ASCO Annual Meeting 2006

Authors: W. Pao, M. N. Balak, G. J. Riely, A. R. Li, M. F. Zakowski, M. Ladanyi, V. A. Miller

Abstract No: 7078

Citation: Journal of Clinical Oncology, 2006

ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 7078

Abstract

Background: We previously reported that in 2 of 5 non-small cell lung cancer (NSCLC) patients with acquired resistance to the tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, tumors biopsied after disease progression contained a second site mutation (T790M) in the epidermal growth factor receptor (EGFR) kinase domain, in addition to a primary drug-sensitive mutation (exon 19 deletion (del) or exon 21 point mutation (L858R)) (Pao et al, PLoS Med '05). No patients had KRAS mutations, which are associated with primary resistance to these TKIs. We sought to determine the frequency of second site EGFR kinase domain and KRAS mutations in tumors from patients with acquired resistance to TKIs, administered either as monotherapy or with chemotherapy.

Methods: 18 patients with NSCLC who responded to either TKI alone (n = 14) or TKI plus chemotherapy (n = 4) and then progressed were re-biopsied. Genomic DNA samples from tumors were examined for EGFR (exons 18 -24) and KRAS (exon 2) mutations. Results: Sequence analysis was successfully performed on tumors from 17 patients. The T790M EGFR mutation was detected in 6 of 13 (46%, 95% CI 19-75%) on TKI monotherapy, and in 0 of 4 (0%, 95% CI 0-53%) on TKI plus chemotherapy. In one autopsy case, the T790M mutation was detected in 5 of 5 sites, which all harbored the same exon 19 del. No other EGFR or KRAS mutations were detected.

Conclusions: Secondary EGFR T790M but not KRAS mutations are commonly associated with acquired resistance to TKI monotherapy. More patients are being studied, and we are trying to elucidate determinants of acquired resistance in the absence of T790M mutations. New therapies are needed to treat and/or suppress the development of acquired resistance to gefitinib or erlotinib. Support: Joan's Legacy, DDCF, K08-CA097980, R21-CA115051.