An open-label phase 1b/2 study of surufatinib in combination with tislelizumab in subjects with advanced solid tumors.

TPS2677 Background: Surufatinib (S) is an inhibitor of VEGFR1, 2, & 3; FGFR1; and CSF-1R. In two phase 3 randomized trials (SANET-ep; NCT02588170 & SANET-p; NCT02589821) S demonstrated a manageable safety profile and statistically significant efficacy. Patients (pts) with extrapancreatic neuroendocrine tumors (epNETs) achieved a median progression free survival (PFS) of 9.2 v 3.8 months (mo) (hazard ratio [HR] 0.334; p<0.0001), and pts with pancreatic NETs (pNETs) achieved a median PFS of 10.9 v 3.7 mo (HR 0.491; p=0.0011), with S v placebo, respectively. S was recently approved for the treatment of pts with epNET in China. Tislelizumab (T) is a humanized immunoglobulin G4 anti-PD-1 monoclonal antibody engineered to minimize binding to Fc-gamma-receptor on macrophages. T is approved in China in combination with chemotherapy for squamous non-small cell lung cancer and has conditional approval for Hodgkin’s lymphoma and locally advanced or metastatic urothelial carcinoma with PD-L1 high expression. The objective of this study is to evaluate the safety and efficacy of combination therapy with S and T, which may have synergistic effects, where inhibition of angiogenesis along with stimulation of an immune response may enhance the overall antitumor activity. Methods: This study (NCT04579757) will include pts, ≥18 years of age, with advanced metastatic solid tumors, who have an Eastern Cooperative Oncology Group performance status of 0 or 1 and have progressed on or are intolerant to standard therapies. The primary objective of part 1 (dose escalation) will be to evaluate the safety and tolerability of S and T to determine the recommended phase 2 dose of the combination. The starting dose in part 1 will be 250 mg of S, orally, daily, and 200mg of T, intravenously, every 3 weeks. The dose of S will be escalated during part 1, while the dose of T will remain fixed. Endpoints include dose limiting toxicities, treatment emergent adverse events, serious adverse events, adverse events leading to discontinuation, electrocardiograms, clinical laboratory abnormalities and vital signs. Antitumor activity will be evaluated as a secondary objective. Six to 12 pts will be enrolled. The primary objective of part 2 (dose expansion) will be to evaluate the objective response rate (ORR) of S in combination with T per RECIST v1.1. The endpoint will be ORR at 12 weeks. Key secondary endpoints include PFS, disease control rate, duration of response, safety endpoints, and PK parameters. Approximately 95 pts with indications of interest will be enrolled: colorectal cancer, neuroendocrine tumors (thoracic and gastroenteropancreatic), small-cell lung cancer, gastric cancer, and soft tissue sarcoma (undifferentiated pleomorphic sarcoma and alveolar soft part sarcoma). Enrollment in the United States is open and ongoing, and enrollment in Europe is planned for fourth quarter 2021. Clinical trial information: NCT04579757.

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397 A phase I/II trial of intracerebroventricular 177Lu DTPA omburtamab radioimmunotherapy for leptomeningeal metastasis from solid tumors

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.397 ◽

2021 ◽

Vol 9 (Suppl 3) ◽

pp. A429-A429

Author(s):

Elena Pentsova ◽

Maria Düring ◽

Charlotte Lybek Lind ◽

John Rømer Nielsen

Keyword(s):

