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X. Mao
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Best abstracts selected from submissions 4 (ID 4)
- Event: ACLC 2018
- Type: Oral Session
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 11/09/2018, 10:50 - 11:30, Crystal Ballroom
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OA07 - Clinical Characterization Of ERBB2 Exon 20 Insertions and Heterogeneity of Outcomes to Afatinib in Chinese Lung Cancers (ID 188)
10:50 - 11:30 | Author(s): X. Mao
- Abstract
Background:
Human epidermal growth factor 2 (HER2, ERBB2) gene alterations have been identified as oncogenic drivers in 2-5% of lung cancers. ERBB2 In-frame insertions in exon 20 (20ins) lead to constitutive activation of receptor and downstream pathways. However, response heterogeneity of different exon 20 insertions to ERBB2 inhibitor afatinib exists. In vitro and structural modeling results suggested that Glycine778 may facilitate inhibitor binding to ERBB2. In this study, our aim was to improve our understanding of clinical characteristics in ERBB2-mutated Chinese lung cancer and investigate the clinical outcomes of specific ERBB2 exon 20 insertions in response to afatinib.
Method:
We reviewed 7520 lung cancer patients whose tissue or plasma biopsies were sequenced in a CLIA-certified sequencing laboratory between 2015 to 2018. Clinical records of 19 patients (18 adenocarcinomas and 1 squamous cell carcinoma) with several different ERBB2 20ins after afatinib treatment were collected for clinical outcomes evaluation.
Results:
ERBB2 20ins were identified in 2.27% (171/7,520) in this Chinese lung cancer cohort. It occurred with a high proportion in females with adenocarcinoma histology. 11.7% (20/171) ERBB2 20ins-positive patients harbored concomitant ERBB2 amplification. Y772_A775dup (119/171, 69.6%) was the most frequently occurred 20ins subtype, followed by G778_P780dup (18/171, 10.5%). For the 19 patients treated with afatinib, they had a median PFS of 4.5 months and median OS of 11.5 months. The overall response rate in this cohort was 15.8% (3/19) and disease control rate was 68.4% (13/19). Next, we interrogated the clinical outcomes of specific 20ins subtype responding to afatinib. We found that patients harboring G778_P780dup (G778) achieved longer median PFS (10 vs 3.3 months, p=0.32) and median OS (19.7 vs 7 months, p=0.16) than non-G778 patients, consisting with in vitro results. Although statistical significance was not achieved due to limited number of G778_P780dup patients, this result warranted further investigation into this phenomenon. Moreover, to the best of our knowledge, we identified the first case of a lung squamous cell carcinoma patient harboring ERBB2 20ins from this cohort. He displayed favorable response to afatinib and achieved partial response with significant tumor shrinkage.
Conclusion:
We interrogated the characteristics of ERBB2 exon 20 insertions in a large cohort from single ethnicity. It demonstrated the response heterogeneity to afatinib among different ERBB2 exon 20 insertion subtypes. It highlighted the importance to correlate drug efficacy with specific ERBB2 exon 20 insertion variants in clinical application.
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Poster Session (ID 8)
- Event: ACLC 2018
- Type: Poster Session
- Track:
- Presentations: 2
- Moderators:
- Coordinates: 11/07/2018, 00:00 - 00:00, Poster Hall
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P071 - Variants Distribution and Heterogeneity of Outcomes to Crizotinib in ALK-Rearranged Chinese Non-Small Cell Lung Cancers (ID 179)
00:00 - 00:00 | Author(s): X. Mao
- Abstract
Background:
ALK-rearranged NSCLC is a unique molecular subgroup with high sensitivity to ALK inhibitors. Crizotinib, a FDA-approved tyrosine kinase inhibitor for ALK-rearranged NSCLCs, showed remarkable response in ALK-positive NSCLC. However, the magnitude and duration of clinical responses to crizotinib among different ALK variants are found to be heterogeneous, and studies about the clinical outcomes showed contradict conclusions.
Method:
We collected sequencing information from 110 ALK-positive Chinese NSCLC patients, whose tissue or plasma biopsies were sequenced in a CLIA-certified genomic profiling laboratory. Sequencing results were reviewed with the intent of studying ALK rearrangement distribution and clinical outcomes to crizotinib.
Results:
A total of 134 (5.6%) ALK rearrangements were identified in a cohort of 1971 NSCLCs, with 39 unique rearrangement partners. EML4 was the most common ALK rearrangement partner, with variant 3 (v3) as the most frequent variants (42.7%) of EML4-ALK fusion, accounting for 71.6% (96/134) of all the rearrangements in 87.3% (96/110) patients. For EML4-ALK positive patients after crizotinib treatment (n=96), survival analysis revealed that patients with EML4-ALK only displayed favorable PFS (10.0 vs 7.2 months, p=0.037) and OS (36.0 vs 20.0 months, p=0.037) than those combined with other fusions. In vitro data reported that variant v3 and v5 was structurally stable and less sensitive to ALK inhibitors due to the lack of TAPE domain. In this study, patients harboring v3 and v5 displayed significantly inferior OS than those with other variants (31 vs 37.6 months, p=0.010). For all the ALK-rearranged patients (n=110), no significant difference was observed between the survival of EML4-ALK and non-EML4-ALK (PFS, 9.4 vs 14.5 months, p=0.61; OS, 35.1 vs 35.5 months, p=0.58), below and above 40-years (PFS, 7.3 vs 11.3 months, p=0.23; OS, 25.4 vs 35.5 months, p=0.69).
Conclusion:
This study demonstrated the distribution pattern of ALK rearrangements in Chinese NSCLCs, and illustrated the clinical outcomes of ALK-positive patients in different sub-groups. We hope this study could improve basic knowledge of ALK rearrangement and might be helpful for clinicians in choosing patients for appropriate medical treatment. Moreover, these findings advocate for more comprehensive ALK genomic profiling and validation of current results of clinical outcomes in large populations. -
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P081 - Clinical Characteristics and Molecular Patterns Of RET-Rearranged Lung Cancer in Chinese Patients (ID 191)
00:00 - 00:00 | Author(s): X. Mao
- Abstract
Background:
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.
Method:
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.
Results:
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.
Conclusion:
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.
