A decade of EGFR inhibition in EGFR-mutated non small cell lung cancer (NSCLC): Old successes and future perspectives

May combine two claims.

Treatment of EGFR-mutated NSCLC patients poses novel therapeutic challenges, including acquired resistance, brain metastases development, and the need to translate treatments to earlier clinical settings such as adjuvant therapy.

“However, despite great breakthroughs have been made, treatment of these molecularly selected patients poses novel therapeutic challenges, such as emerging of acquired resistance, brain metastases development or the need to translate these treatments in earlier clinical settings, such as adjuvant therapy.”

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The most common and best characterized EGFR mutations are in-frame deletions in exon 19 (eliminating LREA residues 747-750) and exon 21 L858R substitutions, together constituting ~80-90% of all EGFR mutations in NSCLC.

“The most common and best characterized EGFR mutations are in-frame deletions in exon 19, which eliminates the conserved motif LREA (residues 747–750), and the exon 21 L858R substitutions, that together constitute ~80–90% of all EGFR mutations in NSCLC.”

Probably not a substantial claim: may not pass S3 (load-bearing).

These mutations are commonly referred to as activating mutations because they are constitutively activated and oncogenic.

“These mutations are commonly referred as “activating mutations” as they are constitutive activated and oncogenic.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

EGFR is a tyrosine kinase receptor activated upon binding to EGF and other growth factor ligands, triggering downstream pathways including RAS/MAPK, PI3K/Akt, and STAT that regulate DNA synthesis and proliferation.

“The Epidermal Growth Factor Receptor (EGFR) is a tyrosine kinase (TK) receptor that is activated upon binding to the Epidermal Growth Factor and other growth factor ligands, triggering several downstream pathways, including RAS/MAPK, PI3K/Akt and STAT that regulate different cellular processes, including DNA synthesis and proliferation.”

• cites [2] Salgia, 2014, Molecular pathways and therapeutic targets in lung cancer, Oncotarget sourceNot checked yet

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• cites [3] Halmos, 2010, EGFR-mutated lung cancer: a paradigm of molecular oncology, Oncotarget sourceNot checked yet

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EGFR mutations are associated with TTF-1 expression.

“In addition, EGFR mutations were also associated with TTF-1 expression [9].”

• cites [9] Simon, 2014, Epidermal growth factor receptor (EGFR) mutations are exceptionally rare in thyroid transcription factor (TTF-1)-negative adenocarcinomas of the lung, OncoscienceNot checked yet

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These somatic EGFR mutations are associated with in vitro sensitivity to Gefitinib and with clinic-pathological characteristics: Asian ethnicity, female sex, adenocarcinoma histology, and never smoking status.

“These somatic mutations were associated with in vitro sensitivity to Gefitinib and with clinic-pathological characteristics preliminary associated with clinical activity [7, 8]: Asian ethnicity, female sex, adenocarcinoma histology and never smoking status.”

• cites [7] Wolf, 2003, Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial, JAMA sourceNot checked yet

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• cites [8] Ben-Porat, 2004, Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non-small-cell lung cancer, J Clin Oncol sourceNot checked yet

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The discovery of EGFR mutations in NSCLC launched the era of personalized medicine in advanced NSCLC and led to a shift in the therapeutic landscape from a one-size-fits-all approach to treatment selection based on molecular characteristics of tumors.

“The discovery of Epidermal Growth Factor Receptor (EGFR) mutations in NSCLC launched the era of personalized medicine in advanced Non Small Cell Lung Cancer (NSCLC), leading to a dramatic shift in the therapeutic landscape of this disease from a “one size fits all” approach to the treatment selection on molecular characteristics of tumors [1, 2].”

• cites [1] Felip, 2011, Personalizing therapy with targeted agents in non-small cell lung cancer, Oncotarget sourceNot checked yet

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• cites [2] Salgia, 2014, Molecular pathways and therapeutic targets in lung cancer, Oncotarget sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

During the last decade, different EGFR TKIs have been developed and three inhibitors (Gefitinib, Erlotinib, and Afatinib) have been approved in EGFR-mutated NSCLC patients.

