Osimertinib Standard of Care in T790M-Positive NSCLC

Second-line treatment with the EGFR-tyrosine kinase inhibitor (TKI) osimertinib resulted in significantly better progression-free survival compared with chemotherapy alone in patients with non–small-cell lung cancer (NSCLC) that is EGFR-T790M positive, according to the results of the AURA3 trial, presented at the IASLC 17^th World Conference on Lung Cancer (abstract PL03.03) and published in the New England Journal of Medicine.

“Osimertinib had statistically superior and clinically meaningful efficacy compared to chemotherapy,” said Vassiliki Papadimitrakopoulou, MD, of the department of thoracic/head and neck medical oncology at the University of Texas MD Anderson Cancer Center, during a press briefing. “There should be no question based on the progression-free survival hazard ratio of 0.30 and progression-free survival of 10.1 months-5.7 months more than chemotherapy-what we should be giving to our patients in this setting.”

Patients with EGFR-mutated NSCLC receive EGFR-TKIs as standard first-line treatment, explained Papadimitrakopoulou. However, the majority of patients will ultimately have disease progression, with about 60% progressing due to T790M.

Osimertinib is selective for both EGFR-TKI sensitizing and T790M resistance mutations. Osimertinib was approved by the US Food and Drug Administration (FDA) based on the results of a pooled analysis of two phase II studies of the drug that showed objective response rates of 66% with a median duration of progression-free survival of 11 months.

The AURA3 trial was a confirmatory trial designed to show superiority of osimertinib to platinum therapy plus pemetrexed. The phase III, open-label study included 419 patients with NSCLC and randomly assigned them 2:1 to osimertinib 80 mg orally (n = 279) or pemetrexed plus either cisplatin or carboplatin (n = 140). All patients were aged 18 or older, had documented EGFR mutations, had disease progression after fist-line EGFR-TKI treatment, and were T790M positive. The primary endpoint of the study was progression-free survival.

At the time of data cutoff (median follow-up time of 8.3 months), patients assigned to osimertinib had significantly improved progression-free survival compared with pemetrexed alone, seeing a 70% reduction in risk of disease progression or death without disease progression (hazard ratio [HR], 0.30; 95% CI, 0.23–0.41; P < .001). The median progression-free survival was 10.1 months for osimertinib compared with 4.4 months for the chemotherapy arm. The median duration of response was 9.7 months for osimertinib compared with 4.1 months with pemetrexed.

These progression-free survival results were consistent with analysis done by blinded independent central review (HR, 0.28; 95% CI, 0.20–0.38; P < .001). Here, the median progression-free survival was 11 months for osimertinib compared with 4.2 months for chemotherapy. Patients assigned to osimertinib also had significantly improved objective response rates compared with platinum therapy (71% vs 31%; odds ratio, 5.39; 95% CI, 3.347–8.48; P < .001).

“The benefit was spread among all the subgroups that were predefined, and it was an impressive benefit,” said Papadimitrakopoulou. “The hazard ratio was less than 0.50 in all subsets of patients that were looked at.”

Among 144 patients with metastases to the central nervous system, the median duration of progression-free survival was 8.5 months with osimertinib compared with 4.2 months for platinum therapy plus pemetrexed (HR, 0.32; 95% CI, 0.21–0.49).

Finally, only 23% of patients assigned to osimertinib had grade 3 or higher adverse events compared with 47% of patients assigned to platinum therapy plus pemetrexed.