Second-generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Research Articles

Clinical outcome of treatment of metastatic non-small cell lung cancer in patients harboring uncommon EGFR mutation

BackgroundUncommon epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) is a rare subset of NSCLC. The aim of this study was to investigate the prevalence, characteristics, and clinical outcomes of metastatic NSCLC harboring uncommon EGFR mutation at Thailand’s largest national tertiary hospital. The secondary objective was to compare treatment efficacy between EGFR-tyrosine kinase inhibitor (EGFR-TKI) and chemotherapy.MethodsThis retrospective chart review included patients that were tested for EGFR-mutation NSCLC during 2014–2018. Patient demographic and clinical data, treatment data, and outcome data were collected and analyzed.ResultsOf the 681 patients that were evaluated for EGFR mutation, 317 (47.0%) had EGFR-mutant NSCLC, and 28 (8.8%) of those harbored uncommon EGFR mutations. The median follow-up was 19.1 months. History of tobacco use was reported in 50% of patients. The most common single mutation among uncommon EGFR was exon 20 insertion (n = 6), followed by L861Q (n = 5) and G719X (n = 4). Thirteen (46%) patients had compound mutations. One hundred percent of male patients with G719X mutation were smokers. Sixteen of 28 patients were treated with EGFR-TKI. Most received first-generation EGFR-TKI, and 29% were treated with chemotherapy alone. The objective response rate was 37.5% in the EGFR-TKI group. Median progression-free survival (PFS) in the EGFR-TKI group was 10.2 months. Median PFS among the 8 patients in the chemotherapy group that received first-line platinum doublet was 6.5 months. Three-year overall survival (OS) among 28 patients was 34%. Three-year OS was significantly better in patients treated with EGFR-TKI.ConclusionsUncommon EGFR mutations was detected in 8.8% of EGFR-mutant NSCLC. Exon 20 insertion was the most common mutation, and 50% of patients had history of tobacco use. First- or second-generation EGFR-TKI demonstrated greater OS benefit than platinum-doublet chemotherapy among patients harboring uncommon EGFR-mutant NSCLC. Survival outcomes were comparable to those reported from previous large cohort studies.

Abstract 4920: A status of re-biopsy for non-small-cell lung cancer patients after first EGFR-TKI failure and incidence of T790M mutation

Abstract Background: Among patients with advanced non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation, T790M mutation is the most common mechanism of drug resistance to first- or second-generation EGFR tyrosine kinase inhibitors (TKIs). However, the proportion of patients with T790M mutation at re-biopsy is varied by studies or biopsy methods. Methods: A total of 126 patients who were treated with first- or second-generation EGFR TKIs and had disease progression in our institution from January 2017 to September 2018 were eligible for this study. We retrospectively evaluated re-biopsy methods and the proportion of patients who harbor T790M mutation. Result: A total of 126 patients (male, 36.5% ; median age, 69 year ) were included. Among 126 patients, 118 patients (93.7%) underwent re-biopsy by any methods: tissue biopsy or cytology sampling in 68 patients and plasma sampling in 50 patients during a first re-biopsy, and 44 patients (37.3%) had T790M mutation. During the first biopsy, in the 68 patients who underwent tissue biopsy or cytology sampling, 32 patients (47%) were positive for T790M mutation, nevertheless there were no tumor samples in 4 patients and only atypical cells in 3 patients and 1 patient was identified transformation to SCLC. In the 50 patients who performed plasma sampling during a first re-biopsy, T790M mutation was detected in only 12 patients (24%). Second re-biopsy was conducted in 19 patients among 74 patients resulted in T790M-negative or unknown after the first re-biopsy, and 10 patients were positive for T790M mutation. Eventually, a total of 80 patients were performed tissue biopsy or cytology sampling, 74 patients (96.1%) were found to have any EGFR mutations and T790M mutation was detected in 39 patients (48.1%). On the other hand, 59 patients underwent plasma sampling and 31 patients (52.5%) were found to have any EGFR mutations and T790M mutation was detected in only 17 patients (28.8%). Totally 54 patients (42.9%) were detected T790M mutation, and 52 patients (41.3%) received Osimertinib subsequently. Conclusion: After progression of first- or second-generation EGFR-TKIs, about 95% of patients underwent re-biopsy, and T790M mutation was present in approximately half of patients who underwent re-biopsy and almost all patients who were positive for T790M mutation could receive Osimertinib. In patients who underwent tissue biopsy or cytology sampling, high frequency of detecting any EGFR mutations contributed to higher detection rate of T790M mutation compared to plasma sampling. To improve the sensitivity for T790M mutation detection, tissue biopsy or cytology sampling should be performed if possible. Citation Format: Tetsuya Sakai, Hibiki Udagawa, Yoshitaka Zenke, Keisuke Kirita, Shigeki Umemura, Shingo Matsumoto, Kiyotaka Yoh, Seiji Niho, Genichiro Ishii, Koichi Goto. A status of re-biopsy for non-small-cell lung cancer patients after first EGFR-TKI failure and incidence of T790M mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4920.

