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EGFR-Mutant NSCLC Gains New First-Line Treatment

— PFS doubled with osimertinib versus standard therapy

Ƶ MedicalToday

MADRID -- Patients with advanced, EGFR-mutant non-small cell lung cancer (NSCLC) lived almost twice as long without disease progression if they started treatment with osimertinib (Tagrisso) rather than standard anti-EGFR therapy, a randomized trial showed.

Initial treatment with osimertinib led to a median progression-free survival (PFS) of 18.9 months compared with 10.2 months for patients who received standard-of-care treatment with a first- or second-generation EGFR inhibitor. Patients with and without brain metastases derived a similar benefit, owing to osimertinib's ability to cross the blood-brain barrier, according to Suresh Ramalingam, MD, of Emory University's Winship Cancer Institute in Atlanta, and colleagues.

Action Points

  • Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

A preliminary analysis of overall survival (OS) showed almost a 40% reduction in the hazard ratio in favor of osimertinib, but the result did not meet the prespecified level of statistical significance, they reported here at the European Society for Medical Oncology annual meeting.

"We believe that the median progression-free survival [benefit] ... , the consistent separation of survival curves early and throughout, added on top of the brain activity, make osimertinib the drug that I would use for my patients when it is approved for first-line therapy," Ramalingam said.

In response to a question, Ramalingham said "from a mechanistic basis, we wouldn't expect the current group of EGFR inhibitors to be effective after patients have been exposed to osimertinib. Clearly, we're working on understanding the mechanisms of resistance after patients have been treated with osimertinib."

Stefan Zimmermann, MD, of Fribourgh Hospital in Switzerland, said he is ready to begin using osimertinib as initial therapy for patients with EGFR-mutant NSCLC.

"It was actually even better than expected," Zimmermann told Ƶ. "There was some concern in the community about the potential loss of a second-line therapy, but I think the fact that it targets everyone upfront for the resistance mutation -- as opposed to searching for the T790M mutation at relapse, and you lose some patients -- makes up for it."

EGFR mutations occur in 15% to 35% of patients with NSCLC. EGFR tyrosine kinase inhibitors (TKIs) are standard of care for first-line treatment of EGFR-mutant NSCLC and lead to a PFS of about 10 months. More than half of patients treated with first- and second-generation EGFR TKIs develop resistance mediated by the T790M mutation, Ramalingam noted.

Osimertinib, a third-generation EGFR inhibitor, selectively inhibits EGFR mutations and T790M resistance mutations and has activity in the central nervous system. The drug currently has approval for treatment of advanced NSCLC and T790-mediated acquired resistance. Preclinical and preliminary clinical data suggest osimertinib might also represent an effective first-line treatment for EGFR-mutant NSCLC.

Ramalingam reported initial findings from the FLAURA double-blind randomized trial to compare osimertinib and standard EGFR TKIs as initial treatment advanced NSCLC and pathology-confirmed Exon 19 deletion/L858R mutations. Eligible patients had no prior EGFR TKI treatment, and enrollment criteria included neurologically stable patients with brain metastases.

Investigators randomized patients to osimertinib or to standard-of-care EGFR TKIs. The trial had a primary endpoint of PFS. Secondary endpoints included response rate, duration of response, disease control rate, and OS, among others.

Data analysis included 556 patients, which provided the statistical power to detect an improvement in PFS from 10 months with standard therapy to 14 months with osimertinib. The global enrollment in the trial resulted in a study population women and Asian patients accounting for more than 60% of total accrual. About 20% of patients in each treatment group had brain metastases at enrollment.

The primary analysis showed that patients randomized to osimertinib had a 54% reduction in the hazard for disease progression or death (95% CI 0.37-0.57, P<0.0001). A subgroup analysis showed that the PFS benefit favoring osimertinib remained consistent across all prespecified patient groups, including patients with brain metastases, who had a median PFS of 19.1 months with osimertinib versus 10.9 months with standard care (HR 0.46, 95% CI 0.36-0.59, P<0.0001).

A preliminary survival analysis showed that treatment with osimertinib was associated with a 37% reduction in the hazard ratio (95% CI 0.45-0.88, P=0.0068). However, the trial design specified a P-value of 0.0015 for statistical significance, meaning that the difference could not be considered statistically significant, said Ramalingham.

A fourth of patients had died at the time of the preliminary analysis. The final survival analysis will occur when mortality reaches 60%. Median OS had yet to be reached in either treatment group.

Analysis of other secondary endpoints showed similar objective response rates (75% to 80%). However, responses to osimertinib lasted twice as long (17.2 versus 8.5 months).

In general, adverse event rates were similar between treatment groups, although osimertinib was associated with fewer grade ≥3 adverse events and a lower discontinuation rate.

  • author['full_name']

    Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined Ƶ in 2007.

Disclosures

FLAURA was supported by AstraZeneca.

Ramalingam disclosed relevant relationships with AstraZeneca, Bristol-Myers Squibb, Genentech, and Boehringer Ingelheim.

Primary Source

European Society for Medical Oncology

Ramalingam S, et al "Osimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients with EGFRm advanced NSCLC: FLAURA" ESMO 2017; Abstract LBA2.