Post-Progression Data Establishes Osimertinib as Frontline Standard of Care for EGFR-Mutant NSCLC

David Planchard MD, PhD

First-line treatment with osimertinib (Tagrisso) resulted in a clinically meaningful delay in time from randomization to progression on subsequent treatment or death (PFS2) compared with standard of care (SOC) EGFR TKIs, establishing the agent as a new standard of care in the frontline setting for patients with EGFR-mutant non—small cell lung cancer (NSCLC), according to an analysis of the FLAURA study presented at the 2018 European Lung Cancer Conference.¹

The most common second-line therapy in the osimertinib arm was platinum-based chemotherapy whereas patients in the SOC arm most frequently received subsequent osimertinib. The median PFS2 was not reached for patients receiving frontline osimertinib (95% CI, 23.7-not calculable [NC]) compared with 20.0 months in patients receiving SOC (95% CI, 18.2-NC), this was equivalent to a 42% reduction in the risk of progression on second-line therapy or death (HR, 0.58; 95% CI, 0.44-0.78; P <.001).

"This is probably the most important data. PFS2 was significantly delayed in favor of osimertinib," lead investigator David Planchard, MD, PhD, Department of Medical Oncology, Institut Gustave Roussy in Villejuif, France, said during his presentation. "There were clinically meaningful improvements in time to discontinuation of treatment, time to first subsequent treatment, PFS2, and time to discontinuation of any EGFR TKI in favor of osimertinib versus standard of care EGFR TKI."

These findings add to results from the FLAURA study that were published in the New England Journal of Medicine.² In this analysis, the median progression-free survival (PFS) seen with osimertinib was 18.9 months compared with 10.2 months for SOC (HR, 0.46; 95% CI, 0.37-0.57; P <.001). Additionally, a nonstatistically significant improvement in overall survival was observed with osimertinib compared with SOC (HR, 0.63; 95% CI, 0.45-0.88; P = 0.007).

“Interim overall survival data were encouraging but not formally statistically significant at the current maturity of 25%,” Planchard explained. At that level of maturity, a P-value of <.0015 was needed to achieve statistical significance. "All hazard ratios showed consistent improvement with osimertinib versus SOC EGFR TKI, which provides further confidence in the encouraging interim OS data," he added, regarding the post-progression analysis.

The phase III FLAURA trial enrolled 556 treatment-naive patients who were equally randomized to oral osimertinib at 80 mg once daily (n = 279) or SOC (n = 277), consisting of either oral gefitinib at 250 mg orally once daily or oral erlotinib at 150 mg once daily. Patients continued to receive treatment until disease progression; treatment beyond progression with subsequent therapy was per investigator discretion and patients on SOC could cross-over to osimertinib following central confirmation of progression and EGFR T790M positivity.

As of the data cutoff on June 12, 2017, frontline treatment was discontinued by 138 patients (49%) in the osimertinib cohort and by 213 patients on SOC (77%). Of those discontinuing, 82 patients (59%) in the osimertinib arm versus 129 patients (61%) on SOC received subsequent treatment. In the osimertinib cohort, 56% received subsequent platinum-based chemotherapy and 35% received EGFR TKIs other than osimertinib. Twenty-one percent of patients in the SOC group received subsequent platinum-based chemotherapy, 33% received EGFR-TKIs, and 43% were treated with osimertinib.

With osimertinib the median time to discontinuation of study treatment or death was 20.8 months (95% CI, 17.2-24.1) compared with 11.5 months (95% CI, 10.3-12.8) with SOC. The median time to discontinuation of any EGFR TKI or death was 23.0 months (95% CI, 19.5-NC) with osimertinib versus 16.0 months with SOC (95% CI, 14.8-18.6).

“The stepwise increase in hazard ratios with each post-progression endpoint provides confidence in the interim overall survival data,” Planchard commented. Adding to this, the invited discussant, Tetsuya Mitsudomi, MD, Kindai University Faculty of Medicine in Osaka Japan, supported the use of time to first and second progression as surrogate endpoints for overall survival.

“Although overall survival is the golden standard that is independent of bias-prone variables and unambiguous, it is also impractical given the length, cost, and expense of clinical trials. In addition, overall survival may capture the impact of subsequent therapies,” said Mitsudomi. “The post-progression outcome endpoints of TFST, PFS2, and TSST are likely to be associated with overall survival; furthermore, time to discontinuation of TKI was longer by 6 months with osimertinib, even with reasonable cross-over from the SOC. In addition, CNS penetration and safety data favor osimertinib.”

Based on data from the FLAURA trial, the FDA is currently considering approval for osimertinib as a frontline therapy or EGFR-mutant NSCLC, with a decision anticipated in the next few months. Osimertinib is currently approved as a second-line therapy for patient with NSCLC harboring the acquired EGFR T790M resistance mutation following a frontline EGFR TKI.

References:

1. Planchard D, Boyer M, Lee J-S, et al. Osimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients (pts) with untreated EGFRm advanced NSCLC: FLAURA post-progression outcomes. Presented at: the 2018 European Lung Cancer Conference; April 11-14; Geneva, Switzerland. Abstract 128O.
2. Soria J-C, Ohe Y, Vansteenkiste J, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non—Small-Cell Lung Cancer. N Engl J Med. 2018;378:113-125. DOI: 10.1056/NEJMoa1713137.

<<< 2018 European Lung Cancer Congress

The median time to first subsequent therapy or death (TFST) was 23.5 months in the osimertinib group (95% CI, 22.0-NC) versus 13.8 months (95% CI, 12.3-15.7) for those receiving SOC (HR, 0.51; 95% CI, 0.40-0.64; P <.0001). Median time to second subsequent therapy or death (TSST) was also prolonged in the osimertinib group (25.9 months in the SOC arm and not reached in the osimertinib group; HR, 0.60; 95% CI, 0.45-0.80).