Journal articles: 'EGFR TKI'

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Simmons, Daniel, Maral DerSarkissian, Rahul Shenolikar, Min-Jung Wang, Angela Lax, Aruna Muthukumar, François Laliberté, and Mei Sheng Duh. "Real-world outcomes among patients with epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer treated with EGFR tyrosine kinase inhibitors versus immunotherapy or chemotherapy in first-line setting." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e19345-e19345. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e19345.

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e19345 Background: While epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the NCCN-recommended first-line (1L) therapy for non-small cell lung cancer (NSCLC) patients (pts) with EGFR mutation (EGFRm), many pts initiate immunotherapy (IO) + chemotherapy (chemo) prior to receiving EGFRm test results. This study assessed clinical outcomes associated with initiating EGFR-TKI vs other therapies in stage IV EGFRm NSCLC. Methods: A retrospective study was conducted in adult pts with stage IV EGFRm NSCLC who initiated 1L EGFR-TKI, IO (+ chemo), or chemo alone from 5/2017-12/2018, using data from Flatiron Health. Treatment patterns were characterized with respect to timing of EGFRm test results. Kaplan-Meier analysis was used to assess the median duration of therapy (mDoT) and time to next therapy (mTTNT), as proxies for progression-free survival. Adjusted hazards ratios (HR) and 95% confidence intervals (CI) representing the effect of 1L therapy on the risk of discontinuing treatment or death (DoT) and risk of initiating second-line therapy or death (TTNT) were reported from multivariable Cox proportional hazards models controlling for differences in demographics, smoking history, histology, cancer stage, ECOG score, NCI index, and year of and time from diagnosis to 1L initiation, across treatment arms. Results: Among 593 study pts, mean age was 67.5 years and 65.4% were female. EGFR-TKI was used as 1L therapy for 77.2% of pts (n=458), IO in 13.3% (n=79) and chemo alone in 9.4% (n=56). 7.2% of EGFR-TKI pts, 54.4% of IO pts, and 57.1% of chemo pts initiated 1L before receiving EGFRm test results. Compared to pts on IO and chemo alone, pts on EGFR-TKI had longer mDoT (EGFR-TKI: 8.7 months [mo]; IO: 4.8 mo; chemo alone: 3.0 mo, p<0.01) and mTTNT (EGFR-TKI: 12.3 mo; IO: 6.5 mo; chemo alone: 4.0 mo, p<0.01). After adjustment, pts on EGFR-TKI vs pts on IO or chemo alone had significantly lower risk of discontinuing therapy or death (DoT) and initiating second-line therapy or death (TTNT) (see Table). Conclusions: A substantial number of stage IV EGFRm NSCLC pts initiated IO or chemo alone in 1L and EGFR-TKI was associated with better clinical outcomes than IO or chemo alone, highlighting the importance of adhering to NCCN-recommended therapy for these pts. [Table: see text]

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Simmons, Daniel, Maral DerSarkissian, Rahul Shenolikar, Min-Jung Wang, Angela Lax, Aruna Muthukumar, François Laliberté, and Mei Sheng Duh. "Real-world outcomes among patients with epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer treated with EGFR tyrosine kinase inhibitors versus immunotherapy or chemotherapy in first-line setting." Journal of Clinical Oncology 38, no. 29_suppl (October 10, 2020): 281. http://dx.doi.org/10.1200/jco.2020.38.29_suppl.281.

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281 Background: While EGFR tyrosine kinase inhibitors (TKIs) are the NCCN-recommended first-line (1L) therapy for non-small cell lung cancer (NSCLC) patients (pts) with EGFR mutation (EGFRm), many pts initiate immunotherapy (IO) + chemotherapy (chemo) prior to receiving EGFRm test results. This study assessed clinical outcomes associated with initiating EGFR-TKI vs other therapies in stage IV EGFRm NSCLC. Methods: A retrospective study was conducted in adults with stage IV EGFRm NSCLC who initiated 1L EGFR-TKI, IO (+ chemo), or chemo alone from 5/2017-12/2018, using Flatiron Health Electronic Health Record data. Treatment patterns were characterized with respect to timing of EGFRm test results. Kaplan-Meier analysis and log-rank tests were used to evaluate the median duration of therapy (DoT) and time to next therapy (TTNT), as proxies for progression-free survival. Adjusted hazards ratios (HR) and 95% confidence intervals (CI) representing the effect of 1L therapy on the risk of discontinuing treatment or death (DoT) and the risk of initiating second-line therapy or death (TTNT) were reported from multivariable Cox proportional hazards models controlling for differences in demographics, smoking history, histology, cancer stage, ECOG score, NCI index, time from diagnosis to 1L initiation, and year of 1L initiation, across treatment arms. Results: Among 593 study pts, mean age was 67.5 years and 65.4% were female. EGFR-TKI was used as 1L therapy for 77.2% of pts (n=458), IO in 13.3% (n=79) and chemo in 9.4% (n=56). 7.2% of EGFR-TKI pts, 54.4% of IO pts, and 57.1% of chemo pts initiated 1L before receiving EGFRm test results. Compared to pts on IO and chemo, pts on EGFR-TKI had longer median DoT (EGFR-TKI: 8.7 months [mo]; IO: 4.8 mo; chemo: 3.0 mo, p<0.01) and median TTNT (EGFR-TKI: 12.3 mo; IO: 6.5 mo; chemo: 4.0 mo, p<0.01). Adjusted analyses showed that compared to pts on IO or chemo, pts on EGFR-TKI had significantly lower risk of discontinuing therapy or death (DoT) and initiating second-line therapy or death (TTNT) (Table). Conclusions: Substantial numbers of pts initiated IO + chemo in 1L and EGFR-TKI was associated with better clinical outcomes than IO + chemo, suggesting the importance of adhering to NCCN-recommended therapy for stage IV EGFRm NSCLC pts. [Table: see text]

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Shenolikar, Rahul, Sizhu Liu, Jenny Tse, Yao Cao, and Aimee Near. "Real-world treatment patterns of metastatic non-small cell lung cancer (mNSCLC) patients receiving epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs)." Journal of Clinical Oncology 39, no. 28_suppl (October 1, 2021): 289. http://dx.doi.org/10.1200/jco.2020.39.28_suppl.289.

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289 Background: Among mNSCLC patients positive for EGFR mutation (EGFRm), first-line (1L) treatment with an EGFR TKI is recommended for best outcomes. This study describes real-world treatment patterns of mNSCLC patients using EGFR TKIs in the 1L setting, including osimertinib, the most recently approved EGFR TKI for 1L use. Methods: Patients with ≥1 claim for an EGFR TKI (1st generation [1G]: gefitinib, erlotinib; 2nd generation [2G]: afatinib, dacomitinib; 3rd generation: osimertinib) from January 1, 2015 – April 30, 2020 were identified in IQVIA’s prescription (LRx) and medical claims (Dx) databases; first date of EGFR TKI was the index date. Patients had 12-month baseline period before index, variable follow-up after index, ≥1 lung cancer diagnosis on index or in baseline, and earliest metastatic cancer diagnosis on or 90 days before index. Kaplan-Meier analysis was used to estimate 1L treatment duration, where treatment discontinuation was defined as >60-day gap in medication supply of the index EGFR TKI. Patient characteristics and treatment patterns were stratified by 1L EGFR TKI. Results: Overall, 2,505 mNSCLC patients received 1L EGFR TKI (982 osimertinib, 1,060 1G, 463 2G). Median ages were 66-69 years, 64.6-67.1% were female, and 32.4-38.9% had central nervous system metastases on or before index. Most patients were commercially insured (50.8-62.9%), 35.3-45.9% had Medicare, and 0.6-3.3% had other payer types. Nearly all patients had 1L EGFR TKI monotherapy (97.6-99.7%). 1L treatment duration was longer for osimertinib compared to 1G or 2G EGFR TKI (median months, 17.8, 8.7, 10.5 respectively). 2L treatment was observed in 32.5% of 1G and 36.3% of 2G EGFR TKI cohorts. Osimertinib monotherapy, chemotherapy, and immunotherapy (monotherapy or combined with chemotherapy) accounted for 58.3%, 7.0%, and 4.3% of 2L treatments after 1L 1G EGFR TKI, respectively, and 60.7%, 4.2%, and 4.8% of 2L treatments after 1L 2G EGFR TKI. Conclusions: In real-world practice, 1L treatment duration is longer with osimertinib compared with other EGFR TKIs. Future studies with longer follow-up are recommended to understand treatment patterns after progression on EGFR TKIs, mainly osimertinib, given its recent approval.

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Ohmori, Tohru, Toshimitsu Yamaoka, Koichi Ando, Sojiro Kusumoto, Yasunari Kishino, Ryou Manabe, and Hironori Sagara. "Molecular and Clinical Features of EGFR-TKI-Associated Lung Injury." International Journal of Molecular Sciences 22, no. 2 (January 14, 2021): 792. http://dx.doi.org/10.3390/ijms22020792.

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The tyrosine kinase activity of epidermal growth factor receptors (EGFRs) plays critical roles in cell proliferation, regeneration, tumorigenesis, and anticancer resistance. Non-small-cell lung cancer patients who responded to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) and obtained survival benefits had somatic EGFR mutations. EGFR-TKI-related adverse events (AEs) are usually tolerable and manageable, although serious AEs, including lung injury (specifically, interstitial lung disease (ILD), causing 58% of EGFR-TKI treatment-related deaths), occur infrequently. The etiopathogenesis of EGFR-TKI-induced ILD remains unknown. Risk factors, such as tobacco exposure, pre-existing lung fibrosis, chronic obstructive pulmonary disease, and poor performance status, indicate that lung inflammatory circumstances may worsen with EGFR-TKI treatment because of impaired epithelial healing of lung injuries. There is limited evidence from preclinical and clinical studies of the mechanisms underlying EGFR-TKI-induced ILD in the available literature. Herein, we evaluated the relationship between EGFR-TKIs and AEs, especially ILD. Recent reports on mechanisms inducing lung injury or resistance in cytokine-rich circumstances were reviewed. We discussed the relevance of cytotoxic agents or immunotherapeutic agents in combination with EGFR-TKIs as a potential mechanism of EGFR-TKI-related lung injury and reviewed recent developments in diagnostics and therapeutics that facilitate recovery from lung injury or overcoming resistance to anti-EGFR treatment.

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Urbanska, Edyta M., Morten Grauslund, Peter R. Koffeldt, Sarah L. B. Truelsen, Johan O. Löfgren, Junia C. Costa, Linea C. Melchior, Jens B. Sørensen, and Eric Santoni-Rugiu. "Real-World Data on Combined EGFR-TKI and Crizotinib Treatment for Acquired and De Novo MET Amplification in Patients with Metastatic EGFR-Mutated NSCLC." International Journal of Molecular Sciences 24, no. 17 (August 23, 2023): 13077. http://dx.doi.org/10.3390/ijms241713077.

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Amplification of the mesenchymal epithelial transition (MET) gene is a mechanism of acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine-kinase-inhibitors (TKIs) in over 20% of patients with advanced EGFR-mutated (EGFRm+) non-small lung cancer (NSCLC). However, it may also occur de novo in 2–8% of EGFRm+ NSCLC cases as a potential mechanism of intrinsic resistance. These patients represent a group with unmet needs, since there is no standard therapy currently approved. Several new MET inhibitors are being investigated in clinical trials, but the results are awaited. Meanwhile, as an alternative strategy, combinations of EGFR-TKIs with the MET/ALK/ROS1-TKI Crizotinib may be used in this setting, despite this use is principally off-label. Thus, we studied five of these MET amplified cases receiving EGFR-TKI and Crizotinib doublet after progression on EGFR-TKI treatment to assess the benefits and challenges related to this combination and the possible occurrence of genomic and phenotypic co-alterations. Furthermore, we compared our cases with other real-world reports on Crizotinib/EGFR-TKI combinations, which appeared effective, especially in patients with high-level MET amplification. Yet, we observed that the co-occurrence of other genomic and phenotypical alterations may affect the response to combined EGFR-TKI and Crizotinib. Finally, given the heterogeneity of MET amplification, the diagnostic methods for assessing it may be discrepant. In this respect, we observed that for optimal detection, immunohistochemistry, fluorescence in situ hybridization, and next-generation sequencing should be used together, as these methods possess different sensitivities and complement each other in characterizing MET amplification. Additionally, we addressed the issue of managing EGFR-mutated NSCLC patients with de novo MET amplification causing primary EGFR-TKI resistance. We conclude that, while data from clinical trials with new MET inhibitors are still pending, adding Crizotinib to EGFR-TKI in NSCLC patients acquiring MET amplification at progression on EGFR-TKI monotherapy is a reasonable approach, with a progression-free survival of 3–19 months.

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Santoni-Rugiu, Melchior, Urbanska, Jakobsen, Stricker, Grauslund, and Sørensen. "Intrinsic resistance to EGFR-Tyrosine Kinase Inhibitors in EGFR-Mutant Non-Small Cell Lung Cancer: Differences and Similarities with Acquired Resistance." Cancers 11, no. 7 (July 1, 2019): 923. http://dx.doi.org/10.3390/cancers11070923.

