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Data Support 'Best Drug First' in EGFR-Mutant NSCLC

— Six-month survival gain with osimertinib, adding to PFS, safety advantages

Last Updated November 6, 2019
MedpageToday

BARCELONA -- Treatment with a resistance-targeting epidermal growth factor receptor (EGFR) inhibitor significantly improved overall survival (OS) as initial therapy for patients with advanced EGFR-positive non-small cell lung cancer (NSCLC), according to final results from a randomized trial.

Patients treated with osimertinib (Tagrisso) had a median OS of 38.6 months, as compared with 31.8 months for patients who started treatment with a conventional EGFR inhibitor. Landmark analyses showed substantial differences in favor of osimertinib after 12, 24, and 36 months of follow-up.

The findings reinforced the analysis of progression-free survival, the primary endpoint for the FLAURA trial, which showed an 8-month advantage for patients initially treated with osimertinib, said Suresh S. Ramalingam, MD, of Emory University's Winship Cancer Center in Atlanta, at the European Society for Medical Oncology (ESMO) annual meeting.

The results also added support to the drug's first-line indication, granted by the FDA in 2018.

"We've shown that osimertinib improves overall survival for patients with EGFR-mutated disease in a clinically and statistically significant manner," he said. "The final overall survival analysis of FLAURA reinforces osimertinib as the standard of care for first-line treatment of patients with EGFR-mutated advanced non-small cell lung cancer."

Summarizing the key data and their implications, invited ESMO discussant Pilar Garrido, MD, of Hospital Universitario Ramon y Cajal in Madrid, said the data from the FLAURA trial "showed a consistent benefit in terms of progression-free survival, safety profile, and now more than 6 months improvement in overall survival. These results are clinically relevant."

During the discussion that followed his presentation, Ramalingam addressed the issue of whether patients might derive greater benefit from starting with a second-generation EGFR inhibitor and then following up with osimertinib when resistance occurs.

"The results of the FLAURA trial clearly show that we should give the best agent first," he said. "I say that because 30% of patients in both arms of the trial did not receive any subsequent therapy after progression, and for the vast majority of them, it was because they died. For those patients, the first-line treatment was the only shot they had. Second, not every patient develops a T790M mutation. If you go by sequencing, only 30%-35% of patients will have a chance to get to have osimertinib, even if they went on to receive second-line therapy."

"You can either give your best drug first, or roll the dice that you will lose the opportunity, in two out of three patients, to give second-line therapy. This is why we feel that the best drug should be given first," he added.

The FLAURA trial provided much of the supporting data for osimertinib's approval as first-line therapy for EGFR-mutated NSCLC. The trial included 556 patients with advanced NSCLC associated with exon 19 deletion/L858R mutations. The patients were randomized to osimertinib or to the treating physician's choice of erlotinib (Tarceva) or gefitinib (Iressa). The primary endpoint was PFS, and OS was a key secondary endpoint.

The primary analysis showed that patients treated with osimertinib had a median PFS of 18.9 months versus 10.2 months for the comparator EGFR inhibitors. The difference represented a 54% reduction in the hazard for disease progression or death in favor of osimertinib (P<0.001). A subgroup analysis showed a consistent benefit with osimertinib, similar to the advantage observed in the overall patient population.

The analysis of OS occurred after 321 deaths, representing a 58% data maturity level. The 6.8-month difference in median OS represented a 20% reduction in the survival hazard in favor of osimertinib (95% CI 0.641-0.997, P=0.0462). Landmark analyses showed that 89% of patients in the osimertinib group were alive at 12 months compared with 83% of the control group, declining to 74% versus 54% at 24 months, and to 54% versus 44% at 36 months.

Time to first subsequent treatment (reflecting durability of treatment activity and tolerability) was almost twice as high in the osimertinib group. The median time to next therapy or death was 25.5 months with osimertinib and 13.7 months with gefitinib and erlotinib, a 52% reduction in the hazard ratio (95% CI 0.393-0.581, P<0.0001). After 36 months of follow-up, three times as many patients in the osimertinib group remained on study treatment (28% vs 9%).

The consistent survival benefit emerged despite the fact that almost half of the patients in control arm crossed over to osimertinib at progression and likely benefited from the treatment, said Ramalingam.

No new safety signals emerged in the interval from the PFS analysis to the OS analysis. In general, adverse event rates were similar in the treatment groups, but osimertinib was associated with fewer grade 3/4 adverse events.

  • author['full_name']

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

Disclosures

FLAURA was supported by AstraZeneca.

Ramalingam disclosed relevant relationships with AstraZeneca, Amgen, Bristol-Myers Squibb, Merck, Roche/Genentech, Loxo, Nektar, Tesaro, Advaxis, Takeda, J.E. Gray, Celgene, Takeda, Array, and Boehringer Ingelheim.

Primary Source

European Society for Medical Oncology

Ramalingam SS, et al "Osimertinib vs comparator EGFR-TKI as first-line treatment for EGFRm advanced NSCLC (FLAURA): Final overall survival analysis" ESMO 2019; Abstract LBA5_PR.