Resistance in EGFR-Mutant Lung Cancer

Transcript:Luis E. Raez, MD: When the patient develops resistance to the tyrosine kinase inhibitors—the 3 ones that we mentioned before—we have another agent, osimertinib, available for second-line treatment. But, the patients have to carry a resistant mutation called T790M to qualify for osimertinib. For that reason, we need to do a new biopsy to prove that the patient carries the resistant mutation, because a patient may have other mutations—other genetic aberrations—and may not benefit from osimertinib. That’s why a biopsy needs to be done. Sometimes it’s not easy to do a second biopsy. That’s why we’re lucky that we now have liquid biopsies available, so we can do a next-generation sequencing analysis or PCR of the tumor in the blood. There are now a lot of technologies that we can use in the blood to obtain information and see if the patient is carrying this T790M-resistant mutation or is carrying other genetic aberrations, so we can see if the patient is going to benefit from osimertinib or not.

Patients who develop resistance carry T790M mutations around 60% of the time. But, the other 40% of the time, they have other genetic aberrations, or they can even transform to a different histology, like small cell lung cancer. So, that’s why it’s very important to do the analysis when the patient develops resistance.

Philip C. Mack, PhD: It is very important—perhaps even essential—to test patients at the time of progression on an EGFR inhibitor. This is presuming that they’ve had a good benefit—they’ve had a response. When the tumor begins to relapse, it is doing so because it is evolving. It has learned some sort of trick to acquire a resistance mechanism to the initial therapy. The identification of the specifics of that resistance mechanism allows us to assign the most appropriate therapy in that course. Remember that the patient’s tumor is still EGFR-dependent in many cases, and we want to take advantage of that dependency with our therapeutics. For instance, the most common abnormality in terms of resistance for EGFR is advent of the T790M resistance mutation. For this, we have a very effective therapy, osimertinib, that can be used in this setting, but it’s only approved for patients who are positively diagnosed with a T790M mutation. So, you must look for that resistance mutation.

As the field began to move further, we identified quite a large array of potential resistance mechanisms to EGFR beyond T790M. The additional 40% to 45% of patients may have MET amplification or HER2 amplification, or even acquire other abnormalities in signal transduction—BRAS mutations or even ALK mutations, in many cases. So, there are therapeutic options for those patients. It’s imperative that we perform the clinical trials necessary to document that these interventions are effective in that setting.

Benjamin P. Levy, MD: We’ve entered a new diagnostic paradigm for patients with EGFR-mutant lung cancer who develop progression and are considering a therapeutic switch. We now know that patients with T790M mutations garner a benefit with osimertinib and Tagrisso, and, based on the AURA3 trial, patients with T790M-mutant lung cancer have more drastic improvements and outcomes when getting osimertinib and Tagrisso than with chemotherapy. Based on this, osimertinib is the standard of care for patients that have a T790M mutation. The question is how you identify the T790M mutation.

We now have more and more data showing that plasma is fairly reliable in identifying T790M mutations, and it’s fairly concordant with tissue. The specificity of plasma T790M hovers in the 90% range, meaning if it’s positive in the plasma, rest assured, it’s probably positive in the tissue. If it’s negative in the plasma, however, the sensitivity is only 60% to 70%, which means it could be positive in the tissue.

The new proposed paradigm, which we do in our clinic, is to start with plasma for a patient who’s EGFR-mutated, progressing on a TKI, and considering a therapeutic switch. If plasma is positive for T790M, you don’t need to do the biopsy. There’s the same chance that the patient’s going to respond to osimertinib whether they’re plasma T790M or tissue T790M tested. So, we generally offer osimertinib. If they’re negative, however, you still need to do the biopsy because you may miss some T790Ms. That’s the proposal that’s been put forth by many authors, and investigators and I think it’s very reasonable.

For patients who are T790M-mutant in the plasma and in the tissue, we have to default to chemotherapy, but I think that “default” is a misnomer. Chemotherapy works in patients that are EGFR-mutated. I tell my patients upfront at that decision point that we’re going to look for the T790M mutation. If it’s positive, I’m going to be able to give you another pill. If it’s negative, however, I’m going to give you chemotherapy that does work and can improve symptoms and outcomes. For those patients, I generally offer platinum with pemetrexed—with or without bevacizumab, depending on the patient. Platinum-pemetrexed in this scenario is very reasonable for a patient outside of a clinical trial, because we have a lot of work to do to understand other targets. Chemotherapy with platinum-pemetrexed is the standard in my mind in the absence of small cell disease—which is in about 5% of patients, in which case you would use a small cell regimen.

Transcript Edited for Clarity