A multicenter, open-label, uncontrolled phase II study of ONO-4538 for cutaneous angiosarcoma (Angio Check study).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS11579-TPS11579
Author(s):  
Yasuhiro Fujisawa ◽  
Koji Yoshino ◽  
Taiki Isei ◽  
Kenjiro Namikawa ◽  
Taku Fujimura ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Primary Objective ◽  
Cytotoxic Agents ◽  
Open Label ◽  
Durable Response ◽  
Dismal Prognosis

TPS11579 Background: Cutaneous angiosarcoma (CAS) is a rare sarcoma and advanced cases face a complex treatment regimen and dismal prognosis. Several cytotoxic agents (anthracycline, taxane, and gemcitabine) and targeted therapies (bevacizumab and sorafenib) have been tested for advanced disease in clinical trials with poor results. Since CAS commonly develops in elderly patients, high-grade adverse events from treatment may not be ideal and thus therapies featuring durable response and low comorbidity are in great demand. Recent studies suggest that CAS has a distinct genomic profile, including higher tumor mutational burden (TMB), compared to angiosarcomas developed in other sites. Moreover, we have shown that CAS with higher PD-1/L1 in the tumor microenvironment had statistically better overall survival compared with those without, indicating CAS susceptibility to immune checkpoint blockade therapy. However, to date, reports of immune checkpoint inhibitors for CAS are nonexistent. Methods: The present study is a phase 2, multicenter, single-arm clinical trial of ONO-4538 (nivolumab, 480 mg IV every 4 weeks) for patients with unresectable or metastatic CAS refractory to first-line paclitaxel. Twenty-three patients with advanced CAS will be enrolled at 11 sites in Japan with a primary objective to assess the confirmed response rate (H0 p < 5%, H1: p > 20%) to nivolumab. Secondary endpoints include PFS, OS, time to response, and adverse events. A correlative aim includes assessing tissue biomarkers using whole-genome sequencing (1023 genes including interferon-gamma associated genes and other known factors associated with response to immune checkpoint inhibitors) for association with response to nivolumab. The study started in April 2020 and remains open with 7 patients enrolled at time of Clinical trial information: UMIN000043039.

scholarly journals Retrospective Multicenter Analysis of the Outcome of a Re-Induction with Immune Checkpoint Inhibitors in Advanced Merkel Cell Carcinoma

2020 ◽  
Vol 2 (11) ◽  
pp. 2202-2207 ◽  
Author(s):  
H. M. Stege ◽  
F. Bradfisch ◽  
M. I. Fleischer ◽  
P. Mohr ◽  
S. Ugurel ◽  
...  
Keyword(s):  
Adverse Events ◽  
Tumor Progression ◽  
Cell Carcinoma ◽  
Merkel Cell Carcinoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Tumor Response ◽  
Checkpoint Inhibitors ◽  
Merkel Cell ◽  
Durable Response

AbstractSignificant progress has been made in the treatment of advanced Merkel cell carcinoma (MCC) by establishing immune checkpoint inhibitors (ICI). Tumor progression, durable response, or adverse events may lead to ICI discontinuation in MCC patients. If in these patients tumor progression occurs, the question remains if re-induction with ICI achieves renewed tumor response. This retrospective multicenter study evaluated patients in with re-induction of anti-PD-1/anti-PD-L1 therapy for advanced MCC. Clinical data were extracted at treatment initiation, tumor response, treatment cessation, and subsequent tumor response to re-induction. Eight patients from seven centers (mean age 67.8 years) were included. The median duration of initial therapy with anti-PD-1/anti-PD-L1 was 9.6 months (2–21 months). Two patients achieved complete response (CR), four patients partial response (PR), one patient stable disease (SD), while in one patient progressive disease (PD) occurred as best overall response (BOR) to ICI. Reason for discontinuation of ICI was PD in three patients and severe adverse events in five patients. Following a median anti-PD-1/anti-PD-L1 therapy-free interval of 9.5 months (3–18 months), re-induction with ICI therapy was initiated. Five of eight patients (62.5%) achieved an objective response upon re-induction, while in three patients, no response could be observed. Notably, adverse events, which had led to the discontinuation of the first ICI treatment line, were not observed upon re-induction. The initial response to immune checkpoint inhibitors seems to be an important marker for successful re-induction. Interestingly, adverse events leading to treatment discontinuation were not observed during re-induction.

