Osimertinib tops standard first-line TKI therapy for advanced NSCLC
Osimertinib nearly doubled progression-free survival (PFS) compared with conventional EGFR tyrosine kinase inhibitors (EGFR-TKIs) given as first-line treatment for EGFR-mutated non-small-cell lung cancer (NSCLC), according to a late-breaking report at the European Society for Medical Oncology (ESMO) 2017 Congress in Madrid, Spain. [ESMO 2017, abstract LBA2_PR]
“First- and second-generation EGFR-TKIs are currently the standard of care [SoC] in first-line treatment of patients with EGFR-mutated NSCLC. However, over 50 percent of patients develop T790M mutation-mediated resistance to drugs such as gefitinib and erlotinib,” said principal investigator Dr Suresh Ramalingam from the Winship Cancer Institute of Emory University, Atlanta, Georgia, US.
Osimertinib is a third-generation EGFR-TKI that potently and selectively inhibits both EGFR mutations and T790M resistance mutations. [J Clin Oncol 2017;35:1288-1296] It is currently approved for patients with T790M mutations whose disease has progressed on or after standard EGFR-TKI therapy. Early clinical data also suggest that osimertinib may be an effective first-line therapy for EGFR-mutated advanced NSCLC. [Cancer Res 2015;75:2489-2500]
The phase III randomized FLAURA trial assessed the efficacy and safety of osimertinib 80 mg once-daily vs SoC (either erlotinib 150 mg or gefitinib 250 mg, once daily) in 556 treatment-naïve patients with locally advanced or metastatic EGFR-mutated NSCLC. Baseline characteristics in terms of gender, age, race, mutation status and central nervous system (CNS) metastases were balanced between the two arms. The primary endpoint was PFS by investigator assessment.
“At the time of analysis, median PFS was 18.9 months for osimertinib vs 10.2 months for SoC, with a hazard ratio [HR] of 0.46 [p<0.0001],” reported Ramalingam. “The PFS benefit was consistent across all subgroups regardless of age, gender, race, smoking history, presence of CNS metastases and type of EGFR mutation. The identical benefit in patients with and without brain metastases suggests that osimertinib is active in the brain; this is important because brain metastasis is common in EGFR-mutated NSCLC.”
The median duration of response was twice longer with osimertinib than with SoC (17.2 vs 8.5 months), and the overall response rate was 80 vs 76 percent.
“Median overall survival [OS] was not reached. OS appeared to favour osimertinib with an HR of 0.63, but did not reach statistical significance at the interim analysis,” he said.
The incidence of grade ≥3 adverse events was lower for osimertinib than for SoC (34 vs 45 percent). “The safety profile of osimertinib was more favourable despite the longer treatment duration compared with SoC,” commented Ramalingam.
“Osimertinib improved PFS by 54 percent vs SoC, with a trend towards improvement in OS and a favourable safety profile. It should be considered as the new SoC for first-line therapy of EGFR-mutated advanced NSCLC,” he concluded.
“FLAURA is undoubtedly a positive study, with osimertinib showing clear CNS benefits over erlotinib and gefitinib and a somewhat better toxicity profile,” commented discussant Professor Tony Mok from the Chinese University of Hong Kong. “However, longer follow-up is needed to confirm the OS benefit and to clarify the mechanism of resistance to first-line osimertinib.”