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Kristopher Frese
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MA22 - New Therapeutics, Pathology, and Brain Metastases for Small Cell and Neuroendocrine Tumour (ID 925)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Small Cell Lung Cancer/NET
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 15:15 - 16:45, Room 206 BD
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MA22.03 - SCLC Circulating Tumour Cell Derived Explants: The Clinical Characteristics of Patients Whose Samples Generate CDX (ID 12969)
15:25 - 15:30 | Author(s): Kristopher Frese
- Abstract
- Presentation
Background
Small cell lung cancer (SCLC) prognosis is dismal, with minimal improvement in recent years. Work with SCLC cell lines and targeted therapies have been disappointing when translated into clinical practice. Circulating tumour cells (CTCs) represent a readily accessible liquid biopsy, which can be used to generate CTC derived explants (CDXs) for the study of SCLC biology and the investigation of biomarkers and therapeutics. These clinically relevant models appear to mirror patient response to therapeutics. Our aim was to assess if the patients whose samples generated a CDX represent the SCLC population, and determine if the clinical features of these patients offer insight into CTC biology.
a9ded1e5ce5d75814730bb4caaf49419 Method
This was a single centre, retrospective analysis of 147 SCLC patients who had participated in The CHEMORES Study in which SCLC patients were asked to donate blood samples for the discovery and validation of novel biomarkers. Paired patient blood samples were taken for CTC enumeration using CellSearch Technology and for attempted CDX model generation. We obtained demographic and clinical information on these patients, and analysed the data for differences between patients whose blood samples generated a CDX and those whose did not.
4c3880bb027f159e801041b1021e88e8 Result
231 paired blood samples were taken from 147 patients, with 45 CDXs successfully generated from 34 patients. CTC number was significantly higher in samples which generated a CDX than those which didn’t, p=0.001. Successful progression samples had a significantly lower CTC number than successful baseline samples, p=0.026. There was no significant difference in age, gender, pack year history, performance status, stage, chemosensitivity or the presence of liver or brain metastases between patients whose samples did and did not generate a CDX. Metastatic burden was significantly higher in patients whose samples generated a CDX, p=<0.001. Progression free (PFS) and overall survival were significantly shorter in patients whose samples generated a CDX, p=<0.001
8eea62084ca7e541d918e823422bd82e Conclusion
CTC number correlates with CDX success, although a specific CTC phenotype may be more important. CTCs at progression may have a more aggressive phenotype than those at baseline. CDXs appeared to represent the SCLC population which is important when translating knowledge gained by studying CDXs into clinical practice. CTCs may play a role in the widespread metastatic dissemination of SCLC and thus survival of patients. Shortened PFS in the absence of difference in chemosensitivity may be due to outliers with particularly long PFS in the unsuccessful group. Further genomic and phenotypic analysis of subpopulations of CTCs may provide further insight.
6f8b794f3246b0c1e1780bb4d4d5dc53Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MS32 - SCLC - From Benchside to Bedside - Clinical Science Session (ID 810)
- Event: WCLC 2018
- Type: Mini Symposium
- Track: Small Cell Lung Cancer/NET
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 13:30 - 15:00, Room 107
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MS32.03 - Liquid Biopsies for Drug Development in SCLC (ID 11542)
14:00 - 14:15 | Author(s): Kristopher Frese
- Abstract
- Presentation
Abstract not provided
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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P2.13 - Targeted Therapy (Not CME Accredited Session) (ID 962)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.13-33 - A Case Report of Exceptional Clinical Response to MEK Inhibition in a Patient with NRAS Mutation Positive NSCLC (ID 13275)
16:45 - 18:00 | Author(s): Kristopher Frese
- Abstract
Background
NRAS mutation occurs in <1% patients with non-small cell lung cancer (NSCLC). Pre-clinical lung cancer models with NRAS mutation have demonstrated response to single agent MEK inhibition with activation of the PI3K-AKT-mTOR pathway as a putative resistance mechanism. There are a paucity of data for MEK inhibition in the clinical setting for NRAS positive disease. To our knowledge, this is the first report of an NRAS positive NSCLC patient to be treated with a MEK inhibitor.
a9ded1e5ce5d75814730bb4caaf49419 Method
A 51 year old female with advanced NSCLC was identified to have an NRAS Q61K mutation in both archival tumour and circulating tumour DNA (ctDNA) within the TARGET study. Tumour was analysed for a panel of 24 genes using an amplicon based NGS assay and circulating tumour DNA using a hybridisation capture technique of 650 genes. The patient was allocated in the Molecular Tumour Board to participate in the Phase I study of LNP3794, a first-in-human dose escalation study of a MEK inhibitor with primary endpoint of safety and tolerability. Serial plasma samples were acquired during treatment for ctDNA analysis and fresh tissue was acquired pre-treatment and on disease progression. A PDX model was implanted from the disease progression sample to explore functional mechanisms of resistance
4c3880bb027f159e801041b1021e88e8 Result
The patient was commenced on LNP3794 in Jun 2015 having previously progressed on first line chemotherapy with extensive lung metastases. Initially she exhibited G3 toxicity with LNP3794, managed by dose reduction and subsequently was well tolerated. Within 6 weeks the patient demonstrated an exceptional response with 44% reduction in tumour by RECIST 1.1, resolution of a number of lesions and with clear symptomatic benefit. She remained on study for 12 months with maintained PR. The NRAS mutant allele fraction in blood fell from 20% to not detectable within 6 months and subsequently started to rise 3 months prior to radiological progression. A PIK3CA Q546K mutation was identified by Foundation Medicine at progression. The PDX is currently growing at a slow rate and the hypothesis of re-sensitisation with a combination of an mTOR inhibitor with MEK inhibition will be explored.
8eea62084ca7e541d918e823422bd82e Conclusion
These data support further evaluation of MEK inhibitors in patients with NRAS positive NSCLC. As a rare population a multi-site study would be required. Combination with inhibitors of the PI3k-AKT-mTOR pathway, if tolerated, may further prolong response and clinical benefit and should also be explored.
6f8b794f3246b0c1e1780bb4d4d5dc53
