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Sreeja Aruketty
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P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.01-26 - Single-Centre Experience of Clinical Outcomes for Advanced Lung Cancer Patients in Phase I Clinical Trials. (ID 13932)
16:45 - 18:00 | Author(s): Sreeja Aruketty
- Abstract
Background
Response rates for patients enrolled in early phase clinical trials have historically been reported as 5-10%. An unprecedented number of novel therapeutic options and emerging therapies in lung cancer (LC) have resulted in greater emphasis on early phase clinical trials and molecular stratification.
We aimed to evaluate outcomes for patients with LC treated since 2015 with novel agents or combination strategies within an expanding early phase clinical trials unit at The Christie Hospital, Manchester, UK.
a9ded1e5ce5d75814730bb4caaf49419 Method
A database of patients consented to phase I clinical trials was interrogated for LC patients recruited over a three-year period. Clinical characteristics including histological sub-type, line of therapy, molecular phenotype, smoking status and ECOG performance status (PS) were collected for each patient. Patient records were reviewed for clinical trial allocation, treatment response, progression-free survival (PFS), and overall survival (OS).
4c3880bb027f159e801041b1021e88e8 Result
Over a three-year period to March 2018, 153 lung cancer patients were consented to Phase I clinical trials of Investigational Medicinal Products, of whom 113 (74%) commenced treatment. The median age of patients treated was 64y (range 28-84) with a male predominance (54%). All patients had a PS of 0-1 and 25% were non-smokers. Histological subtypes included non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC) and mesothelioma. The overall response rate (RR) by RECIST criteria was 27% across all patients, with a disease control rate of 73%. Median PFS was 6 months, and median OS was 11 months in the entire cohort. Compared with patients with NSCLC, patients with SCLC had worse PFS (7mo vs 3mo, p=0.001) and RR (35% vs 0%). The 28 trials recruiting LC patients in the unit during this period involved therapies targeting EGFR and ROS1, PI3K-mTOR-AKT and RAS-RAF-MEK signalling, DNA repair genes, cell-surface protein overexpression and genes implicated in immune signalling. Novel agents included small molecule inhibitors, monoclonal antibodies, and antibody-drug conjugates, in addition to targeted agents combined with chemotherapy or immune checkpoint inhibitor combinations. Patients had between 0-5 prior lines of therapy with no difference in PFS, OS or RR regardless of prior treatment lines.
8eea62084ca7e541d918e823422bd82e Conclusion
Our data demonstrate clear benefit for lung cancer patient participation in early phase clinical trials. Novel therapeutic agents and evolution of early phase clinical trial design have resulted in promising options for patients with NSCLC, with RR>30% within our unit, regardless of prior treatment status. However, outcomes for SCLC patients lag behind and new therapeutic options are urgently needed.
6f8b794f3246b0c1e1780bb4d4d5dc53
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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): Sreeja Aruketty
- 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
