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Michael Boyer
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OA13 - Therapeutics and Radiation for Small Cell Lung Cancer (ID 927)
- Event: WCLC 2018
- Type: Oral Abstract Session
- Track: Small Cell Lung Cancer/NET
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 10:30 - 12:00, Room 203 BD
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OA13.02 - Two Novel Immunotherapy Agents Targeting DLL3 in SCLC: Trials in Progress of AMG 757 and AMG 119 (ID 14538)
10:40 - 10:50 | Author(s): Michael Boyer
- Abstract
- Presentation
Background
Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor characterized by initial response to chemotherapy and radiotherapy followed by relapse or progression with chemoresistant disease. Delta-like ligand 3 (DLL3) is an inhibitory Notch ligand that is specifically upregulated in SCLC. IHC profiling of tumor samples showed DLL3 expression in 86% of SCLC tumors and minimal expression in normal tissue.
We are conducting clinical trials of two novel immunotherapy agents that target DLL3. AMG 757 is a half-life extended bispecific T cell engager (BiTE®) antibody construct that is designed to transiently crosslink DLL3-positive SCLC cells to CD3-positive T cells and induce T cell–mediated tumor cell lysis and concomitant T cell proliferation. AMG 119 is an adoptive cellular therapy that consists of a patient’s autologous T cells that have been genetically modified ex vivo to express a transmembrane chimeric antigen receptor that targets DLL3 on the surface of SCLC cells. Both AMG 119 and AMG 757 showed potent killing of SCLC cell lines with a broad range of DLL3 expression in vitro and inhibition of tumor growth in the SHP-77 human SCLC xenograft model in vivo. AMG 757 was well tolerated in a preclinical multi-dose GLP toxicology study, with no evidence of tissue damage at weekly doses as high as 4.5 mg/kg.
a9ded1e5ce5d75814730bb4caaf49419 Method
NCT03319940 is an open label, phase 1 study evaluating the safety, tolerability and pharmacokinetics of AMG 757 that will initially enroll adult patients with SCLC who have progressed or recurred following platinum-based chemotherapy. Key inclusion criteria: ECOG PS 0–2, life expectancy ≥12 weeks, at least 2 measurable lesions per modified RECIST 1.1 criteria, and adequate organ function. The study will later enroll patients with extended disease SCLC with ongoing clinical benefit following no more than 6 cycles of first-line platinum-based chemotherapy. AMG 757 will be administered as an intravenous infusion once every 2 weeks.
NCT03392064 is an open-label, phase 1 study evaluating the safety, tolerability and efficacy of AMG 119 in adult patients with SCLC whose disease has progressed or recurred after at least one platinum-based regimen. Key inclusion criteria: ECOG PS 0–1, at least 2 measurable lesions per modified RECIST 1.1 criteria, no evidence of CNS metastasis, and adequate organ function. AMG 119 will be administered as a one-time intravenous infusion.
Both of these studies are currently enrolling patients. For more information, please contact Amgen Medical Information: [email protected].
4c3880bb027f159e801041b1021e88e8Only 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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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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P1.01-09 - Pembrolizumab Plus Ipilimumab or Placebo in 1L Metastatic NSCLC with PD-L1 Tumor Proportion Score (TPS) ≥50%: KEYNOTE-598 (ID 12958)
16:45 - 18:00 | Presenting Author(s): Michael Boyer
- Abstract
Background
Pembrolizumab monotherapy significantly prolonged survival vs chemotherapy in previously untreated, advanced NSCLC with PD-L1 expressed on ≥50% of tumor cells (TPS ≥50%) in KEYNOTE-024. Pembrolizumab with chemotherapy led to higher objective response rates (ORRs) vs chemotherapy alone in a similar population in KEYNOTE-021. KEYNOTE-598 (NCT03302234) will evaluate the effects of combination immunotherapy with pembrolizumab and ipilimumab.
a9ded1e5ce5d75814730bb4caaf49419 Method
Eligibility for this randomized, double-blind phase 3 study requires patients be ≥18 years of age and have histologically/cytologically confirmed stage IV metastatic NSCLC, PD-L1 TPS ≥50% per IHC analysis on archival/newly obtained tumor sample, measurable disease per RECIST v1.1, ECOG PS 0/1, absence of EGFR/ALK aberration, and no prior systemic therapy. Patients will be randomized 1:1 to up to 35 administrations of pembrolizumab 200 mg Q3W with 18 cycles of either ipilimumab 1 mg/kg or placebo Q6W. Patients may be eligible for 17 and 9 additional administrations of pembrolizumab and ipilimumab/placebo, respectively. Treatment may be discontinued due to disease progression, intolerable toxicity, or consent withdrawal. Randomization is stratified by ECOG PS (0 vs 1), geography (East Asia vs non–East Asia), and histology (squamous vs nonsquamous). Response is assessed every 9 weeks through week 54, then every 12 weeks per RECIST v1.1 by BICR. Treatment-based decisions may utilize modified RECIST v1.1 for immune-based therapy (iRECIST). Site-assessed progression is verified by BICR before treatment discontinuation. AEs are graded per CTCAE v4.0. Primary endpoints are overall survival and progression-free survival. Secondary endpoints are ORR and duration of response by BICR; time to true deterioration in the composite endpoint of cough, pain in chest, and shortness of breath assessed by EORTC QLQ-LC13 and EORTC QLQ-C30; and safety. Approximately 548 patients will be enrolled. Enrollment began on December 18, 2017; as of April 13, 2018, 33 patients have been enrolled.
