Helena A. Yu, MD
The FDA approval of osimertinib (Tagrisso) as a frontline therapy for patients with non–small cell lung cancer (NSCLC) whose tumors harbor EGFR
mutations, specifically exon 19 deletions or exon 21 L858R substitution mutations, has provided physicians with an alternative and more potent treatment for this patient population.
The April 2018 decision wass based on findings from the double-blind, phase III FLAURA study, in which frontline osimertinib reduced the risk of progression or death by 54% versus standard tyrosine kinase inhibitor (TKI) therapy with erlotinib (Tarceva) or gefitinib (Iressa). Data showed that the median progression-free survival (PFS) was 10.2 months for standard therapy and 18.9 months with osimertinib (HR, 0.46; 95% CI, 0.37-0.57; P
The agent has also seen benefit in patients with central nervous system (CNS) metastases. Real-world clinical data presented at the 2018 European Lung Cancer Congress demonstrated that patients with advanced NSCLC and baseline CNS metastasis showed control of their metastasis after osimertinib treatment. The CNS clinical benefit was observed in 7 patients with brain metastasis at baseline with osimertinib; the objective response rate by RECIST was 70%, including partial responses in 50% and stable disease in 20%.2
Next steps after the approval of osimertinib as the frontline standard of care include how to treat patients who develop resistance to the third-generation EGFR TKI, explains Helena A. Yu, MD.
The regulatory approval is not the only exciting development in the EGFR
-mutant space. Dacomitinib was granted a priority review designation by the FDA in April 2018 for the frontline treatment of patients with EGFR
-positive locally advanced or metastatic NSCLC. The application is based on the phase III ARCHER 1050 trial, in which frontline dacomitinib reduced the risk of disease progression or death by 41% and was associated with an average 6.5-month improvement in response duration versus gefitinib.3
In an interview during the 2018 OncLive®
State of the Science Summit™ on Advanced Non–Small Cell Lung Cancer, Yu, a medical oncologist at Memorial Sloan Kettering Cancer Center, highlighted sequencing strategies in EGFR
-mutant NSCLC, the impact of osimertinib in the frontline setting, and the questions surrounding dacomitinib’s intriguing data in this landscape.
OncLive: You lectured on sequencing EGFR-targeted therapies in NSCLC. Can you provide an overview?
I spoke about treatments for EGFR
-mutant lung cancer. The first part focused on what data are out there. The real key is the news of osimertinib in the first-line setting. The FLAURA study read out late last year, which showed that osimertinib had a doubling of median PFS compared with what was previously the standard of care. I see osimertinib being the standard of care for first-line treatment.
Then, I spoke about resistance mechanisms. That is a key with targeted therapy; these treatments are very effective and they work for a long time, but at some point all patients have progression. It’s key to re-biopsy patients at that point, and to look and see what the different resistance mechanisms are.
With osimertinib, there are patterns that are emerging; off-target resistance is going to be a more dominant factor. Osimertinib is an excellent EGFR inhibitor, so we are seeing less-acquired EGFR
mutations. We sometimes see the EGFR mutation C797S, but it is probably more like 15% rather than the 60% we saw with T790M [after treatment with] erlotinib, afatinib (Gilotrif), and gefitinib.
We need to see what is prevalent and what is common, and the key is looking at combinations to sort of prevent those resistance mechanisms.