FDA Grants Full Approval to Osimertinib for T790M+ NSCLC

Vassiliki A. Papadimitrakopoulou, MD

The FDA has granted a regular approval to osimertinib (Tagrisso) as a treatment for patients with metastatic EGFR T790M mutation-positive non—small cell lung cancer (NSCLC) following prior treatment with an EGFR TKI, based on progression-free survival (PFS) findings from the phase III AURA3 trial.

In the randomized trial, osimertinib demonstrated a median PFS of 10.1 months compared with 4.4 months for standard platinum-based chemotherapy (HR, 0.30; 95% CI, 0.23-0.41; P <.001). The median PFS for patients with central nervous system (CNS) metastases was 8.5 months with osimertinib versus 4.2 months with chemotherapy (HR, 0.32; 95% CI, 0.21-0.49). Osimertinib was originally granted an accelerated approval in November 2015, based on an overall response rates (ORR) of 59% across 2 single-arm studies.

“These results show that osimertinib demonstrated a superior, clinically meaningful efficacy over platinum—pemetrexed, establishing the new standard of care for these patients,” said lead investigator Vassiliki A. Papadimitrakopoulou, MD, form the MD Anderson Cancer Center, when she presented the findings at the IASLC 17th World Conference on Lung Cancer. “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.”

In the open-label study, 419 patients were randomized in a 2:1 ratio to receive osimertinib (n = 279) or a platinum-based chemotherapy doublet (n = 140). Osimertinib was administered once per day orally at 80 mg in a 21-day cycle. The chemotherapy arm included pemetrexed plus carboplatin or pemetrexed plus cisplatin. Pemetrexed was administered at 500 mg/m², carboplatin was given at a dose of 5 AUC, and cisplatin was administered at 75 mg/m².

The median age of patients in the osimertinib arm was 62 years compared with 63 years in the chemotherapy cohort. Nearly all the patients had metastatic disease, and 33% and 36% of those in the osimertinib and chemotherapy arms, respectively, had CNS metastases. Approximately 60% of the participants had received gefitinib (Iressa), 35% had been treated with erlotinib (Tarceva), and nearly 6% had taken afatinib (Gilotrif).

The ORR with osimertinib was 71% versus 31% with chemotherapy (odds ratio, 5.39; 95% CI, 3.47-8.48; P <.001). The 6-month PFS rate was 69% with osimertinib versus 37% with chemotherapy. At 12 months, 44% of those in the osimertinib arm were progression-free versus 10% in the chemotherapy group. Data for overall survival were not yet available.

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 platinum—pemetrexed, the most common toxicities of any grade were nausea (49%), decreased appetite (36%), constipation (35%), and fatigue (28%).

Grade ≥3 AEs were reported in 23% of the osimertinib group versus 47% of the chemotherapy arm. The 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.

Findings from AURA3 were also published in The New England Journal of Medicine. At the time, the lead author, Tony Mok, MD, noted that “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.”

Several clinical trials continue to assess osimertinib, both as a single agent and in novel combinations. A phase III study is exploring osimertinib in the frontline setting following tumor resection, with or without adjuvant chemotherapy (NCT02511106).

Mok TS, Wu YL, Ahn MJ, et al. The AURA3 Investigators. Osimertinib or platinum—pemetrexed in EGFR T790M–positive lung cancer. N Engl J Med. 2017; 376:629-640.