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Activating mutations in the epidermal growth factor receptor gene occur as early cancer-driving clonal events in a subset of patients with non-small cell lung cancer (NSCLC) and result in increased sensitivity to EGFR-tyrosine-kinase-inhibitors (EGFR-TKIs). Despite very frequent and often prolonged clinical response to EGFR-TKIs, virtually all advanced EGFR-mutated (EGFRM+) NSCLCs inevitably acquire resistance mechanisms and progress at some point during treatment. Additionally, 20–30% of patients do not respond or respond for a very short time (<3 months) because of intrinsic resistance. While several mechanisms of acquired EGFR-TKI-resistance have been determined by analyzing tumor specimens obtained at disease progression, the factors causing intrinsic TKI-resistance are less understood. However, recent comprehensive molecular-pathological profiling of advanced EGFRM+ NSCLC at baseline has illustrated the co-existence of multiple genetic, phenotypic, and functional mechanisms that may contribute to tumor progression and cause intrinsic TKI-resistance. Several of these mechanisms have been further corroborated by preclinical experiments. Intrinsic resistance can be caused by mechanisms inherent in EGFR or by EGFR-independent processes, including genetic, phenotypic or functional tumor changes. This comprehensive review describes the identified mechanisms connected with intrinsic EGFR-TKI-resistance and differences and similarities with acquired resistance and among clinically implemented EGFR-TKIs of different generations. Additionally, the review highlights the need for extensive pre-treatment molecular profiling of advanced NSCLC for identifying inherently TKI-resistant cases and designing potential combinatorial targeted strategies to treat them.

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Magnuson, William J., Nataniel H. Lester-Coll, Abraham J. Wu, T. Jonathan Yang, Natalie A. Lockney, Naamit K. Gerber, Kathryn Beal, et al. "Management of Brain Metastases in Tyrosine Kinase Inhibitor–Naïve Epidermal Growth Factor Receptor–Mutant Non–Small-Cell Lung Cancer: A Retrospective Multi-Institutional Analysis." Journal of Clinical Oncology 35, no. 10 (April 1, 2017): 1070–77. http://dx.doi.org/10.1200/jco.2016.69.7144.

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Purpose Stereotactic radiosurgery (SRS), whole-brain radiotherapy (WBRT), and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are treatment options for brain metastases in patients with EGFR-mutant non–small-cell lung cancer (NSCLC). This multi-institutional analysis sought to determine the optimal management of patients with EGFR-mutant NSCLC who develop brain metastases and have not received EGFR-TKI. Materials and Methods A total of 351 patients from six institutions with EGFR-mutant NSCLC developed brain metastases and met inclusion criteria for the study. Exclusion criteria included prior EGFR-TKI use, EGFR-TKI resistance mutation, failure to receive EGFR-TKI after WBRT/SRS, or insufficient follow-up. Patients were treated with SRS followed by EGFR-TKI, WBRT followed by EGFR-TKI, or EGFR-TKI followed by SRS or WBRT at intracranial progression. Overall survival (OS) and intracranial progression-free survival were measured from the date of brain metastases. Results The median OS for the SRS (n = 100), WBRT (n = 120), and EGFR-TKI (n = 131) cohorts was 46, 30, and 25 months, respectively ( P < .001). On multivariable analysis, SRS versus EGFR-TKI, WBRT versus EGFR-TKI, age, performance status, EGFR exon 19 mutation, and absence of extracranial metastases were associated with improved OS. Although the SRS and EGFR-TKI cohorts shared similar prognostic features, the WBRT cohort was more likely to have a less favorable prognosis ( P = .001). Conclusion This multi-institutional analysis demonstrated that the use of upfront EGFR-TKI, and deferral of radiotherapy, is associated with inferior OS in patients with EGFR-mutant NSCLC who develop brain metastases. SRS followed by EGFR-TKI resulted in the longest OS and allowed patients to avoid the potential neurocognitive sequelae of WBRT. A prospective, multi-institutional randomized trial of SRS followed by EGFR-TKI versus EGFR-TKI followed by SRS at intracranial progression is urgently needed.

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Yeo, Min-Kyung, Yoonjoo Kim, Da Hye Lee, Chaeuk Chung, and Go Eun Bae. "Cosuppression of NF-κB and AICDA Overcomes Acquired EGFR-TKI Resistance in Non-Small Cell Lung Cancer." Cancers 14, no. 12 (June 14, 2022): 2940. http://dx.doi.org/10.3390/cancers14122940.

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Background: Acquired resistance after EGFR-tyrosine kinase inhibitor (TKI) treatment is the rule rather than the exception. Overcoming resistance to EGFR-TKIs is essential if we are to develop better therapeutic strategies for lung cancer patients. Here, we examine the effector signaling pathways underlying TKI resistance and propose targets to overcome the resistance of lung adenocarcinoma (LAC) to TKI. Methods: We compared the expression of NF-κB, AICDA, Akt, IL-6, Jak2, and Stat3 by EGFR-TKI-resistant and EGFR-TKI-sensitive LAC cell lines, and by LAC patients treated with EGFR-TKIs; we then evaluated links between expression and treatment responses. We also examined the therapeutic effects of NF-κB and AICDA inhibition in EGFR-TKI-resistant LACs. Results: NF-κB and AICDA were more expressed by EGFR-TKI-resistant LACs than by EGFR-TKI-sensitive LACs. EGFR-TKIs induced a dose-dependent increase in the expression of NF-κB, AICDA, and IL-6. Inhibition of NF-κB suppressed the expression of AICDA, Akt, and IL-6 in EGFR-TKI-resistant and EGFR-TKI-sensitive LACs, whereas knockdown of AICDA suppressed the expression of NF-κB and Akt in both cell types. Treating EGFR-TKI-resistant LACs with an EGFR-TKI, alongside cosuppression of NF-κB and AICDA, had a significant therapeutic effect. Conclusion: Treatment with an EGFR-TKI plus cosuppression of NF-κB and AICDA may be a promising strategy to overcome EGFR-TKI resistance in LACs.

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van de Stadt, Eveline Annette, Maqsood Yaqub, Robert C. Schuit, Imke H. Bartelink, Anke F. Leeuwerik, Lothar A. Schwarte, Adrianus J. de Langen, Harry Hendrikse, and Idris Bahce. "Relationship between Biodistribution and Tracer Kinetics of 11C-Erlotinib, 18F-Afatinib and 11C-Osimertinib and Image Quality Evaluation Using Pharmacokinetic/Pharmacodynamic Analysis in Advanced Stage Non-Small Cell Lung Cancer Patients." Diagnostics 12, no. 4 (April 1, 2022): 883. http://dx.doi.org/10.3390/diagnostics12040883.

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Background: Patients with non-small cell lung cancer (NSCLC) driven by activating epidermal growth factor receptor (EGFR) mutations are best treated with therapies targeting EGFR, i.e., tyrosine kinase inhibitors (TKI). Radiolabeled EGFR-TKI and PET have been investigated to study EGFR-TKI kinetics and its potential role as biomarker of response in NSCLC patients with EGFR mutations (EGFRm). In this study we aimed to compare the biodistribution and kinetics of three different EGFR-TKI, i.e., 11C-erlotinib, 18F-afatinib and 11C-osimertinib. Methods: Data of three prospective studies and 1 ongoing study were re-analysed; data from thirteen patients (EGFRm) were included for 11C-erlotinib, seven patients for 18F-afatinib (EGFRm and EGFR wild type) and four patients for 11C-osimertinib (EGFRm). From dynamic and static scans, SUV and tumor-to-blood (TBR) values were derived for tumor, lung, spleen, liver, vertebra and, if possible, brain tissue. AUC values were calculated using dynamic time-activity-curves. Parent fraction, plasma-to-blood ratio and SUV values were derived from arterial blood data. Tumor-to-lung contrast was calculated, as well as (background) noise to assess image quality. Results: 11C-osimertinib showed the highest SUV and TBR (AUC) values in nearly all tissues. Spleen uptake was notably high for 11C-osimertinib and to a lesser extent for 18F-afatinib. For EGFRm, 11C-erlotinib and 18F-afatinib demonstrated the highest tumor-to-lung contrast, compared to an inverse contrast observed for 11C-osimertinib. Tumor-to-lung contrast and spleen uptake of the three TKI ranked accordingly to the expected lysosomal sequestration. Conclusion: Comparison of biodistribution and tracer kinetics showed that 11C-erlotinib and 18F-afatinib demonstrated the highest tumor-to-background contrast in EGFRm positive tumors. Image quality, based on contrast and noise analysis, was superior for 11C-erlotinib and 18F-afatinib (EGFRm) scans compared to 11C-osimertinib and 18F-afatinib (EGFR wild type) scans.

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Kawano, Yuko, Atsushi Horiike, Azusa Tanimoto, Toshio Sakatani, Ryota Saito, Kyohei Kaburaki, Noriko Yanagitani, et al. "Monitoring of plasma pro-GRP level during EGFR-TKI treatment." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 10604. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.10604.

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10604 Background: Lung cancers harboring mutations in the epidermal growth factor receptor gene (EGFR) respond to EGFR tyrosine kinase inhibitors (EGFR-TKI), but drug resistance invariably emerges. The major acquired mechanisms of resistance are the EGFR T790M mutation or MET gene amplification. Transformation from NSCLC into small-cell lung cancer (SCLC) has been recently identified in acquired resistance to EGFR-TKI. However, it is difficult to predict the transformation during EGFR-TKI treatment because obtaining serial and sufficient specimens for biopsy is difficult. Pro-gastrin-releasing peptide (Pro-GRP) is a specific and sensitive tumor marker for SCLC. We evaluated the plasma Pro-GRP levels in EGFR-mutant NSCLCs and determined whether plasma Pro-GRP levels could predict SCLC transformation in resistance to EGFR-TKI. Methods: From July 2008 to December 2011, 49 patients with EGFR-mutant NSCLC who received EGFR-TKI treatment were enrolled. Plasma was obtained from these patients before EGFR-TKI treatment and when EGFR-TKI treatment failed. Pro-GRP and CEA levels were measured and compared before and after treatment. Results: Patient characteristics for 49 patients (15 men, 34 women) were as follows: median age, 62 years (41–81 years); histology, 46 adenocarcinomas (AD) and 3 non-AD tumors; and EGFR mutation type, 25 exon 19 deletions and 24 exon 21 L858R. All 49 patients had received EGFR-TKI treatment (45 with gefitinib and 4 with erlotinib); the response to EGFR-TKI treatment was PR in 39 patients, SD in 7, PD in 2, and NE in 1. Positive rate of ProGRP and CEA at pre-EGFR-TKI treatment was 2.0% and 57.2% and that at post-EGFR-TKI treatment was 6.1% and 69.4%, respectively. In 3 of 49 patients, the Pro-GRP levels had increased after treatment, but the CEA level did not increase. Objective responses to cytotoxic chemotherapy were noted in all 3 patients after EGFR-TKI treatment. Conclusions: Monitoring of plasma Pro-GRP during EGFR-TKI treatment may be useful for early detection of SCLC transformation in resistance to EGFR-TKI.

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Le, Xiuning, Anna Eisert, Te-Chun Hsia, Nirmal Vivek Raut, Azura Ahmad, Oscar Siu Hong Chan, Charlotte De Bondt, et al. "Patients with EGFR mutant (m) MET-altered NSCLC receiving tepotinib with an EGFR tyrosine kinase inhibitor (TKI): A case series." Journal of Clinical Oncology 41, no. 16_suppl (June 1, 2023): 9070. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.9070.

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9070 Background: Oncogenic activation of MET is a common mechanism of acquired resistance to EGFR TKIs in patients (pts) with EGFRm NSCLC, with MET amplification (amp) constituting the most frequent cause of bypass pathway activation. Currently, there are no approved targeted treatment options for these pts. Data from the Phase II INSIGHT (NCT01982955) and INSIGHT 2 (NCT03940703) studies indicate the combination of the selective MET TKI tepotinib plus an EGFR TKI has encouraging activity. We present a case series of pts with EGFRm MET-altered NSCLC receiving tepotinib plus an EGFR TKI outside of clinical trials. Methods: Access to tepotinib was provided to pts with EGFRm MET-altered NSCLC and resistance to EGFR TKIs through unsolicited compassionate use requests. All pts received tepotinib (500 mg [450 mg active moiety] once daily; first dose by Oct 2022) plus an EGFR TKI. Participating physicians provided case information up to January 2023. Results: 28 cases of pts with EGFRm NSCLC and MET alterations who received tepotinib plus an EGFR TKI were collated. 21 pts had METamp after EGFR TKI treatment, 5 had MET overexpression, and 2 had MET exon 14 skipping. Pts were aged 41–86 years, 15 were Asian, 13 were white, 19 were female, 8 had smoking history, and all had adenocarcinoma histology. METamp was detected by tissue biopsy in 17 pts, and liquid biopsy in 4 pts. Of 12 pts with METamp detected by FISH, gene copy number ranged from 5.3–33.4, and MET:CEP7 ratio from 0.7–15.1. EGFR TKIs received in combination with tepotinib were osimertinib (n = 21, 19 of whom received prior osimertinib), gefitinib (n = 6), dacomitinib (n = 1), afatinib (n = 1), with 1 pt received gefitinib followed by osimertinib. Tepotinib plus EGFR TKI was received by 9 pts as second-line, 9 as third-line, and 10 as fourth-or-later line. Median treatment duration was 8.8 months (range 1.3–20.6), with treatment ongoing in 13 pts (10 with current duration ≥10 months). Per the physician’s assessment, 25/28 pts (89%) had clinical benefit, 16 of whom (57%) were considered to have a partial response (PR). Clinical benefit was reported in 18/21 (86%) pts with METamp (12 PR, 57%), in 5/5 with MET overexpression (2 PR), and 2/2 with MET exon 14 skipping (2 PR). The most reported adverse event (AE) considered related to tepotinib was edema in 15 pts (most commonly peripheral edema). Grade 3 AEs related to tepotinib were reported in 5 pts (including Grade 3 edema in 2 pts), 1 of whom discontinued the combination due to Grade 3 pneumonitis. Conclusions: Tepotinib plus an EGFR TKI showed promising clinical activity in pts with MET-altered NSCLC who have progressed on a previous EGFR TKI, including those with several lines of prior treatment. Clinical benefit was observed irrespective of MET alteration type in this case series of pts treated outside of clinical trials, with a large proportion of patients continuing to benefit from ongoing treatment.

