scholarly journals Optimizing outcomes and treatment sequences inEGFRmutation-positive non-small-cell lung cancer: recent updates

2019 ◽  
Vol 15 (25) ◽  
pp. 2983-2997 ◽  
Author(s):  
Nicolas Girard
Keyword(s):  
Kinase Inhibitors ◽  
Treatment Options ◽  
Resistance Mutation ◽  
First Line ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Line Setting ◽  
Egfr Tki ◽  
Optimum Sequence ◽  
Egfr Tkis ◽  
Viable Treatment

The availability of several EGFR tyrosine kinase inhibitors (TKIs) for the treatment of EGFR mutation-positive NSCLC poses important questions regarding the optimum sequence of therapy. A key consideration is how best to use the third-generation TKI, osimertinib. While osimertinib has demonstrated impressive efficacy and tolerability in a first-line setting, there are currently no standard targeted treatment options following progression. There is an argument, therefore, for reserving osimertinib for second-line use in patients who acquire the T790M resistance mutation after first- or second-generation TKIs. This article reviews recent clinical studies that have assessed the activity of sequential EGFR TKI regimens. These studies support the hypothesis that sequential use of EGFR TKIs represents a viable treatment option in ‘real-world’ clinical practice.

scholarly journals DDIS-17. DEVELOPMENT OF BRAIN-PENETRANT EGFR INHIBITORS FOR CNS MALIGNANCIES

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi66-vi66
Author(s):  
Jonathan Tsang ◽  
Lorenz Urner ◽  
Christopher Tse ◽  
Lynn Baufeld ◽  
Kym Faull ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Tumor Response ◽  
Growth Factor Receptor ◽  
Structure Activity ◽  
Superior Efficacy ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Epidermal Growth ◽  
Egfr Tki ◽  
Egfr Tkis ◽  
Cns Malignancies

Abstract The epidermal growth factor receptor (EGFR) is altered in nearly 60% of glioblastoma (GBM) tumors, however, EGFR tyrosine kinase inhibitors (TKIs) have failed to improve outcomes for patients with GBM. This can be attributed to the inability of clinically available EGFR TKIs (e.g., erlotinib, gefitinib, lapatinib, afatinib, cetuximab) to effectively cross the blood-brain-barrier (BBB) and reach adequate pharmacological levels for a tumor response. Herein, we performed a structure-activity relationship (SAR) to obtain EGFR TKIs with both high brain penetrance and potency against EGFR-activated GBM cells. From over 80 novel compounds synthesized, our lead EGFR TKI—JCN068—exhibited exceptional BBB penetration (350% brain to plasma) while also having optimal ADME properties (60% oral bioavailability, ~5 hr half-life, >100 µg/mL solubility, etc). Moreover, JCN068 demonstrated picomolar potency against purified EGFR kinase, 1000-fold selectivity for EGFR relative to other kinases, and nanomolar activity against EGFR-altered, GBM patient-derived cells in culture. Importantly, JCN068 demonstrated superior efficacy—with negligible toxicity—compared to clinically available small molecule EGFR TKIs (erlotinib and lapatinib) against multiple EGFR-altered patient-derived orthotopic GBM xenografts. Due to these excellent drug-like properties, JCN068 is currently progressing towards clinical development for EGFR-activated GBM patients.

Upfront EGFR TKI with or without brain radiotherapy (RT) in EGFR-driven non-small cell lung cancer (NSCLC) with brain metastases.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e20614-e20614
Author(s):  
Nicolas Villanueva ◽  
Klarissa Son ◽  
Jona Ashok Hattangadi ◽  
Daniel Robert Simpson ◽  
Parag R. Sanghvi ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Late Onset ◽  
Treatment Options ◽  
Progression Free Survival ◽  
Brain Radiotherapy ◽  
Predominantly Female ◽  
Line Setting ◽  
Egfr Mutated ◽  
Egfr Tki ◽  
Egfr Tkis

