Safety and clinical activity of anti-programmed death-ligand 1 (PD-L1) antibody (ab) avelumab (MSB0010718C) in advanced thymic epithelial tumors (TETs).

Purpose The objective was to determine the safety and clinical activity of atezolizumab (MPDL3280A), a humanized programmed death-ligand 1 (PD-L1) antibody, in renal cell carcinoma (RCC). Exploratory biomarkers were analyzed and associated with outcomes. Patients and Methods Seventy patients with metastatic RCC, including clear cell (ccRCC; n = 63) and non–clear cell (ncc; n = 7) histologies, received atezolizumab intravenously every 3 weeks. PD-L1 expression was scored at four diagnostic levels (0/1/2/3) that were based on PD-L1 staining on tumor cells and tumor-infiltrating immune cells (IC) with the SP142 assay. Primary end points were safety and toxicity; secondary end points assessed clinical activity per Response Evaluation Criteria in Solid Tumors version 1.1 and immune-related response criteria. Plasma and tissue were analyzed for potential biomarkers of atezolizumab response. Results Grade 3 treatment-related and immune-mediated adverse events occurred in 17% and 4% of patients, respectively, and there were no grade 4 or 5 events. Sixty-three patients with ccRCC were evaluable for overall survival (median, 28.9 months; 95% CI, 20.0 months to not reached) and progression-free survival (median, 5.6 months; 95% CI, 3.9 to 8.2 months), and 62 patients were evaluable for objective response rate (ORR; 15%; 95% CI, 7% to 26%). ORR was evaluated on the basis of PD-L1 IC expression (IC1/2/3: n = 33; 18%; 95% CI, 7% to 35%; and IC0: n = 22; 9%; 95% CI, 1% to 29%). The ORR for patients with Fuhrman grade 4 and/or sarcomatoid histology was 22% (n = 18; 95% CI, 6% to 48%). Decreases in circulating plasma markers and acute-phase proteins and an increased baseline effector T-cell–to–regulatory T-cell gene expression ratio correlated with response to atezolizumab. Conclusion Atezolizumab demonstrated a manageable safety profile and promising antitumor activity in patients with metastatic RCC. Correlative studies identified potential predictive and pharmacodynamic biomarkers. These results have guided ongoing studies and combinations with atezolizumab in RCC.

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Dual PD-1 and CTLA-4 Checkpoint Blockade Using Balstilimab and Zalifrelimab Combination as Second-Line Treatment for Advanced Cervical Cancer: An Open-Label Phase II Study

Journal of Clinical Oncology ◽

10.1200/jco.21.02067 ◽

2021 ◽

Author(s):

David M. O'Malley ◽

Maryna Neffa ◽

Bradley J. Monk ◽

Tamar Melkadze ◽

Marilyn Huang ◽

...

Keyword(s):

Cervical Cancer ◽

Phase Ii ◽

T Lymphocyte ◽

Checkpoint Inhibitors ◽

Objective Response ◽

Clinical Activity ◽

Advanced Cervical Cancer ◽

Programmed Death Ligand 1 ◽

Programmed Death ◽

Duration Of Response

PURPOSE Balstilimab (antiprogrammed death-1) and zalifrelimab (anticytotoxic T-lymphocyte–associated antigen-4) are two new checkpoint inhibitors emerging as promising investigational agents for the treatment of advanced cervical cancer. This phase II trial (ClinicalTrials.gov identifier: NCT03495882 ) evaluated the combination of balstilimab plus zalifrelimab in patients with recurrent and/or metastatic cervical cancer who relapsed after prior platinum-based therapy. PATIENTS AND METHODS Patients were intravenously dosed with balstilimab 3 mg/kg once every 2 weeks and zalifrelimab 1 mg/kg once every 6 weeks, for up to 24 months. The primary end point was objective response rate (ORR, RECIST version 1.1, assessed by independent central review). Secondary end points included duration of response, safety and tolerability, and survival. RESULTS In total, 155 women (median age, 50 years [range 24-76 years]) were enrolled and treated with balstilimab plus zalifrelimab; 125 patients had measurable disease at baseline and one prior line of platinum-based therapy in the advanced setting, and these patients constituted the efficacy-evaluable population. The median follow-up was 21 months. The confirmed ORR was 25.6% (95% CI, 18.8 to 33.9), including 10 complete responders and 22 partial responders, with median duration of response not reached (86.5%, 75.5%, and 64.2% at 6, 9, and 12 months, respectively). The ORRs were 32.8% and 9.1% in patients with programmed death ligand-1–positive and programmed death ligand-1–negative tumors, respectively. For patients with squamous cell carcinoma, the ORR was 32.6%. The overall disease control rate was 52% (95% CI, 43.3 to 60.6). Hypothyroidism (14.2%) and hyperthyroidism (7.1%) were the most common immune-mediated adverse events. CONCLUSION Promising and durable clinical activity, with favorable tolerability, was seen in this largest trial to date evaluating dual programmed death-1/cytotoxic T-lymphocyte–associated antigen-4 blockade in patients with recurrent and/or metastatic cervical cancer. Further investigation of the balstilimab and zalifrelimab combination in this setting is continuing.