“During the last decade, different EGFR TKIs have been developed and three inhibitors (Gefitinib, Erlotinib and, more recently, Afatinib) have been approved so far in these selected patients (Figure 1).”

May combine two claims.

These mutant kinases present reduced affinity for ATP, accounting for increased sensitivity to EGFR TKIs compared with wild type, since these inhibitors compete with ATP for binding to the catalytic site.

“These mutant kinases present a reduced affinity for the ATP, accounting for the increased sensitivity to EGFR TKIs compared with the wild type counterparts, since these inhibitors compete with ATP for binding to the catalytic site [10–12].”

• cites [10] Meyerson, 2005, Oncogenic transformation by inhibitor-sensitive and -resistant EGFR mutants, PLoS Med sourceNot checked yet

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• cites [11] Varmus, 2006, Lung adenocarcinomas induced in mice by mutant EGF receptors found in human lung cancers respond to a tyrosine kinase inhibitor or to down-regulation of the receptors, Genes Dev sourceNot checked yet

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• cites [12] Eck, 2007, Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity, Cancer Cell sourceNot checked yet

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The clinical development of EGFR inhibitors in NSCLC started before the discovery of EGFR mutations, with initial studies of Gefitinib and Erlotinib conducted in unselected patients in both pretreated and treatment-naïve settings in combination with standard chemotherapy.

“The clinical development of EGFR inhibitors in NSCLC started before the discovery of EGFR mutations, therefore initial studies with Gefitinib and Erlotinib were conducted in unselected patients in both pretreated [52–54] and in treatment-naïve patients in combination with standard chemotherapy [55–58].”

• cites [52] Findlay, 2005, Erlotinib in previously treated non-small-cell lung cancer, N Engl J Med sourceNot checked yet

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• cites [53] Carroll, 2005, Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer), Lancet sourceNot checked yet

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• cites [54] Giordano, 2009, Gefitinib in lung cancer therapy: clinical results, predictive markers of response and future perspectives, Cancer Biol Ther sourceNot checked yet

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• cites [55] Ochs, 2004, Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial—INTACT 2, J Clin Oncol sourceNot checked yet

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• cites [56] Ochs, 2004, Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial—INTACT 1, J Clin Oncol sourceNot checked yet

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• cites [57] Miller, 2005, TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer, J Clin OncolNot checked yet

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• cites [58] Vansteenkiste, 2007, Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva Lung Cancer Investigation Trial, J Clin Oncol sourceNot checked yet

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Oncogene-addicted tumors, such as EGFR-mutated NSCLCs, may present peculiar patterns of metastatization compared with wild type tumors, including more frequent liver involvement at diagnosis, higher tendency to CNS metastatization, higher likelihood of brain metastases detection at first presentation, and diffuse and/or miliary pulmonary metastases.

“Oncogene addicted tumors, such as EGFR mutated NSCLCs, may present peculiar patterns of metastatization compared with wild type tumors, including a more frequent liver involvement at the diagnosis [24], higher tendency to central nervous system metastatization [25–27] and higher likelihood of brain metastases detection at first presentation [28] diffuse and/or miliary pulmonary metastases [28, 29]”

• cites [24] Camidge, 2012, Oncogene status predicts patterns of metastatic spread in treatment-naive nonsmall cell lung cancer, Cancer sourceNot checked yet

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• cites [25] Yokota, 2006, Frequent EGFR mutations in brain metastases of lung adenocarcinoma, Int J Cancer sourceNot checked yet

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• cites [26] Sequist, 2010, EGFR mutation status and survival after diagnosis of brain metastasis in nonsmall cell lung cancer, Neuro Oncol sourceNot checked yet

