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  • 11
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    Effects of MAPK and PI3K Pathways on PD-L1 Expression in Melanoma
    American Association for Cancer Research (AACR) ; 2014
    In:  Clinical Cancer Research Vol. 20, No. 13 ( 2014-07-01), p. 3446-3457
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 20, No. 13 ( 2014-07-01), p. 3446-3457
    Abstract: Purpose: PD-L1 is the main ligand for the immune inhibitory receptor PD-1. This ligand is frequently expressed by melanoma cells. In this study, we investigated whether PD-L1 expression is controlled by melanoma driver mutations and modified by oncogenic signaling inhibition. Experimental Design: Expression of PD-L1 was investigated in a panel of 51 melanoma cell lines containing different oncogenic mutations, including cell lines with innate and acquired resistance to BRAF inhibitors (BRAFi). The effects of targeted therapy drugs on expression of PD-L1 by melanoma cells were investigated. Results: No association was found between the level of PD-L1 expression and mutations in BRAF, NRAS, PTEN, or amplification of AKT. Resistance to vemurafenib due to the activation of alternative signaling pathways was accompanied with the induction of PD-L1 expression, whereas the resistance due to the reactivation of the MAPK pathway had no effect on PD-L1 expression. In melanoma cell lines, the effects of BRAF, MEK, and PI3K inhibitors on expression of PD-L1 were variable from reduction to induction, particularly in the presence of INFγ. In PD-L1–exposed lymphocytes, vemurafenib paradoxically restored activity of the MAPK pathway and increased the secretion of cytokines. Conclusions: In melanoma cell lines, including BRAFi-resistant cells, PD-L1 expression is variably regulated by oncogenic signaling pathways. PD-L1–exposed lymphocytes decrease MAPK signaling, which is corrected by exposure to vemurafenib, providing potential benefits of combining this drug with immunotherapies. Clin Cancer Res; 20(13); 3446–57. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-13-2797
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 12
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    CMP-001-007: Open-label, phase 2 study of intratumoral CMP-001 + pembrolizumab in patients with recurrent or metastatic head and neck squamous cell carcinoma.
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. TPS6089-TPS6089
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. TPS6089-TPS6089
    Abstract: TPS6089 Background: PD-1 blockade ± chemotherapy has recently become a primary systemic therapy recommended by NCCN guidelines for patients (pts) with recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). However, most pts still do not respond to treatment, indicating a large unmet need for pts with unresectable disease. CMP-001 is a toll-like receptor 9 (TLR9) agonist comprising a CpG-A oligodeoxynucleotide packaged in a virus-like particle that can induce type I interferon secretion from tumor-associated plasmacytoid dendritic cells, promoting a Th1-like chemokine milieu in the tumor microenvironment and inducing an antitumor CD8+ T-cell response. In a phase (ph) 1b study in pts with metastatic melanoma, intratumoral (IT) injection of CMP-001 + intravenous (IV) pembrolizumab (pembro) reversed PD-1 blockade resistance, induced responses in injected and noninjected lesions, and had an acceptable safety profile (Milhem et al, SITC 2020). This combination is therefore being tested in pts with HNSCC. Methods: CMP-001-007 (NCT04633278) is an open-label, multicenter, ph 2 study designed to investigate the efficacy and safety of CMP-001 + IV pembro in adult pts with histologically or cytologically confirmed R/M HNSCC considered incurable by local therapies. Eligible pts have undergone a pretreatment tumor biopsy, received no prior systemic therapy in the R/M setting, and have primary tumor locations of oropharynx, oral cavity, hypopharynx, or larynx. In addition, pts must have PD-L1-positive tumors (combined positive score ≥1), known tumor human papillomavirus (HPV) status (for oropharyngeal cancer), and measurable disease per RECIST v1.1 with ≥1 lesion amenable to IT injection. Pts with primary tumors in the nasopharynx are excluded. Enrolled pts will receive CMP-001 10 mg once weekly for 7 doses and every 3 weeks (Q3W) thereafter. The first dose may be administered subcutaneously or via IT injection, with all subsequent doses administered IT. All pts will also receive pembro 200 mg IV Q3W after the CMP-001 injection. Treatment continues until unacceptable toxicity or disease progression. The primary endpoint is investigator-assessed objective response rate (ORR) per RECIST v1.1. Secondary endpoints include safety, duration of response (DOR), progression-free survival (PFS), overall survival, and effects of HPV infection and PD-L1 expression on ORR, DOR, and PFS. Exploratory endpoints include analyses of baseline and changes from baseline in tumor or serum biomarkers related to TLR9, immune checkpoints, and potential predictors of response, as well as serum concentrations of CXCL10 and CMP-001. Refer to clinicaltrials.gov/ct2/show/NCT04633278 for the most current information on enrolling sites. Clinical trial information: NCT04633278.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.15_suppl.TPS6089
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
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  • 13
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    Overall survival of PEGylated pegilodecakin with 5-FU/LV and oxaliplatin (FOLFOX) in metastatic pancreatic adenocarcinoma (PDAC).
