Tagrisso as First-line Standard of Care for EGFR-mutated NSCLC?

The unveiling of the PACIFIC trial data electrified the first ESMO 2017 Presidential Symposium. Minutes later we were all on the edge of our seats again. Could FLAURA possibly outdo PACIFIC?

The AstraZeneca showdown continued with the presentation of Phase III (FLAURA) data for its third-generation, irreversible, EGFR TKI Tagrisso in previously untreated EGFR-mutated advanced NSCLC. Tagrisso significantly prolonged PFS compared with standard of care EGFR TKI (Tarceva or Iressa) (18.9 versus 10.2 months, respectively), corresponding to a 54% reduction in the risk of progression. Dr. Suresh Ramalingam pointed to the early and maintained separation of the KM-curves. These data are impressive given that FLAURA was designed to allow patients in the standard of care EGFR TKI group to cross over to receive Tagrisso upon progression and confirmation of T790M resistance. PFS benefit was consistent in subgroups, including in patients with or without CNS metastases. While ORRs were similar between the two arms (80% vs, 76%), duration of response was doubled with Tagrisso (17.2 months) vs. standard of care (8.5 months). Interim OS analysis (25% maturity) was not significant (p=0.0068). Safety of Tagrisso was comparable to the standard of care.

Tagrisso is currently approved for EGFR-TKI-treated advanced NSCLC patients who harbor T790M resistance mutations (note: Tagrisso’s EU label does not require prior EGFR TKI treatment). More than 50% of patients treated with EGFR TKIs develop EGFR-T790M-mediated resistance. Now that FLAURA shows Tagrisso to be a winner in the upfront setting, should the winner (Tagrisso) take it all? Should all EGFR-mutated (Ex19del/L858R) advanced NSCLC patients now receive first-line Tagrisso?

Professor Tony Mok, the discussant of FLAURA, was confident that Tagrisso is a clear winner in patients with CNS metastases. However, the question of whether Tagrisso should become the new first line standard of care in EGFR-mutated NSCLC patients will depend on the optimal sequence to improve OS.

  • 2009-2015: EGFR TKI → chemotherapy [[MOS: 21.6-30.9 months]]
  • 2015: EGFR TKI → Tagrisso (for T790M) or chemotherapy (for non-T790M) [[MOS: 26.8 months]]
  • 2017: Tagrisso → chemotherapy or other agent [[MOS: ???]]

A real paradigm change will depend on mature data. MOS data from the Phase III AURA3 trial are pending (i.e., the trial that supported full regulatory approval of Tagrisso from the FDA in March 2017) but is hoped to be comparable with that of the Phase II AURA extension study (26.8 months) (AURA extension and AURA3 led to FDA accelerated approval in 2015). Given the FLAURA interim OS data are not statistically significant and immature, the optimal sequence of therapy for EGFR-mutated advanced NSCLC is unclear. Mok suggests that a MOS of >30 months would likely ascertain that upfront Tagrisso is the optimal treatment approach in EGFR-mutated advanced NSCLC patients. Understanding the mechanism and management of Tagrisso resistance upon progression will also be important for guiding future sequencing strategies.


For Decision Resources Group’s 10-year market forecast of Tagrisso in advanced NSCLC, see the NSCLC Disease Landscape & Forecast. Our new Treatment Sequencing solution helps you identify physicians most frequent treatment sequences in commercially important populations and treatment scenarios. For more insights on oncology drug development, follow @RWebsterDRG



  • Ramalingam SS,et al. Osimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients (pts) with EGFRm advanced NSCLC: FLAURA. ESMO. 2017. LBA2_PR.

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