Abstract 2113: KRAS amplification mediates resistance to osimertinib in acquired afatinib-resistant NSCLC harboring exon 19 deletion/T790M in EGFR

Abstract Background: The second mutation of T790M in epidermal growth factor receptor (EGFR) exon 20 mediates resistance to first- and second-generation EGFR tyrosine kinase inhibitors (TKIs; gefitinib, erlotinib, and afatinib). The critical T790M mutation in EGFR has facilitated the development of third-generation mutation-selective EGFR TKIs (rociletinib and osimertinib). We previously reported heterogeneous afatinib resistance in lung adenocarcinoma PC-9 cells, harboring 15bp deletions in EGFR exon 19. Among the afatinib-resistant PC-9 cells, we noted the emergence of T790M in EGFR exon 20 and responses to third-generation EGFR-TKIs. Here, we used afatinib-resistant lung adenocarcinoma PC-9 cells, called AfaR, harboring the exon 19 deletion/T790M in EGFR. Purpose: To identify novel resistance mechanisms in post-afatinib treatment, two osimertinib-resistant cell lines, OsiR1 and OsiR2, were established using increasing concentrations of osimertinib by stepwise dose escalation up to 1 μmol/L over 10 to 12 months. Results: A linear and reversible KRAS amplification and overexpression with increased osimertinib concentrations in OsiR1 and OsiR2 cells, respectively, was detected. OsiR1 cells maintained osimertinib resistance with KRAS amplification after osimertinib withdrawal for 2 months. After osimertinib withdrawal for 2 months, OsiR2 cells exhibited KRAS attenuation and osimertinib sensitivity was entirely recovered in vitro and in vivo. Phospho-EGFR (Y1068) and growth factor receptor-bound protein 2 (GRB2)/son of sevenless homolog 1 (SOS1) complex was found to mediate osimertinib resistance in OsiR1 cells with sustained KRAS activation. The association of phosphorylated EGFR with the GRB2/SOS1 complex leads to KRAS activation. After 2 months of osimertinib withdrawal, the GRB2/SOS1 complex was dissociated, and the EGFR signal but not the GRB2/SOS1 signal was activated. Concomitant inhibition of mitogen-activated protein kinase kinase and EGFR could overcome osimertinib-resistance in OsiR1 cells. Conclusion: We characterized novel acquired resistance mechanisms for third-generation EGFR-TKI, osimertinib, providing insights into the development of novel treatment strategies. Citation Format: Toshimitsu Yamaoka, Ohba Motoi, Yasunari Kishino, Sojiro Kusumoto, Junji Tsurutani, Tohru Ohmori. KRAS amplification mediates resistance to osimertinib in acquired afatinib-resistant NSCLC harboring exon 19 deletion/T790M in EGFR [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2113.

Clinical management of third-generation EGFR inhibitor-resistant patients with advanced non-small cell lung cancer: Current status and future perspectives.

Discovery of activating mutations in epidermal growth factor receptor (EGFR) as a predictive biomarker for first-generation EGFR tyrosine kinase inhibitors (TKIs) has initiated an era of precision oncology for the treatment of advanced EGFR-mutant non-small cell lung cancer (NSCLC). Despite the robust efficacy of first- and second-generation EGFR TKIs, disease relapse is inevitable. EGFR T790M mutation is the predominant cause of disease relapse and third-generation, irreversible EGFR inhibitors designed for targeting EGFR T790M and activating mutations have demonstrated promising clinical activity and tolerability. Unfortunately, disease progression inevitably occurs and heterogenous resistance mechanisms have been reported with limited subsequent treatment strategies available. Till now, treatment approaches for patients progressed from third-generation EGFR TKIs have not been clearly established. In this review, we summarize the recent findings in resistance mechanisms to third-generation EGFR TKIs and emerging treatment approaches for EGFR-mutant patients after resistance to third-generation EGFR TKIs. We further discuss clinical challenges and future perspectives for management of EGFR-mutant patients resistant to third-generation EGFR TKIs.

Effect of osimertinib treatment on lung adenocarcinoma with squamous cell transformation harboring the T790M mutation: A case report and literature review.