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Nakashima, Masanao, Takashi Hirose, Yasunari Oki, Yasunori Murata, Tomohide Sugiyama, Hiroo Ishida, Kentaro Okuda, Toshimitsu Yamaoka, Tohru Ohmori, and Tsukasa Ohnishi. "Clinical benefit of second EGFR-TKI retreatment on overall survival in patients with advanced non-small-cell lung cancer harboring EGFR-mutation positive after failure of the initial EGFR-TKI treatment: A retrospective analysis." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e19164-e19164. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e19164.

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e19164 Background: The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) bring the best result to EGFR-mutation positive non-small cell lung cancer patients, but most lead to drug resistance. These acquired resistances are associated with T790M mutation or Met amplification, HGF expression. To assess whether affects overall survival in these patients, we did a retrospective study comparing survival outcomes in 2nd EGFR-TKI treated patients with controls without 2nd EGFR-TKI screened during the same time period. Methods: We examined overall survival in thirty-two of 52 patients with advanced, EGFR-mutation-positive NSCLC who treated 1st EGFR-TKI (gefitinib) from January 2009 to December 2012. We identified 16 patients who were given 2nd EGFR-TKI (erlotinib) after failure of the initial gefitinib treatment (retreatment group) with 16 patients who were not given 2nd EGFR-TKI but given only chemotherapy (control group), 20 patients who might treat with 2nd EGFR-TKI or chemotherapy at that time were excluded in progress after failure of the initial gefitinib treatment. To assess differences in overall survival, we assessed subsets of clinically comparable 2nd EGFR-TKI retreatment group. Results: Among 16 patients who were given 2nd EGFR-TKI, retreatment group who were given one or two cytotoxic chemotherapy from 1st EGFR-TKI to 2nd EGFR-TKI, median overall survival from initiation of the diagnosis with advanced IIIB/IV stage or surgical recurrent NSCLC was 24.2 months. 16 patients of control group who were given from second to seven line cytotoxic chemotherapy, overall survival was 15.8 months (p=0.021). Retreatment group who were given 2nd EGFR-TKI was significantly longer than control group in EGFR mutation positive patients. Response rate and disease control rate with 2nd EGFR-TKI retreatment are 12.5% and 31.3%. Conclusions: In patients with advanced, EGFR mutation positive NSCLC, retreatment group who were given 2nd EGFR-TKI therapy was associated with improved survival compared with control group who were given only cytotoxic chemotherapy.

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Thomas, Rintu, Shivangi Srivastava, Rajasekhara Reddy Katreddy, Jason Sobieski, and Zhang Weihua. "Kinase-Inactivated EGFR Is Required for the Survival of Wild-Type EGFR-Expressing Cancer Cells Treated with Tyrosine Kinase Inhibitors." International Journal of Molecular Sciences 20, no. 10 (May 22, 2019): 2515. http://dx.doi.org/10.3390/ijms20102515.

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Inhibiting the tyrosine kinase activity of epidermal growth factor receptor (EGFR) using small molecule tyrosine kinase inhibitors (TKIs) is often ineffective in treating cancers harboring wild-type EGFR (wt-EGFR). TKIs are known to cause dimerization of EGFR without altering its expression level. Given the fact that EGFR possesses kinase-independent pro-survival function, the role of TKI-inactivated EGFR in cancer cell survival needs to be addressed. In this study, using wt-EGFR-expressing cancer cells A549 (lung), DU145 (prostate), PC3 (prostate), and MDA-MB-231 (breast), we characterized the TKI-induced dimerization status of EGFR and determined the dependency of cells on kinase-inactivated EGFR for survival. We report that TKI-induced EGFR dimerization is dependent on palmitoylation and independent of its kinase activity, and that mutations of the cysteine residues known to be critical for EGFR’s palmitoylation abolished TKI-induced EGFR dimerization. Furthermore, TKI-induced EGFR dimerization is persistent in TKI-resistant cells, and inhibition of palmitoylation by 2-bromopalmitate, or targeted reduction of the kinase-inactivated EGFR by siRNA or by an EGFR-downregulating peptide, are lethal to TKI-resistant cancer cells. This study suggests that kinase-inactivated EGFR remains to be a viable therapeutic target for wt-EGFR cancers and that inhibiting palmitoylation or downregulating EGFR may overcome TKI resistance.

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Fernandes, Ancilla, Karen E. Skinner, Mark Stephen Walker, Melissa Pavilack, and Ari M. Vanderwalde. "Understanding real-world outcomes in patients with NSCLC who progress on 1st-/2nd-generation EGFR TKIs." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e20589-e20589. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e20589.

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e20589 Background: Epidermal growth factor receptor (EGFR)tyrosine kinase inhibitors (TKIs) are recommended for patients (pts) with EGFR mutation ( EGFRm) positive non-small cell lung cancer (NSCLC). Limited data are available for real-world outcomes in pts who experience progression on 1st-/2nd-generation EGFR TKIs, which was the focus of this study. Methods: A retrospective chart review of pts with advanced NSCLC (stage IIIb/IV) from 10 US community oncology practices was conducted. Patients were included if they were diagnosed 1/1/2008—1/1/2015, were treated with erlotinib or afatinib (TKIs) either first line (1L) or second line (2L), and had disease progression (per clinician’s assessment) prior to 10/31/2015. Pts were classified into cohorts based on TKI initiation (1L or 2L) and EGFRm status. Progression-free survival (PFS) and overall survival (OS) were evaluated for the TKI treatment period and the post-progression period. Results: The study included 364 pts: 77.7% white, 17.3% African American; mean (SD) age 66.3 (11.3) years. PFS and OS were longer for 1L and EGFRm+ pt cohorts during the TKI treatment period. After progression, 25.3% (80/316) pts continued TKI, while around half received chemotherapy (56.3%; 178/316). The effects of other variables evaluated as predictors of PFS and OS were largely nonsignificant. Conclusions: Outcomes were worse after progression irrespective of EGFRm status and whether TKI was initiated 1L or 2L. This finding highlights the need for therapeutic options that improve outcomes in pts after progression on a 1st-/2nd-generation EGFR TKI. [Table: see text]

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Yamada, Yutaka, Hisao Imai, Tomohide Sugiyama, Hiroyuki Minemura, Kenya Kanazawa, Takashi Kasai, Koichi Minato, Kyoichi Kaira, and Takayuki Kaburagi. "Effectiveness and Safety of EGFR-TKI Rechallenge Treatment in Elderly Patients with Advanced Non-Small-Cell Lung Cancer Harboring Drug-Sensitive EGFR Mutations." Medicina 57, no. 9 (September 3, 2021): 929. http://dx.doi.org/10.3390/medicina57090929.

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Background and Objectives: Epidermal growth factor receptor–tyrosine kinase inhibitors (EGFR-TKIs) are effective first-line chemotherapeutic agents for patients with advanced non-small-cell lung cancer (NSCLC) harboring drug-sensitive EGFR mutations. However, the effectiveness of EGFR-TKI rechallenge after first-line EGFR-TKI treatment is not sufficient in elderly patients (over 75 years of age) harboring drug-sensitive EGFR mutations. Therefore, we investigated the effectiveness and safety of EGFR-TKI rechallenge after first-line EGFR-TKI treatment in elderly patients with advanced NSCLC harboring drug-sensitive EGFR mutations. Materials and Methods: Between April 2008 and December 2015, we analyzed 78 elderly patients with advanced NSCLC harboring drug-sensitive EGFR mutations with first-line EGFR-TKI treatment at four Japanese institutions. We retrospectively evaluated the clinical effectiveness and safety profiles of EGFR-TKI rechallenge after first-line EGFR-TKI treatment in elderly patients with advanced NSCLC harboring drug-sensitive EGFR mutations (exon 19 deletion/exon 21 L858R mutation). Results: Twenty-two patients in the cohort were rechallenged with EGFR-TKI. The median age was 79.5 years (range 75–87 years). Despite the fact that it was a retrospective analysis, even with EGFR-TKI rechallenge treatment the response rate was 23%, progression-free survival was 5.3 months, and overall survival was 14.4 months. Common adverse events included rash acneiform, paronychia, diarrhea, and anorexia. There were no treatment-related deaths. Due to the occurrence of adverse events of grade 2 or more, dose reduction was performed in 15 (68.2%) of 22 cases. Conclusions: EGFR-TKI rechallenge treatment after first-line EGFR-TKI treatment in elderly patients with advanced NSCLC harboring drug-sensitive EGFR mutations was one of the limited, safe and effective treatment options for elderly EGFR-positive lung cancer patients.

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Yonesaka, Kimio, Junko Tanizaki, Osamu Maenishi, Koji Haratani, Hisato Kawakami, Kaoru Tanaka, Hidetoshi Hayashi, et al. "Dynamics of HER3 and its correlated gene expression profile in EGFR-mutated NSCLC tumor treated with EGFR-TKI toward enhancing effectiveness of patritumab deruxtecan (HER3-DXd; U3-1402)." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): e21175-e21175. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e21175.

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e21175 Background: Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is a standard first-line therapy for activated EGFR-mutated non-small-cell lung cancer (NSCLC). Treatment options for patients with acquired EGFR-TKI resistance are limited. HER3 mediates EGFR-TKI resistance and is hence a promising target for anticancer treatment. Patritumab deruxtecan (HER3-DXd) is an antibody drug conjugate comprised of a fully human anti-HER3 IgG1 monoclonal antibody, covalently linked to a topoisomerase 1 inhibitor payload, an exatecan derivative, via a tetrapeptide-based cleavable linker. Clinical trials of theHER3-DXd demonstrated its anticancer activity in EGFR-mutated NSCLC. However, the genomic background that regulates HER3 expression is unknown. This study was conducted with the aim to clarify the genomic background for HER3 regulation in EGFR-mutated NSCLC tumors and to explore the strategy for enhancing the anticancer activity of HER3-DXd. Methods: 48 paired samples were obtained before EGFR-TKI treatment and after the acquisition of EGFR-TKI resistance from patients with EGFR-mutated NSCLC. HER3 expression was immunohistochemically quantified with H-score, and genomic alteration and transcriptomic signature were tested in tumors from pre-treatment to post-EGFR-TKI resistance acquisition. For statistical tests, linear regression analysis was performed to investigate whether a factor, including EGFR-TKI administration, affected HER3 expression. Pearson correlation coefficients were calculated to explore the relationships between HER3 expression level and other genomic expression in the tumors. Results: We showed augmented HER3 expression in EGFR-mutated tumors with acquired EGFR-TKI resistance compared to paired pretreatment samples (mean H-score 100.8 vs. 155.9, paired t-test p = 0.0007). Although genomic alterations including EGFR secondary T790M mutation did not correlate with HER3 augmentation, RNA sequencing revealed that repressed PI3K/AKT/mTOR signaling was associated with HER3 augmentation (GSEA; normalized enrichment score -1.78, p = 0.004). Multivariable regression analysis of HER3 augmentation revealed that re-biopsy under continuing EGFR-TKI treatment independently effected HER3 augmentation. Indeed, an in-vitro study also showed that EGFR-TKI increased HER3 expression via repressed AKT phosphorylation in multiple EGFR-mutated cancers, and it finally enhanced the anticancer activity of HER3-DXd. Conclusions: Our findings highlight a rationale for combination therapy with HER3-DXd and EGFR-TKI in EGFR-mutated NSCLC that is currently being evaluated in a clinical trial for patients with EGFR-mutated NSCLC tumors, not only with regard to an acquired resistance to EGFR-TKI but also in EGFR-TKI-naïve tumors (NCT04676477).

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Yonesaka, Kimio, Junko Tanizaki, Osamu Maenishi, Koji Haratani, Hisato Kawakami, Kaoru Tanaka, Hidetoshi Hayashi, et al. "Dynamics of HER3 and its correlated gene expression profile in EGFR-mutated NSCLC tumor treated with EGFR-TKI toward enhancing effectiveness of patritumab deruxtecan (HER3-DXd; U3-1402)." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): e21175-e21175. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e21175.