e20614 Background: The central nervous system (CNS) remains a common site of metastatic disease for NSCLC, especially in EGFR-driven disease. Surgery and RT are upfront treatment options but have potential early and late onset complications. Osimertinib (Osi) is now approved for use in the front-line setting for EGFR-mutated NSCLC and is highly CNS penetrant. A prior retrospective study showed that the use of early generation EGFR TKIs had an inferior overall survival (OS) compared to upfront RT in newly diagnosed brain metastases, but the applicability of this data in the Osi-era is unknown. Methods: This was a single institution retrospective analysis of patients with EGFR mutated NSCLC and brain metastases who were referred to Radiation Oncology from 1/1/2012 to 12/31/2018. We separated EGFR TKIs between Osi and non-Osi. The primary objectives were to evaluate OS, intracranial progression free survival (icPFS), and intracranial response (icORR) among upfront or delayed RT, and type of EGFR TKI. Results: 67 patients with a median age of 64 years old (33-89) were divided into one of four groups: non-Osi TKI with (N = 38) or without RT (N = 12), and Osi with (N = 14) or without RT (N = 3). Fourteen patients who did not get upfront Osi, received Osi with (N = 7) or without RT (N = 7) after intracranial progressive disease (icPD). Patients were predominantly female, never-smokers, and with an ECOG PS 0-1. Brain metastases were mostly asymptomatic and < 10 mm. The OS for the entire population was 26.7 months (95% CI, 23.9-29.5); there was no difference between groups, and use or type of RT versus TKI. The icPFS was 14.3 months (95% CI, 9.1-19.5), icORR was 64.2%, and icDCR was 82.7%, without any difference between groups. Among those patients who did not receive upfront Osi, use in the post-progression setting resulted in a significantly longer OS (54.8 vs. 23.0 months, p = 0.001). Conclusions: We found no statistical difference in OS, icPFS, or icORR in patients treated with upfront RT or EGFR TKI. Results should be confirmed with a prospective study.

Identification of RET fusion as mechanisms of resistance to EGFR tyrosine-kinase inhibitors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21074-e21074
Author(s):  
Zhongxing Bing ◽  
Weiran Wang ◽  
Danhua Wang ◽  
Tonghui Ma
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Next Generation Sequencing Data ◽  
Egfr Mutations ◽  
Egfr Tyrosine Kinase ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Egfr Tki ◽  
Egfr Tkis

e21074 Background: Responses to EGFR-targeted therapy are generally temporary, due to inevitable drug resistance. Although RET fusions have been identified in resistant EGFR-mutant non–small cell lung cancer (NSCLC), their characteristics acquired resistance to EGFR tyrosine-kinase inhibitors (TKIs) are rarely investigated. Methods: We retrospectively reviewed next-generation sequencing data of EGFR+ lung cancer patients, and 8 patients were identified coexisting of EGFR mutations and RET fusion. Their treatment history was collected. Results: The co-occurrence of RET fusion with EGFR oncogenic variations was observed in eight patients, and all of the 8 patients have received previous EGFR-TKI treatment. EGFR mutations were including 4 L858R mutations, 4 exon 19 deletions, and 6 T790M mutations. And the partner genes of RET identified by NGS were including TRIM33 (2/8), GPRC6A (1/8), TLN1 (1/8), KIAA1598 (1/8), SPECC1 (1/8), TRIM24 (1/8) and CCDC6 (1/8). The allelic fractions (AFs) of first-generation EGFR-TKI sensitizing mutations were higher than AFs of EGFR T790M mutations as well as AFs of RET fusion. These RET fusions are fused with rare partner genes, rather than the most common KIF5B in lung cancer. Conclusions: This study extended the knowledge of RET fusion as resistance mechanism to EGFR TKIs in lung cancer. The detection of RET fusions may uncover potential resistance mechanisms of EGFR TKIs, which might inform therapeutic strategies, such as combination-therapy approaches.[Table: see text]

scholarly journals Intrinsic resistance to EGFR-Tyrosine Kinase Inhibitors in EGFR-Mutant Non-Small Cell Lung Cancer: Differences and Similarities with Acquired Resistance

