In:
Cancer Discovery, American Association for Cancer Research (AACR), Vol. 4, No. 9 ( 2014-09-01), p. 1036-1045
Kurzfassung:
EGFR-mutant lung cancers responsive to reversible EGFR inhibitors (gefitinib/erlotinib) develop acquired resistance, mediated by second-site EGFR T790M mutation in & gt;50% of cases. Preclinically, afatinib (irreversible ErbB family blocker) plus cetuximab (anti-EGFR monoclonal antibody) overcomes T790M-mediated resistance. This phase Ib study combining afatinib and cetuximab enrolled heavily pretreated patients with advanced EGFR-mutant lung cancer and acquired resistance to erlotinib/gefitinib. Patients provided post–acquired-resistance tumor samples for profiling EGFR mutations. Among 126 patients, objective response rate (overall 29%) was comparable in T790M-positive and T790M-negative tumors (32% vs. 25%; P = 0.341). Median progression-free survival was 4.7 months (95% confidence interval, 4.3–6.4), and the median duration of confirmed objective response was 5.7 months (range, 1.8–24.4). Therapy-related grade 3/4 adverse events occurred in 44%/2% of patients. Afatinib–cetuximab demonstrated robust clinical activity and a manageable safety profile in EGFR-mutant lung cancers with acquired resistance to gefitinib or erlotinib, both with and without T790M mutations, warranting further investigation. Significance: This article reports the results of a trial combining afatinib and cetuximab in patients with acquired resistance and details the first clinical proof-of-concept for the preclinical hypothesis that a significant proportion of tumors in patients with acquired resistance to gefitinib/erlotinib remain dependent on EGFR signaling for survival. Cancer Discov; 4(9); 1036–45. ©2014 AACR. See related commentary by Gibbons and Byers, p. 991 This article is highlighted in the In This Issue feature, p. 973
Materialart:
Online-Ressource
ISSN:
2159-8274
,
2159-8290
DOI:
10.1158/2159-8290.CD-14-0326
Sprache:
Englisch
Verlag:
American Association for Cancer Research (AACR)
Publikationsdatum:
2014
ZDB Id:
2607892-2
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