scholarly journals Rational Computational Design of Fourth-Generation EGFR Inhibitors to Combat Drug-Resistant Non-Small Cell Lung Cancer

2020 ◽  
Vol 21 (23) ◽  
pp. 9323
Author(s):  
Hwangseo Park ◽  
Hoi-Yun Jung ◽  
Kewon Kim ◽  
Myojeong Kim ◽  
Sungwoo Hong
Keyword(s):  
Lung Cancer ◽  
Hydrogen Bond ◽  
Free Energy ◽  
Small Cell ◽  
Egfr Inhibitors ◽  
Fourth Generation ◽  
Wild Type ◽  
Small Cell Lung ◽  
Triple Mutant ◽  
Exon 20

Although the inhibitors of singly mutated epidermal growth factor receptor (EGFR) kinase are effective for the treatment of non-small cell lung cancer (NSCLC), their clinical efficacy has been limited due to the emergence of various double and triple EGFR mutants with drug resistance. It has thus become urgent to identify potent and selective inhibitors of triple mutant EGFRs resistant to first-, second-, and third-generation EGFR inhibitors. Herein, we report the discovery of potent and highly selective inhibitors of EGFR exon 19 p.E746_A750del/EGFR exon 20 p.T790M/EGFR exon 20 p.C797S (d746-750/T790M/C797S) mutant, which were derived via two-track virtual screening and de novo design. This two-track approach was performed so as to maximize and minimize the inhibitory activity against the triple mutant and the wild type, respectively. Extensive chemical modifications of the initial hit compounds led to the identification of several low-nanomolar inhibitors of the d746-750/T790M/C797S mutant. Among them, two compounds exhibited more than 104-fold selectivity in the inhibition of EGFRd746-750/T790M/C797S over the wild type. The formations of a hydrogen bond with the mutated residue Ser797 and the van der Waals contact with the mutated residue Met790 were found to be a common feature in the interactions between EGFRd746-750/T790M/C797S and the fourth-generation inhibitors. Such an exceptionally high selectivity could also be attributed to the formation of the hydrophobic contact with a Gly loop residue or the hydrogen bond with Asp855 in the activation loop. The discovery of the potent and selective EGFRd746-750/T790M/C797S inhibitors were actually made possible by virtue of the modified protein–ligand binding free energy function involving a new hydration free energy term with enhanced accuracy. The fourth-generation EGFR inhibitors found in this work are anticipated to serve as a new starting point for the discovery of anti-NSCLC medicines to overcome the problematic drug resistance.

EGFR Exon 20 insertion: Prognostic and predictive values in advanced non-small cell lung cancer, a real-world study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9062-9062
Author(s):  
Christos Chouaid ◽  
Thomas Filleron ◽  
Didier Debieuvre ◽  
Maurice Perol ◽  
Nicolas Girard ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Real World ◽  
Small Cell ◽  
Egfr Mutations ◽  
Wild Type ◽  
Small Cell Lung ◽  
First Line ◽  
Exon 20

