ctDNA resistance landscape of lazertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 9601-9601
Author(s):  
Ji-Youn Han ◽  
Myung-Ju Ahn ◽  
Sang-We Kim ◽  
Ki Hyeong Lee ◽  
Eun Kyung Cho ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Resistance Mechanisms ◽  
Third Generation ◽  
Egfr Amplification ◽  
Phase 2 Trial ◽  
Egfr Mutant ◽  
Nsclc Patients ◽  
In Cis ◽  
Egfr Tki ◽  
Egfr Tkis

9601 Background: While EGFR mutant ( EGFRm) non-small cell lung cancer (NSCLC) patients usually experience improved clinical benefit with EGFR TKIs, most eventually progress. Understanding mechanisms of resistance (MoR) may allow for more personalized treatment. Lazertinib is an irreversible third generation EGFR TKI for which MoR are unknown. Obtaining sufficient tumor tissue for genotyping at progression is often difficult. Therefore, we utilized plasma ctDNA from patients treated with lazertinib to explore MoR. Methods: Plasma samples from 47 NSCLC patients in the phase 2 trial of lazertinib (NCT03046992) were collected at screening and progressive disease (PD) and underwent ctDNA NGS of 74 genes using Guarant360. All patients were positive for an EGFR Ex19del or L858R ( EGFRm) and T790M by tissue testing at screening. Acquired, nonsynonymous, characterized mutations detected in a PD sample but not in the screening sample from the respective patient were considered putative MoR, excluding aneuploidy. Patients with detectable plasma EGFRm and/or T790M at screening were evaluable. Results: ctDNA was detected in 47 (100%) screening samples and 43/45 (96%) PD samples (two failed sequencing). An EGFRm was detected in 85% of patients at screening (n = 40), 38 of which had PD ctDNA results and were included in analysis. T790M was detected in 30 patients at screening and subsequently not detected at PD in 21 of these patients, 55% of all 38 included patients. Among the ten patients with T790M detected at PD, on-target MoR were detected in 7 (18% of all included patients) including EGFR C797S (n = 3, 8%), EGFR amplification (n = 3, 8%), and EGFR T854A (n = 1, 3%). All C797S were in cis with T790M. No on-target MoR were detected in patients without T790M detected at PD. Off-target MoR were seen in 34% of patients (13/38) including mutations in PIK3CA (13%; 2 E545K, 2 E542K, 1 E81K), ERBB2 (5%; 1 D769H, 1 V777L), KRAS (3%; 1 G12C), and BRAF (3%; 1 G469A). Gene amplifications were detected in CCND1 (n = 1, 3%) , CCNE1 (n = 2, 5%) , ERBB2 (n = 1, 3%) , FGFR1 (n = 1, 3%) , MET (n = 4, 11%) , and PIK3CA (n = 1, 3%), with some patients having multiple MoR. Conclusions: The spectrum of MoR identified in this cohort of patients treated with lazertinib is similar to that reported in other third generation EGFR TKIs, but with some differences in frequencies. The most common resistance mechanisms are T790M loss and PIK3CA alterations which may address the mechanism of action. Our findings suggest putative MoR of lazertinib and show that ctDNA NGS is an effective way to identify MoR in patients progressing on targeted therapy. Clinical trial information: NCT03046992 .

scholarly journals Triple Trouble: A Case of Multiple Resistance Mechanisms after First Generation EGFR-TKI in NSCLC

2019 ◽  
Vol 12 (2) ◽  
pp. 625-630 ◽  
Author(s):  
Mike Ralki ◽  
Brigitte Maes ◽  
Karin Pat ◽  
Jokke Wynants ◽  
Kristof Cuppens
Keyword(s):  
Kinase Inhibitor ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Standard Of Care ◽  
Resistance Mechanisms ◽  
First Line ◽  
T790m Mutation ◽  
Her2 Mutation ◽  
Egfr Mutant ◽  
Egfr Tki

