Acquired resistance to epidermal growth factor receptor (EGFR) kinase inhibitors associated with a novel T854A mutation in a patient with EGFR-mutant lung adenocarcinoma

Bean, James; Riely, Gregory J.; Balak, Marissa N.; Marks, Jenifer L.; Ladanyi, M.; Miller, V. A.; Pao, William

doi:10.1200/jco.2008.26.15_suppl.8056

Cited by 62 publications

(84 citation statements)

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“…The secondary T790M mutation was reported to occur in 50% of patients with EGFR mutations after EGFR-TKI treatment [11,43,44]. In the present study, the secondary T790M mutation rate was 48.5%, which was consistent with the previously reported rate.…”

Section: Discussionsupporting

confidence: 82%

Survival of lung adenocarcinoma patients with malignant pleural effusion

Tsai

et al. 2012

Eur Respir J

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In the era of targeted therapy, the association between lung adenocarcinoma patient survival and malignant pleural effusions (MPEs) remains unclear. This study investigated the clinical characteristics, survival and epidermal growth factor receptor (EGFR) gene (EGFR) mutation status of lung adenocarcinoma patients with MPE.From June 2005 to December 2010, consecutive pleural effusions were collected prospectively. Patient clinical characteristics, EGFR mutation status, and overall survival were analysed.We collected MPEs from 448 patients in stage IV lung adenocarcinoma at initial diagnosis. Median overall survival for patients with MPEs at initial diagnosis and following disease progression were 14.3 months and 21.4 months, respectively (p50.001). There were 296 (66.1%) patients harbouring EGFR mutations, the mutation rates among patients with an MPE at initial diagnosis and one following disease progression were 68.2% and 56.6%, respectively (p50.044); the L858R mutation rate was also higher among the former (32.6% versus 18.1%; p50.009). Multivariate analysis revealed that patients who: developed MPEs following disease progression, harboured EGFR mutations, and received EGFR-tyrosine kinase inhibitor therapy, had longer overall survival. Patients in stage IV lung adenocarcinoma with MPEs at initial diagnosis have shorter overall survival and higher EGFR mutation rate, especially for L858R, than patients who develop MPEs following disease progression.

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Section: Discussionsupporting

confidence: 82%

Survival of lung adenocarcinoma patients with malignant pleural effusion

Tsai

et al. 2012

Eur Respir J

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“…The high frequency of EGFR T790M mutation in acquired resistance signified the critical role of continued signaling through EGFR in survival of EGFR-mutant lung cancer (31,32). Dual EGFR blockade using an EGFR TKI coupled with an antibody to EGFR has been explored as a promising approach for acquired resistance (13,14,19,20).…”

Section: Discussionmentioning

confidence: 99%

A Phase Ib/II Study of Afatinib in Combination with Nimotuzumab in Non–Small Cell Lung Cancer Patients with Acquired Resistance to Gefitinib or Erlotinib

Lee

Sun

Lim

et al. 2016

Clinical Cancer Research

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Purpose: In this phase Ib/II study, we aimed to assess the safety and efficacy of afatinib plus nimotuzumab (N) in advanced nonsmall cell lung cancer (NSCLC) patients with acquired resistance to gefitinib or erlotinib.Experimental Design: In phase Ib stage, patients received afatinib (40 mg or 30 mg once daily) plus nimotuzumab (100 mg or 200 mg once weekly) for 28-day cycles to determine the recommended phase II dose (RPIID). The safety and efficacy of RPIID dose was evaluated in phase II stage.Results: In total, 50 patients were enrolled (13 to phase Ib and 37 to phase II). In the first dose-finding cohort (afatinib 40 mg plus nimotuzumab 100 mg), one patient experienced dose-limiting toxicity (DLT) of grade 3 diarrhea and in the subsequent cohort (afatinib 40 mg plus nimotuzumab 200 mg), two DLTs (grade 3 diarrhea and grade 3 neutropenia) occurred in 2 of 6 patients. Accordingly, RPIID was determined as afatinib 40 mg plus nimotuzumab 100 mg. In 44 patients treated with RPIID, 7 (16%) patients had grade 3 toxicities; skin rash (7%), diarrhea (5%), acne (2%), and fatigue (2%). The overall response rate was 23% and the median duration of response was 4.3 months (range, 0.7-16.2 months). The median progression-free survival and overall survival were 4.0 months [95% confidence interval (CI), 2.3-5.7 months] and 11.7 months (95% CI, 9.4-14.0 months), respectively.Conclusions: Combination treatment of afatinib and nimotuzumab demonstrated an acceptable safety profile and encouraging antitumor activity in advanced NSCLC patients with acquired resistance to gefitinib or erlotinib. Larger phase III trial is warranted to confirm its efficacy and safety.

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“…24 Afatinib is not only active against EGFR mutations targeted by first generation TKIs like erlotinib or gefitinib, but also appears to have some preclinical activity against EGFR mutations not sensitive to these standard therapies, such as EGFR T790M and exon 20 insertions. 22 Accumulating evidence has demonstrated cross-talk between HER family members in the development of acquired resistance to EGFR-TKI therapy. 26,27 HER2 overexpression also can confer resistance to EGFR-TKIs in cell line models and the HER2 gene was found to be amplified in a significant fraction of both murine and human tumors with acquired resistance to erlotinib.…”

Section: Discussionmentioning

confidence: 99%

“…Afatinib is also a potent ERBB2 kinase inhibitor. 22 Because of afatinib's additional activity against HER2, it is actively investigated for breast cancer and for other EGFR and HER2 driven cancers. 18,[23][24][25] Afatinib monotherapy demonstrated clinical activity in ERBB2-positive breast cancer, including trastuzumab-resistant breast cancer.…”

Section: Discussionmentioning

confidence: 99%