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• cites [27] Liao, 2013, Phase II trial of erlotinib plus concurrent whole-brain radiation therapy for patients with brain metastases from non-small-cell lung cancer, J Clin Oncol sourceNot checked yet

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• cites [28] Yang, 2014, EGFR mutation and brain metastasis in pulmonary adenocarcinomas, J Thorac Oncol sourceNot checked yet

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• cites [29] Mishima, 2011, Association of diffuse, random pulmonary metastases, including miliary metastases, with epidermal growth factor receptor mutations in lung adenocarcinoma, Cancer sourceNot checked yet

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Patients harboring exon 19 deletions present a peculiar pattern of brain metastatization resembling miliary brain metastases, with multiple and small brain tumors with minimal peritumoral edema.

“For instance, Sekine et al. reported that patients harboring exon 19 deletions present a peculiar pattern of brain metastatization that resemble to that of miliary brain metastases, with multiple and small brain tumors with minimal peritumoral edema [32].”

• cites [32] Ogura, 2012, Metastatic brain tumors from non-small cell lung cancer with EGFR mutations: distinguishing influence of exon 19 deletion on radiographic features, Lung Cancer sourceNot checked yet

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A high concordance rate for recurrent somatic alterations has been reported between primary NSCLC and metastases, suggesting that a new biopsy for genomic information to guide treatment decision may not be necessary when archived primary material is present, since key driver oncogenic events seem to occur early in NSCLC tumorigenesis.

“In addition, a high concordance rate for recurrent somatic alterations has been reported between primary NSCLC and metastases, suggesting that a new biopsy for genomic information to guide treatment decision may not necessary when it is present an archived primary material, since key driver oncogenic events seems to occur early in NSCLC tumorigenesis [51].”

• cites [51] Lazar, 2013, Next-generation sequencing reveals high concordance of recurrent somatic alterations between primary tumor and metastases from patients with non-small-cell lung cancer, J Clin Oncol sourceNot checked yet

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De Bruin et al. reported spatial and temporal tumor heterogeneity of driver mutations within NSCLC, raising the possibility that a single-region sampling biopsy could miss clinical-relevant driver events present in specific tumor subclones.

“De Bruin et al. reported spatial and temporal tumor heterogeneity of driver mutations within NSCLC, raising the possibility that a single-region sampling biopsy, as commonly done in clinical practice, could miss clinical-relevant driver events present in specific tumor subclones [49].”

• cites [49] Horswell, 2014, Spatial and temporal diversity in genomic instability processes defines lung cancer evolution, Science sourceNot checked yet

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Several phase III trials demonstrated superiority of EGFR TKIs over chemotherapy in EGFR-mutated NSCLC in the first-line setting in terms of ORR and PFS, but not OS due to extensive cross-over, although a pooled analysis of LUX-Lung-3 and -6 reported a survival advantage.

“Several phase III trials demonstrated the superiority of EGFR TKIs over chemotherapy in EGFR-mutated NSCLC in the first line setting in terms of overall response rate (ORR) and progression free survival (PFS), but not in overall survival (OS) due to the extensive cross-over between treatment arms, although recently a pooled analysis of patients harboring common mutations enrolled in the LUX-Lung-3”

• cites [18] Geater, 2015, Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials, Lancet OncolNot checked yet

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The role of EGFR TKIs in EGFR wild type tumors is more debatable, since the benefit in such patients is modest (~8% with Erlotinib in pretreated NSCLC) and no predictive biomarkers have been reported in this subset.

“The role of these inhibitors in EGFR wild type tumors is instead more debatable, since the benefit in such patient is modest (~8% with Erlotinib in pretreated NSCLC) and no predictive biomarkers have been so far reported in this specific subset of patients [39].”

• cites [39] Goss, 2013, Role of epidermal growth factor receptor inhibitors in epidermal growth factor receptor wild-type non-small-cell lung cancer, J Clin Oncol sourceNot checked yet

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Patients harboring exon 19 deletions are associated with a reduced progression risk than those with exon 21 point mutations and a longer overall survival.