Breast Cancer ◽

Lung Cancer ◽

Small Cell Lung Cancer ◽

Solid Tumors ◽

Cell Lung Cancer ◽

Leptomeningeal Metastasis ◽

Primary Objective ◽

Small Cell ◽

Lobular Breast Cancer ◽

Small Cell Lung

BackgroundLeptomeningeal metastasis (LM) from solid tumors may be diagnosed in approximately 10% of patients with metastatic cancer and can occur with virtually all malignant tumors. Median overall survival (OS) is poor and limited to a few months with LM-directed treatment, including available targeted therapy, immunotherapy and radiation therapy. Omburtamab specifically binds to B7-H3 (CD276), a transmembrane glycoprotein of the immunoglobulin superfamily. The limited expression of B7-H3 on normal cells, including normal brain, combined with the broad expression in various types of solid tumors, makes B7-H3 a target for radioimmunotherapy of LM from solid tumors. In this first-in-human trial the safety and efficacy of intracerebroventricular administration of radiolabeled omburtamab, 177Lu-DTPA-omburtamab, will be evaluated in patients with LM from ductal or lobular breast cancer, non-small cell lung cancer, or melanoma.MethodsThis is an open-label phase I/II study. Part 1 is a dose-escalation phase to be conducted at ~4 sites (US/Europe) with a primary objective of identifying the maximum tolerated dose and/or recommended phase II dose for Part 2 (RP2D). It will follow a 3+3 design with pts receiving up to five 5-week cycles of 177Lu-DTPA-omburtamab. Part 2 is a cohort-expansion phase at ~9 sites (US/Europe) in which a maximum of 48 patients in 3 cohorts (ductal or lobular breast cancer [cohort A], non-small cell lung cancer [cohort B], and melanoma [cohort C]) with up to 16 patients in each will receive up to five 5 week cycles of treatment with intracerebroventricular 177Lu DTPA omburtamab at the RP2D determined in Part 1. The primary objective of Part 2 is to establish the safety of repeat doses of 177Lu-omburtamab. Additional objectives of Parts 1/2 include the evaluation of absorbed radiation doses, PK profile, investigator-assessed response, duration of response, progression-free survival, and OS. Key inclusion criteria include diagnosis of either ductal or lobular breast cancer, non-small cell lung cancer, or malignant melanoma and diagnosis of recurrent or refractory LM; prior standard of care treatment of leptomeningeal disease; acceptable hematological, liver and kidney status; and a life expectancy of >2 months. The study has been approved by each institution’s ethics board, and patients provided informed consent before taking part.Trial RegistrationNCT04315246Ethics ApprovalThe study has been approved by each institution’s ethics board, and patients provided informed consent before taking part.

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Investigation of spleen CXCR4 expression by [68Ga]Pentixafor PET in a cohort of 145 solid cancer patients

EJNMMI Research ◽

10.1186/s13550-021-00822-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Richard Lewis ◽

Stefan Habringer ◽

Malte Kircher ◽

Maike Hefter ◽

Caroline Anna Peuker ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Solid Tumors ◽

Neuroendocrine Tumors ◽

Cell Lung Cancer ◽

Solid Tumor ◽

Small Cell ◽

Cxcr4 Expression ◽

Small Cell Lung ◽

Tumor Patients

Abstract Background The chemokine receptor CXCR4 is frequently overexpressed and associated with adverse prognosis in most hematopoietic malignancies and solid cancers. Recently, CXCR4 molecular imaging using the CXCR4-specific positron emission tomography (PET) tracer Pentixafor ([68Ga]Pentixafor) has become a well-established method to non-invasively measure CXCR4 expression in vivo. In previous Pentixafor imaging studies, highly variable CXCR4 tracer uptake to the spleen was observed. Results We investigated the hypothesis that enhanced spleen [68Ga]Pentixafor uptake and thus CXCR4 expression in patients with solid tumors would indicate an activated spleen state and/or an association with clinical and prognostic features and survival parameters. In this retrospective study, [68Ga]Pentixafor-PET images and patient records of 145 solid tumor patients representing 27 cancer entities were investigated for an association of spleen [68Ga]Pentixafor uptake and clinical characteristics and outcome. Based on this assessment, we did not observe differences in clinical outcomes, measured by progression-free survival, overall survival and remission status neither within the entire cohort nor within subgroups of adrenal cancer, desmoplastic small round cell tumor, neuroendocrine tumors, non-small cell lung cancer, small cell lung cancer and pancreatic adenocarcinoma patients. No tumor entity showed especially high levels of spleen [68Ga]Pentixafor uptake compared to others or a control cohort. However, when investigating laboratory parameters, there was a positive correlation of high spleen [68Ga]Pentixafor uptake with leukocyte and/or platelet counts in neuroendocrine tumors, non-small cell lung cancer and small cell lung cancer. Conclusion Spleen [68Ga]Pentixafor uptake was not associated with stage of disease and clinical outcomes in solid tumor patients. We identified positively associated platelet and/or leukocyte counts with spleen [68Ga]Pentixafor uptake in neuroendocrine tumors, non-small cell lung cancer and small cell lung cancer, suggesting that splenic CXCR4 expression could possibly play a role in systemic immunity/inflammation in some types of solid tumors or a subgroup of patients within solid tumor entities.

