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Osimertinib shows 'consistent improvement' in post-progression endpoints for non-small cell lung cancer
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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.
Perspective
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The FDA approved osimertinib for frontline use after presentation of the FLAURA data in early 2018. Since then, it has been rapidly adopted as the preferred first-line agent for the management of patients with EGFR-mutant NSCLC.
This paradigm shift was based on the significant improvement in median PFS, favorable tolerability and reduction in disease burden, including CNS responses. However, even after the presentation of FLAURA data showed a near-doubling of PFS compared with erlotinib or gefitinib — there remained a prevailing sentiment among some practitioners to try to save osimertinib for those patients with an emergent T790M mutation. In theory, this second-line use would mirror the numerical PFS advantage seen with frontline use of osimertinib (by adding median PFS seen with a first-generation TKI and median PFS with a third-generation TKI). Additionally, this approach would offer sequential use of two active agents.
Although this numerical cumulative PFS benefit appears theoretically reasonable, it is often limited in its practical application for a few reasons. First, emergent T790M mutation is only present in about a half of the patients treated with a first-generation TKI. Second, about one-third to one-half of patients may not even be fit for second or later lines of therapy because of symptomatic decline in performance status due to progressive disease.
This paper by Planchard and colleagues replicates some real-world clinical observations — for example, time to second-line therapy was substantially shorter with first-generation TKI, and only about 60% of patients in each group went on to receive any second-line therapy. Among the subset of patients that progressed on erlotinib or gefitinib, 43% went on to received osimertinib in the second-line setting. Despite receiving osimertinib, PFS2 — or time from randomization to progression on next-line treatment or death from any cause after subsequent treatment — was statistically inferior in the standard-of-care group. This practice-affirming observation supports the use of osimertinib in the first line setting and increases our confidence in the preliminary unconfirmed OS benefit.
This paper adds credence to the belief that we must use our “best” approach first. As data from other clinical trials emerge, our “best” approach may change over time; however, as things stand now, osimertinib should remain our standard first-line approach for patients with newly diagnosed metastatic NSCLC harboring a sensitizing EGFR mutation.
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