Epidermal growth factor receptor (EGFR)-targeted therapy has become standard of care in advanced stages EGFR-mutant non-small cell lung cancer. Acquired resistance to first-line EGFR-tyrosine kinase inhibitor (TKI) and subsequent disease progression is a common problem and mostly due to a secondary mutation (T790M) in EGFR. We report a case of a patient with EGFR-mutated lung adenocarcinoma who developed a complex resistance profile: T790M mutation, HER2 mutation and HER2 amplification after first-line EGFR-TKI. This patient was safely treated with a combination of osimertinib and trastuzumab and achieved a clinically meaningful and clear molecular response.This is the first reported case of acquired resistance to first-line EGFR-TKI based on three resistance mechanisms, treated with molecular targeted combination therapy.

scholarly journals Hypothesis generative head-to-head study comparing efficacy of afatinib and osimertinib based on immunological biomarkers in Japanese NSCLC patients with EGFR mutations (Heat on Beat study)

2020 ◽  
Vol 12 ◽  
pp. 175883592096725
Author(s):  
Kei Morikawa ◽  
Hisashi Tanaka ◽  
Hidetoshi Itani ◽  
Saori Takata ◽  
Satoshi Watanabe ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Immune Checkpoint ◽  
Japanese Patients ◽  
Advanced Lung Cancer ◽  
Treatment Naïve ◽  
Egfr Mutant ◽  
Nsclc Patients ◽  
Egfr Tki ◽  
Egfr Tkis

Background: In the FLAURA trial, superiority of osimertinib over the standard of care (SOC) was not demonstrated in Asian patients; SOC seemed favorable among Japanese patients (hazard ratio 1.39, 95% confidence interval 0.82–2.33). Three reasons are suggested: since rechallenge with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is covered by health insurance in Japan, EGFR-TKI rechallenge rate was higher in SOC than in the osimertinib group, which resulted in a long-term sequential administration of EGFR-TKIs; treatment discontinuation rate was high in the osimertinib group due to adverse events such as interstitial pneumonia among Japanese patients. EGFR-TKIs enhance tumor antigen-specific cytotoxicity of T cells, especially first- and second-generation EGFR-TKIs, which are more active against various cells with wild-type EGFR, including regulatory T cells. Consequently, subsequent immune checkpoint inhibitor therapy seemed more promising in the SOC group. Therefore, optimal first-line EGFR-TKI for EGFR-mutant advanced lung cancer may not have been identified in Japanese patients. Methods: The Heat on Beat study is a randomized, open-label, multicenter, phase II study to compare OS between initial treatment with afatinib and osimertinib in treatment-naïve patients with advanced or recurrent EGFR-mutant NSCLC. Exploration of immunomonitoring through peripheral blood mononuclear cells will also be performed, before, during, and after treatment. Treatment-naïve EGFR mutation-positive non-small cell lung cancer (NSCLC) patients ( N = 100) will be randomized to two groups in a 1:1 ratio. The co-primary endpoints are 3-year survival rate and characterization of immune environment associated with response to afatinib, osimertinib, or immune checkpoint inhibitors. Enrollment will start in May 2020 at 28 sites in Japan and continue for 1 year, with 3-year follow-up. Discussion: Because there is no clinical trial comparing second- with third-generation EGFR-TKI for advanced EGFR-mutant NSCLC, our study would provide a major impact on clinical practice. Trial registration Japan Registry of Clinical Trials, jRCTs031190221, registered date: 25 February 2020, https://jrct.niph.go.jp/en-latest-detail/jRCTs031190221

