BY Geoffrey R. Oxnard, MD
Assistant Professor of Medicine
Dana-Farber Cancer Institute
Harvard Medical School
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. Some of the most exciting results presented at this year’s American Society of Clinical Oncology Annual Meeting have to do with new inhibitors targeting the EGFR T790M mutation. Given that this appears to be an emerging biomarker in the treatment of lung cancer patients, it is worth reviewing the management of patients carrying this mutation. Importantly, it can be seen in several different clinical circumstances where it can mean different things.
Baseline EGFR T790M
The EGFR T790M mutation is rarely seen in a lung cancer at initial diagnosis, prior to treatment with an EGFR kinase inhibitor. The prevalence of baseline T790M is debated in the scientific literature, but using conventional testing methods it is generally though to occur in one to two percent of all EGFR-mutant lung cancers. When seen in this setting, it is most commonly identified in addition to a second drug-sensitive EGFR mutation. Despite that, lung cancers with baseline EGFR T790M are unlikely to respond to standard EGFR kinase inhibitors and should be treated in the first-line setting with standard chemotherapy. Interestingly, the presence of baseline T790M indicates a high likelihood of an underlying germline T790M mutation, discussed further below.
Acquired EGFR T790M
The more common setting where the T790M mutation is seen is as an acquired mutation in EGFR-mutant lung cancer after treatment with an EGFR kinase inhibitor. A repeat tumor biopsy in this setting can identify a new T790M mutation more than half the time. Previous data has suggested that T790M-mediated resistance can be associated with an indolent growth and a relatively favorable prognosis when compared with other types of resistance. Interestingly, there are some types of that resistance less likely to carry T790M – such as progression in the brain only, or recurrence after stopping adjuvant erlotinib – suggesting that these situations may not be fully resistant, and that further treatment with an EGFR kinase inhibitor might make sense.
While there was hope that irreversible EGFR kinase inhibitors like afatinib or dacomitinib might inhibit T790M, response rates to these drugs have been low in patients with resistance to erlotinib or gefitinib. A higher response rate of 30 percent was reported with afatinib plus the EGFR antibody cetuximab, though this activity was seen both in T790M positive and negative resistance.
At ASCO this year, data were presented regarding a new class of drugs called “mutant-selective irreversible EGFR kinase inhibitors” which target T790M-mediated drug resistance. These drugs potently inhibit mutant EGFR protein without inhibiting wildtype EGFR, aiming to induce responses while avoiding EGFR-related toxicities. Data from three trials of three different drugs in this class (AZD9291, CO-1686, and HM61713) were presented, and each drug reported dramatic tumor responses in patients with EGFR-mutant lung cancers after resistance to standard EGFR kinase inhibitors.
In the largest trial, studying AZD9291, a striking difference in activity was seen between tumors with T790M-mediated resistance (a 65% response rate) and those with T790M-negative resistance (a 22% response rate). Additional phase II data will be needed to better understand any differences in activity between these drugs, but T790M does appear to be an emerging biomarker suggesting drug sensitivity.
Clinical trials are ongoing around the world (NCT01802632; NCT01526928; NCT01588145) and are an attractive alternative to standard chemotherapy for these patients.
Germline EGFR T790M
The rarest setting where EGFR T790M can be seen is as a germline mutation where it has been found to be associated with familial lung cancer, particularly in non-smokers. However, the risk of lung cancer in healthy individuals carrying such an inherited mutation is not well understood. Given how rare this condition is – associated with less than 1 in 1000 lung cancers – germline testing is not widely available and is not part of standard practice. In my practice, I only test for germline EGFR T790M when a patient presents with baseline EGFR T790M, a setting where the prevalence of germline mutations is estimated at approximately 50 percent.
To better understand this condition, and to offer patients free genetic counseling and germline testing, my institution has teamed up with the Addario Lung Cancer Medical Institute (ALCMI) to open a prospective trial titled INHERIT: Investigating Hereditary Risk from T790M. Individuals can present to the study website for more information: www.dana-farber.org/T790Mstudy/. If a lung cancer patient harboring baseline T790M undergoes germline testing and is found to be positive for an inherited mutation, they can then invite their relatives to be tested, allowing study of entire families. If we can demonstrate that these families are at a high risk of lung cancer, then perhaps they should be undergoing CT-screening much as is recommended for individuals with a significant smoking history.