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PL03.03: Randomized Phase III Study of Osimertinib vs Platinum-Pemetrexed for EGFR T790M-Positive Advanced NSCLC (AURA3)
Journal of Thoracic Oncology, Volume 12, Issue 1, January 2017, Pages S5 - S6
Abstracts from the IASLC 17th World Conference on Lung Cancer
IASLC 17th World Conference on Lung Cancer
Commentary by Tom Stinchcombe
Osimertinib or Platinum–Pemetrexed in EGFR T790M–Positive Lung Cancer
Osimertinib demonstrated a clinically significant overall response rate (ORR) and progression-free survival (PFS) in patients with EGFR mutant NSCLC with a T790M mutation in a phase 1 trial with an expansion cohort and a single arm phase 2 trial. This phase 3 trial enrolled patients who had experienced disease progression on EGFR TKI and demonstrated a T790M mutation. All patients were required to provide a blood sample for testing for plasma circulating tumor DNA. Patients were randomly assigned to osimertinib or pemetrexed with carboplatin or cisplatin. The primary end-point was PFS as assessed by investigator, and a secondary analysis assessed PFS by blinded independent central review. The PFS was significantly longer with osimertinib compared to platinum-pemetrexed chemotherapy (hazard ratio (HR) of 0.30; 95% CI, 0.23 to 0.42; P<0.001; median 10.1 and 4.4 months, respectively) and higher ORR (71% vs 31%; odds ratio of 5.39; P<0.001). The independent radiological review for PFS was consistent with the investigator assessed PFS. The patient reported outcomes were better in the osimertinib arm. Osimertinib was associated with a lower rate of grade ≥ 3 adverse events. In the subset of patients with CNS metastases (n=144) the PFS was significantly longer was osimertinib (HR of 0.32; 95% CI, 0.23 to 0.49; median 8.5 and 4.2 months, respectively). The response rate for the subset of patients with EGFR T790M detected on plasma testing (n=116) was 77% (95% CI, 68-84) and the median PFS was 8.2 months (95% CI, 6.8 to 9.7).
This phase 3 trial confirms the activity of osimertinib, and T790M mutation testing and the use osimertinib for patients with a known T790M was the standard of care before presentation and publication of the trial. The more interesting questions are the benefit in the first-line setting and if the favorable toxicity profile of osimertinib will facilitate the development of combination therapy. The fact the outcomes with osimertinib were similar in the intent-to-treat and patients with T790M detected on plasma is reassuring since clinicians have adopted circulating tumor DNA tests in clinical practice.
Osimertinib is a potent, irreversible, CNS active, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) selective for sensitizing (EGFRm) and T790M resistance mutations. Osimertinib is indicated for the treatment of patients with locally advanced or metastatic EGFR T790M-positive NSCLC. AURA3 (NCT02151981) is a Phase III, open-label, randomized study assessing the efficacy and safety of osimertinib versus platinum-based chemotherapy plus pemetrexed in patients with EGFR T790M-positive advanced NSCLC, whose tumors progressed on first-line EGFR-TKI therapy.
Eligible patients were ≥18 years with documented EGFRm, radiological disease progression following first-line EGFR-TKI and centrally confirmed T790M-positive (by cobas® EGFR Mutation Test) from a tissue biopsy after disease progression. Asymptomatic, stable CNS metastases were allowed. Patients were randomized 2:1 to osimertinib 80 mg orally, once daily or platinum-pemetrexed (pemetrexed 500 mg/m2 plus either cisplatin 75 mg/m2 or carboplatin AUC5) every three weeks for up to six cycles; pemetrexed could be continued as maintenance treatment. Primary endpoint was progression-free survival (PFS) by investigator assessment according to RECIST v1.1; sensitivity analysis was by blinded independent central review (BICR).
A total of 419 patients were randomized to treatment (osimertinib, n=279; platinum-pemetrexed, n=140). Baseline characteristics were generally balanced across treatment groups: female 64%, Asian 65%, never smoker 68%, CNS metastases 34%, EGFR exon 19 deletion 66%. Osimertinib significantly improved PFS compared with platinum-pemetrexed: hazard ratio [HR] 0.30; 95% CI: 0.23, 0.41; p<0.001 (median 10.1 months vs 4.4 months). The result was consistent with PFS analysis by BICR: HR 0.28; 95% CI: 0.20, 0.38; p<0.001 (11.0 months vs 4.2 months). Objective response rate was significantly improved with osimertinib (71%) vs platinum-pemetrexed (31%); odds ratio 5.39 (95% CI: 3.47, 8.48; p<0.001). Median duration of response was 9.7 months (95% CI 8.3, 11.6) with osimertinib and 4.1 months (95% CI 3.0, 5.6) with platinum-pemetrexed. Grade ≥3 causally-related adverse events (AEs) as assessed by the investigator were reported in 6% of patients (n=16) treated with osimertinib and 34% (n=46) treated with platinum-pemetrexed. Most common causally-related AEs in the osimertinib group: diarrhoea (29% [grade ≥3, 1%]), rash (28% [<1%]); in the platinum-pemetrexed group: nausea (47% [3%]), decreased appetite (32% [3%]).
In patients with EGFR T790M-positive advanced NSCLC following progression on EGFR-TKI treatment, osimertinib demonstrated a superior clinically-meaningful efficacy over platinum-pemetrexed, with a 70% reduction in the risk of disease progression, and well-characterized safety profile, establishing the new standard of care for these patients.
EGFRm, T790M, osimertinib, AZD9291
1 Thoracic/Head and Neck Medical Oncology, the University of Texas, MD Anderson Cancer Center, Houston/TX/United States of America
2 Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou/China
3 Samsung Medical Center, Seoul/Korea, Republic of
4 Emory University, Winship Cancer Institute, Atlanta/GA/United States of America
5 Medical Oncology Department, Thoracic Oncology Unit, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan/Italy
6 Department of Internal Medicine, Division of Medical Oncology, Yonsei University College of Medicine, Seoul/Korea, Republic of
7 Princess Margaret Cancer Center, Toronto/ON/Canada
8 Third Department of Internal Medicine, Wakayama Medical University, Wakayama/Japan
9 Department of Thoracic Oncology, the Netherlands Cancer Institute, Amsterdam/Netherlands
10 Clinical Research Unit, St George Hospital, Clinical Research Unit, Kogarah/NSW/Australia
11 University Hospital Frankfurt, Goethe University, Frankfurt Am Main/Germany
12 Astrazeneca, Cambridge/United Kingdom
13 Key Laboratory of South China, Department of Clinical Oncology, the Chinese University of Hong Kong, Sha Tin/Hong Kong Prc
© 2016 Published by Elsevier B.V.