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 923 ◽  
Author(s):  
Santoni-Rugiu ◽  
Melchior ◽  
Urbanska ◽  
Jakobsen ◽  
Stricker ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Kinase Inhibitors ◽  
Acquired Resistance ◽  
Small Cell ◽  
Small Cell Lung ◽  
Intrinsic Resistance ◽  
Tki Resistance ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Egfr Tki ◽  
Egfr Tkis

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.

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.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e19345-e19345
Author(s):  
Daniel Simmons ◽  
Maral DerSarkissian ◽  
Rahul Shenolikar ◽  
Min-Jung Wang ◽  
Angela Lax ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Stage Iv ◽  
Test Results ◽  
First Line ◽  
Second Line Therapy ◽  
Line Therapy ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Epidermal Growth ◽  
Egfr Tki

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]

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.

2020 ◽  
Vol 38 (29_suppl) ◽  
pp. 281-281
Author(s):  
Daniel Simmons ◽  
Maral DerSarkissian ◽  
Rahul Shenolikar ◽  
Min-Jung Wang ◽  
Angela Lax ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Stage Iv ◽  
Small Cell ◽  
Test Results ◽  
Small Cell Lung ◽  
First Line ◽  
Second Line Therapy ◽  
Line Therapy ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Egfr Tki

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]

scholarly journals Development of EGFR TKIs and Options to Manage Resistance of Third-Generation EGFR TKI Osimertinib: Conventional Ways and Immune Checkpoint Inhibitors

2020 ◽  
Vol 10 ◽  
Author(s):  
Leilei Wu ◽  
Linping Ke ◽  
Zhenshan Zhang ◽  
Jinming Yu ◽  
Xue Meng
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Acquired Resistance ◽  
Resistance Mutation ◽  
Growth Factor Receptor ◽  
Third Generation ◽  
First Line ◽  
Egfr Tkis

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) have been first-line therapy in the treatment of non-small cell lung cancer (NSCLC) harboring EGFR sensitive mutations. Progression inevitably happens after 10–14 months of first- or second-generation EGFR TKIs treatment for acquired resistance. Owing to the successful identification of EGFR T790M, third-generation EGFR TKIs such as osimertinib were developed to target such resistance mutation. Nowadays, osimertinib has shown its efficacy both in first-line and second-line after resistance to previous generations of TKI treatment of EGFR-mutant NSCLC. However, drug resistance also emerges on third-generation EGFR TKIs. Multiple mechanisms of acquired resistance have been identified, and some novel strategies were reported to overcome third-generation TKI resistance. Immune checkpoint inhibitors (ICIs) have dramatically changed the prognosis of selected patients. For patients with EGFR-addicted metastatic NSCLC, ICIs have also revealed a potential role. In this review, we will take stock of mechanisms of acquired resistance to third-generation TKIs and discuss current challenges and future perspectives in clinical practice.

scholarly journals The efficacy of first-line tyrosine kinase inhibitors combined with co-medications in Asian patients with EGFR mutation non-small cell lung cancer

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Vincent Yi-Fong Su ◽  
Kuang-Yao Yang ◽  
Ting-Yu Huang ◽  
Chia-Chen Hsu ◽  
Yuh-Min Chen ◽  
...  
Keyword(s):  
Treatment Failure ◽  
Lower Risk ◽  
Kinase Inhibitors ◽  
Small Cell ◽  
Egfr Mutations ◽  
Small Cell Lung ◽  
First Line ◽  
Risk Of Treatment ◽  
Egfr Tki ◽  
Egfr Tkis