“Recent meta-analyses addressed this question and reported that patients harboring exon 19 deletions are associated with a reduced progression risk than those with exon 21 point mutations [21–23] and a longer OS [22, 23].”

• cites [21] Zhang, 2014, Patients with exon 19 deletion were associated with longer progression-free survival compared to those with L858R mutation after first-line EGFR-TKIs for advanced non-small cell lung cancer: a meta-analysis, PLoS One sourceNot checked yet

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• cites [22] Zhu, 2014, Different efficacy of EGFR tyrosine kinase inhibitors and prognosis in patients with subtypes of EGFR-mutated advanced non-small cell lung cancer: a meta-analysis, J Cancer Res Clin Oncol sourceNot checked yet

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• cites [23] Yang, 2015, Impact of Specific Epidermal Growth Factor Receptor (EGFR) Mutations and Clinical Characteristics on Outcomes After Treatment With EGFR Tyrosine Kinase Inhibitors Versus Chemotherapy in EGFR-Mutant Lung Cancer: A Meta-Analysis, J Clin OncolNot checked yet

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In addition to classic common mutations, ~10% of patients with EGFR mutations may exhibit mutations in codons other than 19 and 21, including exon 18 G719 (~3-4%), exon 20 mutations (~4-5%), uncommon exon 19 insertions, exon 21 L851Q/R, and compound mutations.

“In addition to classic “common mutations” ~10% of patients with EGFR mutations may ehibit mutations in codons other than 19 and 21. Rare mutations could be detected in a small fraction of patients including exon 18 mutations, predominantly at G719 (~3–4%), exon 20 mutations (~4–5%) as well as uncommon mutations in exon 19 (for example, in-frame insertions) and 21 (i.e. L851Q/R), and finally comp”

• cites [33] Papadimitrakopoulou, 2013, Uncommon epidermal growth factor receptor mutations in non-small cell lung cancer and their mechanisms of EGFR tyrosine kinase inhibitors sensitivity and resistance, Lung Cancer sourceNot checked yet

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• cites [34] Yang, 2011, Effectiveness of tyrosine kinase inhibitors on “uncommon” epidermal growth factor receptor mutations of unknown clinical significance in non-small cell lung cancer, Clin Cancer Res sourceNot checked yet

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• cites [35] Costa, 2013, Compound EGFR mutations and response to EGFR tyrosine kinase inhibitors, J Thorac OncolNot checked yet

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The exact mechanism of the association between exon 19 deletions and better outcome remains largely elusive and might involve differential sensitivity to EGFR TKIs, different mechanisms of acquired resistance, and different frequency of compound mutations.

“However, the exact mechanism of this association remains largely elusive and might involve differential sensitivity to EGFR TKIs, different mechanism of acquired resistance as well as different frequency of compound mutations [21].”

• cites [21] Zhang, 2014, Patients with exon 19 deletion were associated with longer progression-free survival compared to those with L858R mutation after first-line EGFR-TKIs for advanced non-small cell lung cancer: a meta-analysis, PLoS One sourceNot checked yet

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The presence of EGFR mutations defines a specific molecular subgroup of NSCLC (~15% of Caucasian patients with adenocarcinomas) that respond to an EGFR TKI in over 60% of patients.

“The presence of EGFR mutations defines a specific molecular subgroup of NSCLC (~15% of Caucasian patients with adenocarcinomas) [37, 38] that respond to an EGFR TKI in over 60% of patients (Table 1).”

• cites [37] Cancer Genome Atlas Research Network, 2014, Comprehensive molecular profiling of lung adenocarcinoma, Nature sourceNot checked yet

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• cites [38] Sequist, 2014, Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs, JAMA sourceNot checked yet

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In 2012, Gerlinger et al. reported evidence of intratumor heterogeneity and spatial separation of subclones in metastatic renal cancer, establishing the branched evolution hypothesis, suggesting that biomarker sampling in a single tumor region may miss the complex genomic landscape of a tumor.