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Efficacy and Safety of Antigen-specific Immunotherapy in the Treatment of Patients with Non-small-cell Lung Cancer: A Systematic Review and Meta-analysis

Current Cancer Drug Targets ◽

10.2174/1568009618666180430124738 ◽

2019 ◽

Vol 19 (3) ◽

pp. 199-209 ◽

Cited By ~ 1

Author(s):

Bing-Di Yan ◽

Xiao-Feng Cong ◽

Sha-Sha Zhao ◽

Meng Ren ◽

Zi-Ling Liu ◽

...

Keyword(s):

Lung Cancer ◽

Systematic Review ◽

Adverse Events ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Specific Immunotherapy ◽

Meta Analysis ◽

Small Cell ◽

Efficacy And Safety ◽

Small Cell Lung

Background and Objective: We performed this systematic review and meta-analysis to assess the efficacy and safety of antigen-specific immunotherapy (Belagenpumatucel-L, MAGE-A3, L-BLP25, and TG4010) in the treatment of patients with non-small-cell lung cancer (NSCLC). Methods: A comprehensive literature search on PubMed, Embase, and Web of Science was conducted. Eligible studies were clinical trials of patients with NSCLC who received the antigenspecific immunotherapy. Pooled hazard ratios (HRs) with 95% confidence intervals (95%CIs) were calculated for overall survival (OS), progression-free survival (PFS). Pooled risk ratios (RRs) were calculated for overall response rate (ORR) and the incidence of adverse events. Results: In total, six randomized controlled trials (RCTs) with 4,806 patients were included. Pooled results showed that, antigen-specific immunotherapy did not significantly prolong OS (HR=0.92, 95%CI: 0.83, 1.01; P=0.087) and PFS (HR=0.93, 95%CI: 0.85, 1.01; P=0.088), but improved ORR (RR=1.72, 95%CI: 1.11, 2.68; P=0.016). Subgroup analysis based on treatment agents showed that, tecemotide was associated with a significant improvement in OS (HR=0.85, 95%CI: 0.74, 0.99; P=0.03) and PFS (HR=0.70, 95%CI: 0.49, 0.99, P=0.044); TG4010 was associated with an improvement in PFS (HR=0.87, 95%CI: 0.75, 1.00, P=0.058). In addition, NSCLC patients who were treated with antigen-specific immunotherapy exhibited a significantly higher incidence of adverse events than those treated with other treatments (RR=1.11, 95%CI: 1.00, 1.24; P=0.046). Conclusion: Our study demonstrated the clinical survival benefits of tecemotide and TG4010 in the treatment of NSCLC. However, these evidence might be limited by potential biases. Therefore, further well-conducted, large-scale RCTs are needed to verify our findings.

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BEBT-109, a pan-mutant-selective EGFR inhibitor with potent antitumor activity in EGFR-mutant non-small cell lung cancer

Translational Oncology ◽

10.1016/j.tranon.2020.100961 ◽

2021 ◽

Vol 14 (2) ◽

pp. 100961

Author(s):

Fushun Fan ◽

Minhua Zhou ◽

Xiaolan Ye ◽

Zhenxian Mo ◽

Yaru Ma ◽

...

Keyword(s):

Lung Cancer ◽

Antitumor Activity ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Egfr Inhibitor ◽

Small Cell Lung ◽

Egfr Mutant

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278 Phase I clinical trial evaluating the safety of ADP-A2M10 SPEAR T-cells in patients with MAGE-A10+ advanced non-small cell lung cancer

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0278 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A303-A303

Author(s):

George Blumenschein ◽

Siddhartha Devarakonda ◽

Melissa Johnson ◽

Victor Moreno ◽

Justin Gainor ◽

...