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e21175 Background: Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is a standard first-line therapy for activated EGFR-mutated non-small-cell lung cancer (NSCLC). Treatment options for patients with acquired EGFR-TKI resistance are limited. HER3 mediates EGFR-TKI resistance and is hence a promising target for anticancer treatment. Patritumab deruxtecan (HER3-DXd) is an antibody drug conjugate comprised of a fully human anti-HER3 IgG1 monoclonal antibody, covalently linked to a topoisomerase 1 inhibitor payload, an exatecan derivative, via a tetrapeptide-based cleavable linker. Clinical trials of theHER3-DXd demonstrated its anticancer activity in EGFR-mutated NSCLC. However, the genomic background that regulates HER3 expression is unknown. This study was conducted with the aim to clarify the genomic background for HER3 regulation in EGFR-mutated NSCLC tumors and to explore the strategy for enhancing the anticancer activity of HER3-DXd. Methods: 48 paired samples were obtained before EGFR-TKI treatment and after the acquisition of EGFR-TKI resistance from patients with EGFR-mutated NSCLC. HER3 expression was immunohistochemically quantified with H-score, and genomic alteration and transcriptomic signature were tested in tumors from pre-treatment to post-EGFR-TKI resistance acquisition. For statistical tests, linear regression analysis was performed to investigate whether a factor, including EGFR-TKI administration, affected HER3 expression. Pearson correlation coefficients were calculated to explore the relationships between HER3 expression level and other genomic expression in the tumors. Results: We showed augmented HER3 expression in EGFR-mutated tumors with acquired EGFR-TKI resistance compared to paired pretreatment samples (mean H-score 100.8 vs. 155.9, paired t-test p = 0.0007). Although genomic alterations including EGFR secondary T790M mutation did not correlate with HER3 augmentation, RNA sequencing revealed that repressed PI3K/AKT/mTOR signaling was associated with HER3 augmentation (GSEA; normalized enrichment score -1.78, p = 0.004). Multivariable regression analysis of HER3 augmentation revealed that re-biopsy under continuing EGFR-TKI treatment independently effected HER3 augmentation. Indeed, an in-vitro study also showed that EGFR-TKI increased HER3 expression via repressed AKT phosphorylation in multiple EGFR-mutated cancers, and it finally enhanced the anticancer activity of HER3-DXd. Conclusions: Our findings highlight a rationale for combination therapy with HER3-DXd and EGFR-TKI in EGFR-mutated NSCLC that is currently being evaluated in a clinical trial for patients with EGFR-mutated NSCLC tumors, not only with regard to an acquired resistance to EGFR-TKI but also in EGFR-TKI-naïve tumors (NCT04676477).

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Pardo Aranda, Nuria, Jordi Remon, Alex Martinez Marti, Ana Maria Martinez de Castro, Susana Cedres Perez, Alejandro Navarro, Eulalia Scheenaard, et al. "Outcome of EGFR mutant patirnts included in a clinical trial after progression on EGFR TKI." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e20555-e20555. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e20555.

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e20555 Background: EGFR mutant(EGFRm) NSCLC patients develop adquired resistance after 12 months on EGFR TKI. Acquired T790mutation(T790M) is the most common mechanism of resistance in around 60% of patients, followed by MET amplification in 20% of cases. Inclusion in a clinical trials at progression may have an impact in patients’ outcome. Methods: We retrospectively assessed the overall survival in EGFRm patients according to post-progression treatment on 1st/2nd generation EGFR TKI: standard vs. experimental (clinical trial). Also, we assessed the survival in the cohort of acquired T790M NSCLC patients(p). X2 test and long rank test P values are described. OS was defined since progression 1st/2nd generation EGFR TKI to death or last follow up Results: 42p EGFRm were enrolled. According to EGFRm subtype (24 p EGFR del19, 14p EGFR L858R, 1p EGFR exon18, 1 EGFR exon20 ,2p unknown). Median age was 58 (33-83) and 27 (64%) females. First-line EGFR TKI was 30% gefitinib / 58 % erlotinib /10 % afatinib/2% dacotinib At PD, in 51 biopsies (b) were performed,11p were biopsy twice.Tumor tissue for molecular determinations was available in in 86% of cases. Druggable molecular alterations were detected in 57% of cases: 20 acquired T790M and 4 MET amplification. According to these results all 24 p were enrolled in a clinical trial (NCT02108964,NCT01802632,NCT02147990,NCT02335944, NCT02151981), and 18p were screening failure; 8p (45%) of them due to abscense of adquired resistance mechanisms. 10 received platinum-based chemotherapy and 6 only received best supportive care. OS metastatic disease was 51 months for patients included in a clinical trial vs 22 months for those on standard treatment (p < 0.001; 95%CI: 14.4-47). OS was: 34 months vs 10 months for those included in a clinical trial vs standard, respectively (p < 0.001; 95%CI: 8.88-25). For T790M tumours, OS post-progression was 25 months Conclusions: Enrolling patients in clinical trials may allow personalised treatment according to mechanisms of resistance improving survival after 1st/2nd generation EGFR TK progression disease.

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Wang, Huijuan, Ruyue Xing, Mina Zhang, Xiaojuan Zhang, Jinpo Yang, Mengmeng Li, and Zhiyong Ma. "The efficacy and clinical survival outcome of different first-line treatments in EGFR-mutant non-small cell lung cancer with brain metastases." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 2028. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.2028.

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2028 Background: Brain metastasis is one of the most important factors for poor prognosis of lung cancer, and the incidence of brain metastasis in EGFR-mutant(m+) advanced NSCLC is more common. The first-generation EGFR TKI is a standard first-line treatment. The purpose of this study is to explore the best method for EGFRm+ NSCLC with brain lesions, and to find out correlative factors influencing survival outcome. Methods: The clinical data of NSCLC with brain metastases was retrospectively analyzed. All patients had received 1st generation EGFR TKI, and patients were divided into 4 group, group A : EGFR TKI monotherapy, group B: EGFR TKI plus chemotheapy(CT),Group C:EGFR TKI plus bevacizumab, group D :EGFR TKI plus CT plus bevacizumab.The efficacy of intracranial and extracranial lesions and survival outcome were analyzed. Results: A total of 584 EGFRm+ advanced NSCLC patients from December 2017 to May 2020 were screened,and 228(39%) had brain metastasis at baseline in the treatment-naive. Among them, 194pts had complete medical record and follow-up data. At the follow-up date (January 1, 2021), 147pts had disease progressed and 78pts had died. Intracranial PFS of group A,B,C,D were 11.1m(n = 97), 11.3m(n = 59)，21.2m(n = 19), and 18.9m(n = 19), respectively. No difference was found between A and B group (P = 0.745), so as C and D group (P = 0.684).But, the intracranial PFS of group C+D(with bevacizumab) was significantly longer than group A+B(11.3m (95%CI 12.2-14.8) vs 21.0m (95%CI 15.2-22.7), P = 0.007).The extracranial PFS of groups A, B, C, and D were 11.0m, 14.3m, 21.7m, and 18.9m, respectively,and the P value were 0.006, 0.002, and 0.011, respectively when compared with group A. The mOS of groups A,B were 27.8m and 24.2m,respectively, but group C and D had not yet reached. The intracranial ORR of group A, B, C, and D were 17.9% (14/78), 37.3% (19/51), 60.0% (9/15), and 66.7% (10/15), respectively. The extracranial ORR were 48.5% (47/97), 81.1% (43/53), 73.7% (14/19), and 73.7% (14/19),respectively. Conclusions: For EGFR-mutant NSCLC with brain metastases, the first-generation EGFR-TKI plus bevacizumab can significantly improve the efficacy of intracranial lesions, delay the progression of intracranial lesions, and prolong suvival time, Although the first-generation EGFR-TKI plus CT could improve extracranial ORR when compared with ERGF-TKI monotherapy, it has limited efficacy on intracranial lesions and could not increase survival time.

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Biliran, Hector Ramos, Xin Yao, Nasir Roberts, Prince Iheukwumere, Renwei Chen, and Ma Carmela Dela Cruz. "Abstract 5831: The TLE1 transcriptional and epigenetic machinery contributes to EGFR targeted therapy resistance in human lung adenocarcinoma." Cancer Research 84, no. 6_Supplement (March 22, 2024): 5831. http://dx.doi.org/10.1158/1538-7445.am2024-5831.

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Abstract In human lung adenocarcinoma that carry Epidermal Growth Factor Receptor (EGFR) sensitizing mutations, targeting the EGFR pathway with the use of EGFR tyrosine kinase inhibitors (EGFR-TKIs) has emerged as a promising therapeutic strategy providing initial clinical benefit to many patients. Unfortunately, resistance to EGFR-TKIs eventually develops leading to disease progression. In addition to genetic mutations, transcriptional and epigenetic mediated changes in gene expression remain an important mechanism contributing to EGFR-TKI resistance. Here, we report a novel function of the transcriptional corepressor Transducin-Like Enhancer of Split-1 (TLE1) in mediating EGFR-TKI resistance in EGFR mutant LUAD cells through its survival promoting gene transcriptional program. In EGFR mutant, EGFR TKI sensitive LUAD cells, sole activation of the TLE1 nuclear function attenuates EGFR TKI sensitivity with concomittant reduction of EGFR-TKI-mediated apoptosis. Conversely, downregulation of endogenous TLE1 expression via siRNAs/shRNAs and deletion of TLE1 gene via CRISPR-Cas9 in EGFR-mutant, EGFR-TKI resistant cells partially restore EGFR-TKI sensitivity via induction of EGFR-TKI apoptosis. Mechanistically, the anti-apoptosis promoting gene transcriptional program of TLE1 is dependent on its functional interaction with the transcriptional repressor HES-1, a downstream Notch target which has been associated with relapse in LUAD patients following EGFR-TKI treatment. Collectively, these studies indicate the TLE1 corepressor as a determinant of resistance to EGFR targeted therapy and raise the possibility that inhibiting TLE1 nuclear function may serve as an adjuct therapy to circumvent EGFR-TKI resistance. Citation Format: Hector Ramos Biliran, Xin Yao, Nasir Roberts, Prince Iheukwumere, Renwei Chen, Ma. Carmela Dela Cruz. The TLE1 transcriptional and epigenetic machinery contributes to EGFR targeted therapy resistance in human lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5831.

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Hong, Sook-hee, Nahyeon Kang, Okran Kim, Soon Auck Hong, Juyeon Park, Joori Kim, Myung-Ah Lee, and Jinhyoung Kang. "EGFR-Tyrosine Kinase Inhibitors Induced Activation of the Autocrine CXCL10/CXCR3 Pathway through Crosstalk between the Tumor and the Microenvironment in EGFR-Mutant Lung Cancer." Cancers 15, no. 1 (December 25, 2022): 124. http://dx.doi.org/10.3390/cancers15010124.

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CXCL10 is a cytokine that is elevated during EGFR-TKI treatment in the tumor microenvironment of lung cancer. Here, we report an original study that the impact of the CXCL10/CXCR3 pathway on EGFR-TKI resistance in EGFR-mutant lung cancer through a cytokine array analysis during in vitro coculture with tumor cells and activated PBMCs treated with EGFR-TKI, as well as the serial analysis of CXCL10 in EGFR-mutant lung cancer transgenic mice during EGFR-TKI treatment. In EGFR-mutant tumor cells cocultured with activated PBMCs, EGFR-TKI treatment increased CXCL10 in the supernatant; this activated CXCR3 in the tumor cells to induce the phosphorylation of Src and the NF-κB subunit, p65, and the expression of HIF-1α. CXCL10 siRNA treatment of EGFR-mutant tumor cells also decreased CXCL10 in the supernatant from coculturing with activated PBMCs, suggesting that the effects of CXCL10 occur via autocrine and paracrine pathways. Importantly, elevated CXCL10/CXCR3 signaling was recapitulated in a transgenic lung cancer mouse model. Our results show that increased CXCL10 levels during early EGFR-TKI treatment stimulate oncogenic signaling of persistent tumor cells to contribute to EGFR-TKI resistance via autocrine and paracrine pathways.

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Mok, Tony, Jin-Ji Yang, and Kwok-Chi Lam. "Treating Patients With EGFR-Sensitizing Mutations: First Line or Second Line—Is There a Difference?" Journal of Clinical Oncology 31, no. 8 (March 10, 2013): 1081–88. http://dx.doi.org/10.1200/jco.2012.43.0652.

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First-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) is a standard treatment for patients with activating EGFR mutations. Six randomized studies have demonstrated consistent improvement in tumor response rate and progression-free survival over platinum-based combination chemotherapy. The only reason to consider EGFR TKI as second-line therapy is that none of the six comparative studies has shown improvement in overall survival, which can be explained by the high proportion of patients from the chemotherapy arm crossing over to the EGFR TKI arm on progression. It is true that patients with EGFR mutations may benefit from second-line EGFR TKI therapy, but we cannot conclude that the benefit is either equal to or inferior to first-line EGFR TKI therapy. To date, there are no direct comparative data between first- and second-line EGFR TKI in patients with activating EGFR mutations. Tumor response rates to second-line EGFR TKI have been inconsistent, which could potentially be explained by the impact of first-line chemotherapy on the abundance of tumor cells with activating EGFR mutations. However, numerous arguments, including assurance on drug exposure, improvement in quality of life, better tolerance by patients with poor performance status, and deferral of whole-brain radiation therapy for patients with brain metastasis, support the general application of first-line EGFR TKI.

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Li, Liu, Jingjing Qu, Jianfu Heng, Chunhua Zhou, Yi Xiong, Haiyan Yang, Wenjuan Jiang, et al. "A large real-world study on the effectiveness of the combined inhibition of EGFR and MET in EGFR-mutant advanced non-small cell lung cancer (NSCLC)." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 9043. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.9043.

