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Martin David Forster
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P1.04 - Immuno-oncology (ID 164)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.04-43 - PD-RAD: A Translational Study Investigating PD-L1 Expression After Radiotherapy for Non-Small Cell Lung Cancer - Trial in Progress (ID 1811)
09:45 - 18:00 | Author(s): Martin David Forster
- Abstract
Background
Radiotherapy (RT) is delivered to 30-50% of NSCLC patients. However, over half of patients progress following RT and mechanisms of resistance are poorly understood. RT has immune-modulatory properties such as the ability to upregulate tumour PD-L1 expression and can recalibrate the immune contexture. Blockade of the PD-1/PD-L1 axis has been shown to enhance the efficacy of RT in several pre-clinical models and the recent PACIFIC trial. Exploiting immuno-regulatory effects of RT therefore has the ability to enhance local and distant anti-cancer effects of RT, especially when combining RT with immunotherapies such as anti-PD-1 or costimulatory agonists.
Method
PDRAD is a prospective UK multi-centre feasibility study of paired pre- and post-treatment biopsies in NSCLC patients receiving palliative or radical RT. The study will recruit up to 30 patients with inoperable disease that is accessible to core biopsy by CT or bronchoscopy within the proposed RT field. Patients with archival baseline histology containing sufficient tumour material are eligible. Consented patients undergo a repeat biopsy in the second week of RT (fig.1). Blood samples will be collected at baseline, repeat biopsy, and following RT to assess immune changes that may correlate with the tumour microenvironment (TME). PDRAD opened to recruitment in November 2018 and will continue recruitment over 16 months.
Research aims include investigating:
Feasibility and acceptability of obtaining paired biopsies
Changes in the immune contexture in irradiated tumour and ‘out of field’ sites
Immune changes in the TME and peripheral blood
Interim feasibility results after recruitment of 15 patients will be presented at World Lung.
Result
Section not applicable
Conclusion
We are at a pivotal point in evolving our knowledge of how the TME may influence responses to RT. The PDRAD study will help to influence further clinical trials, including combination studies with immunotherapies and predictive and prognostic biomarker development within the field.
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P2.01 - Advanced NSCLC (ID 159)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.01-16 - TACTICAL: A Phase I/II Trial to Assess the Safety and Efficacy of MSCTRAIL in Metastatic Lung Adenocarcinoma (ID 794)
10:15 - 18:15 | Author(s): Martin David Forster
- Abstract
Background
Mesenchymal stromal cells (MSCs) migrate to and incorporate into tumour stroma, acting as vehicles for delivering anti-cancer therapies. TNF-related apoptosis inducing ligand (TRAIL) selectively induces apoptosis in malignant cells, however its short biological half-life has limited therapeutic efficacy.
We have transduced MSCs with a lentiviral vector to express TRAIL (MSCTRAIL), demonstrating efficacy in vitro using co-culture assays and in vivo in orthotopic lung metastasis murine model, showing regression of metastases following treatment with intravenous MSCTRAIL [1] and synergistic activity with other systemic anti-cancer therapies.
Given their immune-privileged nature we are now delivering ex vivo MSCTRAIL from pooled third party umbilical cord donors without tissue matching or immunosuppression.
Method
TACTICAL is a phase I/II trial assessing safety and efficacy of MSCTRAIL in combination with first line standard of care (SOC); pemetrexed (500mg/m2) and cisplatin (75mg/m2) and/or pembrolizumab (200mg), in treatment-naive patients with stage IIIB/IV metastatic lung adenocarcinoma. Patients have no actionable driver mutations and ECOG performance status 0-1.
Phase I is a dose de-escalation study; patients receive SOC on day 1 and 4x108 MSCTRAIL cells on day 2 of a 21-day cycle for 3 cycles, with a Bayesian adaptive design recommending dose reductions if severe toxicities occur (Fig.1A). Primary outcomes are recommended phase II dose (RP2D), safety and tolerability of MSCTRAIL.
In phase II, 46 patients will be randomised (1:1) in a double-blind trial to receive SOC and either RP2D of MSCTRAIL or placebo (Fig.1B). Primary outcome is tumour response rate by RECIST (v1.1) at 12 weeks.