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PD-1 Blockade in Advanced Adrenocortical Carcinoma

Journal of Clinical Oncology ◽

10.1200/jco.19.01586 ◽

2020 ◽

Vol 38 (1) ◽

pp. 71-80 ◽

Cited By ~ 21

Author(s):

Nitya Raj ◽

Youyun Zheng ◽

Virginia Kelly ◽

Seth S. Katz ◽

Joanne Chou ◽

...

Keyword(s):

Objective Response Rate ◽

Response Rate ◽

Treatment Options ◽

Objective Response ◽

Progression Free Survival ◽

Clinical Activity ◽

Programmed Death Ligand 1 ◽

Prior Therapy ◽

Programmed Death ◽

Adrenocortical Carcinomas

PURPOSE Adrenocortical carcinomas (ACC) are rare and aggressive malignancies with limited treatment options. This study was undertaken to evaluate the immunogenicity of ACC. PATIENTS AND METHODS Patients with advanced ACC were enrolled in a phase II study to evaluate the clinical activity of pembrolizumab 200 mg every 3 weeks, without restriction on prior therapy. The primary end point was objective response rate. Efficacy was correlated with tumor programmed death-ligand 1 expression, microsatellite-high and/or mismatch repair deficient (MSI-H/MMR-D) status, and somatic and germline genomic correlates. RESULTS We enrolled 39 patients with advanced ACC and herein report after a median follow-up of 17.8 months (range, 5.4 months to 34.7 months). The objective response rate to pembrolizumab was 23% (nine patients; 95% CI, 11% to 39%), and the disease control rate was 52% (16 patients; 95% CI, 33% to 69%). The median duration of response was not reached (lower 95% CI, 4.1 months). Two of six patients with MSI-H/MMR-D tumors responded. The other seven patients with objective responses had microsatellite stable tumors. The median progression-free survival was 2.1 months (95% CI, 2.0 months to 10.7 months), and the median overall survival was 24.9 months (95% CI, 4.2 months to not reached). Thirteen percent of patients (n = 5) had treatment-related grade 3 or 4 adverse events. Tumor programmed death-ligand 1 expression and MSI-H/MMR-D status were not associated with objective response. CONCLUSION MSI-H/MMR-D tumors, for which pembrolizumab is a standard therapy, are more common in ACC than has been recognized. In advanced ACC that is microsatellite stable, pembrolizumab provided clinically meaningful and durable antitumor activity with a manageable safety profile.

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Clinical Activity of Pembrolizumab in a Patient With Metastatic Triple-Negative Breast Cancer Without Tumor Programmed Death-Ligand 1 Expression: A Case Report and Correlative Biomarker Analysis

JCO Precision Oncology ◽

10.1200/po.17.00032 ◽

2017 ◽

pp. 1-6 ◽

Cited By ~ 1

Author(s):

Sajjad Bhatti ◽

Jaimie Heldstab ◽

Carolyn Lehn ◽

Ossama Tawfik ◽

Ryan M. Ash ◽

...

Keyword(s):

Breast Cancer ◽

Case Report ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Clinical Activity ◽

Programmed Death Ligand 1 ◽

Programmed Death ◽

Biomarker Analysis

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Analytical Validation and Clinical Utility of an Immunohistochemical Programmed Death Ligand-1 Diagnostic Assay and Combined Tumor and Immune Cell Scoring Algorithm for Durvalumab in Urothelial Carcinoma

Archives of Pathology & Laboratory Medicine ◽

10.5858/arpa.2017-0555-oa ◽

2018 ◽

Vol 143 (6) ◽

pp. 722-731 ◽

Cited By ~ 7

Author(s):

Magdalena Zajac ◽

Anne-Marie Boothman ◽

Yong Ben ◽

Ashok Gupta ◽

Xiaoping Jin ◽

...

