Osimertinib Extends PFS in Phase III Study for T790M-Mutant NSCLC

Sean Bohen, MD, PhD

The phase III AURA3 study has confirmed the benefits of osimertinib (Tagrisso) seen in phase II studies for patients with EGFR T790M-mutant locally-advanced or metastatic non—small cell lung cancer (NSCLC) who progressed on a frontline EGFR TKI, according to a statement from the manufacturer of the EGFR inhibitor, AstraZeneca.

In the phase III study, osimertinib demonstrated a significant improvement in progression-free survival (PFS) compared with standard platinum-based chemotherapy. Additionally, secondary endpoints of objective response rate (ORR), disease control rate, and duration of response were also improved with osimertinib versus chemotherapy. Further analyses of the study are ongoing, specifically for overall survival, according to AstraZeneca.

The company plans to present results from the AURA3 trial at an upcoming medical meeting. Findings from the phase III trial will serve as confirmatory findings for an accelerated FDA approval received by osimertinib in November 2015.

“These results confirm Tagrisso as a meaningful alternative to benefit EGFR T790M lung cancer patients," Sean Bohen, MD, PhD, executive vice president, Global Medicines Development and chief medical officer at AstraZeneca, said in a statement.

In the open-label study, 419 patients were randomized in a 2:1 ratio to receive osimertinib or a platinum-based chemotherapy doublet. Osimertinib (formally AZD9291) 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.

All patients enrolled in the study were chemotherapy naive, with confirmed progression on erlotinib, gefitinib, or afatinib. Those who progressed on treatment in the chemotherapy were eligible to cross over to receive osimertinib; however, if patient's stopped chemotherapy for any reason other than progression, they were not eligible for cross over. If a clinical benefit was still observed, patients were permitted to receive osimertinib beyond radiographic progression.

The primary endpoint of the study was PFS, which was assessed by blinded independent central review. Response was measured using RECIST v1.1 criteria.

In 2015, osimertinib was granted an accelerated approval for patients with advanced EGFR T790M-mutant NSCLC following progression on a prior EGFR TKI, based on data from 411 patients in two single-arm studies. Along with osimertinib, the FDA also approved the cobas EGFR Mutation Test v2 as a companion diagnostic.

In the first study, labeled AURA2, the ORR with osimertinib was 61% in 210 patients with pretreated EGFR T790M-mutant NSCLC (95% CI, 54-68). In the second trial, which was an extension to the AURA study, the ORR was 57% in 201 patients. In a pooled-analysis of the two studies, the ORR with osimertinib was 59%, with a 12.4-month duration of response.

In February 2016, the European Commission (EC) also granted a conditional marketing authorization to osimertinib for patients with locally advanced or metastatic EGFR T790M-mutant NSCLC; however, this approval was intended for patients regardless of prior treatment with EGFR TKI. The EC noted in its approval that the EGFR T790M alteration could be detected using either tumor or blood testing.

The EC approval was based on data from two phase II studies and one phase I expansion study, which together investigated osimertinib in 474 patients with NSCLC. In the phase II AURA and AURA2 trials, the combined ORR with osimertinib was 66% (95% CI, 61-71) and median PFS was 11 months (95%, CI 9.6-12.4). In the third study, the ORR in treatment-naive patients was 75%.

According to AstraZeneca, the safety profile for osimertinib that was observed in the phase III AURA3 study was consistent with expectation set by the earlier studies. Further findings from patient-reported outcomes will be reported from the phase III study, as a secondary endpoint.

"The AURA3 results demonstrate the benefits of our science-led approach that enabled the rapid development of Tagrisso as a targeted treatment to address the most common cause of resistance to a first-generation EGFR-TKI for patients with metastatic EGFR-mutant lung cancer," said Bohen. "We remain committed to exploring the potential of Tagrisso to further extend its reach and help meet patient need.”

The time from the start of clinical trials to FDA approval for osimertinib was just two and a half years. As it was developed, the agent received fast track and breakthrough therapy designations from the FDA, which helped to expedite its approval.

Several clinical trials continue to assess osimertinib, both as a single agent and in novel combinations. The EGFR inhibitor is being explored with the PD-L1 inhibitor durvalumab, the MEK inhibitor selumetinib, and with the MET inhibitor savolitinib for patients with NSCLC.

A phase III study is exploring osimertinib in the frontline setting following tumor resection, with or without adjuvant chemotherapy (NCT02511106). Additionally, an ongoing phase III study is comparing osimertinib with gefitinib or erlotinib in the frontline setting for patients with EGFR-mutant NSCLC (NCT02296125).

In a combined analysis of the 411 patients in both second-line trials, the FDA reported that the most commonly reported all-grade adverse events (AEs) were diarrhea (42%), rash (41%), dry skin (31%), nail toxicity (25%), eye disorders (18%), nausea (17%), decreased appetite (16%), and constipation (15%). These events were primary grade 1/2, with a low rate of grade ≥3 AEs. The most common grade ≥3 AEs were pneumonia (2%) and pulmonary embolism (2%).