in patients with treatment-naïve EGFR mutant NSCLC, HR = 0.54, 95% CI = 0.36–0.79, P = 0.0015. This improvement was largely attributed to enhanced VEGF expression in EGFR-mutant NSCLC which is targeted by the joint blockade of the EGFR -and VEGF pathways. This influences vascular permeability and improves drug delivery. NEJ026 was a phase III trial that compared erlotinib plus bevacizumab versus erlotinib alone as first-line therapy in advanced, non-squamous EGFR- mutant NSCLC. It showed a PFS benefit of 16.9 months for erlotinib plus bevacizumab versus 13.3 months for erlotinib alone (HR = 0.605; 95% CI = 0.417–0.877; P = 0.016). The median OS was 50.7 months [95% CI = 37.3, not estimable (NE)] in the bevacizumab plus erlotinib combination group and 46.2 months (38.2 - NE) in the erlotinib-only group (HR = 1.007, 95% CI = 0.681–1.490; P = 0.97). This combination is approved in the first line for the treatment of advanced NSCLC adenocarcinoma with del19 or exon 21 L858R mutations without contraindications to bevacizumab. RELAY was a phase III randomized trial that assessed the role of ramucirumab plus erlotinib versus erlotinib alone in metastatic non-squamous NSCLC and demonstrated a median PFS of 19.4 months with ramucirumab and erlotinib versus 12.4 months with erlotinib alone (HR = 0.59; 95% CI = 0.46–0.76; P < 0.0001) with benefits observed in both del19 and exon 21 L858R subsets.
Combining EGFR TKI with chemotherapy has been another strategy to combat the development of drug resistance. The randomized phase II trial demonstrated that the combination of pemetrexed plus carboplatin with gefitinib prolonged PFS when compared with gefitinib monotherapy in EGFR-mutant advanced NSCLC. A phase III trial conducted by Noronhaet al. compared gefitinib plus chemotherapy (pemetrexed plus carboplatin followed by pemetrexed maintenance) versus gefitinib alone in the same setting and reported a significant PFS advantage from gefitinib plus chemotherapy (16 vs 8 months; HR = 0.51; 95% CI = 0.39–0.66; P < 0.001). The estimated median OS was significantly longer in the combination arm (not reached vs 17 months; HR = 0.45; 95% CI = 0.31–0.65; P < 0.001). NEJ009 was a similar study conducted in Japan which demonstrated a significant PFS and ORR advantage in the gefitinib plus pemetrexed and carboplatin arm as compared to gefitinib alone (ORR = 84% vs 67%; P < 0.001; PFS = 20.9 vs 11.9 months; HR = 0.490; P < 0.001). Median OS was also considerably longer than in the gefitinib plus chemotherapy group (50.9 vs 38.8 months; HR = 0.722; P = 0.021). However, the recently updated analysis of NEJ009 at a median follow-up of 84 months reported that there was no significant OS difference between the groups; mean OS was 49 months in the gefitinib group versus 38.5 months in the gefitinib and chemotherapy group, HR = 0.822; 95% CI = 0.639–1.058; P = 0.127. FLAURA2 is an ongoing open-label randomized trial that is evaluating the role of osimertinib plus carboplatin–pemetrexed versus osimertinib alone in the first-line setting in patients with EGFR-mutant NSCLC. The safety run-in analysis reported that the combination was well tolerated with a manageable toxicity profile.
There are no studies that show the tangible benefit of adding an EGFR TKI, before, during, or after chemoradiation, in patients with EGFR- mutant inoperable stage III NSCLC. LAURA is an ongoing phase III trial (NCT03521154) evaluating the role of osimertinib following chemoradiation in patients with stage III NSCLC that is not feasible for resection.
PD-L1 testing and the role of immune checkpoint inhibitors in EGFR-mutant NSCLC (locally advanced and metastatic)
EGFR- mutant NSCLC is often seen to have low programmed death ligand 1 (PD-L1) expression. However, even the fraction showing high PD-L1 expression responds poorly to immune checkpoint inhibitor therapy. The IMMUNOTARGET registry reported that the median PD-L1 expression in the EGFR-mutant subgroup was 3.5%. The ORR to immune checkpoint inhibitors was 12.2%, with a progressive disease rate of 67%, median PFS of 1.8 months for del19 and 2.5 months for exon 21 L858R mutation, and a median OS of 4.9 months (del19) or 10.9 months (exon 21 L858R). The use of pembrolizumab in EGFR-mutant PD-L1-positive advanced NSCLC in treatment-naïve patients was not found to be associated with favorable outcomes. The phase Ib TATTON trial (osimertinib in combination with selumetinib, savolitinib, or durvalumab) showed an increased risk (22%) of interstitial lung disease in patients on concomitant durvalumab and osimertinib, and this led to the premature termination of the CAURAL trial (phase III trial of osimertinib versus osimertinib plus durvalumab in relapsed EGFR T790M mutant NSCLC). IMPower150 was the only trial that has shown a PFS advantage with the ABCP regimen [atezolizumab and bevacizumab with chemotherapy (paclitaxel and carboplatin)] in EGFR- or ALK-altered NSCLC (median PFS = 9.7 vs 6.1 months; unstratified HR = 0.59; 95% CI = 0.37–0.94) for the ABCP combination versus bevacizumab, carboplatin, and paclitaxel. However, because this trial did not evaluate the role played by the anti-VEGF therapy in enhancing the efficacy of immunotherapy, it is difficult to interpret these findings. In the retrospective study conducted by Batraet al., which analyzed the PD-L1 expression among patients with EGFR-mutant NSCLC, it was found that the majority of patients with PD-L1 >50% were smokers and had a higher disease burden at diagnosis. The median PFS in patients with PD-L1 <1% was 10.1 months versus 9.4 months in the PD-L1 >1% group; this difference was not statistically significant.
Future prospects: Fourth generation EGFR TKIs
EAI045 is a selective, non-ATP competitive, allosteric TKI active against L858R, T790M, and C797S mutations. In combination with cetuximab, EAI045 was found to inhibit these mutations in vitro and in vivo but was ineffective in cases of resistance resulting after the emergence of EGFR del19/C797S/T790M mutation. BLU-945 is another fourth-generation EGFR TKI active against EGFR T790M/C797S mutations. Schalm et al. reported that BLU-945 was active against osimertinib-resistant cells, both alone and in combination with osimertinib. TBQ3804, which is currently under evaluation in an ongoing phase I trial (NCT04128085), is a fourth-generation EGFR TKI active against del19/T790M/C797S and L858R/T790M/C797S in pre-clinical studies.
The discovery of EGFR mutations opened the door to targeted therapy in metastatic NSCLC and revolutionized not only the survival outcomes but also the convenience and ease of treatment in patients harboring these molecular drivers. With a myriad of available options, we are now spoiled for choices. Given the inherent differences between the three generations of EGFR TKIs in terms of molecular targets, reversibility of action, CNS penetration, and toxicity profiles, one does need to choose wisely. This review article is the first in a series of articles on the EGFR-mutant NSCLC. In subsequent articles, we will discuss the resistance mechanisms to EGFR TKIs and uncommon EGFR mutations.
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