    American Society of Clinical Oncology (ASCO) ; 2018
    In:  Journal of Clinical Oncology Vol. 36, No. 15_suppl ( 2018-05-20), p. 4119-4119
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 36, No. 15_suppl ( 2018-05-20), p. 4119-4119
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2018.36.15_suppl.4119
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2018
    detail.hit.zdb_id: 2005181-5
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  • 14
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    Responses and durability in NSCLC treated with pegilodecakin and anti-PD-1.
    American Society of Clinical Oncology (ASCO) ; 2018
    In:  Journal of Clinical Oncology Vol. 36, No. 15_suppl ( 2018-05-20), p. 9018-9018
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 36, No. 15_suppl ( 2018-05-20), p. 9018-9018
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2018.36.15_suppl.9018
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2018
    detail.hit.zdb_id: 2005181-5
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  • 15
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    A phase I, open-label, multicenter, single-dose escalation and multi-dose study of a monoclonal antibody targeting CEACAM1 in subjects with selected advanced or recurrent malignancies.
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 15_suppl ( 2020-05-20), p. 3094-3094
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. 3094-3094
    Abstract: 3094 Background: The carcinomembryonic antigen cell adhesion molecule 1 (CEACAM1, CD66a) is a member of the CEA gene family. CEACAM1 interacts homophilically and heterophilically with CEACAM5, and is involved in various anti-proliferative activities. CEACAM1 is expressed on a variety of epithelial and hematological cells, including multiple types of cancer and activated lymphocytes. High CEACAM1 expression in some tumor types is known to be associated with poor disease prognosis. Recently it was demonstrated CEACAM1 is co-expressed on exhausted lymphocytes with other immune checkpoints such as TIM-3 and may regulate downstream activity. CM24 is a novel humanized α-CEACAM1-specific antibody with nM affinity to the N terminal domain of CEACAM1, which blocks intercellular CEACAM1 interactions. Methods: The primary objective was to test the safety and tolerability of CM24 in adult patients with advanced or recurrent cancer. Secondary objectives included assessment of CM24 PK and PD profiles, anti-tumor response and the recommended Phase 2 dose. Patient received IV infusion of CM24 at 7 dose levels ranging between 0.01 and 10 mg/kg in a cycle of 4 doses administered q2wks followed by a 6-week observation only period and additional 6 cycles. Results: 27 patients (median pretreatment of 4 prior regimens; range 2-8, 11 colorectal, 7 melanoma, 4 ovarian, 3 gastric, 2 NSCLC; 13 males, 14 females, mean age of 60 years), were included. Treatment with CM-24 was overall well-tolerated without DLTs up to 10 mg/kg. The most frequent AE was grade 1-3 increased alanine aminotransferase (7 subjects) and the most severe AE was grade 3/4 increase in gamma-glutamyltransferase (4 subjects). Drug-related AEs were observed in 63% of the subjects with grade 3-5 occurred in 3.7%. Eight subjects (29.6%) had stable disease as the best overall response. Median overall survival was 4 (3.4, 8.0) and 6.2 (2.7, 10.2) months for the 3 and 10 mg/kg doses, suggesting dose response. Cmax, AUC and t1/2 increased with increasing dose with the longest t1/2 of 11.2 days obtained at 10mg/kg. The average target occupancy of CM24 at 3mg/kg and 10mg/kg were 75% and 93%, respectively. Conclusions: PK and target-mediated drug disposition analysis suggest that doses higher than 10mg/kg are needed for target saturation at a q2 week regimen while a q3 week regimen is less optimal. A phase 1/2 clinical trial testing CM24 in combination with anti-PD-1 therapy in patients with NSCLC including assessment of CEACAM1 expression is warranted. Clinical trial information: NCT02346955 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2020.38.15_suppl.3094
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
    detail.hit.zdb_id: 2005181-5
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  • 16
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    Updated results from a phase 2 study of the oral vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor rivoceranib for recurrent or metastatic (R/M) adenoid cystic carcinoma (ACC).
