Osimertinib Response Shown in EGFR T790M-Positive NSCLC Patients

Patients with epidermal growth factor receptor T790M-positive non-small-cell lung cancer may respond to osimertinib after prior tyrosine kinase inhibitor therapy

medwireNews: AURA2 findings suggest efficacy for osimertinib in advanced non-small-cell lung cancer (NSCLC) patients with the Epidermal growth factor receptor (EGFR) T790M mutation who have previously received Tyrosine kinase inhibitors (TKIs).

A RECIST objective response to an 80 mg daily oral dose of the irreversible EGFR TKI, selective for the T790M resistance mutation, was achieved by 70% of 199 patients with stage IIIB/IV disease, including a complete response in 3%.

Median progression-free survival (PFS) was 9.9 months and response lasted for a median of 11.4 months. And at data cutoff, after a median of 13.0 months, 58% of patients remained on osimertinib therapy, the investigators report in The Lancet Oncology.

Lead author Glenwood Goss, from The Ottawa Hospital Cancer Centre in Ontario, Canada, and team note that osimertinib was “well tolerated” and had an adverse event profile consistent with the earlier AURA1 study.

In all, 85% of patients experienced one or more adverse events that were possibly related to treatment, with grade 3 or more severe events possibly associated with osimertinib in 12%. The most common grade 3 or 4 events possibly associated with treatment were prolonged QT (2%), decreased neutrophil count (1%) and thrombocytopenia (1%).

Dose interruptions, reductions or discontinuations due to adverse events occurred in 21%, 3% and 5%, respectively. One patient died from a possible treatment-related event.

“The data support osimertinib 80 mg once daily as a potential new treatment option for patients with advanced EGFR Thr790Met-positive NSCLC, and supports a potential change in clinical practice to evaluate tumours for the presence of EGFR Thr790Met after progression”, the AURA2 investigators conclude.

The authors of an accompanying comment caution, however, that as repeated biopsy after disease progression has been shown to be not possible in up to 40% of patients, and that plasma tests are estimated to be 48–70% sensitive, “a substantial fraction” of T790M-positive patients may go undetected and miss the opportunity for targeted treatment.

PFS with first-line osimertinib in the AURA1 trial was comparable to that achieved with sequential first- or second-generation EGFR TKIs and would not preclude further EGFR TKI use, note Luis Paz-Ares, from Hospital Universitario Doce de Octubre & Instituto de Investigación in Madrid, Spain, and co-workers.

“Osimertinib seems to have also a higher [central nervous system] activity than other EGFR [TKIs], which would further support its first-line use in EGFR-mutant NSCLC”, they add.

“In summary, a definitive answer to the question of the best timing for Thr790Met inhibitors treatment will need to be provided by randomised trials, some of which have already completed accrual.”

References

Goss G, Tsai C-M, Shepherd FA, et al. Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol; Advance online publication 14 October 2016. DOI: http://dx.doi.org/10.1016/S1470-2045(16)30508-3

Zugazagoitia J, Ferrer I, Paz-Arez L. Osimertinib in EGFR-mutant NSCLC: how to select patients and when to treat. Lancet Oncol; Advance online publication 14 October 2016. DOI: http://dx.doi.org/10.1016/S1470-2045(16)30506-X

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