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Osimertinib shows 'consistent improvement' in post-progression endpoints for non-small cell lung cancer

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February 6, 2019

First-line osimertinib compared favorably to standard-of-care epidermal growth factor receptor tyrosine kinase inhibitors in patients with untreated EGFR-mutated non-small cell lung cancer, sustaining clinical benefit beyond first progression, according to post-progression data from the randomized phase 3 FLAURA trial.

These results suggest that first-line osimertinib (Tagrisso, AstraZeneca) does not cause any biological changes or resistance to subsequent anticancer therapies that would cause more aggressive disease or rapid progression, according to the researchers.

“Osimertinib is a third-generation, central nervous system-active, epidermal growth factor receptor tyrosine kinase inhibitor that potently and selectively inhibits both EGFR-mutant and EGFR T790M resistance mutations,” David Planchard, MD, PhD, associate professor of medicine in the department of medicine at Gustave Roussy in Villejuif, France, and colleagues wrote. “In the phase 3 FLAURA study of osimertinib vs. standard-of-care EGFR TKIs as first-line treatment for advanced NSCLC harboring EGFR-sensitizing mutations, PFS was significantly improved with osimertinib. Interim OS data were encouraging, but not formally statistically significant.”

In the exploratory, post-progression analysis, researchers evaluated 556 previously untreated patients who had received at least one study drug dose on the FLAURA trial. Patients had EGFR-mutated, locally advanced, metastatic NSCLC eligible for first-line treatment with gefitinib (Iressa, AstraZeneca) or erlotinib (Tarceva; Genentech; Astellas Oncology).

Researchers stratified patients by tumor EGFR mutation status (ex19del or L858R) and race (Asian or non-Asian) and randomly assigned them 1:1 to receive osimertinib 80 mg orally once a day (n = 279) or a standard-of-care EGFR TKI (gefitinib 250 mg orally once a day or erlotinib 150 mg orally once a day; n = 277).

The investigators allowed treatment after progression in cases with potential for ongoing benefit. Also, patients could cross over from a standard-of-care EGFR TKI to open-label osimertinib upon independent verification of disease progression and known T790M-positive mutation.

PFS served as the study’s primary endpoint. Exploratory post-progression endpoints included second PFS, time to second-line treatment, time to third-line treatment and time to discontinuation of any EGFR TKI.

At the time of data cutoff on June 12, 2017, 138 patients (49%) in the osimertinib group and 213 patients (77%) in the standard-of-care group either ceased study treatment or died.
Median time to discontinuation was 20.8 months (95% CI, 17.2-24.1) in the osimertinib group and 11.5 months (95% CI, 10.3-12.8) in the standard TKI group.

A comparable proportion of patients remained on treatment beyond progression, including 91 (67%) of those the osimertinib group and 145 (70%) in the standard-of-care group.

Median post-progression treatment duration was 8.1 weeks (95% CI, 6.3-12.3) in the osimertinib group and 7 weeks (95% CI, 5.9-8.1) in the standard-of-care group.
in the osimertinib group and 129 (61%) in the standard-of-care group began second-line therapy. The most prevalent second-line therapy was platinum-based chemotherapy (n = 46; 56%) in the osimertinib group, and osimertinib (n = 55; 43%) in the standard-of-care group.

The osimertinib group had a significantly longer median time to second-line therapy, at 23.5 months (95% CI, 22-not calculable), vs. the standard-of-care group at 13.8 months (95% CI, 12.3-15.7; HR = 0.51; 95% CI, 0.4-0.64).

Including second treatments, 128 (46%) patients in the osimertinib group and 167 (60%) in the standard-of-care group discontinued any EGFR TKI regimens or died. Median time to discontinuation of any EGFR TKI or death was 23 months (95% CI, 19.5-not calculable) in the osimertinib group and 16 months (95% CI, 14.8-18.6) in the standard-of-care group.

Seventy-three patients (26%) in the osimertinib group and 106 patients (38%) in the standard-of-care group experienced second progression eventsor died. Median second PFS was not reached (95% CI, 23.7-not calculable) in the osimertinib group and was 20 months (95% CI, 18.2-not calculable) in the standard-of-care group.

“All post-progression endpoints showed consistent improvement with osimertinib vs. standard-of-care EGFR-TKI, providing further confidence in the interim overall survival,” the researchers wrote. “[These] clinically meaningful improvements ... advocate first-line use of osimertinib in patients with EGFR TKI in advanced NSCLC and provide further confidence in the encouraging interim data of the FLAURA study.” – by Jennifer Byrne

Disclosures: Planchard reports consultant/advisory or lecturing roles with AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, Novartis, Pfizer and prIME Oncology; peer CME for Roche; honoraria from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer and prIME Oncology; and clinical trials research funding from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, MedImmune, Merck, Novartis, Novocure, Pfizer, Roche, Sanofi and Taiho Pharmaceutical. Please see the study for all other authors’ relevant financial disclosures.

 

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