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. 6040-6040
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 6040-6040
    Abstract: 6040 Background: ACC is a rare tumor that overexpresses VEGF, primarily affecting salivary glands. Often indolent, it can progress, with metastases common in the lungs, liver, and bone. There are no FDA-approved systemic treatments (tx) for R/M ACC. Rivoceranib is an oral tyrosine kinase inhibitor (TKI) that potently and selectively inhibits VEGFR2. Methods: In this single-arm, open-label multicenter trial, patients (pts) with R/M ACC with evidence of ≥20% progression by RECIST v1.1 or new lesions within the preceding 6 months (mos) were eligible, with no limit on prior tx. Pts received rivoceranib 700 mg daily until disease progression or withdrawal with pre-planned dose reductions for toxicity. Primary endpoint was overall response rate (ORR) per RECIST v1.1 by investigator (INV) and by Independent Review Committee (IRC). Secondary endpoints included duration of response (DoR), progression-free survival (PFS), time to progression (TTP), overall survival (OS), and safety exploratory analysis included disease control rate (DCR) and ORR using CHOI criteria by IRC. Results: As of 11/2022, 80 pts (72 evaluable) were enrolled in the US and Korea (53% male; median age, 54 yrs), and 6 pts remain on tx. Primary tumor sites: major (34%) and minor (59%) salivary glands and other (8%). 74 pts (93%) had metastatic disease. 61.3% had prior systemic tx (18% prior VEGFR TKI). INV and IRC-assessed efficacy data are listed in the table. ORR by CHOI was 52.5% (53.1% VEGFR TKI-naive and 50% VEGFR TKI treated). mOS was 25.3 mos (28.3 mos VEGFR TKI-naïve and 22.6 mos VEGFR treated). Common adverse events (AEs) were hypertension (66%), fatigue (64%), and nausea (54%). Grade ≥3 AEs that occurred in 〉 5% of pts were hypertension (43%), stomatitis (8%), fatigue and anemia (6% each). There were 4 Grade 5 AEs (2 epistaxis [1 related], 1 acute respiratory failure, 1 respiratory failure). Conclusions: Updated results with additional 9-month follow-up data continue to demonstrate that Rivoceranib has clinical efficacy and a manageable safety profile in pts with R/M ACC. Clinical trial information: NCT04119453 . [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.6040
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 17
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    Exposure to a Histone Deacetylase Inhibitor Has Detrimental Effects on Human Lymphocyte Viability and Function
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Immunology Research Vol. 2, No. 5 ( 2014-05-01), p. 459-468
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 2, No. 5 ( 2014-05-01), p. 459-468
    Abstract: Histone deacetylase inhibitors (HDACi) have been reported to increase tumor antigen expression, and have been successfully tested as adjuvants for melanoma immunotherapy in mouse models. In this work, we tested the effects of a pan-HDACi on human lymphocytes and melanoma cell lines. Effects of the pan-HDACi panobinostat (LBH589) on cell viability, cell cycle, apoptosis, and DNA damage were determined in peripheral blood mononuclear cells (PBMC) from 2 healthy donors, 13 patients with metastatic melanoma, 2 bone marrow samples from patients with different malignances, and 12 human melanoma cell lines. Intracellular signaling in lymphocytes, with or without cytokine stimulation, was analyzed by phospho-flow cytometry in one of each type. The IC50 in PBMCs was & lt;20 nmol/L compared with & gt;600 nmol/L in melanoma cell lines; & gt;40% apoptotic cell death in PBMCs versus & lt;10% in melanoma cell lines was seen at the same concentration. Phospho-histone variant H2A.X (pH2A.X) increased 2-fold in healthy donor PBMCs at 1 nmol/L, whereas the same effect in the melanoma cell line M229 required 10 nmol/L. pH2A.X was inhibited slightly in the PBMCs of 3 patients with metastatic melanoma at 1 nmol/L and in the melanoma cell line M370 at 10 nmol/L. Panobinostat inhibited phospho-STAT1/3/5/6, -p38, -ERK, -p53, -cyclin D3, and -histone H3 in flow cytometry–gated healthy donor B and T cells, whereas it induced up to 6-fold activation in patients with metastatic melanoma and bone marrow samples. In human lymphocytes, panobinostat alters key lymphocyte activation signaling pathways and is cytotoxic at concentrations much lower than those required for melanoma antitumor activity, resulting in an adverse therapeutic window. Cancer Immunol Res; 2(5); 459–68. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    URL: Article
    DOI: 10.1158/2326-6066.CIR-13-0188
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
    detail.hit.zdb_id: 2732517-9
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  • 18
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    Prevalence of human leukocyte antigen-B27 supertype in the context of positively charged neoepitopes and association with PD-L1 as an immune escape mechanism.