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9043 Background: MET amplification is an important mechanism mediating acquired resistance to EGFR tyrosine kinase inhibitors (TKI). Until now, no consensus exists on the standard treatment strategy for this subset of patients due to the lack of clinical data from large cohort or controlled trials. In our clinical practice, three regimens were commonly administered to patients after MET amplification-mediated EGFR-TKI progression: EGFR-TKI and MET-TKI combination therapy, MET-TKI monotherapy, or chemotherapy. Our study aimed to compare the effectiveness of these three regimens. Methods: Seventy patients with EGFR-mutant advanced NSCLC who progressed from prior EGFR-TKI through the acquisition of MET amplification and received treatment between March 2015 and March 2020 were included in this study. Of them, 38 received EGFR-TKI plus crizotinib, 10 received crizotinib monotherapy, and 22 received platinum-based doublet chemotherapy. Somatic mutation profiling was performed on blood and tissue biopsy samples. Resistance mechanisms to the combination targeted therapy were also explored in 12 patients. Results: The objective response rate (ORR) and disease control rate (DCR) were 47.5% and 84.0% for EGFR-TKI+crizotinib group, 40.0% and 70.0% for crizotinib monotherapy group, and 18.2% and 50.0% for chemotherapy group, respectively. The EGFR-TKI+crizotinib group had significantly better ORR (P = 0.026) and DCR (P = 0.016) than the chemotherapy group but was not statistically different from the crizotinib monotherapy group (ORR, P = 0.73; DCR, P = 0.39). Progression-free survival (PFS) was significantly longer for the EGFR-TKI+crizotinib group than those who received crizotinib monotherapy (5.0 vs 2.3 months, P = 0.004) or chemotherapy (5.0 vs 2.9 months, P = 0.036), but overall survival was comparable (10.0 vs 4.1 vs 8.5 months, P = 0.088). TP53 mutation (58.5%) and EGFR amplifications (42.9%) were the two common concurrent mutations in the three cohorts. PFS was significantly longer for patients with either concurrent TP53 mutation (n = 17) (6.0 vs 2.3 vs 2.9 months, P = 0.009) or concurrent EGFR amplification (n = 13) (5.0 vs 1.2 vs 2.4 months, P = 0.016) who received EGFR-TKI+crizotinib. Potential molecular mechanisms of acquired resistance to EGFR-TKI+crizotinib therapy included EGFR T790M (n = 2), EGFR L718Q (n = 1), EGFR S645C (n = 1), MET D1228H (n = 1), BRAF V600E (n = 1), NRAS Q61H (n = 1), and amplifications in KRAS (n = 2), ERBB2 (n = 1), CDK4 (n = 1), and MYC (n = 2). Conclusions: Our study provides real-world clinical evidence, in the largest cohort to date, that simultaneous inhibition of EGFR and MET improves clinical outcomes of patients with EGFR-mutant NSCLC who acquired MET amplification from prior EGFR-TKI therapy, indicating that combinatorial regimen of EGFR-TKI and MET-TKI could be a more effective therapeutic strategy in this subset of patients.

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Kogure, Yoshihito, Chiyoe Kitagawa, Masahide Oki, and Hideo Saka. "Post-progression survival after treatment with epidermal growth factor receptor-tyrosine kinase inhibitor for advanced non-small cell lung cancer patients harboring epidermal growth factor receptor mutations." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e19005-e19005. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e19005.

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e19005 Background: Non-small cell lung cancer (NSCLC) patients harboring the epidermal growth factor receptor (EGFR) mutation show a survival benefit on treatment with EGFR-tyrosine kinase inhibitor (EGFR-TKI); however, few studies report on post-progression tumor behavior after treatment with EGFR-TKI. Methods: We retrospectively reviewed clinical data of stage IV or recurrent NSCLC patients harboring the EGFR mutation, who received EGFR-TKI as first-line treatment in our institute from 2009 to 2011. Results: Thirty-six patients received EGFR-TKI as first-line therapy. Thirty of these patients with recurrent NSCLC were enrolled in this study. The median age of the patients was76 years (range, 38–97), and the male/female ratio was 4/26. The median progression-free survival (PFS) after EGFR-TKI treatment was 8.2 months. Sites of relapse in patients with progressive disease (PD) were the brain, pleural effusion, bone, and lung (n=5, 13, 6, and 8, respectively). Twenty-one patients received sequential therapy: 11 patients received continued EGFR-TKI treatment beyond PD and 10 patients received second-line therapy. Second-line therapies were platinum-based doublet therapy, monotherapy, and another cycle of EGFR-TKI (n = 6, 2, and 2 patients, respectively). Post-progression survival (PPS) of all the patients after treatment with EGFR-TKI was 9.2 months, whereas that of patients who received EGFR-TKI as second-line chemotherapy was 14 months. Subgroup analysis according to the site of relapse showed that after first-line EGFR-TKI treatment, PFS tended to be higher for patients with a relapse in the brain (11.6 months) than for patients with sites of relapse other than the brain (8.2 months). Conclusions: PPS after EGFR-TKI therapy in patients treated with second-line chemotherapy was similar to the OS of NSCLC patients without an EGFR mutation. Subgroup analysis showed that patients with a relapse in the brain might survive longer.

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Wang, Ran Lin, Tao Li, Jiahua Lv, Chang Sun, and Qiuling Shi. "Clinical benefit of EGFR-TKIs plus radiotherapy for treating EGFR-mutated metastatic non-small cell lung cancer." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e20694-e20694. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e20694.

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e20694 Background: Despite the high response rate and prolonged OS of patients with EGFR mutations treated with gefitinib or erlotinib, there are still major clinical obstacles. The local control rate is still low, only 19.4%–58%, with first-line treatment using EGFR-targeted therapy. The aim of this study is to provide scientific evidence to support the clinical benefits of EGFR-TKI combined with radiotherapy compared to EGFR-TKI alone. Methods: From February 2015 to May 2017, a total of 103 patients with stage IV EGFR-mutated NSCLC treated at Sichuan Cancer Hospital & Institute were analysed retrospectively. 50 patients were treated with EGFR-TKIs (gefitinib or erlotinib) plus radiotherapy (Group TKI-RT) and 53 patients received EGFR-TKIs alone (Group TKI). Tumour response, survival and toxicities were compared between the two groups. Results: Median follow up time was 11.7 months (range: 2.8–36.3 months). The overall response rate (ORR) and disease control rate (DCR) in Group TKI-RT vs. Group TKI were 62% vs. 37.7% (P = 0.014) and 88% vs. 75.5% (P = 0.101), respectively. The median progression-free survival (PFS) and median overall survival (OS) in Group TKI-RT were superior to those of Group TKI (18.87 months vs. 12.80 months, P = 0.035 and 23.10 months vs. 18.30 months, P = 0.011). OS rates in Group TKI-RT and Group TKI were 56.0% vs. 35.8% at 1-year (P = 0.04) and 16.0% vs. 3.8% at 2-year (P = 0.036). Multivariate Cox model found that TKI-RT related to significantly better OS (hazard ratio = 0.209; 95% CI, 0.066 to 0.661; P = 0.008) than TKI alone. Adverse events did not differ significantly between the two groups. Conclusions: Compared with EGFR-TKIs alone, EGFR-TKIs combined with radiotherapy was well tolerated and showed benefit in tumour response and survival for EGFR mutation-positive metastatic NSCLC patients.

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Wu, Shang-Gin, Tzu-Hua Chang, Meng-Feng Tsai, Yi-Nan Liu, Chia-Lang Hsu, Yih-Leong Chang, Chong-Jen Yu, and Jin-Yuan Shih. "IGFBP7 Drives Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibition in Lung Cancer." Cancers 11, no. 1 (January 2, 2019): 36. http://dx.doi.org/10.3390/cancers11010036.

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Patients with epidermal growth factor receptor (EGFR) mutation-positive lung cancer show a dramatic response to EGFR-tyrosine kinase inhibitors (TKIs). However, acquired drug resistance eventually develops. This study explored the novel mechanisms related to TKI resistance. To identify the genes associated with TKI resistance, an integrative approach was used to analyze public datasets. Molecular manipulations were performed to investigate the roles of insulin-like growth factor binding protein 7 (IGFBP7) in lung adenocarcinoma. Clinical specimens were collected to validate the impact of IGFBP7 on the efficacy of EGFR TKI treatment. IGFBP7 mRNA expression in cancer cells isolated from malignant pleural effusions after acquired resistance to EGFR-TKI was significantly higher than in cancer cells from treatment-naïve effusions. IGFBP7 expression was markedly increased in cells with long-term TKI-induced resistance compared to in TKI-sensitive parental cells. Reduced IGFBP7 in TKI-resistant cells reversed the resistance to EGFR-TKIs and increased EGFR-TKI-induced apoptosis by up-regulating B-cell lymphoma 2 interacting mediator of cell death (BIM) and activating caspases. Suppression of IGFBP7 attenuated the phosphorylation of insulin-like growth factor 1 receptor (IGF-IR) and downstream protein kinase B (AKT) in TKI-resistant cells. Clinically, higher serum IGFBP7 levels and tumors with positive IGFBP7-immunohistochemical staining were associated with poor TKI-treatment outcomes. IGFBP7 confers resistance to EGFR-TKIs and is a potential therapeutic target for treating EGFR-TKI-resistant cancers.

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Halmos, Balazs, Helena A. Yu, Yi-Long Wu, Makoto Nishio, Martin Reck, David Sternberg, Stephen Esker, and Tony Mok. "Abstract CT066: HERTHENA-Lung02: A randomized Phase 3 study of patritumab deruxtecan vs platinum-based chemotherapy in locally advanced or metastatic EGFR-mutated NSCLC after progression with a third-generation EGFR tyrosine kinase inhibitor." Cancer Research 83, no. 8_Supplement (April 14, 2023): CT066. http://dx.doi.org/10.1158/1538-7445.am2023-ct066.

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Abstract Background: Standard therapies for patients with epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) that has progressed after treatment with third-generation EGFR tyrosine kinase inhibitors (TKIs) offer only limited benefit. Human epidermal growth factor receptor 3 (HER3) is often expressed in primary NSCLC tumors, and HER3 expression is commonly observed in patients with EGFR mutations. HER3-DXd is a novel antibody-drug conjugate composed of a human anti-HER3 monoclonal antibody (patritumab) linked to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. HER3-DXd demonstrated efficacy and safety in a phase 1 study in patients with EGFRm NSCLC that progressed following an EGFR TKI and platinum-based chemotherapy (PBC) (U31402-A-U102; NCT03260491). In previously reported results from dose-escalation/expansion, HER3-DXd 5.6 mg/kg demonstrated a manageable safety profile and promising efficacy (confirmed objective response rate by blinded independent central review [BICR] of 39%, median duration of response of 7.0 months, and median progression-free survival of 8.2 months) in a subset of patients (n=44) with advanced EGFRm NSCLC that progressed after ≥1 line of PBC and a third-generation EGFR TKI. Trial Design: HERTHENA-Lung02 (NCT05338970) is a global, open-label, randomized, phase 3 trial evaluating the efficacy and safety of HER3-DXd vs PBC in patients (≈560) with metastatic or locally advanced nonsquamous NSCLC with an EGFR-activating mutation (exon 19 deletion or L858R) who have received 1 or 2 lines of EGFR TKI treatment including a third-generation EGFR TKI and had disease progression following treatment with a third-generation EGFR TKI. Patients are randomized 1:1 to receive either HER3-DXd 5.6 mg/kg every 3 weeks or 4 cycles of PBC containing pemetrexed (can be continued as maintenance) with cisplatin or carboplatin. Patients are stratified by prior third-generation EGFR TKI treatment (osimertinib vs other), line of prior third-generation EGFR TKI use (first vs second line), region (Asia vs rest of world), and presence of stable brain metastases (yes vs no). The primary endpoint is progression-free survival by BICR (per RECIST v1.1). The key secondary endpoint is overall survival. Other secondary endpoints include investigator-assessed progression-free survival, objective response rate, duration of response, clinical benefit rate, disease control rate, time to response (all assessed by investigator and BICR per RECIST 1.1), safety, and patient-reported outcomes. Enrollment began May 2022 and is ongoing, with sites in Asia, Australia, Europe, and North America. Citation Format: Balazs Halmos, Helena A. Yu, Yi-Long Wu, Makoto Nishio, Martin Reck, David Sternberg, Stephen Esker, Tony Mok. HERTHENA-Lung02: A randomized Phase 3 study of patritumab deruxtecan vs platinum-based chemotherapy in locally advanced or metastatic EGFR-mutated NSCLC after progression with a third-generation EGFR tyrosine kinase inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT066.

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Li, Guifang, Shunji Gao, Zhixin Sheng, and Bin Li. "The Efficacy of Single-Agent Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy in Biologically Selected Patients with Non-Small-Cell Lung Cancer: A Meta-Analysis of 19 Randomized Controlled Trials." Chemotherapy 61, no. 4 (2016): 179–89. http://dx.doi.org/10.1159/000442344.

