Osimertinib (Tagrisso) reduced the risk of disease progression by 70% compared with a chemotherapy doublet in patients with EGFR T790M-mutant non–small cell lung cancer (NSCLC) who progressed after first-line targeted therapy, according to phase III clinical trial results.
Vassiliki A. Papadimitrakopoulou, MD
Osimertinib (Tagrisso) reduced the risk of disease progression by 70% compared with a chemotherapy doublet in patients withEGFRT790M-mutant nonsmall cell lung cancer (NSCLC) who progressed after first-line targeted therapy, a benefit that was achieved with a dramatically lower rate of serious adverse events, according to phase III clinical trial results.
The positive findings, presented at the IASLC 17th World Conference on Lung Cancer and published simultaneously inThe New England Journal of Medicine,1,2set the stage for a new standard of care for second-line treatment of patients with locally advanced or metastatic NSCLC that harbors the T790M mutation, leading researchers indicated in announcing the results.
In the randomized AURA3 trial, patients who received osimertinib achieved a median progression-free survival (PFS) of 10.1 months (95% CI, 8.3-12.3) compared with 4.4 months (95% CI, 4.2-5.6) for participants treated with a platinum agent plus pemetrexed (HR, 0.30;P<.001).
Additionally, the median PFS duration for patients with central nervous system (CNS) metastases was longer among those who received osimertinib than among participants treated with chemotherapy (8.5 months vs 4.2 months, respectively; HR, 0.32).
The objective response rate also was significantly higher with osimertinib; the ORR was 71% for the tyrosine kinase inhibitor (TKI) versus 31% for chemotherapy (odds ratio, 5.39; 95% CI, 3.47-8.48;P<.001).
“These results show that osimertinib demonstrated a superior, clinically meaningful efficacy over platinumpemetrexed, establishing the new standard of care for these patients,” said Vassiliki A. Papadimitrakopoulou, MD, who presented the findings at the Vienna meeting.
“Patients receiving osimertinib experienced a 70% reduction in the risk of disease progression without severe toxicity, and similar efficacy was seen in patients with CNS metastases at baseline,” said Papadimitrakopoulou, who is a professor in the Department of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston.
The trial marked “the first time a targeted medicine like Tagrisso has shown improvement in progression-free survival over standard platinum-pemetrexed chemotherapy” in this setting, Papadimitrakopoulou noted in a statement.
Tony Mok, MD, the lead author on the journal article, stressed the importance of molecular testing. “With the publication of the AURA3 data, clinicians should perform T790M mutation testing to ensure Tagrisso be given to patients who are most likely to benefit,” said Mok, professor and chair of Medicine at the Chinese University of Hong Kong, in a statement.
Osimertinib, an oral EGFR inhibitor, gained accelerated approval from the FDA in November 2015 along with a companion diagnostic for patients with the T790M mutation whose disease has progressed after prior treatment with an EGFR inhibitor. The mutation develops in approximately 60% of patients who have received first-line EGFR-directed therapy.2
The AURA3 study, conducted to confirm the results that supported the accelerated approval, was an international, multicenter trial in which 1036 patients were screened from August 2014 through September 2015.
After the selection process, 419 patients were randomized 2:1 to receive either osimertinib at 80 mg once daily, or a platinumpemetrexed doublet consisting of pemetrexed (500 mg/m2) plus either cisplatin (75 mg/m2) or carboplatin (AUC5) every 3 weeks for up to 6 cycles. In all, 279 participants received osimertinib, and 140 patients received the platinumpemetrexed regimen.
The study arms were well balanced, researchers noted. The median age was 62 years in the osimertinib group and 63 years in the chemotherapy cohort. Nearly all of the patients had metastatic disease; 33% of the osimertinib group and 36% of the chemotherapy arm had CNS metastases.
For prior EGFR-targeted therapy approximately 60% of the participants had received gefitinib (Iressa), 35% had been treated with erolitinib (Tarceva), and nearly 6% had taken afatinib (Gilotrif).2
The primary endpoint of the study was PFS, as determined by investigator assessment according to RECIST v1.1. Secondary endpoints included response rate, duration, overall survival, and side-effect profiles.
In terms of adverse events, toxicities of grade>3 severity were reported in 23% of the osimertinib group versus 47% of the chemotherapy arm.2The most frequently reported grade >3 events in the chemotherapy arm were neutropenia (12%), anemia (12%), and thrombocytopenia (7%). The incidence of each of those toxicities in the osimertinib arm was 1% or less.2
The most common adverse events of any grade, reported in>10% of participants, associated with osimertinib included diarrhea (41%), rash (34%), dry skin (23%), and paronychia (22%). For those treated with platinumpemetrexed, the most common toxicities of any grade were nausea (49%), decreased appetite (36%), constipation (35%), and fatigue (28%).
As part of the study, researchers also analyzed plasma circulating tumor DNA (ctDNA) to determine whether the T790M mutation could be detected and compared with tissue testing.
Results of this analysis showed that PFS with osimertinib was similar, regardless of selection by tissue or plasma, for T790M-positive status. However, there was a high false-negative rate with ctDNA testing, investigators said. Based on these findings, biopsy testing is recommended for patients with a plasma T790M-negative test have disease progression after first-line EGFR TKI therapy.