Changing causes of death post-epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) era in patients with advanced non-small cell lung cancer (NSCLC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e18132-e18132
Author(s):  
Wen Shuo Wu ◽  
Yuh-Min Chen ◽  
Chun-Ming Tsai ◽  
Jen-Fu Shih ◽  
Yu-Chin Lee ◽  
...  
Keyword(s):  
Causes Of Death ◽  
Hospice Care ◽  
Egfr Mutation ◽  
Kinase Inhibitor ◽  
Cns Metastases ◽  
Mutation Status ◽  
Tki Treatment ◽  
Nsclc Patients ◽  
Egfr Tki ◽  
Egfr Tkis

e18132 Background: EGFR-TKIs are effective against tumor EGFR-mutated NSCLC. Patients with tumor EGFR activating mutation (EGFRmu) (exon 19 deletions or exon 21 L958R) had better survival than those with EGFR wild-type tumors (EGFRwt). Many EGFRmu patients have had disease progression with EGFR-TKI treatment due to central nervous system (CNS) metastases, including meningeal carcinomatosis. The objective of this retrospective study is to compare the causes of death in patients with a known tumor EGFR mutation status who had been treated with EGFR-TKIs. Methods: We retrospectively reviewed the chart records of our advanced NSCLC patients who had received diagnosis, treatment, and supportive and hospice care in our hospital between July 2005 and June 2010. Tumor EGFR mutation status was analyzed using the DNA sequence method. All enrolled patients had a documented cause of death. Results: Ninety-four patients had documented tumor EGFR data, had received EGFR-TKI treatment (either erlotinib or gefitinib), and were with or without previous or salvage systemic chemotherapy. Of them, 36 were EGFRwt and 58 were EGFRmu. Overall survival after starting EGFR-TKI treatment was significantly longer in EGFRmu than in EGFRwt patients (median 68.9 weeks vs. 46.3 weeks, p=0.0058). Twenty-nine patients died of CNS metastases and 65 died of organ(s) failure other than the CNS. Patients who died of CNS metastases had undergone EKGF-TKI treatment significantly longer than those who died of other organ(s) failure (median 32 weeks vs. 7.7 weeks, p=0.0003), with a hazard ratio of 2.308 (95% C.I. 1.452-3.668, p=0.0004). A significantly higher proportion of EGFRmu patients died of CNS metastases (26 of 58, 44.8%) than EGFRwt patients (3 of 36, 8.3%) (p<0.001). Conclusions: EGFRmu NSCLC patients survived longer and had a significantly higher probability of mortality due to CNS metastases than EGFRwt patients. This change in the causes of death due to NSCLC was noted after an era of EGFR-TKI treatment, and will have an important impact on the strategies or management of patient supportive and hospice care.

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 ◽  
2016 ◽  
Vol 61 (4) ◽  
pp. 179-189 ◽  
Author(s):  
Guifang Li ◽  
Shunji Gao ◽  
Zhixin Sheng ◽  
Bin Li
Keyword(s):  
Kinase Inhibitor ◽  
Single Agent ◽  
Growth Factor Receptor ◽  
Controlled Trials ◽  
Wild Type ◽  
Third Line ◽  
Egfr Mutant ◽  
Line Setting ◽  
Egfr Tki ◽  
Egfr Tkis

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.

scholarly journals Genomic Profiling Identifies Outcome-Relevant Mechanisms of Innate and Acquired Resistance to Third-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy in Lung Cancer

2019 ◽  
pp. 1-14 ◽  
Author(s):  
Sebastian Michels ◽  
Carina Heydt ◽  
Bianca van Veggel ◽  
Barbara Deschler-Baier ◽  
Nuria Pardo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Third Generation ◽  
Met Amplification ◽  
Epidermal Growth ◽  
Tki Treatment ◽  
Egfr Mutant ◽  
Egfr Tki ◽  
Egfr Tkis

