Results of Phase III FLAURA Study Show Benefit of Frontline Osimertinib in EGFR+ NSCLC

In results from the phase III FLAURA study of frontline osimertinib (Tagrisso) in patients with <em>EGFR</em>-mutant non&ndash;small cell lung cancer, osimertinib demonstrated a progression-free survival &nbsp;rate of 18.9 months (95% CI, 12.5-21.4), which was significantly improved over standard therapy.&nbsp;

Suresh S. Ramalingam, MD

In results from the phase III FLAURA study of frontline osimertinib (Tagrisso) in patients withEGFR-mutant non—small cell lung cancer (NSCLC), osimertinib demonstrated a progression-free survival (PFS) rate of 18.9 months (95% CI, 12.5-21.4), which was significantly improved over standard therapy.

In the double-blind study that was presented at the 2017 ESMO Congress in Madrid, Spain, the median PFS was 10.2 months (95% CI, 9.6-11.1) for standard therapy, which consisted of erlotinib or gefitinib, representing an 8.7-month improvement in median PFS with osimertinib (HR, 0.46; 95% CI, 0.37-0.57;P<.0001). This represented a 54% reduction in the risk of progression or death with osimertinib compared with standard therapy.

Although medians had not yet been reached for overall survival, at just 25% maturity the hazard ratio already favored osimertinib at 0.63, a 37% reduction in the risk of death (95% CI, 0.45-0.88;P= .0068); however; at this timepoint, aPvalue of .0015 was needed to show statistical signficance for survival, suggesting these findings were not yet meaningful. There had been 58 deaths in the osimertinib arm and 83 in the control group.

“Results of the FLAURA study define a new standard of care for patients withEGFRmutation-positive non—small cell lung cancer," said lead investigator Suresh Ramalingam, MD, Deputy Director, Winship Cancer Institute of Emory University. "There was a 54% reduction in the risk of progression or death with the use of osimertinib compared with standard care.”

Based on findings from the FLAURA study, AstraZeneca, the company developing osimertinib, has already entered approval discussions with relevant health authorities. Osimertinib was initially granted an accelerated approval by the FDA in November 2015 followed by a full indication in March 2017 for pretreated patients with T790M-positive NSCLC.

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

The objective response rate (ORR) with osimertinib was 80% compared with 76% for erlotinib and gefitinib (odds ratio 1.28, 0.85-1.93;P= .2335). The median duration of response with osimertinib was 17.2 versus 8.5 months in the comparator arm.

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 (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 consistent separation of curves here and throughout, and with the brain activity, osimertinib is the drug I would use for all my patients as first-line therapy," said Ramalingam. "For patients with mutations in exon 19 or 21, which are the two most common mutations accounting for 90% ofEGFRmutations, this would be a new standard."

The most common all-grade adverse events (AEs) with osimertinib were diarrhea (58%; 2% grade ≥3) and dry skin (32%; <1% grade ≥3). In the comparator arm, diarrhea occurred in 57% of patients (3% grade ≥3) and dermatitis acneiform was experienced by 48% of patients (5% grade ≥3).

"The safety profile showed clear benefits to patients receiving osimertinib," said Ramalingam. "Treatment was much more tolerated with osimertinib and grade 3/4 all-cause events were almost 12% lower than standard therapies."

Several studies are already assessing treatments following resistances to osimertinib, he noted. The leading resistance mutation has emerged as C797S, and drugs are being developed to block this mechanism along with other pathways. Additionally, combination strategies are being developed.

"What is exciting about osimertinib is its safety profile lends itself better to developing combination approaches, which I think will be key for providing better outcomes to patients," said Ramalingam. "Osimertinib being a more tolerated, more efficacious EGFR drug provides us with a new platform on top of which we can build new therapies."


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.

Overall, 33.7% of patients experienced a grade ≥3 AE in the osimertinib group compared with 44.8% for erlotinib and gefitinib. AEs led to discontinuation for 13.3% and 18.1% of patients in the osimertinib and comparator arms, respectively.