We herein report a case of squamous cell transformation combined with the epidermal growth factor receptor (EGFR) mutation T790M associated with acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in a 73-year-old male patient diagnosed with stage IVA lung adenocarcinoma. Gene alterations were analyzed by collecting and studying pleural effusion at the time of diagnosis. Examination revealed an exon 19 deletion in the EGFR gene. Following treatment with the second-generation EGFR-TKI afatinib, squamous cell carcinoma was identified by performing a re-biopsy of the recurrent site. Although the levels of cytokeratin 19 fragment, which is a tumor marker for the follow-up of squamous cell carcinoma, were increased at that point, the levels of carcinoembryonic antigen, a marker particularly associated with adenocarcinoma, remained within normal limits. The T790M mutation and the original exon 19 deletion were detected simultaneously. The patient received treatment with the third-generation EGFR-TKI osimertinib, achieving a good clinical response. These findings suggest that osimertinib is beneficial for lung adenocarcinoma patients with squamous cell transformation harboring the T790M mutation.

Paired genomic analysis of squamous cell carcinoma transformed from EGFR-mutated lung adenocarcinoma

ObjectivesAdenocarcinoma (ADC) to squamous cell carcinoma (SCC) transformation (AST) is reported in epidermal growth factor receptor (EGFR)-mutated non–small cell lung cancer after tyrosine kinase inhibitor (TKI) failure. However, little is known about the underlying genomic changes during the AST process. Materials and methodsWe retrospectively reviewed our tissue database collected after first- or second- generation EGFR TKI resistance (n = 263) and identified 3 cases of AST. The additional case was acquired from the osimertinib resistance sample. Deep target sequencing (381 genes) using paired samples from 4 patients with AST after EGFR TKI treatment was performed. The histology of each sample was confirmed by TTF-1 and p63 immunohistochemistry. The patients received first- or second-generation EGFR TKI as an initial treatment. ResultsOverall incidence of AST was 1.1% (3/263). Transformed SCC acquired genomic alterations related to the PI3K/AKT/mTOR pathway, in addition to the initial EGFR mutation. In a representative case, two separate sub-clones, with a PTEN nonsense mutation and EGFR p.T790 M mutation, were observed without histologic transformation at the time of gefitinib resistance. After subsequent treatment with osimertinib, SCC transformation was observed with the disappearance of the EGFR p.T790 M mutation and acquired copy number loss in PTEN. Adopting the sub-clonal fraction model elucidates the sub-clonal evolution process of the PTEN mutant sub-clone toward AST under the background of EGFR mutation. The rest of the transformed samples also had acquired genomic alterations in PTEN, LKB1, PIK3CA, or RICTOR, which are related to the PI3K/AKT/mTOR pathway. ConclusionsPaired genomic analysis from our sample provides early clinical evidence of the ADC to SCC lineage transition that might be provoked by an alteration in the PI3K/AKT/mTOR pathway during EGFR TKI treatment. This finding could potentially broaden the known spectrum of EGFR TKI resistance mechanisms.

Real-Life Efficacy of Osimertinib in Pretreated Octogenarian Patients with T790M-Mutated Advanced Non-small Cell Lung Cancer.

The resistance mutation T790M is reported in 50-60% of patients pretreated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). Osimertinib has been approved in these patients, but data in octogenarians remain rare. The objective of this retrospective analysis was to evaluate in real life the efficacy of osimertinib in a population of octogenarian patients. This retrospective multicentric study included pretreated octogenarian patients with EGFR T790M-mutated advanced non-small cell lung cancer (NSCLC) in the setting of the French early access program for osimertinib. The primary endpoints were progression-free survival (PFS) and overall survival (OS) from osimertinib initiation. In total, 43 patients were included (mean age 84.6years; women 90.7%: adenocarcinoma 100%; never smokers 90.5%; at osimertinib initiation: performance status ≥ 2, 42.4%; stage 4, 93.0%; brain metastases 16.3%). Patients received a median of two lines of treatment before osimertinib initiation, and all received first- or second-generation EGFR TKIs before osimertinib (first line in 79.1%). Osimertinib was used as a second-line treatment in 41.9% of cases and third line or more in 58.1%. Median PFS was 17.5 (95% confidence interval [CI] 12.2-19.0) months for the entire population: 20.6 (95% CI 18.8-not reached) months in patients with brain metastases and 16.7 (95% CI 10.4-18.9) months in patients without (p = 0.1). There was no significant difference for osimertinib treatment as second or third line or more (17.1 vs. 18.6months, respectively). OS was 22.8 (95% CI 15.7-not reached) months from osimertinib initiation. The efficacy of osimertinib as second-line treatment or more in octogenarian pretreated patients with EGFR T790M-mutated advanced NSCLC in a real-life setting was similar to that in randomized controlled trials.