9062 Background: In Europe, 10-15% of non-squamous non-small cell lung cancer (nsqNSCLC) have EGFR mutations of which 5-12% are an Exon 20 insertion (20ins). Methods: Analysis of Epidemio-Strategy and Medical Economics (ESME) Advanced and Metastatic Lung cancer (AMLC) Data Platform (NCT03848052), a multicenter real-life database using a supervised, retrospective data collection process. The database includes 13737 advanced nsqNSCLC treated from January 2015 at participating centres. The cut-off date for patient follow-up for this analysis was June 30, 2020. The aim of the study was to assess real-world patient characteristics, treatment patterns and clinical outcomes of advanced nsqNSCLC EGFR 20ins. Overall survival (OS) of EGFR cohorts (20ins, 19del/L858R without 20ins, other EGFR mutations) and EGFR wild-type/not tested cohort were assessed. Results: 1549 (11.3%) nsqNSCLC had an EGFR mutation, 61 (3.9%) of whom being an EGFR 20ins. These 61 patients (pts) are mainly female (68.9%), non-smoker (55.7%), with de novo stage IIIB/IV disease (78.6%), PS 0-1 (76.9%). Median age was 68.0 years (q1-q3: 54-74). PD-L1 status was assessed in 34 (55.7%) pts, mainly (n = 20) before first line and 22 (64.7%) had negative result. Most (63.9%) pts had EGFR 20ins positive result available before first line. Almost all pts (95.1%, n = 58) received a systemic therapy with a median number of 3 (q1-q3: 1-4) lines. In first line setting, 74% of the pts received chemotherapy (mainly chemotherapy combination), 13.7% received EGFR TKI (mainly as monotherapy) and 8.6% received immunotherapy only. Median treatment duration for pts treated with CarboPem (n = 19), CisplatinPem (n = 16) and CarboTaxol (n = 6) were 4.7 (q1-q3: 2.6-6.6), 7.4 (q1-q3: 5.0-12.8) and 3.3 (q1-q3: 2.8-3.8) months, respectively. For afatinib (n = 3), erlotinib (n = 2) and gefitinib (n = 1), median treatment durations were 1.6 (q1-q3: 0.5-2.8); 1.8 (q1-q3: 1.4-2.1) and 2.3 months, respectively. After a median follow up of 36.3 (95%CI: 34.1-39.8) months, median OS was 24.3 (95%CI: 19.1-32.6) months; 1 and 2-years OS rates were 82.5% (95%CI: 69.7-90.2) and 52.6% (95%CI: 37.3-65.9), respectively. For pts with 19del/L858R without 20ins (n = 1049) and those with other EGFR mutations (n = 439) median OS were 35.4 (95%CI: 32.6-37.5) and 41.7 (95%CI: 31.9-53.5), respectively compared to 20.7 (95%CI: 20.0-21.8] months for pts EGFR wild type/not tested (n = 12188). Conclusions: This large, national real-world analysis based on medical chart data’s confirm that EGFR 20ins is a rare disease (0.4% of advanced nsqNSCLC). Currently available EGFR TKIs appear to have low efficacy and response to chemotherapy seems identical to that of EGFR wild-type/not tested pts. Prognosis for NSCLC pts with EGFR 20ins mutations was in line with that of EGFR wild type/not tested but worse than common EGFR mutations highlighting the need for advancements for this rare population.

A Case of EGFR-wild-type Adenocarcinoma of Recurrent Non-small Cell Lung Cancer Responding to Erlotinib

Haigan ◽  
2012 ◽  
Vol 52 (3) ◽  
pp. 315-319
Author(s):  
Masami Morimoto ◽  
Naoki Hino ◽  
Hisashi Matsuoka ◽  
Takanori Miyoshi ◽  
Masaru Tsuyuguchi
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Wild Type ◽  
Small Cell Lung

Treatment in EGFR-mutated Non-small Cell Lung Cancer: How to Block the Receptor and overcome Resistance Mechanisms

2017 ◽  
Vol 103 (4) ◽  
pp. 325-337 ◽  
Author(s):  
Claudia Proto ◽  
Giuseppe Lo Russo ◽  
Giulia Corrao ◽  
Monica Ganzinelli ◽  
Francesco Facchinetti ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Growth Factor Receptor ◽  
Resistance Mechanisms ◽  
Small Cell ◽  
Third Generation ◽  
Small Cell Lung ◽  
Epidermal Growth ◽  
Exon 20 ◽  
Egfr Mutated ◽  
Egfr Tkis