PURPOSE Third-generation epidermal growth factor receptor ( EGFR) tyrosine kinase inhibitors (TKIs) are effective in acquired resistance (AR) to early-generation EGFR TKIs in EGFR-mutant lung cancer. However, efficacy is marked by interindividual heterogeneity. We present the molecular profiles of pretreatment and post-treatment samples from patients treated with third-generation EGFR TKIs and their impact on treatment outcomes. METHODS Using the databases of two lung cancer networks and two lung cancer centers, we molecularly characterized 124 patients with EGFR p.T790M-positive AR to early-generation EGFR TKIs. In 56 patients, correlative analyses of third-generation EGFR TKI treatment outcomes and molecular characteristics were feasible. In addition, matched post-treatment biopsy samples were collected for 29 patients with progression to third-generation EGFR TKIs. RESULTS Co-occurring genetic aberrations were found in 74.4% of EGFR p.T790-positive samples (n = 124). Mutations in TP53 were the most frequent aberrations detected (44.5%; n = 53) and had no significant impact on third-generation EGFR TKI treatment. Mesenchymal-epithelial transition factor ( MET) amplifications were found in 5% of samples (n = 6) and reduced efficacy of third-generation EGFR TKIs significantly (eg, median progression-free survival, 1.0 months; 95% CI, 0.37 to 1.72 v 8.2 months; 95% CI, 1.69 to 14.77 months; P ≤ .001). Genetic changes in the 29 samples with AR to third-generation EGFR TKIs were found in EGFR (eg, p.T790M loss, acquisition of p.C797S or p.G724S) or in other genes (eg, MET amplification, KRAS mutations). CONCLUSION Additional genetic aberrations are frequent in EGFR-mutant lung cancer and may mediate innate and AR to third-generation EGFR TKIs. MET amplification was strongly associated with primary treatment failure and was a common mechanism of AR to third-generation EGFR TKIs. Thus, combining EGFR inhibitors with TKIs targeting common mechanisms of resistance may delay AR.

scholarly journals Combined FGFR and Akt pathway inhibition abrogates growth of FGFR1 overexpressing EGFR-TKI-resistant NSCLC cells

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Mikkel G. Terp ◽  
Kirstine Jacobsen ◽  
Miguel Angel Molina ◽  
Niki Karachaliou ◽  
Hans C. Beck ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Resistance Mechanisms ◽  
Resistant Cell ◽  
Therapeutic Benefit ◽  
Resistant Cell Line ◽  
Nsclc Patients ◽  
Egfr Tki ◽  
Fgfr1 Expression

AbstractEGFR tyrosine kinase inhibitor (TKI) resistance in non-small cell lung cancer (NSCLC) patients is inevitable. Identification of resistance mechanisms and corresponding targeting strategies can lead to more successful later-line treatment in many patients. Using spectrometry-based proteomics, we identified increased fibroblast growth factor receptor 1 (FGFR1) expression and Akt activation across erlotinib, gefitinib, and osimertinib EGFR-TKI-resistant cell line models. We show that while combined EGFR-TKI and FGFR inhibition showed some efficacy, simultaneous inhibition of FGFR and Akt or PI3K induced superior synergistic growth inhibition of FGFR1-overexpressing EGFR-TKI-resistant NSCLC cells. This effect was confirmed in vivo. Only dual FGFR and Akt inhibition completely blocked the resistance-mediating signaling pathways downstream of Akt. Further, increased FGFR1 expression was associated with significantly lower PFS in EGFR-TKI-treated NSCLC patients, and increased FGFR1 were demonstrated in a few post- vs. pre-EGFR-TKI treatment clinical biopsies. The superior therapeutic benefit of combining FGFR and Akt inhibitors provide the rationale for clinical trials of this strategy.