Keyword(s):

Lung Cancer ◽

T Cells ◽

Antitumor Activity ◽

Small Cell Lung Cancer ◽

Dose Level ◽

Cell Lung Cancer ◽

Lentiviral Vector ◽

Small Cell ◽

Small Cell Lung ◽

Human Dose

BackgroundADP-A2M10 SPEAR T-cells are genetically engineered autologous T-cells that express a high affinity MAGE-A10-specific T-cell receptor targeting MAGE-A10+tumors in the context of HLA-A*02. This trial is now complete (NCT02592577).MethodsThis first-in-human dose escalation trial utilized a modified 3+3 design to evaluate safety and antitumor activity. Eligible patients (pts) were HLA-A*02+ with advanced non-small cell lung cancer (NSCLC) expressing MAGE-A10. Pts underwent apheresis; T-cells were isolated, transduced with a lentiviral vector containing the TCR targeting MAGE-A10, and expanded. Pts underwent lymphodepletion (LD) with varying doses/schedules of fludarabine (Flu) and cyclophosphamide (Cy) prior to receiving ADP-A2M10. ADP-A2M10 was administered at Dose Level (DL) 1= 0.1×109, DL2 0.5–1.2×109, and DL3/Expansion= 1.2–15×109 transduced cells.ResultsAs of Jan 10, 2020, 11 pts (6 male/5 female) with NSCLC (3 squamous cell, 7 adenocarcinoma, 1 adenosquamous) were treated. Five, 3 and 3 pts received cells at DL1, DL2, and DL3/Expansion, respectively. The most frequently reported adverse events ≥ Grade 3 were lymphopenia (11), leukopenia (9), neutropenia (8), anemia (6), thrombocytopenia (5), and hyponatremia (5). Three pts reported CRS (Grades 1, 2, and 4, respectively). One pt received the highest dose of LD (Flu 30 mg/m2 Day 1 4 and Cy 1800 mg/m2 Day 1–2) prior to a second infusion and had a partial response (PR). This pt subsequently developed aplastic anemia and died. Responses included: 1 pt – PR, 3 pts - stable disease, 2 pts – progressive disease, 1 pt - too early to determine, 4 pts - off-study prior to tumor assessment. SPEAR T-cells were detectable in peripheral blood from pts at each dose level, and in tumor tissue from pts at DL1 and DL3.ConclusionsADP-A2M10 SPEAR T-cells have shown acceptable safety and no evidence of toxicity related to off-target binding or alloreactivity. Given the minimal antitumor activity and the discovery that MAGE-A10 expression frequently overlaps with MAGE-A4 expression, the clinical program has closed. Several trials with SPEAR T-cells targeting MAGE-A4 are ongoing (https://bit.ly/35htsZK).Trial RegistrationNCT02592577Ethics ApprovalThe trial was conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines and was approved by local authorities. An independent ethics committee or institutional review board approved the clinical protocol at each participating center. All the patients provided written informed consent before study entry.

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P21.07 Immune-Related Adverse Events with Durvalumab Consolidation in a Real-World Cohort of Patients with Non–Small Cell Lung Cancer (NSCLC)

Journal of Thoracic Oncology ◽

10.1016/j.jtho.2021.01.587 ◽

2021 ◽

Vol 16 (3) ◽

pp. S366

Author(s):

G. Bravo Montenegro ◽

M. Serzan ◽

A. Belouali ◽

P. Sackstein ◽

K. Chen ◽

...

Keyword(s):

Lung Cancer ◽

Adverse Events ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Real World ◽

Small Cell ◽

Small Cell Lung

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440 Activity and safety of camrelizumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced non-small-cell lung cancer

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0440 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A466-A466

Author(s):

Guo Gui Sun ◽

Jing Hao Jia ◽

Peng Gao ◽

Xue Min Yao ◽

Ming Da Chen ◽

...

