Abstract B105: Characterization of the activity of AZD9291 in patients (pts) with T790M ‘negative’ advanced non-small cell lung cancer (aNSCLC)
Authors: Jänne Pasi A. , Felip Enriqueta , Kim Dong-Wan , John Thomas , Haggstrom Daniel E. , Ahn Myung-Ju , Thress Kenneth S. , Jenkins Suzanne C. , Mann Helen , Cantarini Mireille V. , Dearden Simon P. , Yang James Chih-Hsin 
Published: May 2016

Abstract
Objective
AZD9291 is an oral, selective, irreversible EGFR-TKI, effective against EGFR-TKI-sensitizing (EGFRm) and resistance T790M mutations. Pre-study tumor samples from pts enrolled into expansion cohorts of a PhI study (AURA, NCT01802632) were tested centrally for T790M status. Pts with T790M positive tumor samples had higher objective response rate (ORR) than pts with no detectable T790M (T790M ‘negative’): 78/127 (61%) and 13/61 (21%), respectively (Jänne et al 2015). Exploratory analyses to characterize AZD9291 activity in pts whose tumors were T790M negative by central test were performed.
Methods
Pts with EGFRm aNSCLC and acquired resistance to EGFR-TKIs were enrolled into expansion cohorts of the AURA study. The T790M status of pre-study tumor samples was determined locally (any method allowed) and/or centrally using the cobasTM EGFR mutation test (Roche Molecular Systems, Inc.). Presence of T790M in plasma derived ctDNA was determined by digital PCR (BEAMing). Pts with a centrally determined tumor based T790M negative status were then classified into one of nine groups according to local tumor status (T790M positive, negative, or unknown) and ctDNA status (T790M positive, negative, or unknown). Clinical outcome is reported for each group.
Results
69 pts with T790M negative tumor status were determined centrally, and received AZD9291; 35 and 21 were also negative by local test and ctDNA, respectively and 7 were negative by all 3 tests; despite a negative central test, T790M positive tumor status was identified in 11 pts by prior local test and 26 by ctDNA.
Confirmed responses by RECIST 1.1, n/N (%) in centrally tested tissue samples with no detectable T790M (Data cut-off 01 May 2015)T790M status of plasma derived ctDNA (Method: BEAMing)PositiveNegativeUnknownTotalT790M status of tumor tissue determined by a local test (Method: Any)Positive2/6 (33)0/1 (0)4/4 (100)6/11 (55)Negative2/14 (14)0/7 (0)2/14 (14)4/35 (11)Unknown2/6 (33)3/13 (23)2/4 (50)7/23 (26)Total6/26 (23)3/21 (14)8/22 (36)17/69 (25)
17 pts with a central T790M negative status responded to AZD9291 treatment. ORR was 55% (6/11) in pts with a central T790M negative/local positive test result. No objective responses (0/7) were observed in pts with T790M negative tumor status by all three tests.
Additional analysis of the sub-groups, by immediate prior TKI, EGFRm status, and duration of response will be available for presentation.
Discussion
In 69 pts with centrally identified T790M negative tumor status, 17 achieved a confirmed response. Of these, 12 were T790M positive by local test, ctDNA, or both. Different sensitivity and specificity of assays, tumor heterogeneity, and ctDNA shedding may explain positive results in this small group of pts classified as central T790M negative. The data support the hypothesis that T790M directed inhibitors are active against T790M driven resistance.
Citation Format: Pasi A. Jänne, Enriqueta Felip, Dong-Wan Kim, Thomas John, Daniel E. Haggstrom, Myung-Ju Ahn, Kenneth S. Thress, Suzanne C. Jenkins, Helen Mann, Mireille V. Cantarini, Simon P. Dearden, James Chih-Hsin Yang. Characterization of the activity of AZD9291 in patients (pts) with T790M ‘negative’ advanced non-small cell lung cancer (aNSCLC). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B105.