Patient Selection for Osimertinib; Thoughts on Sequencing

Jonathan W. Riess, MD, MS: In terms of looking at patients for selection for osimertinib, the key question is whether their tumor harbors the EGFR T790M mutation as a mechanism of resistance to their previous EGFR TKI. So, in terms of testing for that, we can look at your general tumor biopsy and look for T790M or you can look at plasma cell—free DNA, which is tumor DNA that’s shed in the blood and can be picked up and sequenced. In general, I incorporate both plasma cell–free DNA and tumor EGFR T790M testing into my clinical practice.

So, in terms of sequencing therapy for patients with EGFR-mutant lung cancer, I generally look at the first-line approved EGFR TKIs where there’s erlotinib, gefitinib, and afatinib. I have a discussion with the patient regarding the pros and cons of each one. For example, if they’re older patients who are frail and have more comorbidities, I like the side effect profile of gefitinib, so I discuss gefitinib with them. If they are robust, young, and they have an EGFR exon 19 deletion based on the results of LUX-Lung 3 and 6 showing a survival benefit compared with chemotherapy in those studies, I discuss afatinib or erlotinib. We have a discussion based around the patient to individualize which first-line EGFR TKI we think is right for them. And based on that, we put them on either afatinib, erlotinib, or gefitinib.

Hopefully, they derive some benefit for some time. But, when the cancer starts progressing again, I look for the presence of EGFR T790M either in tissue or plasma. And if it’s positive and they’re progressing with the tempo of disease picking up, have high bulk of disease, or they’re more symptomatic, I generally switch to osimertinib in those patients. Also, if they’re T790M-negative, I’ve really looked carefully both at plasma and tissue, and it’s clearly negative, I look for other treatment options such as your standard platinum-based chemotherapy or clinical trials. We have several clinical trials specifically focusing on T790M-negative patients at UC Davis. So, we often discuss those as well.

In terms of the NCCN Guidelines, my practice generally follows the guidelines. They divide them into asymptomatic versus symptomatic. And so, if the patient is clearly symptomatic, that’s an indication for change. I don’t like to wait to get to that point where patients are having substantial symptoms before switching therapy. That’s where I go back, and even if they’re asymptomatic or minimally symptomatic, I look at the bulk of disease, the tempo of disease. And, those also, for many clinicians, inform clinical decision making.

If patients have one lesion that’s growing in particular, they have what we call oligometastatic disease, I will often look to radiate that focus of disease and then continue the same EGFR TKI they’ve been on. And there are data for that showing that you could get some extra mileage and extra additional “progression-free survival”, based upon that strategy of radiating the one site of disease and continuing the TKI that they’ve been on. If they have several lesions, especially if they’re T790M-positive, I move more towards osimertinib. But, if there’s one lesion, for example, that’s isolated and easy to take care of through focal radiation, that’s something that I also look at time to time. And I think that that’s also consistent with the NCCN Guidelines.

Another thing to keep in mind: if I do think they’re progressing, I often will check a repeat brain MRI. Because sometimes with a ton of progression, you also will not infrequently pick up new brain metastases that also may bring in potential radiation or a change in treatment sooner rather than later. So, that’s another thing that I look at as well. There are also data for radiating—for example, SRS (stereotactic radiosurgery)—to an oligometastatic brain lesion, and continuing the TKI that they’ve been on previously. Those are my general approaches to treating EGFR-mutant lung cancer and sequencing treatment, although they’re individualized based on the patient.

Riess case 2:

A 73-year-old woman with progressing EGFR+ adenocarcinoma.

• A 73-year-old woman diagnosed with stage IV adenocarcinoma
• Based on her EGFR+ status, she was treated with erlotinib
• After 9 months her disease progressed, along with the presence of minor symptoms
• Tissue biopsy was impeded by the tumor’s location; therefore, cell-free DNA testing was ordered
• Based on the positive results for a T790M mutation, the patient was switched to osimertinib.
• Her disease continues to be well-controlled on second-line therapy