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Avitinib, a third generation irreversible EGFR inhibitor shows promise in patients with EGFR TKI-resistant non-small cell lung cancer


The first-in-human results from a dose escalation study of Avitinib, a third generation irreversible epidermal growth factor receptor ( EGFR ) inhibitor that has been shown to overcome T790M-induced resistance in preclinical studies, were presented.

Patients with non-small cell lung cancer ( NSCLC ) and EGFR positive mutation that developed resistance to the first generation EGFR tyrosine kinase inhibitors ( TKIs ) were enrolled; both T790M positive and negative patients were eligible.

Oral Avitinib capsules were administered in 5 cohorts once daily in 50 mg, 100 mg, 200 mg, 350 mg, and 550 mg tablets, and 3 cohorts received twice daily oral doses of 175 mg, 250 mg, and 300 mg.
All patients were required to undergo biopsy for genotyping to confirm T790M status prior to treatment and were assessed for pharmacokinetics ( PK ), overall response rate ( ORR ), disease control rate ( DCR ), and adverse events.

As of 5 May 2016, the study enrolled 51 patients; 49% were female, the median age was 55 years, and 86% of patients were T790M mutation positive.

The maximum tolerated dose had not been reached. Pharmacokinetics were dose proportional, and the median plasma half-life was 7.8 ( range: 7.6 to 8.0 ) hours.
Twice daily dosing method reduced the fluctuation coefficient of the plasma concentration by 0.40 fold, and improved the area under the curve ( AUC ) by 1.28 fold, compared to once daily dosing.
No food effects were observed.

At data cut-off, 48 patients were evaluated in the once daily cohorts that demonstrated an ORR of 41.7%, and the DCR was 75.0%.

All responses were observed at dose levels greater than or equal to 200mg daily.

The ORR increased to 57.6% in 33 patients treated daily with Avitinib at greater than or equal to 350mg and DCR was 87.9% in this cohort.
The 33 evaluated patients in the twice daily dosing regimen showed a better ORR of 66.7% and DCR of 94.4%.
The longest duration of response was 11 months and was ongoing at data cut-off.

Adverse events were mostly grade 1 and transient. The most commonly reported drug related adverse effects grade 3 and higher were rash, which occurred in 4% of patients.
ALT/AST elevation in 4%, and 2% of patients had pneumonia ( 2% ).
No hyperglycaemia or grade 3 QTc prolongation were observed. ( Xagena )

Source: ESMO Congress, 2016

XagenaMedicine_2016



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