“In 2012 in a seminal paper Gerlinger and coll. reported evidence of intratumor heterogeneity and spatial separation of subclones in metastatic renal cancer, establishing the “branched evolution” hypothesis [48], suggesting that biomarker sampling in a single tumor region may undetect the complex genomic landscape of a tumor, providing major challenges to clinical implementation of personalized”

• cites [48] Begum, 2012, Intratumor heterogeneity and branched evolution revealed by multiregion sequencing, N Engl J Med sourceNot checked yet

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Zhang et al. did not find substantial differences within the same tumor in driver mutations, suggesting that single-biopsy analysis might be sufficient to identify the majority of known driver mutations in lung adenocarcinomas.

“In contrast, Zhang et al. did not found substantial differences within the same tumor in driver mutations, suggesting that single-biopsy analysis might be sufficient to identify the majority of known driver mutations in lung adenocarcinomas [50].”

• cites [50] Little, 2014, Intratumor heterogeneity in localized lung adenocarcinomas delineated by multiregion sequencing, Science sourceNot checked yet

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Since no survival gain was demonstrated in phase III trials, the use of EGFR TKIs in EGFR-mutated patients in first- or second-line should not influence eventual survival outcome, as demonstrated in the phase II trial of the Spanish Lung Cancer Group.

“Since no survival gain was demonstrated in the phase III trials conducted so far, the use of EGFR TKIs in EGFR-mutated patients in first- or second-line should not influence the eventual survival outcome, as demonstrated in the phase II trial of the Spanish Lung Cancer Group [40].”

• cites [40] Gonzalez-Larriba, 2009, Screening for epidermal growth factor receptor mutations in lung cancer, N Engl J Med sourceNot checked yet

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Others did not find any differences in brain and bone metastases development between EGFR-mutated patients and wild type, or significant differences in number, neuroanatomic location or size of brain metastases.

“However, others did not find any differences in brain and bone metastases development between EGFR-mutated patients and wild type [30] or significant differences in number, neuroanatomic location or size of brain metastases [31].”

• cites [30] Speel, 2014, EGFR mutated non-small cell lung cancer patients: more prone to development of bone and brain metastases?, Lung Cancer sourceNot checked yet

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• cites [31] Shih, 2015, Significance of targeted therapy and genetic alterations in EGFR, ALK, or KRAS on survival in patients with non-small cell lung cancer treated with radiotherapy for brain metastases, Neuro Oncol sourceNot checked yet

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Several mechanisms of primary and acquired resistance to EGFR TKIs have been reported in in vitro NSCLC models and some have also been confirmed in patients.

“Several mechanisms of primary and acquired resistance to EGFR TKIs [67, 68] have been so far reported in in vitro NSCLC models and some have also been confirmed in patients.”

• cites [67] Jänne, 2014, Molecular mechanisms of resistance in epidermal growth factor receptor-mutant lung adenocarcinomas, Eur Respir Rev sourceNot checked yet

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• cites [68] Shaw, 2014, Molecular pathways: resistance to kinase inhibitors and implications for therapeutic strategies, Clin Cancer Res sourceNot checked yet

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The clinical significance of rare EGFR mutants is not always fully understood, with some variants associated with response to EGFR TKIs (e.g., exon 18 G719X), others with resistance (e.g., exon 20 T790M), and others with uncertain clinical significance.

“The clinical significance of these rare mutants is not always fully understood with some variants associated with response to EGFR TKIs (for instance, exon 18 G719X) other associated with resistance (i.e. exon 20 T790M) and other with uncertain clinical significance [33–35].”

