Osimertinib Granted FDA's Full Approval for T790M+ NSCLC

Vassiliki A. Papadimitrakopoulou, MD

Vassiliki A. Papadimitrakopoulou, MD

Osimertinib (Tagrisso) has been granted a full approval 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.

&ldquo;These results show that osimertinib demonstrated a superior, clinically meaningful efficacy over platinum—pemetrexed, establishing the new standard of care for these patients,&rdquo; 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. &ldquo;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.&rdquo;

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 &ge;3 AEs were reported in 23% of the osimertinib group versus 47% of the chemotherapy arm. The most frequently reported grade &ge;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 inThe New England Journal of Medicine. At the time, the lead author, Tony Mok, MD, noted that &ldquo;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.&rdquo;

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).

Reference:

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