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S.M. Ali
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MINI 10 - ALK and EGFR (ID 105)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:T. Yap, T. Li
- Coordinates: 9/07/2015, 16:45 - 18:15, Mile High Ballroom 1a-1f
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MINI10.09 - Comprehensive Genomic Profiling Identifies EGFR Exon 19 Deletions in NSCLC Not Identified by Standard of Care Testing (ID 3042)
17:35 - 17:40 | Author(s): S.M. Ali
- Abstract
- Presentation
Background:
Non-small cell carcinoma (NSCLC) cases harboring deletions in exon 19 of EGFR typically respond to treatment with small molecule inhibitors of EGFR. Detection of EGFR deletions in routine clinical practice is performed using a large variety of assays and testing platforms, with varying performance characteristics that are often not readily available. Using a hybrid capture based comprehensive genomic profiling (CGP) assay we identified 250 consecutive NSCLC cases, obtained from a range of clinical institutions, harboring deletions in EGFR exon 19 and compared data from these cases with available prior EGFR testing results.
Methods:
DNA was extracted from 40 microns of FFPE sections and CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of 678X for 3,769 exons of 236 cancer-related genes plus 47 introns from 19 genes frequently rearranged in cancer. The results were evaluated for all classes of genomic alterations (GA). Clinically relevant genomic alterations (CRGA) were defined as GA linked to drugs on the market or under evaluation in mechanism driven clinical trials.
Results:
Of the 250 cases with exon 19 deletions excluding the C-Helix, consisting primarily of 746-750, 71 (28%) had previous EGFR testing results obtained through standard of care testing at multiple different institutions available for review. Of these 71 cases, 12 (17%) were negative for EGFR alterations, but were identified by CGP as harboring an exon 19 deletion. Of 14 cases with deletions affecting the C-Helix (753-761), 6 had previous EGFR testing results available for review, with 5 (83%) cases having a prior negative result. For select cases clinical histories were reviewed, and the clinical benefit from treatment with small molecule inhibitors of EGFR was observed, consistent with historic norms, including EGFR 746-750 deleted patients responding to erlotinib and afatinib, a patient with EGFR T751_I759>N responding to afatinib, and a patient with EGFR S752_I759del having an ongoing 18 month response to erlotinib.
Conclusion:
CGP in the course of clinical care can identify EGFR exon 19 deletions in NSCLC that may be missed by standard of care testing, including both the canonical 746-750 deletion as well as the less characterized C- Helix deletions. Tumors with either of these alterations that go undetected by standard testing but are identified by CGP can respond to anti-EGFR therapy. Given the proven improved extent and duration of tumor response and patient survival benefit conferred by anti-EGFR targeted therapy in patients whose NSCLC harbor EGFR exon 19 deletions, the 17% false negative rate in patients tested by standard hot spot assays is a concern. Further evaluation of the impact of the increased range and sensitivity of CGP to uncover EGFR alterations in NSCLC that have been missed by non-hybrid capture assays appears warranted.
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ORAL 37 - Novel Targets (ID 146)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:S.S. Ramalingam, E. Thunnissen
- Coordinates: 9/09/2015, 16:45 - 18:15, Mile High Ballroom 4a-4f
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ORAL37.04 - Comprehensive Genomic Profiling (CGP) of Advanced Cancers Identifies MET Exon 14 Alterations That Are Sensitive to MET Inhibitors (ID 3156)
17:17 - 17:28 | Author(s): S.M. Ali
- Abstract
- Presentation
Background:
Amplifications and activating mutations in the c-MET proto-oncogene are known oncogenic drivers that have proven responsive to targeted therapy. Mutations causing skipping of MET exon 14 are also oncogenic, but less well characterized. We undertook comprehensive genomic profiling (CGP) of a large series of advanced cancers to further characterize MET exon 14 alterations.
Methods:
DNA was extracted from 40 microns of FFPE sections from 38,028 advanced cancer cases. CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of >500x using three versions of the FoundationOne test. Hybridization capture baits for the MET gene were identical for all three versions of the test. Base substitution, indel, copy number alteration, and rearrangement variant calls were examined to identify those nearby to the splice junctions of MET exon 14. These genomic alterations were then manually inspected to identify those likely to affect splicing of exon 14, or delete the exon entirely.
Results:
221 cases harboring MET ex14 alterations were identified. These patients had a median age of 70.5 years (range 15-88), with 97 males and 124 females. The cases were lung carcinoma (193), carcinomas of unknown primary (15), brain glioma (6), and one each of adrenal cortical carcinoma, hepatocellular carcinoma, histiocytic sarcoma, renal cell carcinoma, rhabdomyosarcoma, skin merkel cell carcinoma, and synovial sarcoma. The majority were stage IV. Identification of this alteration has lead to treatment with MET inhibitors such as crizotinib, and to durable partial responses or better exceeding 3 months in histiocytic sarcoma (1), sarcomatoid lung carcinoma (1), and nsclc (1+). Multiple patients (5+) have initiated treatment on either crizotinib or MET inhibitors in clinical development, and additional outcome data will be reported. One patient with locally advanced unresectable disease harbored a MET exon 14 skipping alteration. On initiation with treatment with an MET inhibitor, symptomatic relief was observed in 3 days, radiographic response was observed at two weeks, and resection was performed 8 weeks after initiation of the MET inhibitor.
Conclusion:
MET exon 14 alterations define a hereto unrecognized population of advanced cancer cases, particularly in NSCLC. Multiple case reports demonstrate that these alterations confer sensitivity to multiple small molecule MET inhibitors. This finding expands the population of advanced NSCLC patients who can derive benefit from MET-targeted therapies.
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