Afatinib is effective in the treatment of lung adenocarcinoma with uncommon EGFR p.L747P and p.L747S mutations

ObjectivesEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are used as first-line standard treatment for advanced lung adenocarcinoma with mutant EGFR. Nevertheless, few studies have demonstrated the efficacy of first- and second-generation EGFR TKIs in patients harboring the uncommon p.L747P and p.L747S mutations in exon 19 of EGFR. Materials and methodsFrom 2005–2018, we identified patients with lung adenocarcinoma with EGFR p.L747P or p.L747S mutations using DNA and cDNA sequencing or commercial kits and recorded their clinical data. Published data pertaining to these mutations were also reviewed. ResultsTwelve eligible patients were enrolled at National Taiwan University Hospital (NTUH), and ten additional patients were identified in published literature. In NTUH cohort, the direct DNA sequencing had a 60.0% (3 of 5 patients) false-negative rate, and use of commercial kits all caused misidentification of EGFR p.L747P or p.L747S. Of the 7 patients receiving EGFR TKI treatment, five stage-IV lung adenocarcinoma patients that received afatinib had a 80.0% objective response rate (ORR), while two patients administered gefitinib or erlotinib showed a 0% ORR. The median progression-free survival (PFS) rates were 11.97 and 0.92 months (P = 0.012) for afatinib and gefitinib/erlotinib, respectively. No patients (0%) acquired p.T790 M resistance after failure of afatinib (n = 3). Of 10 patients harboring EGFR p.L747P from published literature, six patients used first-generation EGFR TKIs as treatment also showed 0% ORR and 1.00 month median PFS. ConclusionsPatients with the uncommon EGFR mutations p.L747P and p.L747S could be incorrectly classified as having wild-type EGFR or a 19DEL when using direct DNA sequencing or commercial kits. Moreover, use of afatinib may provide significantly improved PFS in patients with advanced lung adenocarcinoma with one of these two EGFR mutations.

Preclinical Modeling of Osimertinib for NSCLC With EGFR Exon 20 Insertion Mutations

IntroductionNSCLC with EGFR exon 20 insertion mutations is the third most common type of EGFR-mutant NSCLC and is resistant to EGFR tyrosine kinase inhibitors (TKIs). This study was conducted to evaluate the efficacies of first- to third-generation EGFR TKIs against NSCLC cells harboring EGFR exon 20 insertion mutations. MethodsWe developed seven EGFR exon 20 insertion-mutant Ba/F3 models and one patient-derived NSCLC (SNU-3173) of subtypes A763insFQEA, V769insASV, D770insSVD, D770insNPG, P772insPR, H773insH, H773insNPH, and H773insAH. Cell viability assays, immunoblotting, and N-ethyl-N-nitrosourea mutagenesis screenings were performed. EGFR exon 20 insertion–mutant structures and couplings with osimertinib, a third-generation EGFR TKI, were modeled and compared. ResultsEGFR exon 20 insertion–mutant NSCLC cells, excluding EGFR A763insFQEA, were resistant to first-generation EGFR TKIs (concentration that inhibits 50% [IC50], 1.1 ± 0.067 to 5.4 ± 0.115 μM). Mutants were sensitive to second-generation EGFR TKIs (IC50, 0.02 ± 0.0002 to 161.8 ± 18.7nM), except EGFR H773insH (IC50, 46.3 ± 8.0 to 352.5 ± 22.7nM). The IC50 ratios for mutant to wild-type cells were higher than those for third-generation EGFR TKIs. Third-generation EGFR TKI osimertinib was highly potent against EGFR exon 20 insertion–mutant cells (IC50, 14.7-62.7 nM), including EGFR H773insH, and spared wild-type EGFR cells. N-ethyl-N-nitrosourea mutagenesis screening of EGFR exon 20 insertion–mutant Ba/F3 cells showed various second sites for EGFR mutations, mostly at exons 20 and 21, including E762K, P794S, and G796D. In addition, osimertinib-resistant cells were established by stepwise exposure to osimertinib and harbored EGFR E762K mutation. ConclusionsOsimertinib is active against EGFR exon 20 insertion–mutant NSCLC and flexibly binds within drug-binding pockets in preclinical models.

Dacomitinib in the Management of Advanced Non-Small-Cell Lung Cancer.

