Brahmer Highlights Next Steps for Osimertinib in EGFR-Mutant NSCLC

Ellie Leick
Published: Monday, Feb 10, 2020

Julie R. Brahmer, MD
Julie R. Brahmer, MD
Results from the phase III FLAURA trial solidified osimertinib (Tagrisso) as the standard frontline option for patients with EGFR-mutated non–small cell lung cancer (NSCLC), and now research efforts are focused on examining combinations with the agent and developing strategies to overcome resistance, according to Julie R. Brahmer, MD.

“The FLAURA trial took patients who had EGFR-positive disease with standard EGFR abnormalities in exon 19 and exon 21 and found that osimertinib increased survival,” said Brahmer. “This was truly a [significant] advancement made in the field.”

The FLAURA trial examined osimertinib, a third-generation EGFR TKI, compared with the first-generation TKIs erlotinib (Tarceva) and gefitinib (Iressa) in patients with EGFR-mutant NSCLC. Osimertinib showed a median overall survival (OS) of 38.6 months (95% CI, 34.5-41.8) versus 31.8 months (95% CI, 26.6-36.0) with erlotinib or gefitinib (HR, 0.80; 95% CI, 0.64-1.00; P = .046).1 The 12-, 24-, and 36-month OS rates were 89%, 74%, and 54% in the osimertinib arm (n = 279), and 83%, 59%, and 44% in the erlotinib or gefitinib arm (n = 277), respectively.2

Furthermore, at 3 years, 28% of patients in the osimertinib arm continued on treatment versus 9% in the comparator arm, and the median exposure was 20.7 months versus 11.5 months, respectively.

“For targeted therapies, we want to use the best drug upfront. At the time of resistance, we will try to determine the mechanism of resistance or refer [patients] for clinical trials,” said Brahmer. “Typically, we turn to chemotherapy if a patient's disease progresses on targeted therapies and we don't have any further [options available]. Chemotherapy is a great backup.”

In an interview with OncLive during the 2020 Winter Lung Conference, Brahmer, co-director of the Upper Aerodigestive Department, Bloomberg Kimmel Institute for Cancer Immunotherapy, and professor of oncology at John Hopkins Medicine, discussed the impact of osimertinib in EGFR-mutant NSCLC, ongoing research with the agent, and the importance of molecular testing.

OncLive: What are some of the key developments that have been made with targeted therapies in lung cancer?

Brahmer: We've seen a great advancement of multiple new options for patients with driver mutations, from osimertinib being offered in the first-line treatment setting for those with the standard EGFR mutations in exon 19 and exon 21 to alectinib (Alcensa) for those with ALK-positive disease. Other driver mutations include BRAF, RET, ROS1, and NTRK alterations. There is a huge opportunity for us to look even further to see what driver mutations we can design therapies [to target]. Emerging therapies are now targeting KRAS G12C. We are very excited to see these inhibitors come into the clinic via clinical trials.

Osimertinib has moved to the frontline setting for patients with EGFR mutations due to the pivotal FLAURA study. Could you provide an overview of the study and its findings?

Patients with EGFR abnormalities in exon 19 and exon 21 were randomized to receive osimertinib or either erlotinib or gefitinib. Patients remained on these therapies until progression. We were able to see an improvement in progression-free survival as well as OS [with osimertinib], which was quite dramatic. [Much better] central nervous system control was observed in patients treated with osimertinib [compared with those] who were treated with either erlotinib or gefitinib.

Are there any circumstances in which you would not give osimertinib over erlotinib or gefitinib?

For most patients with the standard EGFR abnormalities noted on next-generation sequencing, we are choosing osimertinib over erlotinib or gefitinib. Sometimes we can run into particular adverse events where we have to try to drop the dose [of osimertinib] from the standard dose. If that continues to be a problem, we can try to [switch] over [to the first-generation EGFR TKIs], like erlotinib or gefitinib, to see if those patients can tolerate it. However, that does not happen very often because osimertinib tends to be very well tolerated.

What are you doing for patients who develop resistance to osimertinib?

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