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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 due to the EGFR T790M mutation are currently being explored in clinical trials. These include:

1) Next generation tyrosine kinase inhibitors including EGFR T790M inhibitors that specifically target the EGFR T790M mutant protein (Rolfo C, et al. 2014). Recent data from phase I clinical studies have demonstrated that next generation EGFR TKIs including CO-1686 and AZD9291 have demonstrated promising efficacy and good safety profiles in patients with EGFR T790M-positive NSCLC (Sequist LV, et al. 2014, Janne PA, et al. 2014, Kim D, et al 2014).

2) Addition of a second targeted therapy drug that blocks another pathway (e.g. AKT/PI3K or MET) potentially conferring resistance (Lin C, et al. 2014, Reckamp KL, et al. 2014, Gainor JF and Shaw AT, 2014, Nanjo S, et al. 2013, Gadgeel SM and Wozniak A, 2013).

3) Hsp90 inhibitors (Hong YS, et al. 2014, Shimamura T, et al. 2014, Ono N, et al. 2013, Xu L, et al. 2012).

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).

The PD-1 antibody nivolumab has demonstrated clinical activity, a manageable safety profile, and an encouraging survival profile across NSCLC patient subgroups. Early data indicate that tumor PD-L1 expression correlates with objective response. Trials evaluating PD-L1 as a potential predictor of clinical outcomes are ongoing (Brahmer JR, et al. 2014, Gettinger SN, et al. 2014, Vamsidhar V, et al. 2013, Topalian SL, et al. 2012). Additionally, preliminary data from phase I studies have indicated that a combination of the approved CTLA-4 inhibitor Yervoy (ipilimumab) plus nivolumab has a tolerable safety profile and anti-tumor activity in patients with both PD-L1-positive and negative NSCLC (Antonia SJ, et al. 2014). The PD-1 antibody pembrolizumab and the PD-L1 antibody BMS-936559 have also demonstrated efficacy in patients with PD-L1-positive advanced or metastatic NSCLC (Rizvi NA, et al. 2014, Garon EB, et al. 2014, Brahmer JR, et al. 2012).

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 (afatinib): Gilotrif is an approved second generation EGFR inhibitor that significantly increases overall survival and progression-free survival in comparison to standard chemotherapy (pemetrexed/cisplatin) in patients with EGFR mutation-positive advanced NSCLC (Yang JC, et al. 2014, Sequist LV, et al. 2013).

See the 'Drugs' tab 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 106 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.