The use of targeted therapy in the management of epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer is an important milestone in the management of advanced lung cancer. There are several generations of EGFR tyrosine kinase inhibitors available for clinical use. Dacomitinib is a second-generation irreversible EGFR tyrosine kinase inhibitor with early-phase clinical studies showing efficacy in non-small-cell lung cancer. In the recently published ARCHER 1050 phase III study, dacomitinib given at 45mg/day orally was superior to gefitinib, a first-generation reversible EGFR tyrosine kinase inhibitor, in improving both progression-free survival and overall survival when given as first-line therapy. There is no prospective evidence to support the use of dacomitinib as subsequent therapy in patients previously treated with chemotherapy or a first-generation EGFR tyrosine kinase inhibitor such as gefitinib and erlotinib. Dacomitinib has not demonstrated any benefit in unselected patients with non-small-cell lung cancer, and its use should be limited to those with known EGFR-sensitizing mutations. Dacomitinib is associated with increased toxicities of diarrhea, rash, stomatitis, and paronychia compared with first-generation EGFR inhibitors. Global quality of life was maintained when assessed in phase III studies. Overall, dacomitinib is an important first- line agent in EGFR-mutated non-small-cell lung cancer in otherwise fit patients whose toxicities can be well managed.

Advanced Non-Small Cell Lung Cancer: Sequencing Agents in the EGFR-Mutated/ALK-Rearranged Populations.

Personalized therapy based on actionable molecular markers has completely transformed the therapeutic landscape in advanced non-small cell lung cancer (NSCLC). In less than 15 years, multiple molecular targets, led by EGFR and anaplastic lymphoma kinase (ALK), have been identified, and myriad oral tyrosine kinase inhibitors (TKIs) are now available to target these oncogenic drivers, with the expectation that the majority of patients will respond to treatment and that progression-free survival (PFS) will exceed 10 to 30 months, far better than we observed historically with chemotherapy alone. As a result, prognosis has improved dramatically in this subset of patients. Osimertinib has largely displaced first- and second-generation EGFR TKIs, including gefitinib, erlotinib, and afatinib, in the management of EGFR-mutated NSCLC. PFS now exceeds 18 months, and central nervous system penetrance is enhanced. Dacomitinib has the distinction of being the first EGFR TKI to demonstrate a survival advantage compared with older TKIs. Recent data suggest therapeutic additivity, if not synergy, for the concurrent use of chemotherapy, as well as monoclonal antibodies targeting angiogenesis, with EGFR TKIs. Alectinib and brigatinib, very specific ALK inhibitors, have proven superior to the erstwhile standard crizotinib in treatment-naive ALK+ NSCLC; PFS now routinely exceeds 2 to 3 years. In addition, these newer agents have far superior central nervous system penetration. As a result, many patients with ALK+ advanced NSCLC with brain metastases, even some who are symptomatic, can defer or indefinitely avoid brain irradiation. Mechanisms of resistance in ALK are complicated, with multiple new agents being developed in this arena. Although many patients with molecular targets can reasonably expect to live 5 years or more, the emergence of molecular resistance is virtually inevitable. In this regard, systemic platinum-based chemotherapy is the final common therapeutic pathway for virtually all patients with oncogenic drivers. Standard regimens include pemetrexed and carboplatin, as well as the E4599 regimen, combination solvent-based paclitaxel, carboplatin, and bevacizumab. Checkpoint inhibitors, as single agents, have not yielded much benefit, even in those with high levels of PD-L1 expression. However, in a subanalysis of patients with ALK and EGFR mutations enrolled in IMpower150, the addition of atezolizumab to the E4599 regimen led to a major overall survival benefit (hazard ratio < 0.40). In the absence of systemic chemotherapy, combining checkpoint inhibitors with TKIs in this setting remains investigational; several studies have demonstrated untoward pulmonary and hepatic toxicity.

Re-administration of osimertinib in osimertinib-acquired resistant non-small-cell lung cancer

BackgroundOsimertinib is a tyrosine kinase inhibitor (TKI) that is an essential agent for the treatment of epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC). However, there is no established strategy for treatment following acquired resistance to this agent. One potential strategy for treating acquired resistance to EGFR TKIs is re-administration, which has been evaluated mainly using first- or second-generation EGFR TKIs. However, no clinical data are available with which to determine the significance of re-administration of osimertinib, a third-generation EGFR TKI. The aim of this study was to evaluate the efficacy of re-administering osimertinib to patients who had acquired resistance to this agent. Patients and methodsWe reviewed the medical records of consecutive patients with advanced NSCLC harboring EGFR-activating mutations and secondary T790M, who had undergone osimertinib re-administration to treat acquired resistance. ResultsSeventeen patients were re-administered osimertinib after acquiring resistance to osimertinib. Of these, two received osimertinib to treat carcinomatous meningitis without any measurable lesion. Responses were evaluated in the remaining 15 patients. The objective response and disease control rates were 33% and 73%, respectively. Tumor shrinkage by osimertinib re-administration was associated with that due to initial osimertinib treatment (r = 0.585, 95% confidence interval [CI]: 0.104–0.844). In the remaining two patients without measurable lesions, one exhibited improved clinical symptoms following osimertinib re-administration. The median progression-free survival (PFS) time of all 17 patients was 4.1 months (95% CI: 1.9–6.7). The toxicity of re-administration was low, without interruption of the treatment due to adverse events (AEs). Most patients had grade 2 AEs or lower. ConclusionsRe-administration of osimertinib for EGFR-mutant NSCLC yielded modest activity with tolerable toxicity.