• cites [33] Papadimitrakopoulou, 2013, Uncommon epidermal growth factor receptor mutations in non-small cell lung cancer and their mechanisms of EGFR tyrosine kinase inhibitors sensitivity and resistance, Lung Cancer sourceNot checked yet

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• cites [34] Yang, 2011, Effectiveness of tyrosine kinase inhibitors on “uncommon” epidermal growth factor receptor mutations of unknown clinical significance in non-small cell lung cancer, Clin Cancer Res sourceNot checked yet

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• cites [35] Costa, 2013, Compound EGFR mutations and response to EGFR tyrosine kinase inhibitors, J Thorac OncolNot checked yet

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A retrospective study of Memorial Sloan-Kettering Cancer Center reported a significant reduction of risk of recurrence or death (HR 0.43, p=0.001) and a trend toward improved OS (HR 0.50, p=0.076) for patients with resected NSCLC treated with Erlotinib or Gefitinib with or without adjuvant chemotherapy.

“Moreover, a retrospective study of the Memorial Sloan-Kettering Cancer Center reported a significant reduction of risk of recurrence or death (HR 0.43, p = 0.001) and a trend toward improved OS (HR 0.50, p = 0.076) for patients with resected NSCLC treated with Erlotinib or Gefitinib with or without adjuvant chemotherapy [102].”

• cites [102] Rusch, 2012, Distinct clinical course of EGFR-mutant resected lung cancers: results of testing of 1118 surgical specimens and effects of adjuvant gefitinib and erlotinib, J Thorac Oncol sourceNot checked yet

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Neither Afatinib nor Neratinib nor Dacomitinib demonstrated significant activity as single agent in patients harboring T790M mutations.

“neither Afatinib [76] nor Neratinib [77] nor Dacomitinib [78] demonstrated significant activity as single agent in patients harboring the T790M mutations.”

• cites [76] Tan, 2012, Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial, Lancet Oncol sourceNot checked yet

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• cites [77] Soria, 2010, Neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor: results of a phase II trial in patients with advanced non-small-cell lung cancer, J Clin Oncol sourceNot checked yet

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• cites [78] Liang, 2014, A phase 2 trial of dacomitinib (PF-00299804), an oral, irreversible pan-HER (human epidermal growth factor receptor) inhibitor, in patients with advanced non-small cell lung cancer after failure of prior chemotherapy and erlotinib, Cancer sourceNot checked yet

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AZD9291 demonstrated promising activity in a phase I study in patients with EGFR-TKI resistant NSCLC with an ORR of 51% and an ORR of 62% in patients T790M-positive, with no dose-limiting toxicities and a maximum tolerated dose not defined.

“AZD9291 demonstrated promising activity in a phase I study in patients with EGFR-TKI resistant NSCLC with an ORR of 51% and an impressive ORR of 62% in patients T790M-positive, with no dose-limiting toxicities and a maximum tolerated dose not defined [89].”

• cites [89] Kim, 2015, AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer, N Engl J Med sourceNot checked yet

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The RADIANT trial failed to demonstrate a DFS advantage in the overall population (50.5 vs 48.2 months), but a trend toward longer DFS was observed in the subgroup of patients with EGFR mutation (16.5%), albeit not statistically significant (46.4 vs 28.5 months) (HR 0.61, 95% CI 0.38-0.98, p=0.039).

“The study failed to demonstrate a DFS advantage in the overall population (50.5 months vs. 48.2 months), but a trend toward a longer DFS was observed in the subgroup of patients with EGFR mutation (16.5%), albeit not statistically significant (46.4 months vs. 28.5 months) (HR 0.61, 95% CI 0.38–0.98, p = 0.039) [100, 101].”

