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Sara Brett
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P1.01 - Advanced NSCLC (ID 158)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.01-110 - Novel Regimens Versus Standard-of-Care in NSCLC: A Phase II, Randomized, Open-Label, Platform Trial Using a Master Protocol (Now Available) (ID 2288)
09:45 - 18:00 | Author(s): Sara Brett
- Abstract
Background
Although non-small cell lung carcinoma (NSCLC) is intrinsically resistant to immunotherapy agents, a subset of tumors are susceptible to T cell-mediated antitumor effects. Treatment regimens combining agents that target different processes within the cancer immunity cycle have the potential to enhance response in relapsed or refractory NSCLC. GSK3359609 is a humanized IgG4 antibody with potent agonist activity against Inducible T cell Costimulator (ICOS) and no or low depleting effect on antibody-dependent cell-mediated cytotoxicity.
Method
This is a randomized, phase II, open-label, platform trial utilizing a master protocol in patients with advanced NSCLC who have progressed on initial PD1/PDL1-based immunotherapy and platinum-based chemotherapy. The trial will consist of several sub-studies, with each sub-study comparing novel combinations vs. current standard-of-care (SOC). No treatment crossover is allowed. Additional sub-studies may be added over time following protocol amendments. In the first sub-study, patients are centrally randomized by internet to SOC (docetaxel) or novel ICOS drug combination (NIDC) (GSK3359609 + docetaxel) in a 1:2 ratio, stratified by squamous versus non-squamous NSCLC and line of PD1/PDL1; randomization to SOC is minimized thereafter. Primary endpoint is overall survival (OS). Secondary endpoints are survival rate at 12 and 18 months; tumor response according to RECIST 1.1 and iRECIST criteria; pharmacokinetic parameters of the novel immunotherapy; and safety. Exploratory endpoints include tumor and blood-based biomarker evaluations such as tumor mutational burden and gene expression. Interim analysis of OS will be done after approximately 45 deaths in both study groups, with ≥18 deaths in the combination immunotherapy group; final analysis will be done after 85 deaths (35 in combination immunotherapy group). The study will employ a Bayesian decision-making framework based on predictive probability of observing a significant improvement in OS in a future phase III trial. A sample size of ≤70 participants in each combination immunotherapy group and ≥35 participants in the SOC group will provide ≥81% power with a type 1 error of ≤2.3% for each pairwise comparison.
Sub-study 1 will compare the efficacy of GSK3359609 plus docetaxel versus docetaxel alone. At least 105 patients are expected to enroll. GSK3359609/docetaxel will be administered for ≤2 years or 35 visits, or until disease progression, death or unacceptable toxicity. Both drugs are given as an IV infusion (docetaxel 75mg/m2; GSK3359609 80 mg).
Result
Study enrollment has begun and the primary endpoint results of sub-study 1 are expected mid-2020.
Conclusion
The study will provide information on the efficacy of novel immunotherapies used in combination.
GlaxoSmithKline (NCT03739710).
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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
- Now Available
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.04-91 - Target Antigen Levels in NSCLC Define a Clinically Relevant Activation Threshold for NY-ESO-1<sup>c259</sup> TCR T-Cell Therapy (Now Available) (ID 2259)
10:15 - 18:15 | Author(s): Sara Brett
- Abstract
Background
Chimeric antigen receptor (CAR) and T cell receptor (TCR) T cell therapies are innovative ‘living drugs’ with the potential for transformational benefit to patients. T cell therapies, have so far, shown impressive efficacy in haematological malignancies. However, treatment of solid tumours remains challenging. Unlike CARs, that recognize cell surface proteins, TCRs recognize intracellular targets presented in the context of human leukocyte antigen (HLA). NY-ESO-1 and LAGE-1a are tumour-associated intracellular antigens that generate a shared SLLMWITQC peptide bound to HLA-A*02 and expressed on multiple malignancies, including non-small cell lung cancer (NSCLC).
Our TCR T cell product (GSK3377794) consists of autologous, lentivirally (LV) transduced T cells engineered to express an affinity enhanced NY-ESO-1c259 TCR recognizing the SLLMWITQC/HLA-A*02 peptide. Cell therapy trials with NY-ESO-1c259 TCR T cells have shown the highest objective responses to date to solid cancer in patients with synovial sarcoma, metastatic melanoma and multiple myeloma. Recently a partial response in a patient with advanced lung adenocarcinoma was reported with a another TCR-engineered T cell product targeting NY-ESO-1.
The aims of our study were (1) to systematically assess the prevalence of target antigen expression for NY-ESO-1 and LAGE-1a in NSCLC (2) to determine the product-specific threshold of target antigen expression in NSCLC required to induce a specific T cell response, and (3) to explore means to selectively modulate NY-ESO-1/LAGE-1a expression in lung cancer with the aim of increasing patient benefit from TCR T cell treatment.
Method
We established and characterized a NSCLC tumour biobank consisting of: primary patient tumour tissues, patient derived xenograft (PDX) samples and tumour cell lines. Expression of HLA-A*02 was confirmed by flow cytometry and levels of NY-ESO-1/LAGE-1a were measured via RT-qPCR. GSK3377794 response against these samples was determined by IFN-γ secretion and correlated with NY-ESO-1/LAGE-1a expression levels.
Result
Expression of NY-ESO-1 and LAGE-1a antigen varied across the NSCLC tumour biobank samples. GSK3377794 activation correlated with NY-ESO-1/LAGE-1a expression levels in NSCLC. The functional readouts identify a product-specific antigen expression threshold for GSK3377794 in NSCLC, which could translate to a potential patient population that may benefit from GSK3377794 treatment. Our experiments further indicate that it is possible to increase NY-ESO-1/LAGE-1a expression in NSCLC cells by use of epigenetic modifiers enhancing specific targeting by GSK3377794.
Conclusion
To date this is the most comprehensive and systematic analysis that correlates target antigen expression in NSCLC with functional responses of GSK3377794 using a set of clinically relevant sample specimens.