Integrating Osimertinib in Clinical Practice for Non-Small Cell Lung Cancer Treatment.

Treatment of non-small cell lung cancer (NSCLC) is evolving with the use of precision medicine for patients with sensitizing epidermal growth factor receptor (EGFR) mutation. First- and second-generation EGFR tyrosine kinase inhibitors (TKIs) remained the standard of care for patients with EGFR-mutated advanced NSCLC for about a decade. However, treatment resistance eventually develops for most patients who experience initial response to these agents. The most commonly acquired resistance mechanism is the T790M gatekeeper mutation. Poor drug penetration leading to central nervous system (CNS) relapse and dose-limiting toxicities are other concerns. The third-generation EGFR-TKI osimertinib, initially approved as the second-line treatment for patients with T790-mutant NSCLC, demonstrated survival benefits in TKI-naïve EGFR-mutated patients, especially in patients with CNS metastasis. The FLAURA study has shown statistically significant progression-free survival benefit and prolongation of all post-progression outcome endpoints, time to first subsequent therapy, second subsequent therapy, and second progression on subsequent treatment, along with acceptable toxicity and better quality of life outcomes. These data favor osimertinib in the first-line setting for EGFR-mutated NSCLC. This is an important milestone since sequencing the TKI therapy based on accurate prediction of T790M is clinically challenging. In countries like India, T790M testing is not routinely conducted and two-thirds of patients with NSCLC do not receive any second-line therapy. Osimertinib can be administered pragmatically as a first-line therapy. Mature overall survival data from the FLAURA study will be important and could help define the optimal personalized treatment for patients with advanced NSCLC.Funding: AstraZeneca Pharma India Ltd.

Heterogeneous Responses to Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors (TKIs) in Patients with Uncommon EGFR Mutations: New Insights and Future Perspectives in this Complex Clinical Scenario.

Uncommon Epidermal Growth Factor Receptor (EGFR) mutations represent a distinct and highly heterogeneous subgroup of Non-Small Cell Lung Cancers (NSCLCs), that accounts for approximately 10% of all EGFR-mutated patients. The incidence of uncommon EGFR mutations is growing, due to the wider adoption of next-generation sequencing (NGS) for diagnostic purposes, which enables the identification of rare variants, usually missed with available commercial kits that only detect a limited number of EGFR mutations. However, the sensitivity of uncommon mutations to first- and second-generation EGFR Tyrosine Kinase Inhibitors (TKIs) is widely heterogeneous and less well known, compared with classic mutations (i.e., exon 19 deletions and exon 21 L858R point mutation), since most of the pivotal studies with EGFR TKIs in the first line, with few exceptions, excluded patients with rare and/or complex variants. Recently, the third generation EGFR TKI osimertinib further revolutionized the therapeutic algorithm of EGFR-mutated NSCLC, but its role in patients harboring EGFR mutations besides exon 19 deletions and/or L858R is largely unknown. Therefore, a better knowledge of the sensitivity of uncommon mutations to currently available EGFR TKIs is critical to guiding treatment decisions in clinical practice. The aim of this paper is to provide a comprehensive overview of the treatment of NSCLC patients harboring uncommon EGFR mutations with currently approved therapies and to discuss the emerging therapeutic opportunities in this peculiar subgroup of patients, including chemo-immunotherapy combinations, next-generation EGFR TKIs, and novel targeted agents.

Impact on prognosis of rebiopsy in advanced non-small cell lung cancer patients after epidermal growth factor receptor-tyrosine kinase inhibitor treatment: a systematic review

BackgroundOsimertinib, the third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), has become the standard treatment in cases where rebiopsy reveals T790M mutation after the first-line EGFR-TKI treatment. However, the prognosis of patients after rebiopsy, the most important outcome for cancer patients, has not been described sufficiently. This systematic review aimed to clarify whether rebiopsy contributes to improved prognosis in the first- or second-generation EGFR-TKI refractory patients.MethodsUsing free word and control terms related to “non-small cell lung cancer” and “rebiopsy,” we searched studies from Medical Literature Analysis and Retrieval System Online via PubMed, Embase, Cochrane Central Register of Controlled Trials, and World Health Organization International Clinical Trials Registry Platform. We included cohort studies and case reports written in English and judged whether each study answers our research questions.ResultsOf the 144 studies included, only one reported the prognosis of patients with/without rebiopsy showing that in EGFR-TKI refractory non-small cell lung cancer patients, the post-progression survival (PPS) was significantly longer in patients who received rebiopsy and treatment based on a resistant mechanism (median PPS 24.2 months) than those who received rebiopsy and salvage regimen (median PPS 15.2 months, p = 0.002) and who did not receive rebiopsy (median PPS 9.7 months, p < 0.001). Most of the other studies reported the detection rate of T790M mutation or rebiopsy procedure.ConclusionsOnly a few previous studies have investigated the effectiveness of rebiopsy. Hence, further study is needed to determine the prognosis or adverse events of rebiopsy.

