Osimertinib Produces High Response Rate in EGFR T790M-Mutant NSCLC

Tetsuya Mitsudomi, MD, PhD

The third-generation TKI osimertinib (AZD9291) showed a 71% objective response rate (ORR) in patients with EGFR T790M-mutant non—small cell lung cancer (NSCLC) following resistance to frontline anti-EGFR therapy, according to results of the phase II AURA2 trial presented at the 2015 World Conference on Lung Cancer (WCLC).¹

The ORR was comprised of 2 complete responses and 139 partial responses. The stable disease rate at ≥6 weeks was 21%, for a disease control rate of 92%. After a median follow-up of 6.7 months, the median progression-free survival (PFS) was 8.6 months. The median duration of response was 7.8 months (27% maturity).

“A high objective response rate and promising progression-free survival with AZD9291 was observed across lines of therapy,” said lead investigator Tetsuya Mitsudomi, MD, PhD, chief of thoracic surgery at Aichi Cancer Center Hospital in Nagoya, Japan. “The frequency of treatment-related grade 3 or higher adverse events was low, and a total of seven patients discontinued AZD9291 due to treatment-related adverse events.”

Findings from the AURA2 trial add to results from an expansion cohort of the phase II AURA trial, which demonstrated an ORR of 61% with osimertinib in patients with previously treated EGFR T790M-mutant NSCLC (n = 201). In this investigation, which was also presented at WCLC, the median PFS and duration of response were not yet mature.²

Findings from the two studies were the basis for a new drug application for osimertinib, which was submitted earlier this year to the FDA and granted a priority review designation, according to the drug’s developer AstraZeneca. Under the priority review timeline, the FDA will make a decision on the medication in the first quarter of 2016.

“The data support our accelerated development strategy with AZD9291, which has moved with unprecedented speed from first human studies to the US Food and Drug Administration and other regulatory submissions," Antoine Yver, head of oncology, Global Medicines Development at AstraZeneca, said in a statement. "With AZD9291 now under review by global regulatory authorities, we are on track to bring this innovative medicine to patients as quickly as possible to address this critical need.”

Patients with EGFR-mutant NSCLC often respond to first-generation EGFR inhibitors, such as gefitinib and erlotinib, and responses may be prolonged in some instances. However, virtually all patients eventually develop resistance to the therapy. In approximately 50% to 60% of cases, resistance is associated with the presence of the acquired EGFR T790M mutation.

Osimertinib is an oral, irreversible EGFR TKI selective for both EGFR-sensitizing and T790M resistance mutations. Positive phase I data led to phase II-III clinical development, including a trial involving patients with tumors that had developed resistance to prior anti-EGFR therapy.

Investigators in the multicenter AURA2 trial enrolled 210 patients with locally advanced or metastatic NSCLC that had progressed during or after treatment with an approved EGFR TKI. All patients had tumors that tested positive for the T790M resistance mutation. Patients received AZD9291 at a dose of 80 mg once daily, continued until disease progression. The primary endpoint was ORR.

Patients had a median age of 64 and a female predominance (70%). Asians accounted for almost two thirds of the patients, and three fourths of the cohort had never smoked. Tumor histology was adenocarcinoma in 96% of cases. The patients had received a median of one prior therapy, but the range was one to nine.

One patient had the T790M mutation as the only alteration. Two thirds had an exon 19 deletion and a third had the L858R mutation.

Objective response to therapy was consistent across all prespecified subgroups, and ranged from 59% to 78%. Only patients with the L858R mutation appeared to derive less benefit from treatment with osimertinib as compared with the overall cohort (59% overall response rate). At a 6-month analysis, 70% of patients were alive and progression-free and by 9-months the PFS rate was 48%.

Grade ≥3 adverse events occurred in 29% of patients, including drug-related events in 11%. The rate of discontinuation prompted by adverse events was 3%. One death was considered attributable to a drug-related adverse event.

The most common adverse events (any grade) were diarrhea (39%), dry skin (25%), rash (23%), nausea (16%), and paronchia, constipation, pruritus, and fatigue (15% each). Of those events, only diarrhea occurred at grade ≥3 severity and affected two patients.

With respect to specific adverse events of interest, interstitial lung disease occurred in 2% of patients (1% grade ≥3), hyperglycemia in 1%, and QT prolongation in 5% (2% grade ≥3).

“AZD9291 has demonstrated a positive clinical benefit-risk profile across two phase II studies, with encouraging duration of response and progression-free survival data,” said Mitsudomi. “A longer follow-up is needed to fully characterize these efficacy outcomes.”

A phase III trial has already begun, he added, comparing osimertinib and a platinum-based chemotherapy doublet in patients with T790M-positive advanced NSCLC that has progressed following prior EGFR-TKI therapy.

In the first-line setting, early data demonstrated promising efficacy in 60 patients with EGFR-mutant advanced NSCLC treated with osimertinib. In this setting, the 12-month PFS rate was 72% (95% CI, 58-82). The ORR was 75% (95% CI, 62-85), and the longest observed response was ongoing at 18 months.³

“While the data are still preliminary, these latest results from the AURA trial first-line cohort further reinforce the potential of AZD9291 in treatment-naïve EGFR-mutant advanced NSCLC patients,” said lead investigator Suresh S. Ramalingam, MD, chief of Thoracic Oncology and director of Medical Oncology, Emory University School of Medicine.

References

1. Mitsudomi T, Tsai C, Shepherd F, et al. AZD9291 in pre-treated T790M positive advanced NSCLC: AURA2 Phase II study. Presented at: 16th World Conference on Lung Cancer; September 6-9; Denver, CO. Abstract 1406.
2. Yang JC, Ahn M, Ramalingam SS, et al. AZD9291 in pre-treated T790M positive advanced NSCLC: AURA study Phase II extension cohort. Presented at: 16th World Conference on Lung Cancer; September 6-9; Denver, CO. Abstract 943.
3. Ramalingam SS, Yang JC, Lee C, et al. AZD9291 in treatment-naïve EGFRm advanced NSCLC: AURA first-line cohort. Presented at: 16th World Conference on Lung Cancer; September 6-9; Denver, CO. Abstract 1232.

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