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K. Konduri
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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): K. Konduri
- 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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P2.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 207)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.01-088 - <em>nab</em>-Paclitaxel + Carboplatin for Elderly Patients with Advanced NSCLC (ABOUND.70+) (ID 1084)
09:30 - 09:30 | Author(s): K. Konduri
- Abstract
Background:
Treatment of elderly patients with non-small cell lung cancer (NSCLC) is challenging due to comorbidities and reduced tolerability; as a result, these patients often receive suboptimal treatment. In addition, 5-year survival rates are lower in elderly than in younger patients with NSCLC. In a multicenter phase III trial, first-line treatment with nab-paclitaxel plus carboplatin (nab-P/C) significantly increased median overall survival (OS) vs solvent-based paclitaxel plus C in a subset of patients ≥ 70 years of age with advanced NSCLC (19.9 vs 10.4 months; HR 0.583; P = 0.009; Socinski et al. Ann Oncol. 2013;24:314-321). However, 55% of elderly patients treated with nab-P/C required dose reductions and 84% had dose delays, primarily due to adverse events, including myelosuppression. In the open-label, multicenter phase IV ABOUND.70+ trial, the safety and efficacy of 2 different schedules of first-line nab-P/C treatment will be evaluated prospectively in elderly patients with advanced NSCLC.
Methods:
Approximately 284 patients with NSCLC ≥ 70 years of age who are not candidates for curative surgery or radiation therapy will be randomized 1:1 to nab-P 100 mg/m[2] intravenously (IV; 30-minute infusion) on days 1, 8, and 15 plus C AUC 6 on day 1 every 21 days or the same nab-P/C dose every 21 days followed by a 1-week break. Key eligibility criteria include histologically/cytologically confirmed locally advanced or metastatic NSCLC, no prior chemotherapy for metastatic disease, ECOG performance status ≤ 1, adequate organ function, no active brain metastases, and absence of preexisting peripheral neuropathy (PN) grade > 2. Patients will be stratified by ECOG performance status (0 vs 1) and histology (squamous vs nonsquamous). ClinicalTrials.gov identifier NCT02151149.
[a] Additional exploratory endpoints may be defined in the statistical analysis plan if applicable.Key Endpoints Primary Percentage of patients developing either PN grade ≥ 2 or myelosuppression grade ≥ 3 Secondary Safety Progression-free survival OS Overall response rate Exploratory[a] Healthcare resource utilization throughout the study Changes in quality of life
Results:
TPS Abstract Section NA
Conclusion:
TPS Abstract Section NA