• cites [100] Crinò, 2014, Adjuvant erlotinib (E) versus placebo (P) in non-small cell lung cancer (NSCLC) patients (pts) with tumors carrying EGFR-sensitizing mutations from the RADIANT trial, J Clin OncolNot checked yet

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• cites [101] Keshavjee, 2014, A randomized, double-blind phase 3 trial of adjuvant erlotinib (E) versus placebo (P) following complete tumor resection with or without adjuvant chemotherapy in patients (pts) with stage IB-IIIA EGFR positive (IHC/FISH) non-small cell lung cancer (NSCLC): RADIANT results, J Clin OncolNot checked yet

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Data from the LUX-Lung project showed that patients with de novo T790M mutations or exon 20 insertions presented inferior ORR and shorter PFS and OS compared with patients harboring other uncommon mutations, such as exon 18 G719X and exon 21 L861Q, which exhibited a range of sensitivity similar to that of common mutations.

“Patients with de novo T790M mutations or exon 20 insertions presented in general inferior ORR and shorter PFS and OS compared with patients harboring other uncommon mutations, such as exon 18 G719X and exon 21 L861Q, that exhibited a range of sensitivity similar to that of common mutations.”

• cites [104] Wu, 2013, Activity of Afatinib in uncommon Epidermal Growth Factor Receptor (EGFR) mutations: findings from three trials of afatinib in EGFR mutation-positive lung cancer, J Thorac OncolNot checked yet

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To date, three different EGFR TKIs have been approved and no prospective data are available to guide optimal treatment selection in clinical practice.

“To date three different EGFR TKIs have been approved and no prospective data are available to guide optimal treatment selection in clinical practice.”

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Sequist et al. reported preliminary results of the TIGER X study in patients with EGFR-mutated and T790M-positive NSCLC previously treated with an EGFR TKI, with a 59% ORR and median PFS exceeding 12 months, and most common toxicity hyperglycemia.

“Recently, Sequist and coll. reported the preliminary results of the ongoing phase I/II study TIGER X in patients with NSCLC harboring EGFR mutations and T790M-positive that previously received an EGFR TKI. The results, albeit preliminary, are quite impressive with a 59% ORR and a median PFS not yet reached, but exceeding 12 months. The safety profile of this agent is also interesting with the most”

• cites [86] Galasso, 2015, Rociletinib in EGFR-mutated non-small-cell lung cancer, N Engl J Med sourceNot checked yet

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Afatinib received regulatory approval in the first line setting after the LUX-Lung-3 and -6 trials, and Dacomitinib reported promising results in a phase II study.

“Recently, Afatinib received regulatory approval in the first line setting after the publication of the LUX-Lung-3 and -6 trials [79, 80] and another irreversible EGFR inhibitor, Dacomitinib, has reported promising results in a phase II study [81].”

• cites [79] Kato, 2013, Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations, J Clin Oncol sourceNot checked yet

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• cites [80] Kim, 2014, Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial, Lancet Oncol sourceNot checked yet

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• cites [81] Goldberg, 2014, Dacomitinib as first-line treatment in patients with clinically or molecularly selected advanced non-small-cell lung cancer: a multicentre, open-label, phase 2 trial, Lancet Oncol sourceNot checked yet

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Rociletinib irreversibly and selectively inhibits mutant EGFR, including T790M mutation, with minimal activity against wild type EGFR, suggesting that drug tolerability may be superior to first and second generation EGFR inhibitors.

“In vitro and in vivo studies demonstrated that Rociletinib irreversibly and selectively inhibits mutant EGFR, including T790M mutation, with minimal activity against wild type EGFR, suggesting that drug tolerability to this agent may be superior to first and second generation EGFR inhibitors”

• cites [85] Karp, 2013, Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC, Cancer Discov sourceNot checked yet

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WZ4002 is a covalent pyrimidine EGFR inhibitor specifically designed against EGFR T790M that is 30-100 fold more potent against EGFR T790M, and up to 100 fold less potent against wild type EGFR than quinazoline based EGFR inhibitors in vitro, and is effective in murine models of lung cancer driven by EGFR T790M.