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 15_suppl ( 2020-05-20), p. 3083-3083
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. 3083-3083
    Abstract: 3083 Background: Recent evidence suggests efficacy of immune checkpoint blockade may be influenced by human leukocyte antigen (HLA)-B. HLA-B27 supertype has an electronegative binding pocket which favorably binds and displays neoepitopes harboring positively charged amino acids (AAs). Based on immune surveillance, we postulate that B27 tumors that have favorable neoepitopes should face negative selective pressure, and B27 tumors with favorable neoepitopes that develop could be more likely to upregulate immune escape mechanisms. Here we evaluate the relationship between prevalence of B27 and positively charged neoepitopes and assess association between positively charged neoepitopes and expression of PD-L1. Methods: TCGA datasets from head and neck squamous cell (HNSC), lung squamous cell (LUSC), and melanoma (SKCM) patients were evaluated. HLA alleles were determined with OptiType and supertype was based on 2008 criteria. Nonsynonymous mutations were annotated with Ensembl VEP and VAtools. pVAC-Seq using NetMHCpan algorithm predicted neoepitopes 9 AAs in length. Favorable B27 neoepitopes were defined as those having new positively charged AA substitutions (H/K/R) from negative or uncharged wildtype AAs. RNA-seq data for the PD-L1 gene were normalized on transcripts per million and log2 transformed. Linear regression tests were performed between PD-L1 gene expression values and fraction of nonsynonymous mutations resulting in neoepitopes with new positively charged AAs in patients with B27. Results: Data from 497 HNSC, 494 LUSC, and 468 SKCM patients were analyzed. B27 was observed in 20.1%, 23.2%, and 26.5% of HNSC, LUSC, and SKCM patients, respectively, with a significant difference seen between HNSC and SKCM by chi-square test (χ² = 5.14, p = .023). Of new charged AAs resulting from nonsynonymous mutations, 76.3% in HNSC, 74.0% in LUSC, and 72.0% in SKCM were positively charged (p 〈 .05 between all histologies, paired t-tests). In B27 patients, association between PD-L1 gene expression and fraction of neoepitopes with new positively charged AAs was seen in HNSC (r = 0.25 p = .036) and SKCM (r = 0.30 p = .007), but not LUSC (r = -0.12 p = .296). Conclusions: With increasing fraction of positively charged neoepitopes, a decrease in prevalence of B27 was observed, suggesting improved binding and immune elimination of tumors with favorable neoepitopes. In B27 tumors that develop despite having favorable neoepitopes, upregulation of PD-L1 could be a putative mechanism to evade immune detection.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2020.38.15_suppl.3083
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
    detail.hit.zdb_id: 2005181-5
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  • 19
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    Dose expansion results of the bifunctional EGFR/TGFβ inhibitor BCA101 with pembrolizumab in patients with recurrent, metastatic head and neck squamous cell carcinoma.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. 6005-6005
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 6005-6005
    Abstract: 6005 Background: Pembrolizumab (P) is approved to treat patients (pts) with recurrent, metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). BCA101 is a first-in-class bifunctional EGFR antibody fused to a TGFβ immune modulating payload which is well tolerated and has clinical activity as monotherapy and in combination with pembrolizumab in advanced solid tumors (ESMO 2022 731MO). Here we report the results from the interim analysis of an expansion cohort combining BCA101+P as first line therapy in R/M HNSCC. Methods: This ongoing single-arm, open-label multicenter dose expansion cohort enrolled pts with R/M HNSCC with a tumor PD-L1 CPS≥1 with no prior systemic therapy for R/M disease, ECOG 0-1, and measurable disease (RECIST v1.1). Pts received BCA101 (1500 mg IV on days 1, 8, 15) with P (200 mg IV on day 1) every 21-days. Primary endpoint: safety; secondary endpoints: overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), overall survival (OS). Exploratory: molecular and immunologic predictors of response. A Simon optimal two-stage design was employed: among 18 evaluable pts in stage 1, 〉 3 pts in response triggered continuation to stage 2 enrolling 21 additional pts