First- and Second-Generation EGFR-TKIs Are All Replaced to Osimertinib in Chemo-Naive EGFR Mutation-Positive Non-Small Cell Lung Cancer?

Activating mutations of the epidermal growth factor receptor gene (EGFR) are a driving force for some lung adenocarcinomas. Several randomized phase III studies have revealed that treatment with first- or second-generation EGFR tyrosine kinase inhibitors (TKIs) results in an improved progression-free survival (PFS) compared to standard chemotherapy in chemonaive patients with advanced non–small cell lung cancer (NSCLC), selected based on the presence of EGFR mutations. Patients treated with second-generation EGFR-TKIs have also shown an improved PFS relative to those treated with first-generation EGRF-TKIs. Osimertinib is a third-generation EGFR-TKI that still irreversibly inhibits the activity of EGFR after it has acquired the secondary T790M mutation that confers resistance to first- and second-generation drugs. Its efficacy has been validated for patients whose tumors have developed T790M-mediated resistance, as well as for first-line treatment of those patients with EGFR mutation–positive NSCLC. Although there are five EGFR-TKIs (gefitinib, erlotinib, afatinib, dacomitinib, and osimertinib) currently available for the treatment of EGFR-mutated lung cancer, the optimal sequence for administration of these drugs remains to be determined. In this review, we addressed this issue with regard to maximizing the duration of the EGFR-TKI treatment.

Management of CNS metastases in patients with EGFR mutation-positive NSCLC.

Central nervous system (CNS) metastases are a frequent and severe complication associated with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). The first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) have shown considerable efficacy in EGFR-mutated NSCLC. However, their limited potential to cross the blood-brain barrier (BBB) renders them less effective in the management of CNS metastases in NSCLC. Osimertinib, a third-generation irreversible EGFR-TKI with good potential to cross the BBB, has shown significant clinical activity and acceptable safety profile in patients with EGFR-positive NSCLC brain and leptomeningeal metastases. The progression-free survival (PFS) of up to 15.2 months in CNS metastases patients in the FLAURA trial and the CNS objective response rates (ORRs) of 54% and 43% in the AURA/AURA2 and BLOOM trials, respectively, have established the role of osimertinib in patients with NSCLC with CNS metastases. The AURA3 trial also reported a PFS of 8.5 months and overall ORR of 71%. These data have supported osimertinib to be recognized as a "preferred" first-line treatment for EGFR-positive metastatic NSCLC by the National Comprehensive Cancer Network (NCCN). With limited treatment options available, upfront administration of osimertinib in patients with NSCLC irrespective of EGFR T790M and CNS metastases may improve the overall response rate and potentially reduce the adverse effects of radiotherapy. Our review focuses on the management of EGFR-mutated NSCLC CNS metastases in the context of recent NCCN guidelines.

Dacomitinib, a second-generation irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) to treat non-small cell lung cancer.

Dacomitinib (PF-00299804, Vizimpro) was developed as a second-generation, oral, irreversible inhibitor of human epidermal growth factor receptor (EGFR)- 1, -2 and -4 tyrosine kinase. On September 27, 2018, the United States Food and Drug Administration (FDA) approved dacomitinib for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) with EGFR exon 19 deletion or exon 21 L858R substitution mutations. On January 8, 2019, the Ministry of Health, Labour and Welfare of Japan approved this second-generation EGFR tyrosine kinase inhibitor (TKI) for the treatment of EGFR mutation-positive inoperable or recurrent NSCLC. The European Commission also approved dacomitinib on April 3, 2019, as monotherapy for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR activating mutations. Approval of dacomitinib was based on a randomized, multicenter, open-label, active-controlled trial (ARCHER 1050; ClinicalTrials.gov Identifier NCT01774721) which demonstrated the safety and efficacy of dacomitinib compared to gefitinib in 452 patients with unresectable and metastatic NSCLC. Dacomitinib represents a powerful new treatment option compared with first-generation EGFR-TKIs. In this paper, we review the clinical and preclinical studies of dacomitinib and discuss the drug's clinical value.