Abstract The real-world efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR-activating mutations remains unclear. We conducted a retrospective cohort study using data from the claims database of Taipei Veterans General Hospital to perform direct comparisons of these three EGFR-TKIs (gefitinib, erlotinib, and afatinib) combined with co-medications (metformin, statins, antacids, and steroids). Stage IIIB and IV NSCLC patients with EGFR mutations receiving EGFR-TKIs as first-line treatment for > 3 months between 2011 and 2016 were enrolled. The primary endpoint was time to treatment failure (TTF). Patients who had received co-medications (≥ 28 defined daily doses) in the first 3 months of EGFR-TKI therapy were assigned to co-medications groups. A total of 853 patients treated with gefitinib (n = 534), erlotinib (n = 220), and afatinib (n = 99) were enrolled. The median duration of TTF was 11.5 months in the gefitinib arm, 11.7 months in the erlotinib arm, and 16.1 months in the afatinib arm (log-rank test, P < 0.001). After adjustments, afatinib showed lower risk of treatment failure compared with gefitinib (hazard ratio [HR] 0.54, 95% confidence interval [CI] 0.41–0.71) and erlotinib (HR 0.62, 95% CI 0.46–0.83). The risk of treatment failure in patients treated with EGFR-TKIs who received concomitant systemic glucocorticoid therapy was higher than in those treated with EGFR-TKI monotherapy (HR 1.47, 95% CI 1.08–2.01). Afatinib or erlotinib use was associated with a lower risk of treatment failure in patients with advanced NSCLC harboring EGFR mutations compared to gefitinib use. Concurrent use of systemic glucocorticoids was linked to higher risk of treatment failure.

scholarly journals Preclinical characterization of mobocertinib highlights the putative therapeutic window of this novel EGFR inhibitor to EGFR exon 20 insertion mutations

2020 ◽  
Author(s):  
Pedro E. N. S. Vasconcelos ◽  
Ikei S. Kobayashi ◽  
Susumu S. Kobayashi ◽  
Daniel B. Costa
Keyword(s):  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
Therapeutic Window ◽  
Mechanisms Of Resistance ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Exon 20 ◽  
Egfr Tki ◽  
Insertion Mutations ◽  
Egfr Tkis

AbstractBackgroundEpidermal growth factor receptor (EGFR) exon 20 insertion mutations account for 10% of all EGFR mutations and are mostly insensitive to approved EGFR-tyrosine kinase inhibitors (EGFR-TKIs). Novel EGFR-TKIs have been developed or repurposed for these mutants. A limited number of preclinical studies have detailed these EGFR-TKIs. We sought to use commercially available mobocertinib (TAK-788) to characterize the preclinical therapeutic window of this EGFR-TKI against EGFR mutations and to probe possible on-target mechanisms of resistance (EGFR-C797S).MethodsWe used models of EGFR mutations to probe representative 1st, 2nd, 3rd generation, and in-development EGFR exon 20-active (poziotinib, mobocertinib) TKIs. We also introduced EGFR-C797S to these models to identify mechanisms of resistance.ResultsCells driven by the most common EGFR exon 20 insertion mutations (A767_V769dupASV, D770_N771insSVD, H773_V774insH and others) were inhibited by in-development EGFR TKIs at doses below those affecting EGFR-wildtype; albeit more common EGFR mutations (exon 19 deletions and L858R) were inhibited more readily by mobocertinib and poziotinib. Mobocertinib was able to inhibit phosphorylation of EGFR in multiple preclinical models. The presence of EGFR-C797S led to >200-fold resistance in proliferation assays probing mobocertinib and osimertinib. Review of clinical studies of mobocertinib disclosed responses that could be lasting.ConclusionsThis is one of the initial reports to characterize the novel EGFR TKI mobocertinib and highlights its broad activity against EGFR mutants plus the therapeutic window to EGFR exon 20 insertion mutations; as well as EGFR-C797S as a possible mechanism of resistance. Further clinical development of mobocertinib merits continuation.

Sign in / Sign up

Export Citation Format

Share Document