Early safety from a phase I, multicenter, open-label clinical trial of talimogene laherparepvec (T-VEC) injected (inj) into liver tumors in combination with pembrolizumab (pem).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3015-3015 ◽  
Author(s):  
J. Randolph Hecht ◽  
Miklos Pless ◽  
Antonio Cubillo ◽  
Aitana Calvo ◽  
Hong Jae Chon ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Adverse Events ◽  
Dose Escalation ◽  
Liver Tumors ◽  
Checkpoint Inhibitors ◽  
Cell Cancer ◽  
Median Number ◽  
Primary Objective ◽  
Open Label ◽  
Dose Escalation Study

3015 Background: T-VEC is a genetically modified, oncolytic HSV-1 designed to selectively replicate within tumors and produce GM-CSF to enhance systemic antitumor immunity. The safety and efficacy of T-VEC in treatment of advanced melanoma has been demonstrated as monotherapy and in combination with checkpoint inhibitors (Andtbacka JCO 2015, Chesney JCO 2017, Ribas Cell 2017). T-VEC has also demonstrated tolerable safety for intrahepatic inj (Hecht JCO 2018). This phase 1b, multicenter, open-label, dose escalation study (NCT02509507) evaluates the safety of intrahepatic inj of T-VEC in combination with intravenous (IV) pem in patients (pts) with hepatocellular carcinoma (HCC) or liver metastases (mets). Methods: The primary objective is to assess the maximum tolerated concentration (MTC) of T-VEC inj into liver tumors based on the incidence of dose-limiting toxicities (DLTs). DLT rate was evaluated with the mTPI up-and-down design. Eligible pts were ≥ 18 years, had progressive HCC or breast cancer, colorectal cancer, gastroesophageal cancer, melanoma, non-small cell lung cancer, or renal cell cancer liver mets, with measurable liver tumors suitable for inj. This dose escalation study comprised 2 groups: A (non-HCC) and B (HCC). T-VEC was given initially at 106 plaque-forming units (PFU)/mL followed by up to 4 mL of 107 PFU/mL (cohort 5) or 108 PFU/mL (cohort 6) every 21 (±3) days (Q21D). Inj volume was based on lesion size. Pem (200 mg) was given IV Q21D. Results: Here we report on three cohorts: A5 (107 PFU/mL T-VEC + pem), A6 (108 PFU/mL T-VEC + pem), and B5 (107 PFU/mL T-VEC + pem). Twenty-nine pts were treated: 7 in A5, 17 in A6, 5 in B5. Median age was 61 years (range: 30, 76). Median number of inj was 4 and median treatment duration was 88 days. One DLT of cholestatic hepatitis was observed out of 6 DLT evaluable pts in cohort A5. No DLTs were observed in cohort A6 and B5. MTC was 108 PFU/mL in non-HCC patients; exploration of MTC in the HCC population is ongoing. Treatment-emergent adverse events (TEAEs) were consistent across cohorts. The most common treatment-emergent treatment-related adverse events (TETRAE) were pyrexia (79.3%), chills (37.9%), and nausea (37.9%). Eight pts (27.6%) had grade 3/4 TEAEs: 2pts (6.9%) related to the combination therapy and the rest not related to treatment. No fatal AEs were observed. Conclusions: T-VEC intrahepatic inj in combination with IV pem at standard doses has thus far been demonstrated as feasible and tolerable to continue further investigation. Clinical trial information: NCT02509507 .

scholarly journals IMMU-04. IMMUNE-RELATED ADVERSE EVENTS STRONGLY PREDICT SUPERIOR OUTCOMES IN BRAIN METASTASES PATIENTS RECEIVING LOCAL TREATMENT AND IMMUNE CHECKPOINT INHIBITORS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii105-ii105
Author(s):  
Alexander Hulsbergen ◽  
Asad Lak ◽  
Yu Tung Lo ◽  
Nayan Lamba ◽  
Steven Nagtegaal ◽  
...  
Keyword(s):  
Sensitivity Analysis ◽  
Adverse Events ◽  
Brain Metastases ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Local Treatment ◽  
Sensitivity Analyses ◽  
Immortal Time Bias ◽  
The Brain

Abstract INTRODUCTION In several cancers treated with immune checkpoint inhibitors (ICIs), a remarkable association between the occurrence of immune-related adverse events (irAEs) and superior oncological outcomes has been reported. This effect has hitherto not been reported in the brain. This study aimed to investigate the relation between irAEs and outcomes in brain metastases (BM) patients treated with both local treatment to the brain (LT; i.e. surgery and/or radiation) and ICIs. METHODS This study is a retrospective cohort analysis of patients treated for non-small cell lung cancer (NSCLC) BMs in a tertiary institution in Boston, MA. Outcomes of interest were overall survival (OS) and intracranial progression-free survival (IC-PFS), measured from the time of LT. Sensitivity analyses were performed to account for immortal time bias (i.e., patients who live longer receive more cycles of ICIs and thus have more opportunity to develop an irAE). RESULTS A total of 184 patients were included; 62 (33.7%) were treated with neurosurgical resection and 122 (66.3%) with upfront brain radiation. irAEs occurred in 62 patients (33.7%). After adjusting for lung-Graded Prognostic Assessment, type of LT, type of ICI, newly diagnosed vs. recurrent BM, BM size and number, targetable mutations, and smoking status, irAEs were strongly associated with better OS (HR 0.33, 95% CI 0.19 – 0.58, p &lt; 0.0001) and IC-PFS (HR 0.41; 95% CI 0.26 – 0.65; p = 0.0001). Landmark analysis including only patients who received more than 3 cycles of ICI (n = 133) demonstrated similar results for OS and IC-PFS, as did sensitivity analysis adjusting for the number of cycles administered (HR range 0.36 – 0.51, all p-values &lt; 0.02). CONCLUSIONS After adjusting for known prognostic factors, irAEs strongly predict superior outcomes after LT in NSCLC BM patients. Sensitivity analysis suggests that this is unlikely due to immortal time bias.

