Fulfilling the Promise of Precision Medicine in EGFR-Mutant NSCLC

Several factors must be considered when a patient with EGFR-mutant non–small cell lung cancer (NSCLC) develops resistance to an EGFR tyrosine kinase inhibitor (TKI), according to Edward S. Kim, MD. It is imperative to reassess the biomarker landscape and understand the mechanisms of action of available agents to inform the next step in their treatment journey, he said.

“It is short-sighted to say that we are not going to have a better EGFR TKI down the road or another generation [of agents]. We will see multiple TKIs out there that target different mutations,” Kim said. “We will continue to be able to slice up this EGFR domain and figure out which mutations pair with which drug, and those drugs…[may] have fewer adverse effects. That is fulfilling that promise of precision medicine. That is the future—not just for EGFR but also for other biomarkers that are still yet to be determined.”

Before making the decision to stop treatment with the drug after scans identify disease progression, it is important to consider whether the patient is symptomatic or still experiencing some benefit, Kim said. If the patient is not experiencing symptoms and may still be deriving benefit, continuing treatment may be acceptable. Before deciding to switch to a different approach, performing another biopsy could provide critical insight into how the tumor has changed.

In an interview with OncLive® during an Institutional Perspectives in Cancer webinar on lung cancer, Kim, physician-in-chief of City of Hope Orange County and vice physician-in-chief of City of Hope National Medical Center, highlighted efforts being made to overcome resistance to EGFR TKIs in patients with EGFR-mutated NSCLC and factors to consider when determining sequential treatment.

OncLive^®: What efforts are being made to overcome resistance to EGFR TKIs?

Kim: The fact that we talk about resistance is natural. We always start with agents; eventually they stop working, and then we have to figure out what the next plan is. Patients need to know what is next [in their treatment journey]. This was a big struggle with chemotherapy. With chemotherapy, many resistance questions [persisted], whether we were dealing with platinum resistance or taxane resistance. [We were] studying mechanisms of action and [understanding] what drugs could be used sequentially.

I remember that when docetaxel was first approved, some people felt that you could not use a taxane after giving a taxane in the first-line setting; that was actually proved to be false. Data showed that although [carboplatin and paclitaxel] were both taxanes, they were slightly different in their mechanisms of action, and they could be used sequentially.

[Moreover], before we decide that the drug has stopped working radiographically and [make the] clinical decision to stop that drug, [we need to consider some factors]. We know that sometimes disease grows very slowly and [patients] will still benefit and not have symptoms; in those cases, I like to continue to treat patients. Immunotherapy has taught many of us that we should not just react to a scan that shows a growth.

When we decide that we are going to switch, however, we really need to rebiopsy or reassess the biomarker landscape in that tumor; that can be done [by analyzing] the tissue or the blood. Reassessing how the tumor may have changed, evolved, or [developed] new mutations is important. We are [now] seeing combinations of drugs [or certain] chemotherapy [approaches] that [seek to] improve [outcomes] for patients. [Regimens] with or without immunotherapy, angiogenesis inhibitors, and VEGF inhibitors [are all under exploration]. We are trying to work on that [development]; this applies not only to the field of EGFR but also to [those of] ALK and some of the other biomarkers. Importantly, [we are also looking at biomarkers for] immunotherapy.

What is on the horizon for EGFR-positive NSCLC treatment?

To predict the future of EGFR is challenging right now. We have come so far. Now [EGFR TKIs are being evaluated] in the earlier-stage setting. Some studies are testing neoadjuvant approaches to optimize surgery. In other settings where we find EGFR mutations, such as locally advanced stage IIIB [disease that] is unresectable, those will also be looked at. Combination studies are also being done. However, we do know that it is very important to test for EGFR mutations up front and ensure that if a patient’s tumor does have [a mutation], that we do not start them on immunotherapy first. I would love to see some of these drugs make it into a high-risk population that does not have cancer, but those patients do not necessarily have EGFR mutations. As such, I would say we are still a little way off from finding the right target for that.

What is your advice for colleagues treating these patients in practice?

Do the testing. In a newly diagnosed patient, it is important to establish their biomarker profile. In breast cancer, you would never initiate therapy without knowing the estrogen receptor, progesterone receptor, and HER2 status up front. In lung cancer, we actually have more biomarkers; we have more that need to be tested. If you have a [patient who] has a driver mutation, you give the TKI. That is the paradigm. It is disconcerting to see that [not everyone is] testing for biomarkers, and, more importantly, [using this information] to drive treatment choices—especially in the United States.