targeting an ORR 〉 35%. Results: From 2/2022 to 1/2023, 20 pts enrolled while 18 were evaluable (had first restaging scans) in stage 1. Pts were more often men (n=13, 65%) with a median age of 66 (range: 31-77). Oropharynx (10, 50%) [7/10 (70%) were HPV/p16-pos] and oral cavity (7, 35%) were the most common primary subsites (larynx/hypopharynx: 3). Fifteen (75%) had distant metastatic disease. The ORR in stage 1 was 44% (8 PRs, 4 SD) with a clinical benefit rate (CBR=PR+SD) of 67%; 7/12 (58%) HPV-neg pts achieved a response. Median DOR not reached, but median time on-treatment was 6.7 months (range: 2.7-11.0+) among responders. Ten pts discontinued therapy; all but 1 for PD (n=1 for toxicity). Grade 3+ treatment-related adverse events (TRAEs) were observed in 4 pts (20%, most common: anemia). No treatment-related deaths were observed. Acneiform rash was the most common TRAE of any grade (15, 75%). PFS and OS estimates are forthcoming. Eight (44%) had baseline PD-L1 CPS scores of 0-19, while ten (56%) were ≥20. Stage 2 is actively enrolling with completion of accrual expected by the meeting. Conclusions: Stage 1 of this dose expansion cohort of BCA101+P shows encouraging anti-tumor activity with additive potential, particularly among HPV-neg pts; and the combination is well tolerated among this R/M HNSCC population. Further investigation is warranted. Study funded by Bicara Therapeutics and conducted in collaboration with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. USA (NCT04429542). Clinical trial information: NCT04429542 . [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.6005
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 20
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    A first-in-human phase I study of FS118, an anti-LAG-3/PD-L1 bispecific antibody in patients with solid tumors that have progressed on prior PD-1/PD-L1 therapy.
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 15_suppl ( 2019-05-20), p. TPS2652-TPS2652
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. TPS2652-TPS2652
    Abstract: TPS2652 Background:PD-1/PD-L1 checkpoint inhibitors demonstrated remarkable anti-tumor activity, but only a minority of patients achieve full clinical benefit with deep and durable responses. Translational studies suggest resistance to cancer immunotherapy can be mediated by additional immune checkpoints e.g. lymphocyte-activation gene 3 (LAG-3). The combination of LAG-3 and PD-1 mAbs synergistically improved anti-tumor response in murine models and early clinical trials. In a small cohort, TIL LAG-3 expression enriched for responsiveness in PD-1/PD-L1 relapsed/refractory patients. FS118 is a novel bispecific antibody incorporating a LAG-3 binding Fc-region into a PD-L1-specific IgG1 antibody to potentially deliver superior anti-tumor efficacy while limiting immunotherapy-related adverse effects by dual targeting. Methods: The FiH study (NCT03440437) is being conducted in adult patients with solid tumors who failed prior PD-1/PD-L1 treatment. Primary objectives of the study are to determine safety, PK and the maximum tolerated/recommended Phase 2 dose of FS118. Secondary objectives include preliminary evidence of efficacy, immunogenicity, PD profile and exposure/response correlation. 50 subjects from four study sites in the USA are planned to enrol in dose escalation initiated with accelerated titration (5 single subject cohorts) followed by 3+3 design and expansion cohorts. FS118 is administered weekly IV in 21-day treatment cycles until progression, unacceptable toxicity, withdrawal, or death. Patients are followed for safety, overall survival and initiation of subsequent therapy. DLT clearance, dose escalation and cohort expansion (to further characterise safety, PK/PD or clinical efficacy) are supervised by a safety review committee (SRC). Translational studies assess PD-L1/LAG-3 receptor occupancy, soluble PD-L1/LAG-3 levels and the correlation of FS118 exposure with selected PD markers of target engagement and response. Translational endpoints include TIL analysis, transcriptomic profiles and target expression analyses on tumor tissues. Cohorts 1 through 6 have been completed, enrollment in cohort 7 began December 2018. Clinical trial information: NCT03440437.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2019.37.15_suppl.TPS2652
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
    detail.hit.zdb_id: 2005181-5
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