Result
Translational work will include measuring: biomarkers of response; T, B, NK cell function in reaction to allogeneic MSCs; tracking migration of MSCs radiolabelled with 89Zirconium-oxine through serial PET imaging.
Conclusion
TACTICAL is the first clinical trial of this novel cell and gene therapy and if successful will pave the way for future allogeneic MSC cancer therapies.
1. Loebinger, M.R., et al., Mesenchymal stem cell delivery of TRAIL can eliminate metastatic cancer. Cancer Res, 2009. 69(10): p. 4134-42.
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P2.04 - Immuno-oncology (ID 167)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.04-68 - Retrospective Analysis of Immune Checkpoint Inhibitors in NSCLC: Immune-Related Adverse Events and Outcomes (ID 2244)
10:15 - 18:15 | Author(s): Martin David Forster
- Abstract
Background
In the United Kingdom, immune check-point inhibitors (ICPi) including pembrolizumab, atezolizumab and nivolumab are routinely used in advanced NSCLC. These agents are associated with immune-related adverse events (irAE). We present a single centre experience of a tertiary lung cancer centre on the incidence and severity of irAE, with hospitalisation episodes and duration. Patient outcomes were compared with radiological assessment of response, Neutrophil to Lymphocyte ratio (NLR) and Platelet to Lymphocyte ratio (PLR). High NLR and PLR may predict for poorer outcomes following ICPi treatment .
Method
This was a single-centre retrospective analysis of the electronic records of NSCLC patients who received treatment with an ICPi between January 2017 and December 2018. Patients on clinical trials were excluded. NLR and PLR were derived from the most recent pre-treatment peripheral blood sampling. The subjective response as recorded in radiological reports of cross-sectional imaging was noted. The first response was defined as the response reported in the first scan after initiation of treatment and the best response was defined as best recorded response across all scans following treatment. Kaplan Meier survival analyses were performed.
Result
Patient characteristics and response Patient Characteristics N=46 % Median age 64.8 (range 48.1 to 81.9) Male 28 60.9 Female 18 39.1 Treatment Atezolizumab 7 15.2 Pembrolizumab 39 84.8 Line of treatment First 20 43.5 Second 20 43.5 Third 6 13 Histology Adenocarcinoma 34 73.9 Squamous 8 17.4 Other NSCLC 4 8.7 First response to treatment Progressive disease 18 39.1 Stable disease 3 6.5 Partial response 10 21.7 Complete response 1 2.2 Mixed response 10 21.7 Not assessed 4 8.7 Best response to treatment Progressive disease 17 37 Stable disease 3 6.5 Partial response 11 23.9 Complete response 2 4.3 Mixed response 9 19.6 Not assessed 4 8.7 irAE and grade (54 events) Anorexia, G1-2 2 3.7 Arthritis, G1-2 1 1.9 Arthritis, G3 1 1.9 Diarrhoea, G1-2 4 7.4 Diarrhoea, G3 4 7.4 Diarrhoea, G5 1 1.9 Endocrinopathies, G1-2 6 11.1 Fatigue, G1-2 12 23 Fatigue, G3 3 5.6 Liver dysfunction, G1-2 1 1.9 Nausea/Vomiting, G1-2 6 11.1 Pneumonitis, G3 1 1.9 Pruritus/Rash, G1-2 10 18.5 irAE hospitalisation events 9 19.6 Median length of hospitalisation 8.5 days (range 1 to 19) Mean NLR 5.90 (range 0.98 to 28.04) Mean PLR 272.02 (range 83.5 to 893.3) First recorded radiological response was a predictor of best radiological response and OS, p=0.003. NLR and PLR above mean were predictive factors for decreased OS (HR 3.99, 95% CI 2.01 to 14.35, p=0.0009; HR 2.09, 95% CI 0.84 to 4.87, p=0.119).
Conclusion
Most patients experienced at least 1 irAE. 1 in 5 had irAE grade 3 or above requiring hospitalisation. The burden of irAE and increased hospitalisation time and costs are likely to increase secondary to the increased use of ICPi in combination with platinum-doublet chemotherapy in the first-line setting for advanced NSCLC. Response at first radiological assessment was a predictor of outcome. NLR and PLR are potential readily measurable predictive biomarkers.