Keyword(s):

Urothelial Carcinoma ◽

Tumor Cells ◽

Immune Cells ◽

Immune Cell ◽

Objective Response ◽

Clinical Activity ◽

Programmed Death Ligand 1 ◽

Programmed Death ◽

Sensitivity Specificity ◽

Tumor Area

Context.— Clinical responses to anti–programmed death receptor-1 and anti–programmed death ligand-1 (PD-L1) agents are generally improved in patients with high PD-L1 expression compared with those with low/negative expression across several tumor types, including urothelial carcinoma. Objective.— To validate a PD-L1 immunohistochemical diagnostic test in urothelial carcinoma patients treated with the anti–PD-L1 monoclonal antibody durvalumab. Design.— The Ventana PD-L1 (SP263) assay was validated for intended use in urothelial carcinoma formalin-fixed, paraffin-embedded samples in studies addressing sensitivity, specificity, robustness, and precision, and implemented in study CD-ON-MEDI4736-1108 (NCT01693562). Efficacy was analyzed in patients classified according to prespecified PD-L1 expression cutoffs: PD-L1 high (if >1% of the tumor area contained tumor-associated immune cells, ≥25% of tumor cells or ≥25% of immune cells stained for PD-L1; if ≤1% of the tumor area contained immune cells, ≥25% of tumor cells or 100% of immune cells stained for PD-L1) and PD-L1 low/negative (did not meet criteria for PD-L1 high). Results.— The assay met all predefined acceptance criteria for sensitivity, specificity, and precision. Interreader and intrareader precision overall agreement were 93.0% and 92.4%, respectively. For intraday reproducibility and interday precision, overall agreement was 99.2% and 100%, respectively. Interlaboratory overall agreement was 92.6%. In study CD-ON-MEDI4736-1108, durvalumab demonstrated clinical activity and durable responses in both PD-L1–high and PD-L1–low/negative subgroups, although objective response rates tended to be higher in the PD-L1–high subgroup than in the PD-L1–low/negative subgroup. Conclusions.— Determination of PD-L1 expression in urothelial carcinoma patients using the Ventana PD-L1 (SP263) assay was precise, highly reproducible, and clinically relevant.

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Clinical outcome of patients with thymic epithelial tumors

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.14148 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 14148-14148

Author(s):

G. Palmieri ◽

L. Montella ◽

G. Merola ◽

C. Merola ◽

E. Matano ◽

...

Keyword(s):

Clinical Status ◽

Patient Characteristics ◽

Clinical Activity ◽

Preliminary Evaluation ◽

Treatment Schedule ◽

Epithelial Tumor ◽

Thymic Epithelial Tumors ◽

Epithelial Tumors ◽

Egfr Expression ◽

Therapeutic Choice

14148 Advanced chemorefractory thymic epithelial tumors still represent a challenge in clinical oncology. Neoplastic thymoma cells express EGFR. We evaluated the clinical activity of Cetuximab, a chimeric human-mouse monoclonal IgG1 antibody blocking ligand binding to EGFR, in five cases of advanced chemorefractory thymic epithelial tumor. Materials and Methods: Patient Characteristics and response evaluation. Patients’ characteristics and responses to treatment are represented in the table . The patients were assessed for EGFR expression in the primitive tumor, being considered this data as a basis for an anti EGFR treatment. Moreover they were evaluated as concerns clinical status and biochemistry and imaged by a combined PET-CT. Treatment schedule: The patients received intravenous cetuximab (C225, Erbitux, Merck KgaA, Darmstadt, Germany) over 1 hour at 400 mg/m2 loading dose followed by the weekly administration of 250 mg/m2. The first dose of 400 mg/m2 was given during the course of 2 hours. Subsequent weekly treatments were given at a dose of 250 mg/m2 during the course of 1 hour. This preliminary evaluation suggests for the first time that cetuximab may be a useful therapeutic choice in advanced pretreated thymic tumors. Despite the need for prolonged follow-up of the patients and further confirmatory studies, the EGF/EGFR pathway seems to play a pivotal role in thymic tumor. [Table: see text] No significant financial relationships to disclose.

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