Frontline Osimertinib Approaches European Approval for NSCLC

Sean Bohen, MD, PhD

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval of osimertinib (Tagrisso) as a first-line treatment for patients with non—small cell lung cancer (NSCLC) whose tumors harbor activating EGFR mutations, according to AstraZeneca, the manufacturer of the third-generation, irreversible EGFR TKI.

The CHMP recommendation is based on the phase III FLAURA study, in which frontline osimertinib reduced the risk of progression or death by 54% versus standard TKI therapy—erlotinib (Tarceva) or gefitinib (Iressa). In the double-blind study, the median progression-free survival (PFS) was 10.2 months (95% CI, 9.6-11.1) for standard therapy and 18.9 months (95% CI, 15.2-21.4) with osimertinib (HR, 0.46; 95% CI, 0.37-0.57; P <.0001).

Based on these findings, the FDA previously approved osimertinib for use in this setting. The positive CHMP opinion will now be sent to the European Commission for a final regulatory decision.

“This positive recommendation acknowledges Tagrisso’s potential as a new first-line standard of care for patients with EGFR-mutated NSCLC in Europe. It reflects the strength of the FLAURA data that show Tagrisso delivered a statistically-significant and clinically-meaningful improvement in progression-free survival over the EGFR-TKI comparator arm across all prespecified patient subgroups, including those with or without central nervous system metastases,” Sean Bohen, MD, PhD, executive vice president, Global Medicines Development and Chief Medical Officer at AstraZeneca, said in a statement.

In the FLAURA trial, 556 treatment-naïve patients with EGFR-positive locally advanced or metastatic NSCLC were randomly assigned to osimertinib (n = 279) or a standard TKI (erlotinib or gefitinib; n = 277). Patients with CNS metastases were allowed on the trial and all patients had exon 19 deletions or L858R mutations. Daily oral therapy was given with 80 mg of osimertinib, 250 mg of gefitinib, or 150 mg of erlotinib.

The PFS benefit with osimertinib extended across all prespecified subgroups. In patients with CNS metastases (n = 116), the median PFS with osimertinib was 15.2 months (95% CI, 12.1-24.4) compared with 9.6 months (95% CI, 7.0-12.4) with standard therapy (HR, 0.47; 95% CI, 0.30-0.74; P = .0009). In those without CNS involvement (n = 440), the median PFS was 19.1 months (95% CI, 15.2-23.5) and 10.9 months (95% CI, 9.6-12.3), for osimertinib and the control arm, respectively (HR, 0.46; 95% CI, 0.36-0.59; P <.0001). Across all patients, CNS progression occurred in 6% treated with osimertinib versus 15% for erlotinib and gefitinib.

The objective response rate with osimertinib was 77% compared with 69% for erlotinib and gefitinib. The median duration of response with osimertinib was 17.6 months versus 9.6 months in the comparator arm.

Medians had not yet been reached for overall survival, but at just 25% maturity, HR favored osimertinib at 0.63, a 37% reduction in the risk of death (95% CI, 0.45-0.88; P = .0068). However, those results have not yet been shown to be statistically significant. At the time of the analysis, there had been 58 deaths in the osimertinib arm and 83 in the control group.

The most common all-grade adverse events (AEs) were diarrhea (58%) and dry skin (32%) in the experimental group compared with diarrhea (57%) and dermatitis acneiform (48%) in the control group.

Overall, 33.7% of patients experienced a grade ≥3 AE in the osimertinib group compared with 44.8% for erlotinib and gefitinib. Patients in the osimertinib group were less likely to discontinue treatment because of AEs (13.3% vs 18.1%).

Ramalingam S, Reungwetwattana T, Chewaskulyong B, et al. Osimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients (pts) with EGFRm advanced NSCLC: FLAURA. Presented at: 2017 ESMO Congress; Madrid, Spain; September 9-12, 2017. Abstract LBA2_PR.