Suresh A. Ramalingam, MD, discusses some of the changes to the NCCN guidelines in NSCLC, specifically with <em>EGFR</em>-mutation–positive disease, and how the frontline recommendation of osimertinib will impact clinical practice.
Suresh S. Ramalingam, MD
Among the notable updates in the National Comprehensive Cancer Network's (NCCN) recently released treatment guidelines for nonsmall cell lung cancer1(NSCLC) is the category 2A recommendation to give osimertinib (Tagrisso), a third-generation irreversible EGFR inhibitor designed to inhibit both EGFR-sensitizing and EGFR T790M-resistance mutations, in the first-line setting for patients whose disease isEGFRmutant, explains Suresh A. Ramalingam, MD.
Osimertinib was also given a category 1 recommendation as a subsequent therapy after patients progressed on treatment with standard EGFR tyrosine kinase inhibitors (TKIs) erlotinib (Tarceva), gefitinib (Iressa), and afatinib (Gilotrif). The FDA granted a breakthrough therapy designation to a supplemental biologics license application for osimertinib as a frontline treatment for patients with metastaticEGFR-mutationpositive NSCLC in October 2017. The application was based on findings from the double-blind, phase III FLAURA trial, in which frontline osimertinib was associated with a 54% reduction in the risk of progression or death compared with standard therapy.2
Additional data showed that the median progression-free survival (PFS) was 10.2 months (95% CI, 9.6-11.1) for standard therapy and 18.9 months (95% CI, 12.5-21.4) with osimertinib (HR, 0.46; 95% CI, 0.37-0.57;P<.0001). Though overall survival data remain immature, there is an encouraging trend that favors osimertinib.
Moreover, the phase III findings of the AURA3 trial demonstrated a benefit with osimertinib in patients withT790M-positive NSCLC who also had central nervous system (CNS) metastases and progressed on first-line therapy with an EGFR TKI.3In the subset analysis of patients with CNS metastases in AURA3, the overall response rate was 70% with osimertinib versus 31% for patients treated with platinum-based doublet chemotherapy (odds ratio, 5.13; 95% CI, 1.44-20.64;P= .015).
In an interview withTargeted Oncology, Ramalingam, deputy director of Winship Cancer Institute of Emory University, discussed some of the changes to the NCCN guidelines in NSCLC, specifically withEGFR-mutationpositive disease, and how the frontline recommendation of osimertinib will impact clinical practice.
TARGETED ONCOLOGY:Regarding EGFR-mutant NSCLC, what are the most notable updates to the NCCN guidelines?
Ramalingam: The most important update is the introduction of osimertinib in the frontline space, and that follows the FLAURA data that we presented at the 2017 ESMO Congress a couple of months ago. That study compared osimertinib to erlotinib or gefitinib for first-line therapy in patients with either exon 19 and 21 alterations. That study showed superiority for osimertinib; the median PFS was improved from 10.2 months [with standard therapy] to 18.9 months. The hazard ratio was 0.46.
We also saw that osimertinib had activity in the brain more so than the other 2 drugs. Based on that, the trial announced that osimertinib was superior to current standard-of-care TKIs in the first- line setting. The NCCN guidelines follow the results of the trial to recommend osimertinib as an option in the first-line space.
TARGETED ONCOLOGY:The guidelines emphasize testing for EGFR/ALK/ROS1. How can the results of these tests guide physician’s choice of therapy?
We now know that for every patient with nonsquamous NSCLC, molecular testing is critical even before we start treatment for advanced-stage disease. EGFR exon 19 and 21 alterations are associated with high sensitivity to EGFR inhibition. I believe patients should have testing for EGFR mutations, BRAF mutations, ALK translocations, and ROS1 translocations before they start therapy. Those are the 4 oncogenes where there is a proven therapy available for patients with those abnormalities.
The other thing is regarding tissue-based testing. For EGFR, plasma testing is now an option if tissue is not available. If the plasma testing reveals that the patient has exon 19 or 21 alterations, then they can also derive benefit from EGFR TKI therapy. That is another option that has emerged now in the field.
TARGETED ONCOLOGY:What is the significance of osimertinib now being recommendation as a therapeutic option in the frontline setting for EGFR-mutant patients?
In the United States, these data clearly show that osimertinib is superior to current therapies. It is safer from a toxicity standpoint, and it has benefits when it comes to activity against brain metastases. For these reasons, I believe osimertinib will be a preferred first-line therapy forEGFR-mutationpositive disease.
If the NCCN recommends giving osimertinib in the first-line setting, what is the optimal second-line option for those who progress on the third-generation EGFR inhibitor?
At this point, we are still learning about the resistance mechanisms in patients who get first-line osimertinib. Platinum-based chemotherapy is active in patients withEGFRmutations, so for somebody who progresses on osimertinib in a clinically significant manner, chemotherapy would be the present standard of care. However, it is my belief that we will soon be developing treatments based on knowledge of resistance to osimertinib.
TARGETED ONCOLOGY:Taking an overall look at the NCCN guideline updates in lung cancer, what do these recommendations say about the way the paradigm is changing?
It is clear that individualized therapy is resulting in better outcomes for patients with these molecular abnormalities. In testing for mutations, we now have first-line therapy options, even second-line targeted therapy options, for many of these patients. I believe that for patients with a defined driver mutation with targeted agents, they should have the option to receive these targeted therapies.