Response to osimertinib following treatment with EGF816 in patients with T790M EGFR mutant NSLCLC.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20673-e20673 ◽  
Author(s):  
Kathryn Cecilia Arbour ◽  
Lecia V. Sequist ◽  
Zofia Piotrowska ◽  
Mark G. Kris ◽  
Paul K. Paik ◽  
...  
Keyword(s):  
Clinical Benefit ◽  
Cross Resistance ◽  
Third Generation ◽  
Eligibility Criteria ◽  
T790m Mutation ◽  
Previously Treated ◽  
Egfr Mutant ◽  
Egfr Tki ◽  
Egfr T790m ◽  
Egfr Tkis

e20673 Background: Third generation (3rd gen) epidermal growth factor (EGFR) tyrosine kinase inhibitors (TKIs) have been developed to treat EGFR T790M-mediated resistance to EGFR TKIs by inhibiting EGFR T790M, as well as EGFR L858R and EGFR exon 19 deletions. The mechanisms of resistance to third-generation EGFR TKIs are largely unknown and clinical cross-resistance among 3rd gen EGFR TKIs has not been routinely evaluated. Osimertinib is an FDA-approved irreversible 3rd gen EGFR TKI. In patients with EGFR T790M mutant NSCLC, the response rate (ORR) to osimertinib is 61%. EGF816 is a covalent, irreversible, 3rd gen EGFR TKI in clinical development. In early phase data of EGF816, the ORR was 47% and disease control rate was 87% in patients with EGFR T790M mutant NSCLC. To assess clinical cross-resistance between EGF816 and osimertinib, we evaluated the clinical outcomes of patients treated with osimertinib in patients previously treated with EGF816 during the phase I/II trial. Methods: Patients with metastatic EGFR mutant lung adenocarcinoma were identified who were previously treated with EGF816 and received osimertinib after progression of disease on EGF816 (NCT02108964). All patients had documented T790M mutation prior to treatment with EGF816. The best overall response to osimertinib was determined by RECIST 1.1 criteria. Duration of clinical benefit was defined as duration of osimertinib therapy. Results: Fourteen (3 men, 11 women, median age 58 [range 33-77]) patients met eligibility criteria at our centers. The ORR to subsequent osimertinib therapy was 14% (1 CR, 1 PR, 8 SD, 4 POD). Patients continued treatment with osimertinib for a median of 9 months (95% CI 3.8-10.1, [median follow up 11 months, range 1-13 months]). 5 patients are still on osimertinib to date (one patient each 3+, 6+, 8+, 11+, and 12+ months). Conclusions: This series suggests a potentially meaningful clinical benefit for patients with sequential therapy with two different third-generation EGFR inhibitors, emphasizing the importance of understanding resistance mechanisms (genetic alteration of target, bypass signaling, pharmacology, etc.) and raising the possibility of the need for multiple third generation EGFR TKIs in clinical practice.

Oncogene HSPH1 modulated by the rs2280059 genetic variant diminishes EGFR-TKIs efficiency in advanced lung adenocarcinoma

2020 ◽  
Vol 41 (9) ◽  
pp. 1195-1202
Author(s):  
Yankang Li ◽  
Nasha Zhang ◽  
Li Zhang ◽  
Yemei Song ◽  
Jie Liu ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Nucleotide Polymorphisms ◽  
Epidermal Growth ◽  
Tki Treatment ◽  
Nsclc Patients ◽  
Egfr Tki ◽  
Egfr Tkis

Abstract Although epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy is effective for most advanced non-small-cell lung cancer (NSCLC) patients with mutant EGFR, some patients show little or no response. Germline variations, such as single-nucleotide polymorphisms (SNPs), have been proved to be involved in disease progression after EGFR-TKI therapy. In this study, we hypothesized that the functional HSPH1 SNP may affect gene expression and, thus, prognosis of NSCLC patients treated with EGFR-TKIs. We systematically examined impacts of HSPH1 SNPs on NSCLC survival in two independent cohorts consisted of 319 EGFR-TKI treated stage IIIB/IV NSCLC patients. The promoter rs2280059 polymorphism was significantly associated with patient survival in both cohorts. In vitro and In vivo assays elucidated that rs2280059 G allele shows higher capability to drive HSPH1 promoter activities. Silencing HSPH1 significantly increases the antineoplastic effects of gefitinib on NSCLC cells. Our findings demonstrated potential implications of HSPH1 in clinic, which may lead to better understanding and outcome assessment of EGFR-TKI treatment.

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