EGFR T790M is a point mutation in the EGFR gene that is associated with resistance to epidermal growth factor receptor (EGFR) kinase inhibitors like erlotinib and gefitinib. Since its initial discovery in 2005, the T790M mutation has been the subject of much research aiming to better understand drug resistance in non-small cell lung cancer (NSCLC). However, the role of T790M as a biomarker for the clinical care of lung cancer patients over the same time period has been less clear. With striking new data presented at the 2014 Annual Meeting of the American Society for Clinical Oncology (ASCO), EGFR T790M has now gained a clear position as a key clinical biomarker in lung cancer care.

It must be noted that the T790M resistance mutation can be seen in two different clinical circumstances – after treatment with an EGFR kinase inhibitor, or at initial diagnosis of cancer. The mutation has a different incidence and meaning in these two circumstances, therefore each deserves to be considered and discussed separately.

Acquired EGFR T790M

The most common setting where the T790M mutation is seen is in patients with NSCLC carrying a drug-sensitive EGFR mutation (e.g. exon 19 deletion or L858R) that have developed resistance after treatment with an EGFR kinase inhibitor. When such patients undergo a re-biopsy after development of resistance, testing of the tumor invariably demonstrates presence of the known drug-sensitive mutation, and approximately half the time shows the acquisition of a new T790M mutation. The likelihood of detecting T790M is somewhere in the range of 50% to 60% – it is usually present in a subset of the tumor cells, therefore more sensitive testing methods can definitely increase the chance of detecting the mutation.

At ASCO this year, exciting new data was presented regarding a new class of drugs that target T790M-mediated drug resistance. These new drugs, initially discovered at my institution (Dana-Farber Cancer Institute) in 2010, are called mutant-selective irreversible EGFR kinase inhibitors because they inhibit mutant EGFR (which is driving tumor growth) without inhibiting wildtype EGFR (which is present in healthy cells). This is intended to allow high therapeutic dosing without the toxicities of most EGFR inhibitors - rash and diarrhea. In the laboratory, such drugs are more much potent than other EGFR inhibitors against cells with the T790M mutation.

Efficacy data from phase I trials of three of these drugs were presented at ASCO 2014: AZD9291, CO-1686, and HM61713. Each drug reported dramatic tumor responses in patients with NSCLC and acquired resistance to standard EGFR kinase inhibitors, and patients generally did not complains of the rash and diarrhea seen with standard EGFR inhibitors. But is it clear that T790M is a biomarker for these drugs, or do all patients have a chance of responding? The results from the AZD9291 trial answered this question most clearly, studying 155 patients with central testing for T790M – 65% of T790M-positive tumors responded while 22% of T790M-negative tumors responded. Furthermore, a portion of the T790M-negative patients had not been on an EGFR inhibitor immediately prior to receiving AZD9291 – in those that had just received an EGFR inhibitor the response rate was 11%, while it was 36% in those that had just been on some other treatment.

Which patients are likely to have T790M-mediated drug resistance? It is hard to predict without a biopsy. It has been suggested that T790M is associated with more indolent growth characteristics and an overall favorable prognosis when compared to T790M-negative drug resistance therefore we tend to see it more commonly in slowly progressing lung nodules. However, even patients exhibiting aggressive symptomatic progression on an EGFR inhibitor can be positive for T790M. At present, the only way to determine whether T790M is present is to perform a new biopsy of the tumor, and to have this specimen submitted for repeat EGFR genotyping. In the future, we are optimistic that blood tests will be available (many are in development) that will allow noninvasive determination of which patients have T790M-mediated resistance.

Pre-treatment or “baseline” EGFR T790M

Rarely, the EGFR T790M mutation can be detected in a tumor at initial diagnosis of NSCLC, prior to treatment with an EGFR kinase inhibitor, and it is most commonly identified in addition to a second drug-sensitive EGFR mutation. The prevalence of baseline T790M is debated, but using conventional testing methods it is generally though to occur in 1-2% of all lung cancers carrying an EGFR mutation. Some labs, using highly sensitive assays, can find T790M in a larger proportion of tumors; however, recent research has suggested that such assays are vulnerable to false positive results, so it is unclear whether these findings have clinical meaning. In patients with baseline T790M detected using a standard genotyping assay, treatment with EGFR kinase inhibitors has a poor outcome – these tumors rarely respond, so standard treatment is cytotoxic chemotherapy. There is hope that the mutant-selective irreversible EGFR-kinase inhibitors described above will have activity against the rare tumors with baseline T790M, but no such data has yet been reported.

Importantly, identification of baseline T790M on routine genotyping also may indicate a risk for an even more rare condition – presence of an inherited germline EGFR T790M mutation. Germline EGFR mutations have been reported in a handful of families in the literature and have generally been associated with inherited lung cancer risk independent of smoking exposure. However, germline EGFR testing is not widely available and the risk of lung cancer in healthy individuals carrying such an inherited mutation is not well understood. To better understand this condition, my institution has teamed up with the Addario Lung Cancer Medical Institute (ALCMI) to open a multi-centered prospective trial of germline EGFR testing in lung cancer patients with baseline T790M, titled INHERIT: Investigating Hereditary Risk from T790M. Individuals can present to the study website for more information: www.dana-farber.org/T790Mstudy/. Those interested in participating can consent by phone and, if eligible for the study, get free genetic counseling by phone and free genetic testing through the mail. Patients found to be positive for an inherited mutation can then invite relatives to be tested. Through this prospective study, we hope to describe a large number of families in an unbiased fashion.

Conclusion

The clinical development of new EGFR kinase inhibitors with unique activity against T790M-mediated acquired resistance has clarified the role of the EGFR T790M mutation as a biomarker in lung cancer care. For NSCLC patients that have developed resistance to EGFR kinase inhibitors, genotyping for EGFR T790M (which currently requires a repeat tumor biopsy) can be used to help determine whether a patient has a high chance of responding to this new class of EGFR inhibitors. For the rare NSCLC patients with baseline EGFR T790M at initial diagnosis, treatment with a standard EGFR kinase inhibitor is not recommended, and germline EGFR testing should be considered, preferably on a clinical trial.