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Objective: To determine the efficacy of first-generation single-agent epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy in advanced non-small-cell lung cancer patients with known EGFR mutation status, we undertook this pooled analysis. Method: We searched for randomized controlled trials (RCTs) in Medline, Embase, the Cochrane Controlled Trials Register, the Science Citation Index, and the American Society of Clinical Oncology annual meetings. Results: Out of 2,129 retrieved articles, 19 RCTs enrolling 2,016 patients with wild-type EGFR tumors and 1,034 patients with mutant EGFR tumors were identified. For these EGFR mutant patients, single-agent EGFR-TKI therapy improved progression-free survival (PFS) over chemotherapy: the summary hazard ratios (HRs) were 0.41 (p < 0.001) for the first-line setting and 0.46 (p = 0.02) for the second-/third-line setting. For those EGFR wild-type patients, single-agent EGFR-TKI therapy did not do as well as chemotherapy in the first-line setting (HR = 1.65, p = 0.03) and in the second-/third-line setting (HR = 1.27, p = 0.006). No statistically significant difference was observed in terms of overall survival (OS). Using platinum-based doublet chemotherapy as a common comparator, indirect comparison showed the superior efficacy of single-agent EGFR-TKI therapy over EGFR-TKIs added to chemotherapy in PFS [HR = 1.35 (1.03, 1.77), p = 0.03]. Additionally, a marginal trend towards the same direction was found in the OS analysis [HR = 1.16 (0.99, 1.35), p = 0.06]. Interestingly, for those EGFR wild-type tumors, single-agent EGFR-TKI therapy was inferior to EGFR-TKIs added to chemotherapy in PFS [HR = 0.38 (0.33, 0.44), p < 0.001] and OS [HR = 0.83 (0.71, 0.97), p = 0.02]. Conclusions: For these EGFR mutant patients, single-agent EGFR-TKI therapy prolonged PFS over chemotherapy. However, single-agent EGFR-TKI therapy was inferior to chemotherapy in PFS for those EGFR wild-type patients. Single-agent EGFR-TKI therapy could improve PFS over the combination of EGFR-TKIs and chemotherapy in these EGFR mutant patients. However, EGFR-TKIs combined with chemotherapy could provide additive PFS and OS benefit over single-agent EGFR-TKI therapy in those EGFR wild-type patients.

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Ying, Xiaozhen, Shuiyun Han, Chenxue Jiang, Xiaojiang Sun, Yaping Xu, and Weimin Mao. "Impact of different timing of radiation therapy in patients with brain metastases from epidermal growth factor receptor-mutant non-small cell lung cancer." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e20667-e20667. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e20667.

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e20667 Background: To perform a retrospective analysis of patients with brain metastases (BM) from epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) to evaluate the preferred treatment timing of EGFR-tyrosine kinase inhibitors (TKIs) in this population. Methods: Of 94 initial or recurrent patients diagnosed BM from EGFR-mutant NSCLC between Jan 1, 2012, and Jun 31, 2016, 30 received upfront brain RT followed by EGFR-TKI, 39 EGFR-TKI combined with concurrent brain RT, and 25 upfront EGFR-TKI then brain RT. Disease-specific-graded prognostic assessment was similar among all 3 groups. The primary endpoint was overall survival (OS), and the second endpoint was intracranial progression-free survival. Results: Although the median OS was not significantly different among the upfront RT, concurrent treatment, and upfront EGFR-TKI groups (29.0 vs 24.0 vs 17.0 months; P = 0.186), however, it was longer in the upfront RT group compared with the upfront EGFR-TKI group (P = 0.035). On subgroup analysis, the exon 19 deletions patients had longer OS than the exon 21 mutations patients in upfront EGFR-TKI group (23.0 vs 15.0 months; P = 0.048), but the upfront RT (34.0 vs 23.0 months; P = 0.186) and the concurrent treatment groups (24.0 vs 13.0 months; P = 0.827) did not. According to multivariate COX analysis, KPS (≥ 70) and intracranial metastasis alone was associated with a longer OS. The median intracranial progression-free survival was significantly improved in patients receiving upfront RT compared with those receiving concurrent treatment or upfront EGFR-TKI (not reached vs 40.0 vs 9.0 months; P = 0.003). Conclusions: The present study suggests that the use of upfront brain radiotherapy, and the deferral of EGFR-TKI may result in superior OS in patients with brain metastases from EGFR-mutant NSCLC. Also, upfront brain radiotherapy management could significantly reduce the risk of intracranial progression. A prospective, multi-institutional, randomized trial of upfront EGFR-TKI then RT versus upfront RT followed by EGFR-TKI is urgently needed, especially based on different subgroup population.

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Sun, Yue Mei, Ming Xiu Zhou, and Ming Zeng. "Management of medical inoperable and tyrosine kinase inhibitor-naive early-stage lung adenocarcinoma with epidermal growth factor receptor mutations: A retrospective multi-institutional analysis." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e21082-e21082. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e21082.

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e21082 Background: The clinical value of combined local radiation and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) and for medical inoperable and TKI-naïve early-stage lung adenocarcinoma patients with EGFR mutations is not yet determined. In this study, we aimed to pool multi-institutional data to compare the therapeutic effect of EGFR-TKI alone and combined radiation and TKI on the survival outcomes in this patient subgroup. Methods: 132 cases of medical non-operable stage I to III EGFR mutant lung adenocarcinoma were retrospectively reviewed based on data from 5 centers. Among the patients, 65 cases received combined radiation and EGFR-TKI therapy (R+TKI) (49.2%), while 67 cases had EGFR-TKI (50.8%) treatment alone. All patients were followed until death. Results: For R+TKI group, the median overall survival (OS) after primary therapy was 42.6 months, while that of the TKI alone group was 29.4 months (log-rank p < .001). In terms of progression-free survival (PFS), the median PFS in these two treatment groups were 24 months and 14.7 months respectively (log-rank p < .001). Multivariate analysis showed that R+TKI was independently associated with improved OS (adjusted HR: 0.420; 95% CI, 0.287 to 0.614; p < .001) and PFS (adjusted HR: 0.420; 95% CI, 0.291 to 0.605; p < .001) compared to TKI alone. Subgroup analysis confirmed the significant OS benefits in stage III patients and RFS benefits in stage II/III patients. Conclusions: Upfront radiation to primary sites with TKI to follow was a feasible option for patients with EGFR-mutant medical inoperable non-small-cell lung carcinoma (NSCLC) during first-line EGFR-TKI treatment, with significantly improved PFS and OS compared with TKI alone

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Zhou, Caicun, Xuefei Li, Shengxiang Ren, Guohua Yang, and Wei He. "Quantitative test of mutant EGFR and its effect on efficacy of EGFR TKI in advanced NSCLC." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e22186-e22186. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e22186.

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e22186 Background: It is reported that abundance of EGFR mutation is related with efficacy of EGFR TKI in advanced NSCLC patients with positive EGFR mutations. This study was designed to investigate influence of EGFR mutations and their abundance on efficacy of EGFR TKI. Methods: 141 advanced NSCLC treated with EGFR TKI and available tissue for EGFR mutations were enrolled into the study. EGFR mutation was detected with the kit of AmoyDx ARMS and concentration of mutant EGFR was detected with the method of a quantitative competitive allele specific Taqman PCR technology (qCAST). In this assay, copies from EGFR mutants were calibrated by standard curve respectively, and the mutation rates were estimated through normalizing by copies of a conserved sequence in EGFR exon2. The relationship between abundance of EGFR mutations and efficacy of EGFR TKI was analyzed. Results: The median age of patients was 59 years old, and in which 54.3% were male, 71.7% ex-somkers. Among all of the patients, adenocarcinoma accounted for 57.7%, squamous cell carcinoma 27.2%, adeno-squamous cell carcinoma 7.6%, and others 7.6%. 46.7% of patients harbored EGFR mutations, and in which 48.7% existed more than 20% abundance of EGFR mutations. Overall response rate was 31.4% and progression free survival was 5.0 months. The final analysis data will be reported at the conference. Conclusions: The abundance of EGFR mutations might affect the efficacy of EGFR-TKI, and quantitation of mutant EGFR may better predict for efficacy of EGFR TKI in advanced NSCLC.

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Bi, Nan, Luhua Wang, Kunpeng Xu, Hong Ge, Mingyan E, Li Zhang, Jianzhong Cao, et al. "Real-world treatment patterns and clinical outcomes in EGFR-mutant unresectable locally advanced NSCLC (LA-NSCLC): A retrospective multicenter study of 367 patients." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 9047. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.9047.

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9047 Background: The chemoradiation therapy (CRT) is the standard care for unresectable LA-NSCLC. The addition of EGFR-TKIs in first-line treatment of EGFR-mutant subpopulation is debatable. Methods: We retrospectively collected data for patients with unresectable stage III NSCLC harboring EGFR mutations from nine major academic cancer institutions in China from Jan 2012 to December 2018. Patients with ALK rearrangements were excluded. Patients were categorized into three subgroups according to the primary treatment: 1) RT+TKI: Combined RT and EGFR-TKI with/out chemotherapy; 2) no TKI: CRT alone; 3) upfront TKI: EGFR-TKI followed by RT at local-regional progression. PFS and OS were calculated from the date of diagnosis. Log-rank test was used to assess for differences and Cox proportional hazards model was used to adjust for covariates. Results: A total of 367 patients met selection criteria were included in the study. Patients receiving TKI were older (≥60 years: 54.7% TKI v 36.4% and RT+TKI 33.3% CRT; P = 0.001), and more patients receiving CRT had uncommon EGFR mutations ( 10.3% CRT v 2.3% RT+TKI and 4.0% TKI; P = 0.020). Other baseline characteristics were well balanced among groups. With a median follow-up of 40.8 months, the median PFS and OS were 16.6 and 55.4 months for the entire cohort. The median PFS and OS for the three subgroups were shown in the table. On multivariable analysis, after adjusting for age, KPS status, smoking status, stage, and type of EGFR mutations, TKI+RT was independently associated with improved PFS (HR, 0.57; 95% CI, 0.41 to 0.78 ) and OS (HR, 0.61; 95% CI, 0.39 to 0.97) relative to upfront TKI; TKI+RT was also associated with improved PFS (HR, 0.38; 95% CI, 0.27 to 0.54 ) relative to CRT, but not OS (HR, 0.66; 95% CI, 0.40 to 1.11). Conclusions: The use of upfront EGFR-TKI with deferred RT at progression was associated with inferior OS in patients with EGFR-mutant unresectable LA-NSCLC. First-line use of radiotherapy and EGFR-TKI was associated with the longest PFS and OS, which requires further prospective, randomized evaluation. [Table: see text]

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Narumi, Sodai, Yasuhiro Miki, Shuko Hata, Masahito Ebina, Mikiyoshi Saito, Kazushige Mori, Makoto Kobayashi, et al. "Anterior Gradient 2 is Correlated with EGFR Mutation in Lung Adenocarcinoma Tissues." International Journal of Biological Markers 30, no. 2 (April 2015): 234–42. http://dx.doi.org/10.5301/jbm.5000131.

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Background Epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor (TKI) has demonstrated a promising therapeutic response in lung adenocarcinoma patients with EGFR gene mutations. However, the predictive factors for this therapy have not been established, except for the EGFR gene mutation status of carcinoma cells. Methods We first performed microarray analysis in EGFR-TKI–sensitive lung adenocarcinoma cell lines. The results indicated anterior gradient 2 (AGR2) as a potential surrogate marker of EGFR-TKI. Therefore, we then evaluated the correlation between the status of AGR2 immunoreactivity and clinicopathological factors including overall survival (OS), progression-free survival (PFS) and clinical response to EGFR-TKI, in 147 cases of surgically resected lung adenocarcinoma. The biological significance of AGR2 was further evaluated by transfecting small interfering RNA (siRNA) against AGR2 in these cells. Results The status of AGR2 immunoreactivity was significantly higher in lung adenocarcinoma cases with EGFR gene mutations than in those with the wild type (p<0.0001), but there were no significant differences in OS, PFS and response of EGFR-TKI between the AGR2 high and low carcinoma cases. Knockdown of AGR2 gene expression following siRNA transfection resulted in a significantly lower response to EGFR-TKI in EGFR-mutated PC-3. Conclusions AGR2 could serve as an adjunctive surrogate protein marker possibly reflecting EGFR gene mutations in lung adenocarcinoma patients. Results from in vitro analysis indicated that AGR2 could be a potential clinical biomarker of EGFR-TKI therapeutic sensitivity in lung adenocarcinoma cells.

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Beau-Faller, Michele, Nathalie Prim, Anne-Marie Ruppert, Isabelle Nanni, Benjamin Besse, Fabienne Escande, Sarab Lizard, et al. "Rare epidermal growth factor receptor (EGFR) mutations in 10,117 patients with non-small cell lung cancer (NSCLC) evaluated by the French ERMETIC IFCT network: Clinical, molecular, and survival data." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 10507. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.10507.

