Management of NSCLC Disease Progression After First-Line EGFR Tyrosine Kinase Inhibitors: What Are the Issues and Potential Therapies?

Drugs ◽  
2016 ◽  
Vol 76 (8) ◽  
pp. 831-840 ◽  
Author(s):  
Raffaele Califano ◽  
Ourania Romanidou ◽  
Giannis Mountzios ◽  
Lorenza Landi ◽  
Federico Cappuzzo ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Disease Progression ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
First Line ◽  
Egfr Tyrosine Kinase ◽  
Egfr Tyrosine Kinase Inhibitors

Prospective study for usefulness of circulating-free DNA on prediction of third generation EGFR tyrosine kinase inhibitors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21510-e21510
Author(s):  
Hironori Yoshida ◽  
Chiho Nakashima ◽  
Naohisa Matsumoto ◽  
Kentaro Iwanaga ◽  
Noriyuki Ebi ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Disease Progression ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Egfr Mutations ◽  
Plasma Samples ◽  
Egfr Tyrosine Kinase ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Nsclc Patients ◽  
Egfr T790m

e21510 Background: Most non-small lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations develop resistance when exposed to EGFR-tyrosine kinase inhibitors (TKIs). T790M develops in about half of patients treated with TKI and can be detected by tumor tissue and cfDNA hotspot tests. However, co-occurring mutations at other loci may impact efficacy. We conducted a prospective, multi-center, observational study to assess the detection rates and predictive values of plasma-based EGFR T790M detection methods for Japanese NSCLC patients treated with osimertinib. Methods: NSCLC patients with tumor EGFR mutations and disease progression after treatment with 1st- or 2nd-generation EGFR-TKI were enrolled. Plasma was collected at the time of clinical disease progression, before osimertinib treatment. The collected plasma was tested for EGFR T90M by in-house plasma MBP-QP and ddPCR assays and compared to clinically tested cobas (Roche) results (including tissue, plasma). The primary endpoint was to demonstrate comparability of our MBP-QP system to cobas using plasma-based EGFR T790M detection to predict the therapeuitic effect of osimertinib via objective response rate (ORR) and disease control rate (DCR). As an exploratory analysis, we used Guardant360 to retrospectively test available banked plasma samples collected describe time points. Results: From Feb 2017 to Jan 2019, 145 patients enrolled. T790M was detected by cobas in 57 cases (44 tissue, 16 plasma, 3 both). ORR and DCR in plasma cobas-positive cases were 62.5% and 81.3%, respectively. MBP-QP found T790M in 9 patients with ORR and DCR 66.7% and 77.8%. ddPCR found 17 cases with ORR and DCR 70.6% and 82.4%. ORR was not correlated to AF. In plasma samples from 54 patients, Guardant360 detected T790M in 57%. Co-occurring alterations such as amplification or minor mutations in EGFR or other genes such as TP53 did not impact ORR, but in the group with poor response to osimertinib, the number of detected gene alterations tended to be large. Two patients with small cell carcinoma transformation had RB1 mutations and MYC amplification. Conclusions: Regardless of the test system, the detection of T790M could predict a good therapeutic effect of osimertinib, but there was no difference in response to osimertinib depending on EGFR T790M AF. Compared to single-gene assessment of EGFR, NGS of cfDNA may be useful for guiding treatment decisions for patients with TKI-resistant NSCLC. Clinical trial information: UMIN000025930.

First experience with osimertinib in patients with T790M mutation previously treated with EGFR – TKIs in Croatia.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20518-e20518
Author(s):  
Marko Jakopovic ◽  
Lela Bitar ◽  
Branka Cucevic ◽  
Sanja Plestina ◽  
Ivica Mazuranic ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Disease Progression ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
T790m Mutation ◽  
Egfr Tyrosine Kinase ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Previously Treated ◽  
Line Setting ◽  
Egfr T790m

e20518 Background: EGFR T790M mutation is responsible for around 60% cases of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in patients who have lung cancer with an activating EGFR mutation. Methods: We administered osimertinib 80 mg once daily in 8 patients with advanced lung cancer who had radiologically documented disease progression after previous treatment with first and second-line EGFR tyrosine kinase inhibitors. Results: We treated 8 patients with osimertinib with stage IV lung adenocarcinoma. Four patients were males and four were females, median age 62 (raging from 54 to 82). Four patients were never smoker, and four were ex-smokers. All patients had initially deletion 19 in EGFR gene and then developed T790M mutation. In all patients T790M was proven from tumor tissue. Majority of patients were ECOG 1. All patients were previously treated with first or second line EGFR TKIs (erlotinib, gefitinib or afatinib) and had radiologically documented disease progression. Three patients were treated with osimertinib in third line setting, 2 in fourth, one in fifth, one in sixth and one even in tenth line setting. Median time to response was 4 weeks (raging from 3 to 7). All 8 patients had partial response (PR) with still no recorded disease progression. Duration of response is from 7 to 46 weeks and still ongoing. No significant side effects were observed. Conclusions: Osimertinib is highly active in patients with lung adenocarcinoma which harbor EGFR T790M mutation who had had disease progression during prior therapy with EGFR tyrosine kinase inhibitors. There were no serious side effects of treatment.

scholarly journals Drug Tolerance to EGFR Tyrosine Kinase Inhibitors in Lung Cancers with EGFR Mutations

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1590
Author(s):  
Kenichi Suda ◽  
Tetsuya Mitsudomi
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Drug Tolerance ◽  
Lung Cancers ◽  
Egfr Tyrosine Kinase ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Egfr Mutated

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) serve as the standard of care for the first-line treatment of patients with lung cancers with EGFR-activating mutations. However, the acquisition of resistance to EGFR TKIs is almost inevitable, with extremely rare exceptions, and drug-tolerant cells (DTCs) that demonstrate reversible drug insensitivity and that survive the early phase of TKI exposure are hypothesized to be an important source of cancer cells that eventually acquire irreversible resistance. Numerous studies on the molecular mechanisms of drug tolerance of EGFR-mutated lung cancers employ lung cancer cell lines as models. Here, we reviewed these studies to generally describe the features, potential origins, and candidate molecular mechanisms of DTCs. The rapid development of an optimal treatment for EGFR-mutated lung cancer will require a better understanding of the underlying molecular mechanisms of the drug insensitivity of DTCs.

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