In non-small cell lung cancer (NSCLC), the identification of epidermal growth factor receptor (EGFR) mutations and the parallel development of EGFR tyrosine kinase inhibitors (TKIs) have radically changed the therapeutic management strategies. Currently, erlotinib, gefitinib, and afatinib are all approved as standard first-line treatment in EGFR-mutated NSCLC. However, despite the proven efficacy, some EGFR-mutated NSCLCs do not respond to EGFR TKIs, while some patients, after a favorable and prolonged response to EGFR TKIs, inevitably progress within about 10-14 months. Epidermal growth factor receptor-dependent mechanisms, activation of alternative pathways, or phenotypic transformation can cause the resistance to EGFR TKIs. The exon 20 p.Thr790Met point mutation (T790M) is responsible for about 60% of cases of resistance when progression occurs. A third-generation TKI, osimertinib, improved outcome in patients harboring T790M after first- and second-generation TKI treatment. However, resistance develops even after treatment with third-generation drugs. To date, the Cys797Ser (C797S) mutation in exon 20 of EGFR is the most well-known resistance mutation after osimertinib. Fourth-generation TKIs are already under development. Nevertheless, additional information is needed to better understand and effectively overcome resistance. The aim of this review is to report recent advances and future perspectives in the treatment of EGFR-mutated NSCLC, highlighting the resistance mechanisms that underlie disease progression.

Successful treatment of pulmonary lymphangitic carcinomatosis by anlotinib in 14 Chinese patients with advanced non-small cell lung cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21064-e21064
Author(s):  
Shencun Fang ◽  
Wanwan Cheng ◽  
Yingming Zhang ◽  
Haitao Zhang ◽  
Si Li ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Lymphatic Metastasis ◽  
Small Cell ◽  
Smoking History ◽  
Wild Type ◽  
Small Cell Lung ◽  
The Impact ◽  
Lymphangitic Carcinomatosis

e21064 Background: Pulmonary lymphangitic carcinomatosis (PLC) occurs in 6%-8% of intrathoracic metastases among malignant tumor. The median survival was only 2.0 months from time of pulmonary symptoms to death in cases during 2000-2018, which is a poor prognosis. Effective interventions were needed besides standard chemotherapy and symptomatic support. Anlotinib showed a critical effect on lymphangiogenesis, and lymphatic metastasis in mouse models of lung adenocarcinoma, it might be a therapeutic option for tumor lymphatic metastasis. In this study, we retrospectively analyzed the efficacy and safety of anlotinib for PLC in patients with Non-small Cell Lung Cancer (NSCLC). Methods: We retrospectively investigated NSCLC patients with PLC at our hospital between May 2018 and November 2020, who received anlotinib monotherapy or combined therapy for PLC. Data were analyzed for progression-free survival (PFS), overall survival (OS), objective response rate(ORR), disease control rate(DCR) and adverse events (AE). The impact of clinical and genomic factors on PFS and OS were also assessed. Results: A total of 14 patients were enrolled with a median age of 64 years. 10(71.4%) were male, 4(28.6%) has smoking history, 10(71.4%) of patients had a performance status of 2-3. 9, 3, 2 patients had TP53 mutation, EGFR mutation, ALK fusion respectively. 9(64.3%) patients received anlotinib monotherapy. Of 14 patients, 8 achieved partial response (PR), 5 presented stable disease (SD), 1 had progressed disease. The ORR and DCR were 57.1% and 92.9% respectively. The median PFS was 3.1 months (95% CI: 2.0-4.2), the median OS for 1, 2, ≥3 line were 13 months, 7.2 months, 5.2 months, respectively. Median PFS and OS (≥3 line) were significantly longer for patients with TP53-mutant tumors compared with those with TP53–wild-type tumors (median PFS: 7 vs. 1.1 months, median OS (≥3 line): 6.8 vs. 1.9 months). No difference of PFS and OS (≥3 line) was found between EGFR or ALK alteration and the corresponding wild type patients. The most frequently reported AEs were high blood pressure (11, 78.6%), hand foot syndrome (6, 42.9%), diarrhea (5, 35.7%), fatigue (4, 28.6%), hoarseness (3, 21.4%), proteinuria (2, 14.3%) and stomatitis (2, 14.3%). Conclusions: Anlotinib presented favorable efficacy in patients with pulmonary lymphangitic carcinomatosis and conferred considerable survival benefit compared with previous studies, especially in patients harboring TP53 mutations. The AEs were manageable. These indicated that anlotinib can be a promising therapeutic treatment of PLC. More clinical data is needed to validate this finding.

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