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10507 Background: The EGFR exon 19 deletion and exon 21 L858R mutation are associated with response to EGFR-TKI. However, the correlation with response to EGFR-TKI remains unclear for rare exon 18 and 20 EGFR mutations. We investigated the clinical features of NSCLC patients with exon 18 and exon 20 EGFR mutations, analyzed response to EGFR-TKI and patient's survival. Methods: Between 2005 and 2011, all rare exon 18 and 20 EGFR mutations were collected from 10117 cases of NSCLC in 15 of 28 French NCI molecular genetic laboratories. Results: During the study period, EGFR mutations were identified in 1048 (10.35%) out of the 10117 performed tests and 108 rare mutations (10.3%) were identified in 103 patients, including 25 never identified mutations. Among them, 48 mutations were localized at exon 18 and 60 at exon 20, with 3 out of the 4 identified T790M exon 20 mutations associated with L858R mutation. Only 5 other rare mutations were associated with EGFR 19 or 21 mutations. 38 patients received EGFR-TKI (erlotinib, n=32; gefitinib, n=6). Among the 36 evaluable patients, best response on TKI was progression in 18 patients (50%), stabilization in 11 (30.5%) and partial response in 7 (19.4%). Tumor control rate observed in exon 18 mutations was 61% (8/13) and 50% (13/26) in exon 20 mutations. For the EGFR-TKI treated patients, the median PFS was 6 months (2-53). Median OS was 15 months (1-92), with no difference between the EGFR-TKI treated patients or not. Conclusions: Prevalence of rare EGFR mutations was 1.06% of all tested NSCLC and 10.35% of all EGFR mutations. Tumor control on TKI was observed in half of the patients. Reports of NSCLC harboring rare mutations are important to help the decision-making process in this subset of patients.

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Kodama, Tatsuya, Keisuke Watanabe, Masaharu Shinkai, and Takeshi Kaneko. "No Therapeutic Effect of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Retreatment Despite T790M Disappearance: Case Report of 3 Cases." Chemotherapy 63, no. 4 (2018): 198–202. http://dx.doi.org/10.1159/000491937.

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Background: T790M is a major cause of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance, but the clinical significance of T790M disappearance is unknown. Case Report: We report 3 cases of pulmonary adenocarcinoma which did not respond to EGFR-TKI retreatment even with T790M disappearance. T790M mutations were detected in the pleural effusions after the tumors had acquired EGFR-TKI resistance. T790M mutations disappeared from cancer cells in the pleural effusion after a break from the treatment drug and cytotoxic agent administration. However, no therapeutic effect was obtained despite EGFR-TKI reinitiation. Conclusions: Responsiveness to EGFR-TKI might not be restored in some cases, although the disappearance of T790M mutations is confirmed.

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Hung, Hsiu-Ying, Yen-Han Tseng, Chia-Miao Liao, Sung-Yi Chen, Ta-Peng Wu, Yu-Chin Lee, and Yuh-Min Chen. "The Efficacy of Traditional Chinese Herbal Medicine in the Treatment of EGFR Mutated Stage IV Pulmonary Adenocarcinoma Patients Who Received First-Line EGFR-TKI Treatment." Integrative Cancer Therapies 16, no. 1 (May 5, 2016): 126–31. http://dx.doi.org/10.1177/1534735416645181.

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Background. Chinese herbal medicine (CHM) has been used for thousands of year in Eastern countries. First-line epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) treatment is the standard treatment in stage IV pulmonary adenocarcinoma patients who had tumor EGFR mutations. This study was to find the efficacy of CHM on lung cancer treatment. Materials and Methods. We retrospectively reviewed chart records of our stage IV EGFR-mutated pulmonary adenocarcinoma patients who received first-line EGFR-TKI treatment from January 2010 to September 2014. Results. Total, 527 patients were studied. Among them, 34 patients received CHM treatment, including 24 patients who received CHM treatment from the beginning of first-line EGFR-TKI treatment and 10 patients who started to receive CHM treatment after their disease had progressed to EGFR-TKI treatment. Median progression-free survival (PFS) of first-line EGFR-TKI treatment was numerically better in patients who also received CHM than those who did not (12.1 months vs 10.5 months, P = .7668). Overall survival of those 24 patient who received CHM treatment together with EGFR-TKI was 30.63 months (95% CI = 11.7 to not reached), compared to 23.67 months in the remaining patients (95% CI = 21.37-26; hazard ratio = 0.75; P = .399). No increase of CHM-related toxicities was found during CHM treatment, compared with EGFR-TKI treatment alone ( P > .05). Conclusion. Alternative CHM treatment during first-line EGFR-TKI treatment did no harm to the patients and PFS and overall survival was numerically better, although not significant, than those patients who did not receive CHM treatment.

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Zhu, Leilei, Shanshan Gao, Xianya Zhao, and Ying Wang. "Identification of biomarkers, pathways, and therapeutic targets for EGFR–TKI resistance in NSCLC." Life Science Alliance 6, no. 12 (October 10, 2023): e202302110. http://dx.doi.org/10.26508/lsa.202302110.

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This study aimed to map the hub genes and potential pathways that might be involved in the molecular pathogenesis of EGFR–TKI resistance in NSCLC. We performed bioinformatics analysis to identify differentially expressed genes, their function, gene interactions, and pathway analysis between EGFR–TKI-sensitive and EGFR–TKI-resistant patient-derived xenotransplantation samples based on Gene Expression Omnibus database. Survival analysis was performed via the GEPIA database (GEO). The relationship between the key gene ITGAM and the therapeutic candidates was retrieved from DGIdb. A total of 1,302 differentially expressed genes were identified based on GEO. The PPI network highlighted 10 potential hub genes. Only ITGAM was linked to poor DSF in NSCLC patients. A total of 10 drugs were predicted to be potential therapeutics for NSCLC with EGFR–TKI resistance. This study indicates the hub genes related to EGFR–TKI resistance in NSCLC through bioinformatics technologies which can improve the understanding of the mechanisms of EGFR–TKI resistance and provide novel insights into therapeutics.

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Sone, Takashi, Kazuo Kasahara, Koji Kurokawa, Asao Sakai, Toshiyuki Kita, Shingo Nishikawa, Kazuyoshi Watanabe, Hiroki Shirasaki, and Taro Yoneda. "EGFR-TKI after disease progression with central nervous system metastasis in advanced non-small cell lung cancer with EGFR mutations." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e19083-e19083. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e19083.

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e19083 Background: Several retrospective studies have reported that continued treatment with EGFR-TKI after developing progressive disease (PD) by RECIST improved survival compared to TKI-free treatment in NSCLC patients with EGFR mutations. However, it is unclear which patients would benefit from EGFR-TKI after PD. We hypothesized that patients with CNS progression only, without systemic deterioration, would show a good prognosis with EGFR-TKI after PD. Methods: In order to clarify the survival benefits in patients treated by EGFR-TKI after developing PD, particularly patients with CNS metastasis alone, NSCLC patients with EGFR mutations who were treated with EGFR-TKI and showed progression were analyzed retrospectively. The patients were categorized into two groups: patients continuing with EGFR-TKI treatment after progression (continuation group) and patients switched to chemotherapy or BSC (discontinuation group). Patients were also classified into two groups by site of progression: patients who showed deterioration involving only CNS metastasis (CNS group) and patients who showed progression of the primary lesion, lymph nodes, bone, liver, adrenal glands, CNS, or other sites (systemic group). Differences in post-EGFR-TKI progression survival (PPS) and overall survival were compared between the groups. Results: A total of 75 patients, including 54 women, 56 never smokers, 73 patients with adenocarcinomas, and 57 patients with good PS (0, 1), were analyzed. There were 40 patients with deletions in exon 19, 29 patients with L858R, and 6 with minor mutations. The continuation group (n=36) had a significantly longer PPS than the discontinuation group (n=39) (16.2 m vs. 8.5 m, p<0.01). Although it was not significant, the CNS group (n=14) showed longer PPS than the systemic group (n=61) (17.3 m vs. 9.2 m, p=0.10). The PPS of 9 patients (continuation and CNS groups) was 21.0 m, while PPS of 34 patients (discontinuation and systemic group) was 7.2 m. Conclusions: In this retrospective analysis, continued treatment with EGFR-TKI after PD resulted in longer PPS. A prospective study of patients with progression involving only CNS metastasis treated with EGFR-TKI is needed.

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Riess, Jonathan W., Mark D. Krailo, Sukhmani Kaur Padda, Susan G. Groshen, Heather A. Wakelee, Karen L. Reckamp, Marianna Koczywas, et al. "Osimertinib plus necitumumab in EGFR-mutant NSCLC: Final results from an ETCTN California Cancer Consortium phase I study." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): 9014. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.9014.

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9014 Background: Osimertinib (Osi) is standard of care in 1st line (1L) EGFR mut NSCLC and TKI resistant T790Mpos NSCLC but acquired resistance emerges; outcomes are less robust in T790Mneg, C797Xpos and EGFR exon 20 insertion (ex20ins) disease. We examined Osi with the EGFR monoclonal antibody Necitumumab (Neci) in select settings of EGFR TKI resistance. Methods: Pts were accrued to 5 expansion cohorts (ExC) at recommended phase 2 dose (RP2D) of Osi 80 mg daily and Neci 800 mg D1 + D8 of q21d cycle. ExC (18 pts/cohort): A) T790Mneg progressive disease (PD) on 1st/2nd gen TKI as last therapy, B) T790Mneg PD on 1st/2nd gen TKI and PD on 3rd gen TKI, C) T790Mpos PD on 1st/2nd gen TKI and PD on 3rd gen TKI, D) EGFR ex20ins PD on chemotherapy, E) PD on 1L osi. In ExC A-C, T790M was confirmed centrally (tissue) by ddPCR. Additional correlative studies include: tissue NGS (> 400 gene panel), EGFR FISH, plasma for PK and serial EGFR ctDNA by ddPCR. Adverse events were graded (Gr) by CTCAEv5; ORR, PFS by RECIST 1.1. Primary pre-specified efficacy endpoint ≥3/18 pts responding per cohort. Results: 101 patients accrued (100 evaluable). Efficacy is summarized in the Table. Drug related Gr 3 AEs were seen in 38% of pts, mainly rash (21%). ORR among all pts was 19% (95% CI 12-28%) that varied across cohorts (Table). In ExC A-C, 69% pts had detectable EGFR activating mutations in ctDNA, with decline in mutant allele frequency (AF) on treatment in 80% and ctDNA clearance in 33%. Conclusions: Osi/Neci is feasible and tolerable at the RP2D. EGFR ctDNA was detectable at baseline in the majority of pts with decrease in AF on treatment. Osi/Neci was active in select settings of EGFR-TKI resistance, meeting its prespecified efficacy endpoint in T790Mneg PD on 1st/2nd gen TKI as last therapy (ExC A), EGFR ex20ins post-chemo (ExC D) and PD on 1L osimertinib (ExC E). mPFS in the EGFR ex20ins cohort was within the range of current EGFR Exon 20 ins agents in development. EGFR monoclonal antibodies with osimertinib warrant further study in settings of de novo and acquired EGFR dependent resistance to EGFR-TKI. Clinical trial information: NCT02496663. [Table: see text]

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Wu, Shang-Gin, Tzu-Hua Chang, Yih-Leong Chang, Meng-Feng Tsai, Chong-Jen Yu, and Jin-Yuan Shih. "IGFBP-7 to confer resistance to the epidermal growth factor receptor tyrosine kinase inhibitor." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e20572-e20572. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e20572.

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e20572 Background: Lung cancer is a leading cause of cancer death worldwide. The EGFR mutation-positive patients of lung adenocarcinoma had dramatic response to EGFR tyrosine kinase inhibitors (TKIs). However, acquired drug resistance developed invariably after one year treatment course of EGFR TKI. IGFBP-7, a secreted 31 kDa protein, exhibits low affinity for IGF but binds strongly to insulin. No previous studies had been mentioned the correlation between the protein and acquired EGFR TKI resistance. Methods: cDNA microarray was used to screen differentially expressed genes between EGFR TKI-sensitive (PC9 and HCC827) and acquired EGFR TKIs-resistance cell lines (PC9/gef and HCC827/gef). The expression levels of the screened genes were validated by RT -PCR and Western blot analysis. Molecular manipulations (silencing or overexpression) were performed to investigate the effects of IGFBP-7 on gefitinib resistance in vitro. In addition, clinical specimens were collected to validate the imact of IGFBP-7 on the efficacy of EGFR TKI treatment . Results: IGFBP-7 is over-expressed in gefitinib-resistant cells. The IGFBP-7 mRNA expression in the malignant pleural effusion of patients with acquired resistance to EGFR TKI was significant higher than that in the treatment-naïve patients. Knockdown IGFBP-7 reverses gefitinib resistance in PC9/gef cells. Knockdown IGFBP-7 could increase gefetinib induced-apoptosis through the regulation of BIM. IGFBP-7 affected the mechanism of EGFR TKI resistance resulted from inhibition of IGF-IR.. In clinical practice, low IGFBP-7 serum level is associated with longer progression free survival (PFS) of EGFR TKI as the first line treatment. Furthermore, lower IGFBP-7 level of resected tumor predicts a longer 5-year tumor relapse-free survival. Positive IGFBP-7 immunoihistochemical stain could predict a shorter PFS of the first-line EGFR TKI treatment. Conclusions: IGFBP-7 confers resistance to the EGFR TKI and may be a target for future treatment investigation.

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von Kieseritzky, Kathrin. "NSCLC: Neuer EGFR-TKI wirksam." Im Fokus Onkologie 22, no. 1 (February 2019): 27. http://dx.doi.org/10.1007/s15015-019-0038-1.

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Wedekind, Silke. "EGFR-TKI-Sequenz beeinflusst Prognose." Pneumo News 10, no. 2 (April 2018): 58. http://dx.doi.org/10.1007/s15033-018-0910-2.

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Roos, Martin. "Zusatznutzen von EGFR-TKI bestätigt." Im Focus Onkologie 18, no. 12 (December 2015): 8. http://dx.doi.org/10.1007/s15015-015-2202-6.

