Up to 20% of lung adenocarcinomas in the United States and Europe and 50% in Asia have activating mutations of the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). The identification and subsequent targeting of mutations with EGFR–tyrosine kinase inhibitors (TKIs) led to significant advances in treatment of EGFR-mutant lung cancer. Newer-generation EGFR-TKIs resulted in improvement in outcomes, with less toxic side effects and better tolerability. Resistance to EGFR-TKIs remains a significant barrier, and better understanding of resistance mechanisms is needed. Efforts are ongoing to incorporate targeted therapy into treatment of patients with earlier-stage disease.
Key points
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The identification and targeting of epidermal growth factor receptor (EGFR) mutations have been a paradigm shift in thoracic oncology and resulted in significant improvements in outcomes.
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Osimertinib is active against common EGFR mutations and the T790M resistance mutation and is considered standard of care in the first-line treatment of patients with advanced/metastatic non–small cell lung cancer (NSCLC).
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One of the main challenges in the treatment of EGFR-mutated lung cancer is the development of resistance to EGFR–tyrosine kinase inhibitors (TKIs), necessitating an urgent need to better understand mechanisms of resistance.
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EGFR-TKIs have been evaluated in earlier-stage disease as well as in combination with several other agents; however, at the current time, these approaches remain investigational.
Background
The discovery of the epidermal growth factor receptor (EGFR) and development of targeted drugs have led to substantial gains in the treatment of non–small cell lung cancer (NSCLC). EGFR belongs to the HER/ErbB family of growth factor receptors. These receptors consist of an extracellular ligand binding domain, a transmember structure and an intracellular tyrosine kinase domain. When the EGFR extracellular domain binds one of its ligands, it forms a dimer with other EGFR and HER family members and activates several downstream pathways, resulting in increased cell proliferation and angiogenesis and a decrease in apoptosis.
EGFR receptors are overexpressed in 40% to 80% of NSCLCs. Despite high levels of EGFR protein expression, clinical responses to EGFR–tyrosine kinase inhibitors (TKIs) were observed in approximately only 10% to 18% of patients with chemorefractory disease. ,
In 2004, Lynch and colleagues identified 25 patients with clinically significant responses to gefitinib and a median duration of survival that exceeded 18 months. Gene sequencing in 9 patients revealed 8 had heterozygous mutations within the tyrosine kinase domain of EGFR, which activate the kinase domain and are sensitive to inhibition with gefitinib. Although the overexpression of EGFR in NSCLC was the biomarker that brought EGFR-TKIs into clinical use with early modest positive results, it is the identification and targeting of EGFR mutations that have been a paradigm shift in thoracic oncology.
Approximately 10% to 20% of lung adenocarcinomas in the United States and Europe and 40% to 50% in Asia have activating mutations of the tyrosine kinase domain of EGFR. Exon 19 deletions and L858R point mutations account for 90% of the EGFR mutations and are highly predictive of response to EGFR-TKIs. ,
Diagnosis
The gold standard for diagnosis of EGFR-mutant lung cancer is direct DNA sequencing of tumor tissue DNA.
Tissue testing can be done as an individual EGFR test or as part of a larger panel of genes with next-generation sequencing technologies. Liquid biopsies, utilizing various nucleic acid sequencing methods to identify mutations in circulating tumor DNA, are becoming more frequently utilized. This method is appealing when tissue is insufficient or when obtaining additional tissue is impractical. Collectively, these methods have excellent specificity and patient outcomes are similar whether mutations are detected via tissue or circulating tumor DNA. , The sensitivity is reported to be approximately 80%; therefore, negative tests should be interpreted with some caution.
