In this edition of “How I will treat my next patient,” I highlight two studies that previously reported significant progression-free survival (PFS) improvements and more recently, at the European Society for Medical Oncology Congress, overall survival (OS) benefit. I reflect on the significance of these new reports in the wake of previously reported data and guidelines from the National Comprehensive Cancer Network (NCCN).
Dr. Alan P. Lyss
Osimertinib in advanced NSCLC
In the double-blind, phase 3 FLAURA trial, 556 patients with EGFR-mutated (EGFRm), advanced non–small cell lung cancer (NSCLC) received osimertinib or a standard tyrosine kinase inhibitor (TKI) as initial treatment. PFS, the primary endpoint, was clinically and statistically better for osimertinib (18.9 months vs. 10.2 months; hazard ratio 0.46; P less than .001), overall and in all major subgroups. There were fewer grade 3-4 adverse events and fewer permanent treatment discontinuations with osimertinib.
At the time of initial publication, OS data were immature, but because of the substantial survival improvements previously noted, osimertinib was approved by the Food and Drug Administration for first-line treatment of EGFRm stage IV NSCLC patients in April 2018 (N Engl J Med. 2018; 378:113-25).
More recently, at ESMO 2019, Suresh Ramalingam, MD, of the department of hematology and medical oncology at Emory University, Atlanta, and colleagues reported the OS results. Crossover to osimertinib was allowed for patients on the standard TKI arm when they had progressive disease and a T790M mutation. Osimertinib produced a median OS of 38.6 months, compared with 31.8 months for standard TKI (HR, 0.799; P = .0462), a 24-month OS rate of 74% vs. 59% (with no overlap in the 95% confidence intervals), and a 36-month OS rate of 54% vs. 44%. These benefits were interpreted to be statistically significant and clinically meaningful.
The 31.8-month median OS for standard TKI was competitive with the highest reported OS for standard therapy, perhaps because crossover to osimertinib was permitted.
What this means in clinical practice
The report by Dr. Ramalingam and colleagues – and the next abstract I will review – remind me of the famous “You had me at Hello” line from “Jerry Maguire.”
For patient education – and perhaps for some national regulatory agencies – it is good that we now have definition of what the average OS is with osimertinib, compared with standard TKI followed by osimertinib. However, very few oncologists in the United States likely use the latter strategy anymore. It was clear when the impressive PFS and toxicity information appeared in 2018 in the New England Journal of Medicine that osimertinib is the best tolerated, most durably effective front-line treatment for EGFRm mNSCLC, regardless of disease extent, sex, nationality, type of EGFRm (L858R amino acid substitution in exon 21 or exon 19 deletion), or presence/absence of central nervous system metastases.
In NCCN guidelines, osimertinib was listed as the preferred TKI, prior to the OS report at ESMO 2019. The challenges going forward will be to identify high-risk patient subsets who might benefit from drug combinations or novel new agents.