KRAS and EGFR Amplifications Mediate Resistance to Rociletinib and Osimertinib in Acquired Afatinib-Resistant NSCLC Harboring Exon 19 Deletion/T790M in EGFR.

The critical T790M mutation in EGFR, which mediates resistance to first- and second-generation EGFR tyrosine kinase inhibitors (TKI; gefitinib, erlotinib, and afatinib), has facilitated the development of third-generation mutation-selective EGFR TKIs (rociletinib and osimertinib). We previously reported heterogeneous afatinib-resistant mechanisms, including emergence of T790M-EGFR, and responses to third-generation EGFR TKIs. Here, we used afatinib-resistant lung adenocarcinoma cells [AfaR (formerly AFR3) cells], carrying exon 19 deletion/T790M in EGFR To identify the novel resistance mechanisms in post-afatinib treatment, RocR1/RocR2 and OsiR1/OsiR2 cells were established using increasing concentrations of rociletinib and osimertinib, respectively. Attenuation of exon 19 deletion and T790M was confirmed in both rociletinib-resistant cells; in addition, EGFR and KRAS amplification was observed in RocR1 and RocR2, respectively. Significant KRAS amplification was observed in the osimertinib-resistant cell lines, indicating a linear and reversible increase with increased osimertinib concentrations in OsiR1 and OsiR2 cells. OsiR1 cells maintained osimertinib resistance with KRAS amplification after osimertinib withdrawal for 2 months. OsiR2 cells exhibited KRAS attenuation, and osimertinib sensitivity was entirely recovered. Phospho-EGFR (Y1068) and growth factor receptor-bound protein 2 (GRB2)/son of sevenless homolog 1 (SOS1) complex was found to mediate osimertinib resistance in OsiR1 cells with sustained KRAS activation. After 2 months of osimertinib withdrawal, this complex was dissociated, and the EGFR signal, but not the GRB2/SOS1 signal, was activated. Concomitant inhibition of MAPK kinase and EGFR could overcome osimertinib resistance. Thus, we identified a heterogeneous acquired resistance mechanism for third-generation EGFR TKIs, providing insights into the development of novel treatment strategies.

Gustave Roussy Immune Score Is a Prognostic Factor for Chemotherapy-Naive Pulmonary Adenocarcinoma With Wild-Type Epidermal Growth Factor Receptor.

BackgroundThe Gustave Roussy Immune Score (GRIm-Score) was developed based on the Royal Marsden Hospital (RMH) prognostic score for the purpose of a better patient selection for immunotherapy phase I trials. This scoring system is simply calculated by neutrophil-to-lymphocyte ratio, lactate dehydrogenase (LDH), and serum albumin concentration. The aim of our study was to determine whether GRIm-Score is a practically useful prognostic biomarker for advanced non-small cell lung cancer (NSCLC) patients treated with cytotoxic chemotherapy or epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI).MethodsThis retrospective and single institutional study collected 185 adenocarcinomas without active EGFR mutation, 115 squamous cell carcinomas treated with first-line cytotoxic chemotherapy, and 140 NSCLCs with mutant EGFR treated with first- or second-generation EGFR-TKI monotherapy. These treatments were initiated between July 2007 and March 2018 at our hospital. We compared overall survival (OS) and progression-free survival (PFS) between high and low GRIm-Score groups. Using multivariate Cox proportional hazard analyses, we also found prognostic factors of survival times.ResultsThe OS and PFS of low GRIm-Score group were significantly longer than those of high-score group in wild-type EGFR adenocarcinoma (low vs. high; median OS, 18.4 vs. 5.1 months, P < 0.01, and median PFS, 5.8 vs. 3.7 months, P = 0.01) and EGFR-mutant NSCLC (median OS, 38.9 vs. 10.4 months, P < 0.01, and median PFS, 15.9 vs. 5.0 months, P < 0.01). Subsequent multivariate analyses detected high GRIm-Score in wild-type EGFR adenocarcinoma as a poor prognostic factor of OS (hazard ratio (HR) 2.20, 95% CI 1.47 - 3.31, P < 0.01), and in the EGFR-mutant NSCLC as a poor prognostic factor of PFS (HR 1.89, 95% CI 1.00 - 3.55, P = 0.049).ConclusionsHigh GRIm-Score was an independent prognostic biomarker of OS of first-line cytotoxic chemotherapy for wild-type EGFR adenocarcinoma and of PFS of first- or second-generation EGFR-TKI for EGFR-mutant NSCLC. Therefore, GRIm-Score is not only a specific selection marker for experimental immunotherapy trials, but may also be a promising and useful pretreatment prognostic maker for specific NSCLC subsets in the real-world practice.