Treatment
Epidermal Growth Factor Receptor–Tyrosine Kinase Inhibitors for Advanced/Metastatic Disease
Multiple phase III trials of EGFR-TKIs have improved radiographic response and progression-free survival (PFS) for patients with EGFR mutations in the first-line metastatic setting compared with chemotherapy. Newer-generation TKIs have improved on the gains seen with first-generation EGFR-TKIs ( Table 1 ). EGFR-TKIs have reduced toxic effects and perform better with respect to quality-of-life measures.
| Study | Epidermal Growth Factor Receptor Status | N | Primary Outcome | Design | Outcomes |
|---|---|---|---|---|---|
| IPASS,11 Asia, 2009 | EGFR unselected | 1217 EGFR+ positive= 261 | PFS | Gefitinib vs carboplatin + paclitaxel | 12-mo PFS, 24.9% (gefitinib) vs 6.7% (HR 0.74; P <.001) Subgroup EGFR-positive (HR 0.48; P <.001) |
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| EURTAC, Europe, 2012 | EGFR selected | 173 | PFS | Erlotinib vs cisplatin + docetaxel or gemcitabine | Median PFS 9.7 mo (erlotinib) vs 5.2 mo (HR 0.37; P <.0001) |
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| LUX-Lung 3, Europe, North and South America, and Australia, 2013 | EGFR selected | 345 | PFS | Afatinib vs cisplatin + pemetrexed | Exon 19 del and L858R EGFR mutations, n = 308 Median PFS 13.6 mo (afatinib) vs 6.9 mo (HR 0.47; P = .001) |
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| LUX-Lung 6, Asia, 2014 | EGFR selected | 364 | PFS | Afatinib vs cisplatin + gemcitabine | Median PFS was 11.0 mo (afatinib) vs 5.6 mo (HR 0.28; P <.0001) |
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| ARCHER 1050, 2017 | EGFR selected | 452 | PFS | Dacomitinib vs gefitinib | Median PFS 14.7 mo (dacomitinib) vs 9.2 mo (gefitinib) (HR 0.59; P <.0001) |
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| FLAURA, 2018 | EGFR selected | 556 | PFS | Osimertinib vs standard TKI (erlotinib or gefitinib) | Median PFS 18.9 mo (osimertinib) vs 10.2 mo (standard TKI) (HR disease progression or death 0.46; P <.001) |
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Despite the current standard approach to use EGFR-TKIs in EGFR-mutated patients, earlier trials identified a benefit in an unselected population of patients with NSCLC. Gefitinib demonstrated improved response rates in the third-line setting for unselected NSCLC patients who had progressed through 2 lines of chemotherapy and initially was granted accelerated Food and Drug Administration (FDA) approval. Erlotinib was approved the following year based on the BR.21 trial that showed improved PFS and OS (6.7 months vs 4.7 months: hazard ratio [HR] 0.7; P <.001). Later, the phase III trial, ISEL, comparing gefitinib to placebo failed to replicate a survival benefit in a similar population, and gefitinib lost its FDA approval but continued to be used outside of the United States. It was not until more than 10 years later that gefitinib was granted approval status in the United States and erlotinib’s approval was restricted to patients whose tumors possessed an EGFR mutation.
Although early trials identified certain clinical characteristics (ie, female smokers and never smokers) of patients who derived the greatest benefits, it is now known that the presence of specific EGFR mutations are a more robust predictor of response to EGFR-TKIs. In the IPASS trial, overall response rates (ORRs) for patients with and without an EGFR mutation who received gefitinib were 71.2% versus 1.1%, respectively. Subgroup analysis showed gefitinib was beneficial for EGFR-positive patients (HR 0.48; P <.001) but was detrimental for those without mutations (HR 2.85; P <.001) compared with chemotherapy. This PFS benefit was demonstrated in multiple prospective phase III trials comparing EGFR-TKIs with chemotherapy. With longer follow-up, first-generation EGFR-TKIs have not demonstrated a survival benefit, largely attributed to the crossover design of these studies, which allowed patients on the control arm to eventually get the more effective therapy.
The second generation EGFR-TKIs, afatinib and dacomitinib, irreversibly bind to the tyrosine kinase of EGFR and other ErbB family members and are approved in the front-line metastatic setting based on demonstrated improvements in PFS in several large phase III trials (see Table 1 ). Survival data from ARCHER 1050, which compared first-line dacomitinib to gefitinib, showed a median overall survival (OS) of 34.1 months with dacomitinib, compared with 26.8 months in the gefitinib arm, representing a more than 7-month improvement in survival, albeit with more grade 3 toxicities reported in patients receiving dacomitinib.
