Future Directions for Precision Medicine in Advanced NSCLC - Episode 1

Advances in Frontline Therapy for EGFR+ NSCLC


Benjamin P. Levy, MD: Advanced lung adenocarcinoma remains an exceptional example of precision medicine in oncology, as we persist in exploring new therapeutic targets and evaluating new ways to sequence and combine novel agents. In this OncLive Peer Exchange® discussion, “Future Directions for Precision Medicine in Advanced Non—Small Cell Lung Cancer,” I am joined by a panel of my colleagues in thoracic oncology clinical research. We will delve into some of the latest data surrounding the use of targeted therapies in non–small cell lung cancer, including research being presented at the 2018 World Conference on Lung Cancer in Toronto, and will talk about the practical implications for treatment of metastatic disease.

I am Dr Benjamin Levy, assistant professor of oncology and clinical director of medical oncology for Johns Hopkins Sidney Kimmel Cancer Center at Sibley Memorial Hospital in Washington, DC.

Participating today on our distinguished panel are Dr Lyudmila Bazhenova, medical oncologist and professor of medicine and lung cancer team leader at the UC [University of California] San Diego Moores Cancer Center; Dr Shirish Gadgeel, professor in the Department of Internal Medicine, Division of Hematology/Oncology, at the University of Michigan; Dr Mohammad Jahanzeb, professor of clinical medicine, medical director of Sylvester Deerfield at the University of Miami, Miller School of Medicine; and Dr Anne Tsao, professor, Department of Thoracic/Head & Neck Medical Oncology, and director of the Mesothelioma and Thoracic Chemo-Radiation Programs at the University of Texas MD Anderson Cancer Center.

We’ll start out with EGFR—a relevant mutation in roughly 15% of advanced non—small cell lung cancer adenocarcinoma, at least in patients with an unenriched population. We know that first- or second-generation TKIs [tyrosine kinase inhibitors] outperform chemotherapy in a patient who is EGFR mutation—positive, in terms of response rate and progression-free survival [PFS]. But we’ve seen some practice-changing data over the past 12 to 18 months that have begun to alter the therapeutic landscape. Some of the practice-changing data have to do with, of course, osimertinib. Anne, do you want to talk about the osimertinib data and where we are with that right now?

Anne S. Tsao, MD: Osimertinib is a third-generation EGFR [epidermal growth factor receptor] tyrosine kinase inhibitor, which, during the FLAURA trial, was compared with the investigator’s choice of erlotinib or gefitinib—our first-generation EGFR tyrosine kinase inhibitors. It was a 1:1 randomization for patients who had sensitive EGFR mutations—so that’s your del [deletion] XL19, L858R. These patients were randomized 1:1 to receive osimertinib or either gefitinib or erlotinib. The conclusion to this study was an incredible progression-free survival benefit with osimertinib. The response rate was roughly equivalent—about 76% to 80%—but the median PFS was significantly prolonged at 18.9 months with osimertinib compared with about 10.2 months with the first-generation EGFR TKIs; this translated into a hazard ratio of about 0.46. Although the data are still immature, this undoubtedly translated into an 18-month median OS [overall survival] benefit. The hazard ratio there was about 0.6—so clearly, at least in my practice, I changed to give osimertinib frontline for all my sensitive EGFR-mutation patients.

Benjamin P. Levy, MD: The PFS advantage was definitely compelling and a little unexpected—it was fairly commensurate with the phase I osimertinib experience and CNS [central nervous system] activity.

Anne S. Tsao, MD: Absolutely. That’s the additional benefit that we saw—that there was a delay or a prolongation until the first CNS event. In many of my patients whom I treat with frontline who have CNS metastases, I don’t necessarily send them for radiation treatment anymore. I’m giving them osimertinib, and then I see if we can get the CNS metastases to regress. This has worked for my patients thus far.

Benjamin P. Levy, MD: Let me ask you about the CNS metastases and what your trigger is to give radiation up front: Is there a threshold where you’re not comfortable with the activity we’ve seen here and these patients who may need SRS [stereotactic radiosurgery] before instituting osimertinib frontline?

Anne S. Tsao, MD: It would be the same as before: If a patient has any sort of impending herniation, you don’t have time to consider osimertinib in those cases. If it’s small enough that they can go for a craniotomy, that’s still what you should do. If there’s a large enough CNS lesion that causes neurologic complications, I don’t think you have time to wait for osimertinib to work—and so I still administer SBRT [stereotactic body radiation therapy] to those patients. The only alteration is to delay brain radiation as long as possible. It used to be that our patients with EGFR mutation had these diffuse brain metastases across both hemispheres, and we used to do whole brain treatments in those patients. I don’t do that anymore—instead, I will administer osimertinib.

Benjamin P. Levy, MD: The third exciting element of this trial was the adverse event profile with this drug in the context of what we generally see with first and second-generation TKIs. Are you seeing any adverse events that weren’t reported in the trial or things that we have to look out for with this drug?

Anne S. Tsao, MD: Many of our patients love this [because] you don’t have the rash or diarrhea. To a small degree, you might experience it a bit but certainly nothing like [what you might experience with] the prior EGFR TKIs. The only word of caution I have is you can potentially get some QTc [corrected QT interval] prolongation. In a patient with a prior cardiac history or known QTc prolongation, I always check an echocardiogram, just to be sure. I also try to get rid of any other concomitant medications that could potentially lead to problems.

Benjamin P. Levy, MD: I’ve seen some cytopenia. I don’t know whether anyone else has seen these in their experience.

Anne S. Tsao, MD: A little neutropenia.

Shirish M. Gadgeel, MD: But none that led to any clinical consequences. It was mainly laboratory based. Going back to CNS—an important practical implication of these drugs, both in EGFR and the ALK space, having CNS activity, is that we often know the patient has brain metastasis before we know the molecular alteration. We should make no assumptions if brain metastases are perceived to be initiated because we won’t know for certain until we receive the full results of the molecular analysis. Once we have decided what systemic therapy we are going to use, we determine a treatment for the brain metastases.

Benjamin P. Levy, MD: I agree with that. There’s an opportunity to educate our radiation oncologists to make sure they’re aware of the data, which are fairly new over the past year. There’s an opportunity here to make sure the radiation oncologists are aware of the CNS activity so we can hold off, if possible, in giving an active drug, both below and above the neck.

Mohammad Jahanzeb, MD, FACP: There’s a distinction that at academic centers, it’s easier to educate radiation oncologists who are embedded within the tumor board. In the community, however, where these patients may be seen by the oncologist who sees a whole range of disorders and cancers—they see 1 such patient a year—they should perhaps refrain from referring the patient to the radiation oncologist until there is a real need because it becomes very difficult once you send the patient to the radiation oncologist, and they start planning radiation, to then undo that activity. Patients say, “Well, the other doctor wants to radiate. What’s going on? You guys don’t agree.” I would just say that if you don’t think a patient needs adjuvant radiation, we should wait for the mutations, ideally.

Benjamin P. Levy, MD: It underscores the importance of tissue genotyping and gets them an answer in a relatively quick fashion.

Transcript Edited for Clarity