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Y. Choi
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MA07 - ALK-ROS1 in Advanced NSCLC (ID 385)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
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MA07.07 - Ceritinib in ROS1-Rearranged Non-Small-Cell Lung Cancer: An Update of Korean Nationwide Phase II Study (ID 5953)
11:42 - 11:48 | Author(s): Y. Choi
- Abstract
- Presentation
Background:
ROS1 rearrangement is a distinct molecular subset of non-small-cell lung cancer (NSCLC). We investigated the efficacy and safety of ceritinib in patients with ROS1-rearranged NSCLC.
Methods:
We enrolled 32 patients with advanced NSCLC who tested positive for ROS1 rearrangement by fluorescent in situ hybridization (FISH). ROS1 immunohistochemistry (IHC) and next-generation sequencing (NGS) was performed in available tumor samples. Ceritinib 750mg was administered once daily and the primary endpoint was objective response rate (ORR) by central independent radiologic review. The secondary endpoints included disease control rate (DCR), duration of response, progression-free survival (PFS), overall survival (OS), toxicity and concordance between FISH and IHC. ROS1 fusion partners were identified with the use of next-generation sequencing (NGS) in available tumor samples.
Results:
Between June 7, 2013, and February 1, 2016, a total of 404 patients underwent ROS1 prescreening, and 32 ROS1+ (by FISH) patients were enrolled. All patients except two (who did not respond to ceritinib) were crizotinib naïve. The median age of all patients was 62 years, and there were 24 females (75%). The majority of patients (84%) were never smokers, and all had adenocarcinoma histology. The median number of previous treatments before study enrollment was 3 (range, 2-7) and 17 (53%) patients had received three or more lines of chemotherapy. At the time of the data cut-off (April 18, 2016), the median follow-up was 7.5 months, and 15 (47%) patients had discontinued treatment. Of the 32 patients enrolled, 28 patients were evaluable for response by independent radiologic review. ORR was 63% (95% CI, 45.7-79.3), with 1 complete response and 19 partial responses. The median duration of response was 10.0 months (range, 0.4+-18.4+). Among 11 tumors that were tested by NGS, we identified 7 ROS1 fusion partners including ROS1-CD74, ROS1-SLC34A2, and ROS1-EZR. The median progression-free survival was 19.3 months (95% CI, 7.2-not reached), with 17 (53%) patients still in follow-up for progression. The median overall survival was not reached at the time of the data cut-off. Of 5 patients with retrospectively confirmed brain metastases, intracranial disease control was reported in 4 patients (80%). Gastrointestinal adverse events (vomiting, nausea, diarrhea) mostly grade 1-2, were the most frequent adverse events (80%); these events were manageable.
Conclusion:
Ceritinib demonstrated potent clinical activity in patients with advanced, ROS1-rearranged NSCLC, who received at least one prior line of platinum-based chemotherapy. ROS1 rearrangement defines a second molecular subgroup of NSCLC for which ceritinib is highly active (ClinicalTrials.gov number, NCT01964157).
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P1.02 - Poster Session with Presenters Present (ID 454)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.02-024 - The Molecular Breakdown: A Comprehensive Look at Non–Small-Cell Lung Cancer with ALK Rearrangement (ID 4999)
14:30 - 14:30 | Author(s): Y. Choi
- Abstract
Background:
Chromosomal rearrangements of anaplastic lymphoma kinase (ALK) compose approximately 4-6% of non–small-cell lung cancer (NSCLC) and the patients can be prescribed with targeted therapy. Nevertheless, acquired resistance towards existing ALK-specific inhibitors is inevitable in most cases. This suggests that a detailed molecular characterization of NSCLC with ALK rearrangement and dissection of ALK-specific signaling pathway are strongly needed.
Methods:
Approximately 3000 NSCLC cases with EGFR and KRAS wild types were screened for ALK alterations by immunohistochemistry (IHC). From the 158 ALK IHC-positive samples, we further validated ALK rearrangement through fluorescence in situ hybridization and RNA color-coded probes. We then performed targeted deep sequencing using a customized panel embedded with 81 select set of cancer associated genes in 129 ALK-positive cases for their molecular characterization. Additional clinical analysis and drug viability assays between EML4-ALK long and short forms were assessed as well. We also conducted multiplexed direct mRNA expression profiling using a panel of 770 essential key driver genes that take part in most cancer pathways. Target gene silencing, overexpression, migration assay, and immunoprecipitation were conducted for functional analysis of identified molecules.