Osimertinib, a third-generation, irreversible EGFR-TKI, inhibits common EGFR mutations as well as the T790M resistance mutation. FLAURA evaluated osimertinib in the first-line setting compared with first-generation EGFR-TKIs; 556 patients with EGFR-positive advanced NSCLC were randomized to osimertinib versus investigator choice of erlotinib or gefitinib. The primary endpoint of PFS was significantly longer with osimertinib (18.9 months vs 10 months; HR 0.46; P <.001). These results were practice changing and osimertinib is now the preferred first-line agent for EGFR mutation–positive NSCLC. OS was immature at last report of trial data, but a press release in August 2019 indicates the trial met its secondary endpoint of OS.
Does mutation type matter?
A combined planned analysis from LUX-Lung 3 (afatinib vs cisplatin/pemetrexed) and LUX-Lung 6 (afatinib vs cisplatin/gemcitabine) showed afatinib did not improve OS. OS was improved, however, with afatinib for the subgroups of patients with exon 19 deletions in both trials. An association with improved PFS in patients with exon 19 deletion mutations was observed in several first-generation TKI studies, including IPASS (HR 0.38 for del19 vs HR 0.55 for L858R) and EURTAC (HR 0.30 del19 vs 0.55 for L858R). but were not statistically significant.
Although exon 19 deletions and L858R point mutations account for 90% of mutations, several other mutations, including G719X, L861Q, S7681, EGFR fusions, and exon 20 insertions, have been reported but show variable response to TKIs. The G719X mutations are sensitizing mutations, whereas the exon 20 insertions and de novo T790M mutations typically are resistant to first-generation and second-generation EGFR-TKIs.
Exon 20 mutations confer a poor response to EGFR-TKIs but efforts to treat this subgroup are ongoing. TAK-788 and poziotinib are investigational EGFR/HER2 inhibitors with antitumor activity in this population. , In addition, there are preclinical data and a case report to indicate osimertinib, at a dose of 180 mg, may be able to overcome this inherent resistance, and a clinical trial is ongoing. ,
Dealing with resistance
Resistance to first-generation and second-generation EGFR-TKIs typically develops within 9 months to 14 months. , EGFR pThr790Met (T790M) point mutations are identified in greater than 50% of patients who develop disease progression on first-line TKIs. , Other mechanisms of resistance have been identified, including mutations in PIKC3 and BRAF, small cell transformation, and amplification of HER2, MET, and MAPK1.
Osimertinib is active against common EGFR mutations and the T790M resistance mutation. In AURA3, osimertinib was compared with carboplatin/pemetrexed in T790M-positive patients with disease progression after first-line EGFR-TKI therapy. PFS was significantly longer with osimertinib compared with chemotherapy (10.1 months vs 4.4 months, respectively; HR 0.41; P <.001). In patients with central nervous system metastases, a population with an overall worse prognosis, PFS was longer, at 8.5 months versus 4.2 months, respectively, in the chemotherapy arm (HR 0.32).
Efforts to characterize mechanisms of resistance to osimertinib are ongoing, but reports to date have demonstrated a heterogeneous group of mechanisms, including acquired EGFR mutations, predominantly C797; off-target mutations; rearrangements; fusions; and transformation to squamous or small cell lung cancer. , Targeting mutations or rearrangements involving RET, ALK, and BRAF have been reported with some success in case reports. ,
Combination Therapy in the Advanced/Metastatic Setting
In efforts to overcome resistance to EGFR-TKIs or improve on single-agent activity in the first-line setting, several combinations have been studied.
