Lung Cancer Support Group

Addressing Tarceva Resistance in EGFR Positive Patients

Tarceva has an impressive 60% response rate for EGFR positive patients. They are principally non-smokers and light former smokers with adenocarcinoma or subtypes like BAC. While this response rate is impressive, Tarceva administration frequently generates a secondary mutation at T790M causing the drug to become ineffective. The new mutation appears to develop in response to Tarceva in this chess game where the tumor acts to preserve itself as doctors try to eradicate it. One study found 48% of Tarceva-resistant tumors with the T790 mutation, and no pre-treated tumors with it. Chen, Clinicopathologic and Molecular Features of Epidermal Growth Factor Receptor T790M Mutation and c-MET Amplification in Tyrosine Kinase Inhibitor-resistant Chinese Non-small Cell Lung Cancer. Pathol Oncol Res. 2009 Apr 21.

Various drugs are being tested to overcome Tarceva resistance.

Tykerb and Erbitux

A recent study found a combination of Lapatinib (Tukerb) and Cetuximab (Erbitux) showed promise in fighting T790M in cell studies.

“Combined lapatinib and cetuximab treatment resulted in significantly enhanced cytotoxicity against gefitinib-resistant T790M cells in vitro and in vivo. Taken together, these data suggest that treatment with a combination of lapatinib and cetuximab, which induces dimeric dissociation and EGFR down-regulation, appears to be an effective strategy for treatment of patients with EGFR TKI-resistant NSCLC.” Kim, Combined lapatinib and cetuximab enhance cytotoxicity against gefitinib-resistant lung cancer cells, Mol Cancer Ther. 2008 Mar;7(3):607-15.

The study is still preliminary, the drug combination has not demonstrated effectiveness with humans, and potential side effects remain an issue. One promising item is that the combination involves two FDA approved drugs, which a physician could prescribe off-label if he chose.

Vandetanib

Vandetanib, Zactima, or ZD 6174 is a combined VGFR and EGFR inhibitor. “Vandetanib retained significant efficacy in vivo against xenografts harboring the T790M mutation, providing a strong scientific rationale for investigating vandetanib in clinical settings where acquired resistance through emergence of EGFR T790M mutations limits the effectiveness of highly selective EGFR-TKIs. Ishihara, Effects of Vandetanib on Lung Adenocarcinoma Cells Harboring Epidermal Growth Factor Receptor T790M Mutation In vivo. Cancer Res 2009;69(12):5091-8.




Diagnosing T790M Mutation

The first step is comfirming the T790M mutation and at least one company has a commercial kit to confirm the mutation. www.DXSdiagnostics.com. Some major cancer hospitals test internally. Uhara, Simple polymerase chain reaction for the detection of mutations and deletions in the epidermal growth factor receptor gene, Clin Chim Acta. 2009 Mar;401(1-2):68-72. Epub 2008 Nov 24

New studies are looking at detecting T790M mutation through un-intrusive DNA testing.
“ EGFR T790M can be detected using plasma DNA from gefitinib- or erlotinib-resistant patients. This noninvasive method may aid in monitoring drug resistance and in directing the course of subsequent therapy.” Noninvasive detection of EGFR T790M in gefitinib or erlotinib resistant non-small cell lung cancer. Clin Cancer Res. 2009 Apr 15;15(8):2630-6. Epub 2009 Apr 7. See also Seequist, Toward Noninvasive Genomic Screening of Lung Cancer Patients, Journal of Clinical Oncology, Vol 27, No 16 (June 1), 2009: pp. 2589-2591

Note that other mutations may also play a role in Tarceva resistance. Bean, MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib, PNAS December 26, 2007 vol. 104

Causes

What causes the T790M impact. One theory is that “PTEN loss partially uncouples mutant EGFR from downstream signaling and activates EGFR, thereby contributing to erlotinib (Tarceva) resistance.” Sos, PTEN loss contributes to Erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR, Cancer Res. 2009 Apr 15;69(8):3256-61.

Conclusions

T790M appears to be a significant cause of resistance to Tarceva, and testing to confirm the mutation makes sense. Newer drugs show promise in addressing resistance. Precisely which drug is best is not known, but the cell studies are sufficiently promising that patients with T790M mutation may want to consider one. Which drug is best is unknown, but there are enough promising studies with different drugs, to believe that one will have an impact, translating cell studies to human ones.
Posted on 06/13/09, 12:06 pm