4c3880bb027f159e801041b1021e88e8 Result
"Section not applicable"
8eea62084ca7e541d918e823422bd82e Conclusion
"Section not applicable"
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P1.04 - Immunooncology (Not CME Accredited Session) (ID 936)
- 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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P1.04-11 - Exploring the Germ-Line Contribution to Exceptional Response to PD-1/PD-L1 Inhibition in Patients with NSCLC by Whole Genome Sequencing (ID 12646)
16:45 - 18:00 | Author(s): Michael Boyer
- Abstract
Background
Responses to immune checkpoint inhibitors (CPI) may vary between individuals because of somatic mutation differences in the tumour and/or germ-line differences in immunological tolerance. To explore the latter, this ongoing study evaluates patients with metastatic non-small cell lung cancer (NSCLC) treated with single agent PD-1 or PD-L1 inhibitors recruited from a treatment pool of 420 patients (total) / 137 (active since 1 August 2017).
a9ded1e5ce5d75814730bb4caaf49419 Method
Rare and common germ-line DNA variants are analysed in exceptional responders and non-responders by whole genome sequencing (WGS) (Illumina HiSeqX Ten). Exceptional responders are defined as patients with complete or partial response of more than 12 months or stable disease of more than 24 months (per RECIST), and a concurrent immune-related adverse event of any grade. Non-responders are defined as patients with best response of progressive disease, having received at least 4 cycles or 2 months of treatment.
In these individuals, the burden of rare and common variants in immune tolerance genes is analysed and compared to the Medical Genome Reference Bank (MGRB), comprising WGS of 1144 well-elderly individuals. Comparisons are made with Fisher Exact test. Genetic risk scores for auto-immune conditions are calculated for these cohorts, MGRB and NSCLC patients included in The Cancer Genome Atlas. Scores are calculated using curated risk alleles and OR weightings derived from the NHGRI-EBI GWAS catalogue.
4c3880bb027f159e801041b1021e88e8 Result
Recurrent rare variants (Exome Aggregation Consortium (ExAC) frequency < 1%) were found within responders sequenced to date (n=20), including variant A, a frameshift mutation in a protein kinase not present in ExAC, with allelic frequency (AF) of 1.27% in MGRB and 17.5% of our cohort (p<0.0001). Multiple common variants (ExAC ≥1%) were more frequent within the cohort compared with population standard. Among these, three functional variants within gene B, encoding a protein involved in modulating immune-responsiveness, (variant B.1, B.2 and B.3, ExAC AF: 1.3%, 0.99% and 2.3%), were found seven times (total) across six individuals (one compound heterozygous B.2/B.3). The exceptional responders cohort was enriched for subjects with higher genetic risk for Disease A, psoriasis and psoriatic arthritis compared with control groups.
8eea62084ca7e541d918e823422bd82e Conclusion
Preliminary findings suggest individuals harbouring functional variants in genes promoting immune tolerance may be more responsive to PD-1/PD-L1 inhibitors. This may be due to higher basal immune activation, requiring greater reliance on inhibitory checkpoints to maintain homeostasis. Ordinarily, this would be clinically undetectable, however the addition of a pharmacological CPI may more effectively break immune tolerance in this primed environment.
6f8b794f3246b0c1e1780bb4d4d5dc53
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PL04 - Take Action - Key Messages from WCLC 2018 and Goals for 2019 (ID 852)
- Event: WCLC 2018
- Type: Plenary Session
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 15:15 - 16:30, Plenary Hall
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PL04.06 - Targeted Therapy (ID 11659)
16:05 - 16:15 | Presenting Author(s): Michael Boyer
- Abstract
- Presentation
Abstract not provided
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YI01 - Young Investigators Session (ID 988)
- Event: WCLC 2018
- Type: Young Investigator Session
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/23/2018, 08:00 - 11:30, Room 106
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YI01.12 - Writing a Successful Abstract (ID 14681)
10:15 - 10:30 | Presenting Author(s): Michael Boyer
- Abstract
- Presentation
Abstract not provided
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