Epidermal growth factor receptor–tyrosine kinase inhibitors plus epidermal growth factor receptor monoclonal antibodies
Preclinical data that combination afatinib and cetuximab could overcome resistance mediated by the acquired T790M mutation provided the rationale for a phase Ib trial of 126 patients with acquired resistance to erlotinib or gefitinib. An ORR of 29% was observed. This study enrolled patients regardless of T790M status and there were no significant differences in response based on T790M status. Incidence rates of adverse events were high (94% all grades and 50% grades 3/4). Osimertinib has largely replaced this regimen due to better efficacy and tolerability for patients with acquired T790M mutations. For patients with non–T790-acquired resistance, this could be considered, given the responses seen in the T790M-negative population.
Epidermal growth factor receptor–tyrosine kinase inhibitors plus chemotherapy
Studies evaluating combination chemotherapy and EGFR-TKIs were first conducted in unselected populations with no known EGFR mutations. SATURN was a phase III trial of maintenance erlotinib after chemotherapy that showed a statistically significant 1-month OS improvement with erlotinib maintenance. Prospective molecular analysis identified the magnitude of benefit was far greater among patients with EGFR mutations (PFS 44.6 months with erlotinib vs PFS 13.0 months with placebo) than those without EGFR mutations (PFS 12.0 months with erlotinib vs PFS 8.9 months with placebo).
Two studies in patients with known EGFR mutations have shown promising results combining gefitinib with carboplatin and with pemetrexed. A phase III Japanese trial (NEJ009) evaluating gefitinib plus chemotherapy versus gefitinib alone demonstrated an improvement in PFS (20.9 months vs 11.2 months, respectively; HR 0.493; P <.001) and OS (52.2 months vs 38.8 months, respectively; P = .013). Similar improvements in PFS and OS were seen in a randomized phase III study from Tata Memorial Hospital in Mumbai, India. Given advances with osimertinib in the FLAURA trial, it is unclear how this combination compares to osimertinib alone or osimertinib plus chemotherapy. FLAURA2 will compare osimertinib alone versus osimertinib plus platinum-based chemotherapy in the front-line setting for locally advanced/metastatic EGFR-mutated NSCLC.
Epidermal growth factor receptor–tyrosine kinase inhibitors plus anti–vascular endothelial growth factor agents
Combination of vascular endothelial growth factor (VEGF) monoclonal antibodies with EGFR-TKIs is an appealing strategy based on the JO25567 phase 2 trial, which showed that the addition of bevacizumab to erlotinib in EGFR-mutant patients improved PFS (16.0 months vs 9.7 months without bevacizumab; HR 0.54; P = 0.0015). The NEJ026 study, with similar design, showed an improved PFS with erlotinib and bevacizumab (16.9 months vs 13.3 months without bevacizumab) in an interim analysis (HR 0.605; P = .0157). Preliminary results of an ongoing phase 1/2 study of 49 patients treated with osimertinib and bevacizumab reported an ORR of 69% and HR for 12-month PFS of 0.70 (95% CI, 0.57–0.84). TORG1833 is a similar ongoing phase 2 trial evaluating osimertinib in combination with ramucirumab, a monoclonal antibody targeted against the VEGF-receptor (VEGFR2). RELAY, a phase 3 trial, is randomizing patients with metastatic EGFR-mutant patients to erlotinib in combination with ramucirumab versus placebo. Preliminary results reported at American Society of Clinical Oncology 2019 annual meeting demonstrated dual blockade led to an improvement in PFS compared with erlotinib plus placebo (19.4 months vs 12.4 months, respectively; HR 0.591; P <.0001). Final results from these trials are awaited.
Immunotherapy for epidermal growth factor receptor–mutant non–small cell lung cancer
A meta-analysis, including CheckMate 057 (nivolumab), Keynote-0.001 (pembrolizumab), POPLAR, and OAK (atezolizumab), which all compared immunotherapy to docetaxel in previously treated patients, concluded that immune checkpoint inhibitors do not improve OS in patients with EGFR-mutant lung cancer. In a subgroup analysis from IMpower 150, the 91 patients with EGFR mutations maintained an OS improvement with the addition of atezolizumab to bevacizumab and chemotherapy, suggesting this combination may be able to overcome the lack of benefit seen with immunotherapy in other trials. Further studies are needed to determine the role of immunotherapy in this disease.
