scholarly journals Lung Adenocarcinoma Harboring EGFR T790M and In Trans C797S Responds to Combination Therapy of First- and Third-Generation EGFR TKIs and Shifts Allelic Configuration at Resistance

2017 ◽  
Vol 12 (11) ◽  
pp. 1723-1727 ◽  
Author(s):  
Zhen Wang ◽  
Jin-Ji Yang ◽  
Jie Huang ◽  
Jun-Yi Ye ◽  
Xu-Chao Zhang ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Lung Adenocarcinoma ◽  
Third Generation ◽  
Allelic Configuration ◽  
In Trans ◽  
And Shifts ◽  
Egfr T790m ◽  
Egfr Tkis

The concomitant EGFR T790M/C797S in trans and cis in three osimertinib-resistant lung adenocarcinoma patients.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e20105-e20105
Author(s):  
Chunling Liu ◽  
Jidong Li ◽  
Hailong Liu ◽  
Rong Du ◽  
Nan Fang ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Lung Adenocarcinoma ◽  
Poor Prognosis ◽  
Third Generation ◽  
Gene Test ◽  
In Trans ◽  
Vegfr Inhibitor ◽  
In Cis ◽  
Egfr Tki ◽  
Egfr T790m

e20105 Background: EGFR C797S mutation is an important cause of Osimertinib resistance. Previous studies showed that patients harboring EGFR C797S in trans with T790M are sensitive to a combination of first- and third-generation EGFR tyrosine kinase inhibitors (TKI). However, patients harboring EGFR C797S in cis with T790M are resistant to combination therapy or each single reagent. Methods: We performed next-generation sequencing on peripheral blood samples from patients with advanced lung adenocarcinoma who had been undergoing targeted therapy. Total DNA was extracted from formalin-fixed, paraffin-embedded tissue sections and quantified. Targeted regions of 14 lung cancer-associated genes were amplified by PCR, barcoded and sequenced using an Illumina MiSeq 500 platform. Results: Among 6489 Lung adenocarcinoma patients sample, we identified concomitant trans and cis EGFR T790M/C797S in three patients with very poor prognosis. All three patients were sensitive to the first-generation EGFR TKI, and took Osimertinib when disease progressed. When resistant to Osimertinib, the patients went to genetic testing to find new target therapy. Patient No. 1 was a 66-year-old man with mutations of EGFR exon 19del (25.08%), EGFR T790M (10.08%) / C797S (5.37%) in trans and in cis, TP53 exon8 mutation (12.35%). This patient died 20 days after the genetic testing without any further treatment. Patient No. 2 was a 53-year-old woman who carried gene mutations including EGFR exon 19del (0.51%), EGFR T790M (0.57%) and C797S (0.47%) in trans and in cis. She was treated with the combination of first- and third-generation EGFR TKI, and disease progressed after 50 days. She died half months after the gene test. Patient No. 3 was a 63-year-old woman whose gene mutation included EGFR L858R (77.49%), EGFR T790M (40.94%) and EGFR C797S (5.46%) in trans and in cis, also combined with EGFR amplification. Treatment with vascular endothelial growth factor receptor (VEGFR) inhibitor Anlotinib was attempted, but the patient died within one month after the gene test. Conclusions: We firstly reported three cases with concomitant EGFR T790M/C797S in trans and EGFR T790M/C797S in cis mutation in the word. Physicians tried either the EGFR TKI inhibitor combination therapy or VEGFR inhibitor, but neither of them had an effect on these patients. All three patients had very poor prognosis and died within two months of the gene test, indicating that the concomitant of the cis and trans mutation could be a very important prognostic prediction factor.

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.

