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Poster Session (ID 8)
- Event: ACLC 2018
- Type: Poster Session
- Presentations: 2
- Coordinates: 11/07/2018, 00:00 - 00:00, Poster Hall
P011 - Concurrent ALK/EGFR Alterations in Chinese Lung Cancers: Frequency, Clinical Features, and Differential Response to Therapy (ID 152)
00:00 - 00:00 | Author(s): B. Li
ALK rearrangement and EGFR alterations are oncogenic driver mutations in lung cancers. Generally considered mutually exclusive, some studies suggested that these two mutations might occur concomitantly. Limited studies have reported the underlying association of molecular features and drug response to EGFR-TKIs in lung cancers with such co-alterations. Here, we performed next-generation sequencing (NGS) analysis in Chinese lung cancer patients, and evaluated distinct features of EML4- vs. non-EML4-ALK fusions in EGFR-mutated cases.
A retrospective review was performed on genomic profiling data from either tissue or plasma of 419 ALK-rearranged lung cancer patients, sequenced in a CLIA-certified laboratory from 2015 to 2017. Patient characteristics (n=21) and clinical outcomes of patients harboring concurrent EGFR and ALK alterations were collected.
Among the 419 ALK-rearranged lung cancers, a total of 21 patients (5.01%) were detected harboring concurrent ALK and EGFR (exon 18-20) genomic alterations. The concomitant rate of EGFR in patients harboring EML4-ALK (3.06%, 11/359) was dramatically lower than in non-EML4-ALK patients (16.67%, 10/60, p<0.001). Four EML4-ALK and 1 non-EML4-ALK patients were found to have de novo ALK/EGFR co-mutations whereas 1 EML4-ALK and 3 non-EML4-ALK patients acquired their ALK alterations after EGFR TKI treatment. For dual-positive patients who received past EGFR-TKI with unknown ALK status before the treatment, EML4-ALK/EGFR patients (n=6) commonly had shorter PFS to EGFR-TKI as well as higher relative ALK/EGFR allele frequency compared to non-EML4-ALK/EGFR (n=6; mPFS, 5.45 vs 15 months, p=0.11; mRAF, 1.52 vs 0.41, p=0.01), suggesting that EML4-ALK was more likely to be de novo whereas non-EML4-ALK acquired after EGFR-TKI. In addition, we found that for 9 dual-positive patients who had prior first-generation EGFR-TKI treatment, the clinical efficacy of single TKI use varied greatly, and patients might benefit from combination therapy of ALK+EGFR TKIs.
This study revealed that EML4-ALK/EGFR and non-EML4-ALK/EGFR co-alterations displayed distinct prevalence in Chinese lung cancer patients. Our analyses suggested that non-EML4-ALK might be an acquired gene alteration and function as a resistance mechanism to EGFR-TKI, which might explain the observed discrepancy in prevalence as our sequencing cohort consisted of both previously treated or untreated patients. In addition, we observed that patients with dual ALK/EGFR alterations may benefit from combinatorial TKIs therapy.
P081 - Clinical Characteristics and Molecular Patterns Of RET-Rearranged Lung Cancer in Chinese Patients (ID 191)
00:00 - 00:00 | Author(s): B. Li
Rearrangement of RET is identified as an oncogenic alteration in lung cancer. However, studies about characteristics of RET rearrangement in lung cancers are still limited, and several reports were conflicting. Our aim was to demonstrate the clinical and molecular features of RET rearrangement in Chinese lung cancers.
We reviewed genomic profiling data of biopsies (including either tissue or plasma) from 6125 lung cancer patients sequenced in a CLIA-certified laboratory from 2015 to 2017. Patient characteristics, including age, gender and histology classification were collected.
A total of 106 RET rearrangements in 84 patients (1.37%, 84/6125) were identified. RET rearrangement had a tendency to occur in female, adenocarcinoma, with a median age of 58 years. KIF5B-RET fusion was the most frequently occurred subtypes, identified in 53.8% (57/106) RET rearrangements and 67.9% (57/84) of patients, followed by CCDC6-RET and NCOA4-RET. Besides, several rare and novel RET fusion partners were identified, to the best of our knowledge, including TSSK4, SORBS1, SIRT1, PTPRK, ADD3-AS1, PRKG1, IL2RA, CCNYL2, CCDC186 and ANKS1B. We further investigated the concurrent and exclusive genomic alterations in RET-rearranged patients. TP53 was the most commonly seen concurrent mutation, occurring in 42.5% (20/47) of patients, which was followed by EGFR (14.9%, 7/47). KIF5B-RET subtype was fully mutual exclusive with EGFR mutation, suggesting that KIF5B-RET was a strong oncogenic driver mutation. RET fusion partners of the 7 patients harboring concurrent EGFR and RET rearrangement were all non-KIF5B. In addition, we observed that allelic fraction of first-generation EGFR-TKI sensitizing mutation was higher than non-KIF5B-RET in each individual patient, indicating that non-KIF5B-RET fusion might function as a potential acquired resistance mechanism to EGFR tyrosine kinase inhibitors. Clinical outcomes of cabozantinib, a RET kinase inhibitor, were available in six patients with RET-rearrangement, and the median treatment period of cabozantinib for these patients was 5 months. A stage IV adenocarcinoma patient developed resistance to osimertinib and followed NGS revealed that he harbored concurrent CCNYL2-RET fusion and EGFR mutation. After the combinatorial treatment of osimertinib and cabozantinib, he achieved stable disease (SD) with a PFS of 5 months before disease progression.
Lung cancer patients with RET-rearrangement displayed identifiable clinical characteristics and heterogeneous molecular distribution. The investigation of clinical and molecular pattern of RET-rearrangements might be helpful to provide basic knowledge for personalized diagnosis and clinical considerations. Further investigations are needed in the fields of potential sensitivities among different fusion variants and resistance mechanism to RET inhibition.