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Yamaoka, Toshimitsu, Tohru Ohmori, Motoi Ohba, Satoru Arata, Yasunari Kishino, Yasunori Murata, Sojiro Kusumoto, et al. "Acquired Resistance Mechanisms to Combination Met-TKI/EGFR-TKI Exposure in Met-Amplified EGFR-TKI–Resistant Lung Adenocarcinoma Harboring an Activating EGFR Mutation." Molecular Cancer Therapeutics 15, no. 12 (September 9, 2016): 3040–54. http://dx.doi.org/10.1158/1535-7163.mct-16-0313.

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Lin, Luping, and Trever G. Bivona. "Mechanisms of Resistance to Epidermal Growth Factor Receptor Inhibitors and Novel Therapeutic Strategies to Overcome Resistance in NSCLC Patients." Chemotherapy Research and Practice 2012 (August 29, 2012): 1–9. http://dx.doi.org/10.1155/2012/817297.

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The epidermal growth factor receptor (EGFR) is a well-characterized oncogene that is frequently activated by somatic kinase domain mutations in non-small cell lung cancer (NSCLC). EGFR TKIs are effective therapies for NSCLC patients whose tumors harbor an EGFR activating mutation. However, EGFR TKI treatment is not curative in patients because of both primary and secondary treatment resistance. Studies over the last decade have identified mechanisms that drive primary and secondary resistance to EGFR TKI treatment. The elucidation of mechanisms of resistance to EGFR TKI treatment provides a basis for the development of therapeutic strategies to overcome resistance and enhance outcomes in NSCLC patients. In this paper, we summarize the mechanisms of resistance to EGFR TKIs that have been identified to date and discusses potential therapeutic strategies to overcome EGFR TKI resistance in NSCLC patients.

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Mink, Sheldon R., Surabhi Vashistha, Wenxuan Zhang, Amanda Hodge, David B. Agus, and Anjali Jain. "Cancer-Associated Fibroblasts Derived from EGFR-TKI–Resistant Tumors Reverse EGFR Pathway Inhibition by EGFR-TKIs." Molecular Cancer Research 8, no. 6 (June 2010): 809–20. http://dx.doi.org/10.1158/1541-7786.mcr-09-0460.

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Wulandari, Laksmi, and Edward Pandu Wiriansya. "COMPARISON OF CHEMOTHERAPY RESPONSE AND ADVERSE EFFECTS OF DOUBLE-PLATINUM PLUS EGFR-TKI VERSUS DOUBLE-PLATINUM ALONE ON NSLCLC PATIENTS WITH DISEASE PROGRESSION AND EGFR-TKI TREATMENT." Folia Medica Indonesiana 53, no. 4 (December 28, 2017): 276. http://dx.doi.org/10.20473/fmi.v53i4.7161.

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EGFR-TKI is the first-line therapy for EGFR-mutant patients. Nevertheless, patients will have disease progression (median PFS 10 – 12 months) due to resistance. The treatment options are still limited in developing countries for such cases, thus double-platinum chemotherapy is the next option. Although IMPRESS study reported no difference in terms of PFS and OS between double-platinum alone and double-platinum plus EGFR-TKI, several local studies reported benefit of continuing EGFR-TKI in combination with double-platinum chemotherapy (treatment beyond progression). This study aimed to compare chemotherapy effects of double-platinum plus EGFR-TKI versus double-platinum alone on patients with NSCLC progression after EGFR-TKI treatment. This was an analytical descriptive study using prospective cohort design, involving 30 patients with disease progression following EGFR-TKI treatment that met inclusion criteria in Dr. Soetomo Hospital. Subjects were divided into two groups: arm A (double-platinum plus EGFR-TKI) and arm B (double-platinum alone). Subjects were observed until 4 cycles of double-platinum chemotherapy. Subjective response (body weight and EQ5D questionnaire) was analyzed, chest CT scans were evaluated using RECIST criteria, and adverse effects were monitored. This study was conducted in accordance with GCP principles and has received ethics certificate from Dr. Soetomo Hospital ethics committee (No. 08/Panke.KKE/I/2017). The results showed that subject characteristics between two arms were insignificantly different (p=0.05). The most common EGFR mutation was exon 21 (50% on arm A and 60% on arm B). Chi square was tested on subjective response parameter (EQ5D (p=0.483)). T2 free sample was tested on semi-subjective parameter (body weight (p=1.00)). Comparison test on both groups after cycle 2 and 4 showed p value=0.05. Statistical test on adverse effect between both groups showed p value=0.526. As a conclusion, there was no significant difference between double-platinum and double-platinum plus EGFR-TKI on patients who had disease progression following EGFR-TKI treatment.

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Xu, Yu-Fen, Yao Xu, Xia Li, and Xin-Mei Yang. "Serum α-1 Acid Glycoprotein is a Biomarker for the Prediction of Targeted Therapy Resistance in Advanced EGFR-positive Lung Adenocarcinoma." Combinatorial Chemistry & High Throughput Screening 21, no. 10 (February 26, 2019): 755–59. http://dx.doi.org/10.2174/1386207322666190119163024.

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Objective: To determine the levels of α-1 acid glycoprotein (ORM1) in the sera of advanced lung adenocarcinoma (LUAD) patients with epidermal growth factor receptor (EGFR) mutation before treatment and after acquirement of EGFR tyrosine kinase inhibitor (EGFR-TKI) resistance, and to explore the clinical cut off value of ORM1 for targeted therapy resistance in LUAD. Methods: Enzyme-linked immunosorbent assay was used to determine serum ORM1 levels. Receiver operating characteristic curve was applied to evaluate the serum ORM1 level in the resistance of EGFR-TKI and the cut off value of ORM1 for the diagnosis of EGFR-TKI resistance. Results: The serum ORM1 concentrations in the healthy group, before and after drug resistance were 1.687 ± 0.103, 1.868 ± 0.101, and 1.731 ± 0.088 µg/ml, respectively. The serum ORM1 concentrations before and after drug resistance were higher than that of the healthy group, whereas the serum ORM1 concentrations in the resistant group were lower than those before drug treatment. In comparison to healthy group, the area under curve (AUC) of the serum ORM1 concentration was 0.918 ± 0.029 with sensitivity of 90.5% and specificity of 78.6% in the patient before EGFR-TKI treatment, while the AUC was 0.644 ± 0.062 with sensitivity of 69.0% and specificity of 66.7% in the resistance group. When compared to those before treatment, the AUC of serum ORM1 concentration was 0.880 ± 0.038 with a sensitivity of 92.9% and specificity of 73.8% in the resistance group. The cutoff value of serum ORM1 was 1.778 µg/ml for advanced EGFR-positive LUAD and 1.723 µg/ml after resistance to EGFR-TKI. Conclusion: Serum ORM1 has an important diagnostic value for the diagnosis of EGFR-positive LUAD and EGFR-TKI resistance in patients especially with advanced EGFR-positive LUAD. Our findings suggest that serum ORM1 is a biomarker in the prediction of EGFR-TKI resistance in EGFR-positive LUAD.

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Janne, Pasi A., Christina S. Baik, Wu-Chou Su, Melissa Lynne Johnson, Hidetoshi Hayashi, Makoto Nishio, Dong-Wan Kim, et al. "Efficacy and safety of patritumab deruxtecan (HER3-DXd) in EGFR inhibitor-resistant, EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC)." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 9007. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.9007.

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9007 Background: Patients (pts) with advanced EGFRm NSCLC have limited treatment options after failure of EGFR TKI and platinum-based chemotherapy (PBC). HER3-DXd is an antibody drug conjugate consisting of a fully human monoclonal antibody to HER3 attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. We previously presented efficacy/safety data (median follow-up, 5.4 mo) from an ongoing study of HER3-DXd in EGFRm NSCLC after failure of EGFR TKI therapy. We now present extended follow-up of pts receiving the recommended dose for expansion (5.6 mg/kg IV Q3W). Methods: This Ph 1 dose-escalation/expansion study included pts with locally advanced or metastatic EGFRm NSCLC with prior EGFR TKI therapy (NCT03260491). Pts with stable brain metastases (BM) were allowed. The primary endpoint was confirmed ORR by blinded independent central review (BICR) per RECIST v1.1; secondary endpoints included DOR, PFS and safety. Results: At data cutoff (Sept 24, 2020), 57 pts were treated with HER3-DXd 5.6 mg/kg IV Q3W; median follow-up, 10.2 mo (range, 5.2-19.9 mo). Median number of prior anticancer regimens was 4 (range, 1-10). 100% had prior EGFR TKI (86% prior osimertinib [OSI]) and 91% had prior PBC. 47% had a history of BM. Median treatment duration was 5.5 mo (range, 0.7-18.6 mo); treatment was ongoing in 18 pts (32%). Confirmed ORR by BICR was 39% (22/57; 95% CI, 26.0%-52.4%; 1 CR, 21 PR, 19 SD) with 14/22 responses occurring within 3 mo of starting HER3-DXd. DCR was 72% (95% CI, 58.5%-83.0%). Median DOR was 6.9 mo (95% CI, 3.1 mo-NE), and median PFS was 8.2 mo (95% CI, 4.4-8.3 mo). Antitumor activity was observed across diverse mechanisms of EGFR TKI resistance, including those not directly related to HER3 ( EGFR C797S, MET or HER2 amp, and BRAF fusion). Among pts with prior PBC, ORR was 37% (19/52; 95% CI, 23.6%-51.0%); in pts with prior OSI and PBC, ORR was 39% (17/44; 95% CI, 24.4%-54.5%). Among 43 pts evaluable for HER3 expression, nearly all expressed HER3; median membrane H-score by IHC was 180 (range, 2-280). Median H-score (range; N) was 195 (92-268; 15) in pts with CR/PR, 180 (4-280; 15) with SD, 126.5 (2-251; 6) with PD, and 180 (36-180; 7) in pts unevaluable for best overall response. The most common grade ≥3 adverse events (AEs) were thrombocytopenia (30%), neutropenia (19%), and fatigue (14%). Drug-related interstitial lung disease by central adjudication occurred in 4 pts (7%; 1 grade ≥3 [2%]; no grade 5). 6/57 pts (11%) had AEs associated with treatment discontinuation (none were due to thrombocytopenia). Conclusions: HER3-DXd 5.6 mg/kg IV Q3W demonstrated antitumor activity across various EGFR TKI resistance mechanisms in heavily pretreated metastatic/locally advanced EGFRm NSCLC. The safety profile was consistent with previous reports. A Ph 2 study of HER3-DXd in pts with EGFRm NSCLC after failure of EGFR TKI and PBC has been initiated (NCT04619004). Clinical trial information: NCT03260491.

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Riess, Jonathan W., Susan G. Groshen, Karen L. Reckamp, Heather A. Wakelee, Geoffrey R. Oxnard, Sukhmani Kaur Padda, Marianna Koczywas, et al. "Osimertinib (Osi) plus necitumumab (Neci) in EGFR-mutant NSCLC: An ETCTN California cancer consortium phase I study." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 9057. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.9057.

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9057 Background: Osi (3rd gen EGFR TKI) has robust activity in 1st line EGFR mutant NSCLC and TKI resistant T790Mpos NSCLC but progressive disease (PD) occurs and outcomes with Osi alone are poor in T790Mneg, C797Xpos and EGFR exon 20 insertion (ins20) disease. This study examined the EGFR monoclonal antibody Neci with Osi in select settings of EGFR TKI resistance. Methods: Using a 3+3 design, Neci was examined in advanced EGFR mutant NSCLC at dose levels (DL) of 600 mg (DL1) & 800 mg (DL2) D1, D8 IV q21 days + Osi 80 mg qd. Four expansion cohorts (ExC; 18 each) included: A) T790Mneg PD on 1st/2nd gen TKI as last therapy, B) T790Mneg PD on 3rd gen TKI, C) T790Mpos PD on 3rd gen TKI, D) EGFR ex20ins PD on chemotherapy. Central T790M testing by ddPCR in ExC A-C. Additional studies performed include: NGS panel of > 400 genes, EGFR FISH, plasma for PK and serial EGFR ctDNA by ddPCR as exploratory analyses. Adverse events (AEs) graded (Gr) by CTCAEv5 with ORR and PFS by RECIST 1.1. Results: Dose escalation and ExC B completed accrual. In total 55 pts were evaluable (Table). 1 pt had DLT at DL2, Gr 3 sinus bradycardia. Drug related Gr 3 AEs were seen in 27% (15) of pts, mainly rash (7;13%). ctDNA showed decreased mutant allele frequency with therapy in all pts studied with detected EGFR at baseline, with complete plasma clearance in a pt with detectable C797S. Conclusions: The RP2D (Osi 80 mg qd and Neci 800 mg D1, D8 IV on q21d cycle) is feasible and tolerable. In ExC A,T790Mneg pts with 1st/2nd gen EGFR TKI as last treatment, using curtailed sampling, the pre-specified efficacy signal was reached for Osi + Neci comparing favorably to Osi alone in analogous pts from the AURA trial. Clinical activity was also seen in EGFR-dependent resistance (T790Mpos C797Spos) after PD on 3rd gen TKI and in EGFR ins 20. Clinical trial information: NCT02496663. [Table: see text]

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Journal articles on the topic 'EGFR TKI'

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