“WZ4002 is a covalent pyrimidine EGFR inhibitor specifically designed against EGFR T790M that is 30–100 fold more potent against EGFR T790M, and up to 100 fold less potent against wild type EGFR than quinazoline based EGFR inhibitors in vitro and is effective in murine models of lung cancer driven by EGFR T790M [84].”

• cites [84] Eck, 2009, Novel mutant-selective EGFR kinase inhibitors against EGFR T790M, Nature sourceNot checked yet

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The BR.19 study demonstrated no advantage in DFS and OS in the overall population and in the small subgroup of EGFR-mutated patients (4%), and a possible detrimental effect.

“The results of the study demonstrated not only no an advantage in both DFS and OS in the overall population and in the small subgroup of EGFR-mutated patients (4%), but also a possible detrimental effect.”

• cites [98] Kernstine, 2013, Gefitinib versus placebo in completely resected non-small-cell lung cancer: results of the NCIC CTG BR19 study, J Clin Oncol sourceNot checked yet

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Combining second-generation EGFR TKIs with other targeted agents, such as Afatinib plus Cetuximab and Neratinib plus Temsirolimus, has recently reported promising results, albeit toxicity profile could limit clinical implementation.

“However, the role of second generation EGFR TKIs in acquired resistance is not definitely thrown over, since combining these agents with other targeted agents, such as the dual combination Afatinib plus Cetuxumab [82] and Neratinib plus Temsirolimus [83], has recently reported promising results, albeit toxicity profile of these combinations could limit their clinical implementation.”

• cites [82] Pao, 2014, Dual inhibition of EGFR with afatinib and cetuximab in kinase inhibitor-resistant EGFR-mutant lung cancer with and without T790M mutations, Cancer Discov sourceNot checked yet

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• cites [83] Turnbull, 2014, Phase I study of neratinib in combination with temsirolimus in patients with human epidermal growth factor receptor 2-dependent and other solid tumors, J Clin Oncol sourceNot checked yet

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May combine two claims.

HM61713 was well tolerated and reported promising activity in EGFR-mutated NSCLC patients previously treated with an EGFR-TKI, with more prominent activity in T790M-positive tumors (ORR 29.2%, DCR 75.0%) than T790M-negative (ORR 11.8%, DCR 55.9%).

“This inhibitor was well tolerated and reported a promising activity in EGFR-mutated NSCLC patients previously treated with an EGFR-TKI with a more prominent activity in T790M-positive tumors (ORR 29.2%, DCR 75.0%) than T790M-negative (ORR 11.8%, DCR 55.9%) [90].”

• cites [90] Kim, 2014, Clinical activity and safety of HM61713, an EGFR-mutant selective inhibitor, in advanced non-small cell lung cancer (NSCLC) patients (pts) with EGFR mutations who had received EGFR tyrosine kinase inhibitors (TKIs), J Clin Oncol sourceNot checked yet

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May combine two claims.

Yasuda et al. described the chemical structure of the exon 20 mutation D770_N771insNPG, showing that the three amino-acid insertion forms a wedge that locks the C helix of EGFR in its inward, active position; therefore, clinical resistance of this mutant is not due to steric hindrance with inhibitor binding, but simply not sensitizing to EGFR TKIs inhibition.

“Recently, Yasuda et al. described the chemical structure of the exon 20 mutations D770_N771insNPG, showing that the three amino-acid insertion forms a “wedge” that lock the C helix of the EGFR in its inward, active position. Therefore, the clinical resistance of this mutant is not due to steric hindrance with inhibitor binding, but simply not sensitizing to EGFR TKIs inhibition [36].”

• cites [36] Oxnard, 2013, Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer, Sci Transl MedNot checked yet

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May combine two claims.

Exon 19 in-frame deletions and point-mutation L858R of exon 21 account for more than 90% of all EGFR mutations and are associated with sensitivity to EGFR TKIs.

“Exon 19 in-frame deletions and point-mutation L858R of the exon 21 account for more than 90% of all EGFR mutations and are associated with sensitivity to EGFR TKIs.”