Keyword(s):

Lung Cancer ◽

Adverse Events ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Advanced Nsclc ◽

Small Cell ◽

Large Sample Size ◽

Small Cell Lung ◽

Previously Treated ◽

Line Chemotherapy

BackgroundEffective options are limited for patients with non–small-cell lung cancer (NSCLC) whose disease progresses after first-line chemotherapy. Camrelizumab is a potent anti-PD-1 monoclonal antibody and has shown promising activity in NSCLC. We assessed the activity and safety of camrelizumab for patients with previously treated, advanced NSCLC patients with negative oncogenic drivers.MethodsPatients who progressed during or following platinum-based doublet chemotherapy were enrolled. All patients received camrelizumab(200 mg)every 3 weeks or in combination with chemotherapy until loss of clinical benefit. The primary endpoint was objective response rate (ORR), other endpoints included disease control rate (DCR), progression-free survival (PFS) and safety.ResultsBetween Aug 5, 2019, and Jun 19, 2020, we enrolled 29 patients, 25 patients were available evaluated, ORR and DCR was 36% (9/25) and 92% (23/25), respectively. 25 of 29 patients were still receiving the treatment, the median PFS was not yet achieved. Compared with those without reactive cutaneous capillary endothelial proliferation (RCCEP), patients with RCCEP had higher ORR (60% vs. 28.6%). Treatment-related adverse events (AEs) occurred in 69.0% of patients (all Grade), and the most common were RCCEP (37.9%), pneumonitis (6.9%), and chest congestion (6.9%). Treatment-related grade 3 to 4 adverse events occurred in 10.3% of patients.ConclusionsIn patients with previously treated advanced NSCLC, camrelizumab demonstrated improved ORR and DCR, compared with historical data of the 2nd line chemotherapy, with a manageable safety profile. While patients with RCCEP derived greater benefit from camrelizumab. Further studies are needed in large sample size trials.

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Effect of Systemic Corticosteroid Therapy on the Efficacy and Safety of Nivolumab in the Treatment of Non-Small-Cell Lung Cancer

Cancer Control ◽

10.1177/1073274820985790 ◽

2021 ◽

Vol 28 ◽

pp. 107327482098579

Author(s):

Kengo Umehara ◽

Kaori Yama ◽

Keisuke Goto ◽

Azusa Wakamoto ◽

Tae Hatsuyama ◽

...

Keyword(s):

Lung Cancer ◽

Adverse Events ◽

Small Cell Lung Cancer ◽

Survival Time ◽

Cell Lung Cancer ◽

Objective Response ◽

Small Cell ◽

Control Group ◽

Small Cell Lung ◽

Corticosteroid Administration

Introduction: Corticosteroids are used to treat immune-related adverse events (irAEs) associated with nivolumab. However, patients with non-small-cell lung cancer who are administered corticosteroids before the initiation of nivolumab treatment are commonly excluded from clinical trials. The appropriate timing for corticosteroid administration in relation to nivolumab treatment, effects of corticosteroids on the efficacy of nivolumab, and resulting adverse events are not clearly understood. In this study, the effects of differences in the timing of corticosteroid administration on nivolumab efficacy and the resulting adverse events were examined. Methods: A retrospective study was conducted with 109 patients who were treated with nivolumab at Sapporo Minami-Sanjo Hospital between December 2015 and March 2018. Results: Of the 109 patients treated with nivolumab, 12 patients were administered corticosteroids before the first cycle of nivolumab (pre-CS), and 33 patients were administered corticosteroids after the first cycle of nivolumab (post-CS). These 2 groups were compared with the control group comprising 64 patients who were not administered corticosteroids (non-CS). The objective response rate in the post-CS group was significantly higher than that in the non-CS group, and the disease control rate in the pre-CS group was significantly lower than that in the non-CS group. The overall survival time and progression-free survival time in the pre-CS group were significantly shorter than those observed in the non-CS group; however, these did not differ from those in the post-CS group. Conclusions: These results suggest that corticosteroids administered to patients with non-small-cell lung cancer after initiation of nivolumab treatment did not affect the disease prognosis. Thus, corticosteroids can be administered immediately for rapid treatment of irAEs.

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