Occurrence of HER2 amplification in EGFR-mutant lung adenocarcinoma with acquired resistence to EGFR-TKIs.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8047-8047 ◽  
Author(s):  
Giuseppe Altavilla ◽  
Carmela Arrigo ◽  
Chiara Tomasello ◽  
Mariacarmela Santarpia ◽  
Patrizia Mondello ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Acquired Resistance ◽  
Resistance Mutation ◽  
Egfr Mutations ◽  
Rapid Progression ◽  
Her2 Amplification ◽  
Egfr Inhibition ◽  
Egfr Mutant ◽  
Egfr T790m ◽  
Egfr Tkis

8047 Background: Patients with EGFR-mutant lung adenocarcinoma develop progression of disease on TKIs therapy after a median of 12 months;this acquired resistance is mainly due to a secondary mutation in EGFR (T790 M) in about 50% of patients, amplification of MET in 15%, PIK3CA mutations in 5%, an unknown mechanism in almost 30% and a SCLC transformation in some pts. Recently, Takezawa and colleagues pointed out that HER2 amplification is a mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers without EGFR T790M mutation. To aid in identification and treatment of these patients we examined a cohort of patients whose cancers were assessed with tumor biopsies at multiple times before and after their treatment with TKIs. Methods: 41 lung adenocarcinomas pts. (20 male, 21 female, median age 55 years) with EGFR mutations at 19 or 21 exons received TKIs as first line of treatment. 31 pts. (75%) showed a clinical response and relapsed after a mTTP of 12 months. At the time of relapse a new biopsy was performed, histologic samples were reviewed to re-confirm the diagnosis, EGFR, MET and HER-2 amplification were identified by FISH, while EGFR mutations have been tested by DNA sequencing. Results: At the time that drug resistence was acquired all 31 pts. retained their original activating EGFR mutations, 16 pts. developed EGFR T790M resistance mutation with pronunced EGFR amplification in 5, 4 pts. developed MET amplification, 3 pts. were found to have a diagnosis of small cell lung cancer. HER2 amplification was observed in four pts. (13%), with dramatic progression and a median OS of 5 months after treatment with CDDP + pemetrexed. Notably all 4 cases were EGFR T790M negative. Conclusions: Among pts. with acquired resistence to EGFR TKIs the presence of HER2 amplification defines a clinical subset with a more adverse prognosis and rapid progression. Interestingly, recent data suggest that afatinib combined with cetuximab could have promising activity in pts. with acquired resistance due to HER2 amplification.

scholarly journals Molecular mechanisms of acquired resistance to third-generation EGFR-TKIs in EGFR T790M-mutant lung cancer

2018 ◽  
Vol 29 ◽  
pp. i28-i37 ◽  
Author(s):  
C. Ricordel ◽  
L. Friboulet ◽  
F. Facchinetti ◽  
J -C Soria
Keyword(s):  
Lung Cancer ◽  
Molecular Mechanisms ◽  
Acquired Resistance ◽  
Third Generation ◽  
Egfr T790m ◽  
Egfr Tkis

Drug Combinatorial Therapies for the Treatment of KRAS Mutated Lung Cancers

2019 ◽  
Vol 19 (23) ◽  
pp. 2128-2142 ◽  
Author(s):  
Hao He ◽  
Chang Xu ◽  
Zhao Cheng ◽  
Xiaoying Qian ◽  
Lei Zheng
Keyword(s):  
Lung Cancer ◽  
Adjuvant Therapy ◽  
Combination Therapy ◽  
Clinical Benefit ◽  
Poor Prognosis ◽  
Egfr Mutations ◽  
Kras Mutations ◽  
Lung Cancers ◽  
Egfr Tki ◽  
Egfr Tkis

: KRAS is the most common oncogene to be mutated in lung cancer, and therapeutics directly targeting KRAS have proven to be challenging. The mutations of KRAS are associated with poor prognosis, and resistance to both adjuvant therapy and targeted EGFR TKI. EGFR TKIs provide significant clinical benefit for patients whose tumors bear EGFR mutations. However, tumors with KRAS mutations rarely respond to the EGFR TKI therapy. Thus, combination therapy is essential for the treatment of lung cancers with KRAS mutations. EGFR TKI combined with inhibitors of MAPKs, PI3K/mTOR, HDAC, Wee1, PARP, CDK and Hsp90, even miRNAs and immunotherapy, were reviewed. Although the effects of the combination vary, the combined therapeutics are one of the best options at present to treat KRAS mutant lung cancer.

Sign in / Sign up

Export Citation Format

Share Document