Results:
We found that most ALK genomic breaks occurred at intron 19 (92.7%), which conjoined with partner genes through non-homologous end joining repair system. ALK fusion profiling exhibited that 82% of fusions were EML4-ALK (129/158), 2.4% were HIP1-ALK (4/158), 1.8% KIF5B-ALK (3/158), 1 case was KLC1-ALK, and the rest were unrecognized ALK fusions (21/158). From the unknown partners, we identified 3 novel ALK fusion partners: GCC2, LMO7, and PHACTR1. We also identified 4 novel somatic mutations of ALK: T1151R, R1192P, A1280V, and L1535Q. RNA expression profiling further revealed that NSCLC with ALK rearrangement showed higher expression of ITGB3 with statistical significance. Combinatorial treatment of ALK (crizotinib) and ITGB3 (LM609 antibody) decreased cell migration and invasive properties of ALK-positive cell lines. Furthermore, from our new classification system of EML4-ALK variants, the cases with short EML4-ALK form showed more advanced stages and more frequent metastases than the cases with long form in NSCLCs.
Conclusion:
This is the primary mass-scale study of ALK-rearranged NSCLC to our knowledge. Through this integrated analysis, we provide genomic details and clinical insight of NSCLC with ALK rearrangement. Also, we suggest a novel therapeutic approach of treating ALK-rearranged NSCLC patients with ALK and ITGB3 inhibitors.
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P3.02c - Poster Session with Presenters Present (ID 472)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02c-005 - MET Exon 14 Skipping in Quintuple-Negative (EGFR-/KRAS-/ALK-/ROS1-/RET-) Lung Adenocarcinoma (ID 6012)
14:30 - 14:30 | Author(s): Y. Choi
- Abstract
Background:
MET exon 14 (METex14) skipping has been reported as a potentially targetable driver mutation in lung adenocarcinoma. We aimed to evaluate the prevalence and clinicopathologic characteristics of lung adenocarcinoma harboring METex14 skipping in patients with lung adenocarcinoma in which targetable genomic alterations are not available.
Methods:
We screened 795 patients with lung adenocarcinoma and 45 patients with quintuple-negative (EGFR-/KRAS-/ALK-/ROS1-/RET-) lung adenocarcinomas were finally included to identify the patients harboring METex14 skipping by using RT-PCR with probes overlapping an exon 13–15 junction. In addition, we summarized recent articles reported about METex14 skipping in lung cancer.
Results:
Based on the present study, seventeen patients (37.8%) had tumors harboring METex14 skipping alterations. Diverse genomic sequence variants causing METex14 skipping were identified. The median age of the METex14 skipping-positive patients was 73 years (range, 55–81 years), 8 patients (47.1%) were female, and 7 (41.2%) had never smoked. The predominant subtype was acinar followed by the solid type. The MET immunohistochemistry test for METex14 skipping demonstrated 100% (95% CI, 79.6–100) sensitivity and 70.4% (95% CI, 51.5–84.2) specificity. In literature reviews, we included 619 patients with lung cancer harboring METex14 skipping. The median age of the patients was 68 years (range, 41-84), 60% (251/418) were female, and 50% (58/116) were never smoker. MET immunochemical stain was positive in 62.3% (48/77), MET amplification was identified in 14.6% (45/309) of the patients. The prevalences of METex14 skipping were 12.9% (20/155) in sarcomatoid carcinoma, 3.9% (11/282) in adenosquamous carcinoma, 2.6% (398/15050) in adenocarcinoma, 2.1% (26/1226) in squamous cell carcinoma, and 0.8% (2/243) in large cell carcinoma, respectively.
Conclusion:
The prevalence of METex14 skipping was relatively high in patients with quintuple-negative (EGFR-/KRAS-/ALK-/ROS1-/RET-) lung adenocarcinomas. Lung adenocarcinomas harboring METex14 skipping were associated with old age, acinar or solid histolgy, and MET protein overexpression. Identification of subpopulation harboring METex14 skipping can be an important step toward developing targeted therapies for patients with lung cancer.