Earlier-stage Disease
Despite complete surgical resection, approximately 30% to 55% of patients with NSCLC develop disease recurrence after surgery. Cisplatin-based chemotherapy has improved survival for patients with stages IIA–IIIA disease (stage IB >4 cm is now categorized as stage IIA in the AJCC Cancer Staging Manual , eighth edition). , Given significant efficacy of EGFR-TKIs over chemotherapy in the metastatic setting, there has been interest in evaluating EGFR inhibitors in earlier-stage disease. Three large phase 3 trials have evaluated their use in the adjuvant setting.
As in the metastatic setting, earlier adjuvant EGFR-TKI trials enrolled unselected patients. EGFR mutation subgroup analysis from RADIANT, a phase 3 trial that compared 24 months of erlotinib to placebo in patients with resected stages IB–IIIA NSCLC, showed improved disease-free survival (DFS). Due to hierarchical testing, this was not statistically significant and survival curves overlapped by 48 months. This trial did not meet its DFS and OS endpoints in the entire trial population of patients who were selected only for EGFR overexpression.
SELECT, a single-arm phase 2 trial of EGFR-mutant stages IA–IIIA patients, evaluated 2 years of adjuvant erlotinib after standard adjuvant chemotherapy. The median DFS and OS have not been reached, but 5-year OS is 86%, an improvement based on historical controls. A majority of patients with recurrence (26/40) were retreated with erlotinib for a median duration of 13 months.
ADJUVANT and EVAN were phase 3 trials that randomized completely resected patients with EGFR mutations to gefitinib and erlotinib, respectively, versus chemotherapy. ADJUVANT enrolled patients with stages II–IIIA disease and EVAN enrolled only patients with stage IIIA disease. , Both studies demonstrated improved DFS with the EGFR-TKI, but OS data are immature. A meta-analysis, including ADJUVANT and EVAN, showed a statistically significant improvement in 5-year OS (HR 0.48).
Neoadjuvant EGFR-TKIs also have been evaluated. EMERGING/CTONG 1103, an ongoing phase 2 trial comparing erlotinib to chemotherapy in stage IIIA-N2 EGFR mutation–positive NSCLC, recently reported an improvement in PFS with erlotinib compared with chemotherapy (21.5 months vs 11.9 months, respectively; HR 0.42; P = .0003).
Despite earlier negative trials in an unselected NSCLC population, there has been renewed interest given positive findings from more recent trials for patients with EGFR mutations. Larger studies are needed to determine the optimal sequencing and potential benefit of EGFR targeted therapy in this setting. In the United States, the ALCHEMIST EGFR study ( NCT02193282 ) is a phase 3 randomized trial evaluating adjuvant erlotinib versus observation for patients with surgically resected stages IB (>4 cm)–IIIA ( AJCC Cancer Staging Manual , seventh edition) after completion of standard adjuvant chemotherapy. It remains unclear whether this strategy ultimately can improve long-term survival or cure rates for patients with earlier-stage disease.
Summary
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The identification of EGFR sensitizing mutations and the development of targeted EGFR-TKIs have transformed the way EGFR-mutant lung cancer is treated and drastically improved on the previous standard.
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Osimertinib currently is considered the standard of care for the treatment of metastatic disease.
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Given the successes of TKIs in the metastatic setting, efforts are ongoing to incorporate them into the treatment paradigm for earlier-stage disease, but chemotherapy remains the standard adjuvant therapy at this time.
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Ongoing efforts to combine TKIs with other modalities offer promise; however, there is an urgent need to better understand the mechanisms of acquired resistance because chemotherapy remains the standard second line after disease progression on osimertinib.
Disclosure
Dr E.M. McLoughlin has nothing to disclose. Dr R.D. Gentzler has the following disclosures in the past 3 years: personal fees outside the submitted work from Merck, Takeda, Pfizer AstraZeneca, and Bristol Myers Squibb and research funding to his institution from Merck , Takeda , Pfizer Helsinn , and Bristol Myers Squibb .
References
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