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Best abstracts selected from submissions 4 (ID 4)
- Event: ACLC 2018
- Type: Oral Session
- Presentations: 1
- Coordinates: 11/09/2018, 10:50 - 11:30, Crystal Ballroom
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): M. Jin
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.
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.
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.
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
- Presentations: 1
- 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): M. Jin
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.