scholarly journals How to Best Exploit Immunotherapeutics in Advanced Gastric Cancer: Between Biomarkers and Novel Cell-Based Approaches

2021 ◽  
Vol 10 (7) ◽  
pp. 1412
Author(s):  
Michele Ghidini ◽  
Angelica Petrillo ◽  
Andrea Botticelli ◽  
Dario Trapani ◽  
Alessandro Parisi ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Advanced Gastric Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Clinical Implementation ◽  
T Cell Therapy ◽  
Dismal Prognosis

Despite extensive research efforts, advanced gastric cancer still has a dismal prognosis with conventional treatment options. Immune checkpoint inhibitors have revolutionized the treatment landscape for many solid tumors. Amongst gastric cancer subtypes, tumors with microsatellite instability and Epstein Barr Virus positive tumors provide the strongest rationale for responding to immunotherapy. Various predictive biomarkers such as mismatch repair status, programmed death ligand 1 expression, tumor mutational burden, assessment of tumor infiltrating lymphocytes and circulating biomarkers have been evaluated. However, results have been inconsistent due to different methodologies and thresholds used. Clinical implementation therefore remains a challenge. The role of immune checkpoint inhibitors in gastric cancer is emerging with data from monotherapy in the heavily pre-treated population already available and studies in earlier disease settings with different combinatorial approaches in progress. Immune checkpoint inhibitor combinations with chemotherapy (CT), anti-angiogenics, tyrosine kinase inhibitors, anti-Her2 directed therapy, poly (ADP-ribose) polymerase inhibitors or dual checkpoint inhibitor strategies are being explored. Moreover, novel strategies including vaccines and CAR T cell therapy are also being trialed. Here we provide an update on predictive biomarkers for response to immunotherapy with an overview of their strengths and limitations. We discuss clinical trials that have been reported and trials in progress whilst providing an account of future steps needed to improve outcome in this lethal disease.

scholarly journals Questionnaire-based detection of immune-related adverse events in cancer patients treated with PD-1/PD-L1 immune checkpoint inhibitors

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Luisa Maria Griewing ◽  
Claudia Schweizer ◽  
Philipp Schubert ◽  
Sandra Rutzner ◽  
Markus Eckstein ◽  
...  
Keyword(s):  
Adverse Events ◽  
Cancer Patients ◽  
Weight Change ◽  
Immune Checkpoint ◽  
Detection Rate ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Patient Questionnaire ◽  
Organ Specific ◽  
Tumor Entities

Abstract Background Immune checkpoint inhibitors (ICI) have become standard treatment in different tumor entities. However, safe treatment with ICI targeting the PD-1/PD-L1 axis requires early detection of immune-related adverse events (irAE). There exist different questionnaires of drug manufacturers for the detection of irAE that have not been validated so far. Methods The prospective non-interventional ST-ICI trial studied treatment with PD-1/PD-L1 ICI alone or combined with radiotherapy. In the current analysis, the detection rate of self-reported irAE with a patient questionnaire containing 41 different questions was compared to clinician-reported irAE. Results Between April 2017 and August 2019, a total of 104 patients were prospectively enrolled. NSCLC (44%) and HNSCC (42%) were the most frequent tumor entities. A total of 784 questionnaires were collected. A total of 29 irAE were reported by clinicians. The most frequent irAE was hypothyroidism (9%), followed by skin reactions (5%), hepatitis (4%), diarrhea (3%), and pneumonitis (3%). Questions that became significantly more often positive at time points of clinician-reported irAE were “weight change”, “difficulty to grip things”, “bloody or mucous stool” and “insomnia”. Self-reported organ-specific questions detected at least 50% of clinician-reported irAE of gastrointestinal, lung, endocrine, and skin irAE. It was not possible to detect hepatic irAE with the questionnaire. Conclusion Questionnaires can help to detect gastrointestinal, lung, endocrine, or skin irAE, but not hepatic irAE. Questions on “weight change” and “insomnia” may help to increase the detection rate of irAE, besides organ-specific questions. These results are a valuable contribution to the future development of a specific and practicable questionnaire for early self-reported detection of irAE during ICI therapy in cancer patients. Trial registration ClinicalTrials.gov, NCT03453892. Registered on 05 March 2018.

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