Original ResearchFirst-line osimertinib in patients with epidermal growth factor receptor–mutant non–small-cell lung cancer and with a coexisting low allelic fraction of Thr790Met
Introduction
Osimertinib, an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), inhibits exon 19 deletions (Ex19del) and exon 21 codon p.Leu858Arg (L858R) point mutations and EGFR p.Thr790Met (T790M) in non–small-cell lung cancer (NSCLC) [1,2]. Osimertinib showed longer progression-free survival (PFS) and overall survival (OS) than standard EGFR-TKIs (gefitinib or erlotinib) in the first-line treatment of EGFR mutation–positive NSCLC (FLAURA trial) [3,4]. Early findings show that Thr790Met-mutant clones can pre-exist at levels below the threshold of detection, resulting in gefitinib resistance [5,6]. Several reports have identified Thr790Met in naively treated EGFR-mutant patients. Low allelic Thr790Met was noted in 38% of naively treated patients with EGFR-mutant NSCLC and associated with shorter PFS (7.7 versus 16.0 months) [[7], [8], [9], [10]]. We previously reported the coexistence of Thr790Met in 35% of un-treated patients with EGFR mutation–positive NSCLC [8,9] and with a Thr790Met allelic frequency of less than 1% [8,9]. Erlotinib median PFS was shorter in patients with the Thr790Met mutation. Similarly, in the EURTAC trial [10], low-level pre-treatment Thr790Met mutations were detected. Once again, PFS on erlotinib was shorter for those with Thr790Met mutations [11]. We hypothesised that low allelic frequency Thr790Met mutations could be used for customising treatment with Thr790Met-specific inhibitors [11].
A meta-analysis on the coexistence of EGFR Thr790Met mutations and sensitising mutations in pre-treatment NSCLC reviewed the sensitivity of the mutation detection methods. The Thr790Met was observed in pre-treatment samples in studies using intermediate (detection limit <5% and >0.1%; odds ratio, 2.23) and highly sensitive methods (detection limit <0.1%; odds ratio, 1.74), but not in those using low-sensitivity methods (detection limit >5%; odds ratio, 1.28) [12].
Treatment with a Thr790Met-targeting EGFR TKI [13] was developed because 49% of EGFR-mutant NSCLCs acquired EGFR Thr790Met mutation during treatment with the first- and second-generation EGFR TKI, although other genetic defects can occur, such as PIK3CA mutations [14]. Early studies indicate that low allelic fraction of Thr790Met could be undetectable by direct sequencing in EGFR-mutant NSCLC and provides resistance to gefitinib [15,16]. The Thr790Met pre-exists in cis with activating EGFR mutations (ex19del mutations and Leu858Arg mutations). Pre-existing EGFR Thr790Met was present in 3 of 7 EGFR-mutant NSCLC non-responders to gefitinib and was not present in 19 responder patients [17]. In addition to H1975 cells, the Thr790Met allele is present in parental EGFR-mutant cell lines with a frequency of 0.078% in HCC4006 and 0.0360% in PC9 cells [18] and even more diluted in our experience (Supplementary Appendix).
Based on our studies [9,10,[19], [20], [21], [22], [23]] and many others [12], we designed a phase II clinical trial assessing the efficacy of osimertinib as a first-line treatment for patients with pre-treatment Thr790Met.
Section snippets
Study design and participants
The AZENT study (ClinicalTrials.gov identifier: NCT02841579) was a multicentre, single-arm, open-label, phase IIa trial conducted at 6 centres in Spain. Eligible patients were aged 18 years or older with a histologically or cytologically confirmed diagnosis of locally advanced or metastatic NSCLC, centrally confirmed sensitising EGFR and Thr790Met mutations by tissue biopsy using the peptide nucleic acid-quantitative-polymerase chain reaction (PNA-Q-PCR) assay [9], Eastern Cooperative Oncology
Patients
Between 30th August 2016 and 17th August 2018, 51 patients were screened (Appendix Fig. 1) of whom 22 patients with advanced NSCLC harbouring pre-treatment sensitising EGFR and Thr790Met mutations were enrolled and started to receive first-line osimertinib. On 17th December 2018, the AZENT data monitoring committee, on review of the interim analysis, determined that there was evidence to support continued accrual; however, the trial was closed to further accrual because of the funder's decision.
Discussion
There are a ceaseless number of resistance mechanisms to osimertinib, including MET amplification, MET H1094Y mutations and acquisition of EGFR mutations, such as C797S, G724, L792 and L718/G719. In addition, a variety of other genetic alterations exist, for instance, RET fusions, BRAF fusions, K-Ras mutations, FGFR amplification and histological transformation [[26], [27], [28]]. At progression in the present study, we found MET amplification in one case, K-Ras mutations in two cases and one
Role of the funding source
AstraZeneca funded the study and provided the study drug. The study was designed by lead investigators (NK, RR and MAM-V) in conjunction with representative of MEDSIR and representative of the study funder. MEDSIR collected the study data and was involved in the data analysis and interpretation in collaboration with the authors. The manuscript was written by the lead investigators in collaboration with MEDSIR. All authors had full access to all the data in the study.
Author contributions
RR wrote the manuscript with input of all authors.
RR, MAM and NK conceived the study and were in charge of overall direction and planning.
MM, IS, SVI, GLV, MC, JMS, JGG and JG collected data.
MAM performed the experiments.
MS, AM and GM processed the experimental data and made the statistical analysis.
All authors provided critical feedback and helped shape the research, analysis and manuscript.
Conflict of interest statement
The authors declare that there is no conflict of interest.
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Current address: Merck Healthcare KGaA Darmstadt, Germany.