How is Molecular Testing Used to Select Upfront Therapy in Patients with EGFR Mutations?

Jonathan W. Riess, MD, MS:In terms of looking at where I select the best frontline EGFR TKI for my patient, I look at several different characteristics. There are a number of approved options first-line. You have erlotinib, afatinib, and now gefitinib is back and approved here in the United States. And, there are also some promising data looking at adding bevacizumab to erlotinib in terms of progression-free survival in a Japanese population, but the data hasn’t been presented yet and is still ongoing in terms of a non-Asian population. In general, my standard EGFR TKI has been erlotinib. I think that for many doctors in the community, erlotinib is something that they’re familiar with, have used for a number of years, and feel comfortable with in terms of managing the side effects and the dose reductions.

In terms of gefitinib, it generally may have more modest side effects and may be a bit better tolerated. So, for example, in older patients—I call them my little old ladies who have EGFR-mutant non—small cell lung cancer—I used to give them erlotinib 100 mg daily. Start with a dose reduction in terms of mitigating potential side effects, in terms of people who are older, who may have some compromised performance status, maybe much smaller than your average patient. Now, I think for those patients, gefitinib is a very reasonable option, so that’s something I look at for those types of patients in terms of having a manageable toxicity profile. That’s where, I, in my practice, have used gefitinib.

In terms of afatinib, there has been some data looking at patients with EGFR exon 19 deletions with a pooled analysis of the afatinib versus chemotherapy. LUX-Lung studies showed that there was an overall survival benefit of afatinib versus chemotherapy. Whether that’s an artifact of the trial designs or represents something real compared to other EGFR TKIs, it may be more the former than the latter. I think it’s unclear, but I do discuss with my patients, who have EGFR exon 19 deletions who are very fit, the possibility of using afatinib rather than erlotinib based on that data. Afatinib binds more potently to EGFR, both mutant and wild-type, so there tends to be potentially more rash, paronychia, some stomatitis; a little more intensive side effect profile. But, I do discuss it. I balance that with this potential for a modest benefit over other EGFR TKIs.

For example, in the LUX-Lung 7 study that compared erlotinib to gefitinib, there was a modest progression-free survival benefit. So, I do discuss this with my patients, and it’s something that I look at for patients with EGFR exon 19 deletions. The fact of the matter is, as long as you put them on a frontline EGFR TKI if they have an EGFR activating mutation, these all three are NCCN category 1 recommendations. I generally start with erlotinib, and there are also some provocative data with a several month progression-free survival benefit adding bevacizumab. That’s something I’ve talked about with patients. I know some practitioners do it more than I do. I have not added bevacizumab very much, as I’m waiting for additional data from non-Asian patients with EGFR-mutant lung cancer to come out and be presented and published. But, I do think that that’s also something that is being used more and more, and can offer a potential progression-free survival benefit balanced with the added toxicity of bevacizumab, and the need to not just do an oral daily medicine, but have an every-3-week infusion.

In terms of doing repeat molecular testing in patients with EGFR-mutant non—small cell lung cancer, I think that has really become standard of care now. We have an approved EGFR tyrosine kinase inhibitor, osimertinib, that’s active against the T790M resistance mutations, which represents about 50% to 60% of the pie for resistance for EGFR-mutant non–small cell lung cancer that’s progressed on a previous generation EGFR inhibitor. So, I generally obtain molecular testing on these patients, on every patient that develops resistance to a first-line EGFR TKI.

Riess case 1:

A 44-year-old female with relapsed stage IV adenocarcinoma.

• This is a 44-year-old female diagnosed with stage IV adenocarcinoma
• Tissue-based mutation testing showed an EGFR mutation with exon 19 deletion
• She was subsequently treated with afatinib
• After 11 months she became mildly symptomatic with small, nonspecific pulmonary nodules
• Follow up CT scan showed growth of the primary lesion
• The patient reported worsening of her cough
• Cell-free DNA testing was ordered and was negative for both the EGFR driver mutation and for T790M
• Subsequent tissue biopsy showed the presence of T790M
• The patient was switched to osimertinib and continues to respond well to therapy with minimal toxicity