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T790M EGFR mutation: consider continuation of EGFR inhibition and clinical trials

You indicated that your patient's cancer has an EGFR-T790M mutation .

The T790M aberration is primarily associated with resistance to treatment with the first generation EGFR tyrosine kinase inhibitors (TKI) Tarceva (erlotinib) or Iressa (gefitinib) (Kosaka, et al. 2006). However the aberration has also been observed in some TKI-naive non-small cell lung cancers (NSCLC). In both cases, the T790M mutation is associated with significantly reduced response to first generation EGFR TKI therapy (Su KY, et al. 2012).

Consider clinical trials

Several treatment modalities for addressing EGFR TKI resistance are currently being explored in clinical trials. These include 1) addition of a second targeted therapy drug to Tarceva - such as a MET inhibitor in the case of MET amplification, or another targeted drug that blocks another pathway potentially conferring resistance, 2) second generation tyrosine kinase inhibitors such as Gilotrif (afatinib), and 3) Hsp90 inhibitors (Nanjo S, et al. 2013, Gainor JF and Shaw AT, 2014, Gadgeel SM and Wozniak A, 2013, Xu L, et al. 2012). Your patient could consider one of the clinical trials listed below.

Several classes of drugs have shown broad efficacy in NSCLC patients and may be additional treatment options to consider for the patient:

Immunotherapy has recently made significant progress in patients with NSCLC. In particular, strategies targeting the PD-1/PD-L1 axis (PD-1 is an inhibitory receptor expressed by T cells) have shown promising results in lung cancer patients (Forde PM, et al. 2013). Several clinical studies have reported durable tumor regression and prolonged stabilization of disease in patients with NSCLC treated with PD-L1 antibodies such as BMS-936559, or PD1 antibodies such as nivolumab. Tumor expression of PD-L1 was correlated with objective response (Brahmer JR, et al. 2012, Vamsidhar V, et al. 2013, Topalian SL, et al. 2012). PD1/PD-L1 inhibitors are investigational and can be accessed through clinical trials.

The approved MEK inhibitor Mekinist (trametinib) demonstrated tolerability and clinical activity in advanced NSCLC when given in combination with docetaxel (Gandara DR, et al.2013). Other MEK inhibitor combinations are being tested in clinical trials.

Drugs to consider:

Gilotrif: Gilotrif (afatinib) is a second generation EGFR inhibitor recently approved by the FDA. A large phase III clinical trial demonstrated that Gilotrif significantly increases the period of progression-free survival in comparison to the standard chemotherapy combination (pemetrexed/cisplatin) in patients with EGFR mutation-positive NSCLC (Sequist LV, et al. 2013).

dacomitinib: Dacomitinib is also a second generation EGFR inhibitor that is in clinical testing. Preliminary data suggests that dacomitinib has demonstrated 'encouraging efficacy' as first-line treatment in NSCLC patients as measured by progression-free survival (PFS) rates. Patients with EGFR mutation-positive NSCLC experienced tumor shrinkage (Mok, et al. 2011). In another study, dacomitinib demonstrated significantly improved PFS in comparison to Tarceva (erlotinib) in EGFR mutation-positive NSCLC patients (Ramalingam SS, et al. 2012). Preclinical data indicate that dacomitinib can achieve responses in tumors harboring T790M (Brzezniak C, et al. 2013).

See 'Drugs' tab below to learn about additional drugs to consider.


Clinical Trials

Details of your patient's condition will determine eligibility for any specific trial. We encourage shared decision-making between patients and physicians.
The selected criteria return 100 trials.

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Potentially Relevant Drugs

Drug Other names Drug Target Manufacturer Status
The information above is selected based upon the information you provided and the guidance of our editorial board. It is not necessarily comprehensive and may not reflect information that is not publicly available. The specifics of your patient's situation may suggest options not included here, or may exclude some options that we have shown.