Virtual Library
Start Your Search
Akihiro Nishiyama
Author of
-
+
P1.01 - Advanced NSCLC (ID 158)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
-
+
P1.01-47 - Prospective Study for Usefulness of Plasma DNA on Prediction of Third Generation EGFR Tyrosine Kinase Inhibitors (S-PLAT Study) (Now Available) (ID 1112)
09:45 - 18:00 | Author(s): Akihiro Nishiyama
- Abstract
Background
The AURA and FLAURA studies have shown that EGFR T790M mutation detected in cfDNA is correlated with efficacy of osimertinib as measured via overall response rate (ORR), and progression-free survival (PFS). However, the following clinical-related questions have been raised: Can other different assay systems confirm the results mentioned above? Does T790M level affect osimertinib treatment efficacy? Do mutations at loci other than EGFR influence treatment efficacy?
Method
This is a prospective observational study, joining 27 Japanese hospitals. Plasma samples from patients with non-small cell lung cancer (NSCLC) who acquired resistance to EGFR-TKI (gefitinib, erlotinib, afatinib) were collected between Feb 2017 and Jan 2019. We tested T790M by MBP-QP method which has been newly developed using cfDNA and investigated the concordance with the result by cobas EGFR mutation Test v.2 (tissue and/or plasma) which is commercially available. We also checked the allele frequency (AF) of T790M in cfDNA by ddPCR and the mutational status of cancer related actionable genes by cfDNA specific NGS (Guardant360). The major objectives were ORR, disease control rate (DCR) to osimertinib and PFS in patients with T790M positive by MBP-QP method.
Result
Among 145 NSCLC patients who acquired resistance to 1st or 2nd EGFR-TKI, T790M was detected in 57 patients by cobas (tissue and/or plasma), and these patients received osimertinib (80mg daily). T790M was detected by cobas in 16 patients from plasma, 44 patients from tissue, 3 patients from both samples. Among assessable patients, ORR, DCR and PFS in patients with T790M positive by cobas from plasma were 66.7%, 86.7%, 194 days, those of tissue were 53.5%, 97.7%, 186 days, respectively. In these 57 patients, MBP-QP also could detect T790M from 10 patients from plasma, and ORR, DCR and PFS in patients with T790M positive by MBP-QP from plasma were 75.0%, 87.5%, 184 days, respectively. These results suggest that T790M detection from cfDNA not only by cobas but also MBP-QP is correlated with RR of osimertinib. Now, using ddPCR and Guardant360, we have been investigating about the relationship between T790M AF and RR to osimertinib, and the influence of mutations at loci other on efficacy of osimertinib.
Conclusion
cfDNA analysis can be predictive for osimertinib efficacy, just as re-biopsy. Whether comprehensive approach including AF and coexistence of other actionable genes is more precisely informative for drug efficacy has been continuously analyzed.
-
+
P2.14 - Targeted Therapy (ID 183)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
-
+
P2.14-56 - Osimertinib Overcomes Alectinib Resistance Caused by Amphiregulin in a Leptomeningeal Carcinomatosis Model of EML4-ALK Lung Cancer (ID 1543)
10:15 - 18:15 | Author(s): Akihiro Nishiyama
- Abstract
Background
Central nervous system (CNS) metastasis, such as brain metastasis and leptomeningeal carcinomatosis (LMC), occurs in 20–40% of all patients with cancer. Anaplastic lymphoma kinase (ALK) is a clinically validated drug target and ALK rearrangements are found in approximately 3-5% of non-small cell lung cancer (NSCLC). ALK tyrosine kinase inhibitor (TKI) shows dramatic clinical efficacy in ALK-rearranged NSCLC patients, and the second-generation ALK-TKI alectinib is effective against CNS metastasis of ALK-rearranged NSCLC. However, the patients with ALK-rearrangement acquire resistance to alectinib over time and develop recurrent LMC metastasis. This study aimed to clarify the mechanism of resistance to alectinib in LMC and seek a novel therapeutic strategy.
Method
Alectinib-resistant cell line (A925L/AR) was established by continuous treatment with alectinib in the LMC mouse model inoculated with the alectinib-sensitive human lung cancer cell line, A925LPE3, which harbors the EML4-ALK gene fusion. The tumor level was measured by in vivo imaging system. To clarify the mechanism of alectinib resistance, tumor cell culture supernatants, patient cerebrospinal fluid (CSF), and patient serum were measured using ELISA kits for EGFR ligands.
Result
A925L/AR cells were moderately resistant to various ALK-TKIs, such as alectinib, crizotinib, ceritinib, and lorlatinib, compared with parental cells in vitro. A925L/AR cells acquired resistance through epidermal growth factor receptor (EGFR) activation due to overexpression of its ligand, amphiregulin. EGFR-TKIs and anti-EGFR antibodies re-sensitized A925L/AR cells to alectinib in vitro. In the LMC model with A925L/AR cells, combined treatment with alectinib and an EGFR-TKI, such as erlotinib and osimertinib, successfully controlled LMC progression. Imaging mass spectrometry showed accumulation of EGFR-TKIs in the tumor lesions. Moreover, notably high amphiregulin levels were detected in the cerebrospinal fluid from ALK-rearranged NSCLC patients with alectinib-resistant LMC compared with those in EGFR-mutated NSCLC patients with EGFR-TKI-resistant LMC or patients without LMC.
Conclusion
We demonstrated that EML4-ALK lung cancer cells acquired moderate resistance to alectinib in the leptomeningeal space due to amphiregulin-triggered EGFR activation. Moreover, combined use of alectinib and EGFR-TKIs, including the third-generation inhibitor osimertinib, could overcome resistance in the LMC model. Our findings may provide rationale for clinical trials to investigate the effects of novel therapies dual-targeting ALK and EGFR in ALK-rearranged NSCLC with alectinib-resistant LMC.
