Adaptive Design for a Confirmatory Basket Trial in Multiple Tumor Types Based on a Putative Predictive Biomarker

Purpose ROS1 gene fusions demonstrate oncogenic activity, and patients with non–small-cell lung cancer (NSCLC) harboring a ROS1 fusion benefit from the use of a ROS1 inhibitor; however, clinical response to ROS1 inhibitors remains largely uncharacterized outside of NSCLC. ROS1 fusions have been identified in multiple tumor types but have not been reported in cutaneous melanoma. Patients and Methods Tumors from 22 patients with acral lentiginous melanoma (ALM) were analyzed with targeted RNA sequencing to detect fusions in ROS1, NTRK1, NTRK2, NTRK3, and ALK genes. A patient harboring a ROS1 fusion was enrolled in a phase I basket trial of a ROS1/TRK/ALK inhibitor (entrectinib). An additional 78 tumors with different subtypes of melanoma were screened by ROS1 immunohistochemistry. Results Targeted sequencing identified a GOPC- ROS1 fusion in a patient with ALM. The patient underwent a dramatic and durable response to entrectinib, with a RECIST (version 1.1) partial response of −38% at 3 months and −55% at 11 months. The response is ongoing, and the patient has not developed any new lesions. No additional ROS1 fusions were identified by immunohistochemistry, resulting in a frequency of 3.0% in ALM and 1.3% in all melanomas. Conclusion ROS1 fusions occur and can respond to targeted therapy in cutaneous melanoma; however, they may be specific to ALM subtype. This report expands knowledge of ROS1 inhibitor response outside of NSCLC and identifies new therapeutic options for a subset of patients with ALM.

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Statistical Design and Considerations of a Phase 3 Basket Trial for Simultaneous Investigation of Multiple Tumor Types in One Study

Statistics in Biopharmaceutical Research ◽

10.1080/19466315.2016.1193044 ◽

2016 ◽

Vol 8 (3) ◽

pp. 248-257 ◽

Cited By ~ 18

Author(s):

Cong Chen ◽

Xiaoyun (Nicole) Li ◽

Shuai Yuan ◽

Zoran Antonijevic ◽

Rasika Kalamegham ◽

...

Keyword(s):

Statistical Design ◽

Phase 3 ◽

Multiple Tumor ◽

Basket Trial ◽

Tumor Types

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CTNI-55. THE CDK4/6 INHIBITOR ABEMACICLIB IN PATIENTS WITH RECURRENT MENINGIOMA AND OTHER PRIMARY CNS TUMORS

Neuro-Oncology ◽

10.1093/neuonc/noab196.280 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi72-vi73

Author(s):

Elizabeth Coffee ◽

Katherine Panageas ◽

Robert Young ◽

Tara Morrison ◽

Ahmad Daher ◽

...

Keyword(s):

Brain Tumors ◽

Single Agent ◽

Pituitary Tumors ◽

Molecular Characteristics ◽

Multiple Cancer ◽

Who Grade ◽

Multiple Tumor ◽

Primary Brain Tumors ◽

Basket Trial ◽

Tumor Types

Abstract BACKGROUND Medical therapies for recurrent brain tumors are limited. Abemaciclib is a small molecule CDK4/6 inhibitor that has demonstrated antitumor activity in multiple cancer types and crosses the blood-brain barrier. METHODS We conducted a phase II trial of single-agent abemaciclib in patients with recurrent primary brain tumors utilizing a novel CNS basket trial design with multiple tumor types accrued to separate cohorts including patients with recurrent IDH-wildtype gliomas (Cohort A), any recurrent gliomas requiring cytoreductive surgery (Cohort B), and any other recurrent primary brain tumors (Cohort C) including IDH-mutant gliomas, meningiomas, and other tumor types. In all patients, abemaciclib was administered orally at 200mg twice daily for each 28-day cycle. In cohort B abemaciclib was administered 4-7 days prior to surgery then resumed after recovery. Neuroimaging disease assessments were performed every two cycles. Cohorts were individually assessed for efficacy, tumoral molecular characteristics, and exploratory biomarker analyses. Next generation sequencing was performed on patients who had prior surgery. RESULTS To date, a total of 61 patients have enrolled and initiated treatment with abemaciclib. Cohort A enrolled 9 patients with IDH-wildtype WHO grade II and III astrocytomas. Cohort B enrolled 10 patients with astrocytomas of varying IDH-status. Cohort C is a diverse group of 42 patients including 22 treatment-refractory meningiomas, 10 IDH-mutant gliomas (5 astrocytomas, 5 oligodendrogliomas), 3 ependymomas, 3 primary CNS lymphomas, 2 pituitary tumors, 1 glioneuronal rosette forming tumor, and 1 diffuse midline glioma. A total of 7 grade 3 toxicities occurred in 6 patients: fatigue (3), neutropenia (2), colitis (1) and seizure (1); no grade 4 toxicities occurred. CONCLUSIONS We present the results of a novel CNS basket trial looking at the efficacy of abemaciclib across multiple recurrent primary brain tumors. Efficacy results will be presented, highlighting an update on promising results in the 22 patients with recurrent meningiomas.

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Targeting AURKA in Cancer: molecular mechanisms and opportunities for Cancer therapy

Molecular Cancer ◽

10.1186/s12943-020-01305-3 ◽

2021 ◽

Vol 20 (1) ◽

Cited By ~ 1

Author(s):

Ruijuan Du ◽

Chuntian Huang ◽

Kangdong Liu ◽

Xiang Li ◽

Zigang Dong

Keyword(s):

Cancer Therapy ◽

Molecular Mechanisms ◽

Aurora Kinase ◽

Interacting Proteins ◽

Multiple Tumor ◽

Oncogenic Pathways ◽

Wide Range ◽

The Family ◽

Tumor Types ◽

Cancer Tissues

AbstractAurora kinase A (AURKA) belongs to the family of serine/threonine kinases, whose activation is necessary for cell division processes via regulation of mitosis. AURKA shows significantly higher expression in cancer tissues than in normal control tissues for multiple tumor types according to the TCGA database. Activation of AURKA has been demonstrated to play an important role in a wide range of cancers, and numerous AURKA substrates have been identified. AURKA-mediated phosphorylation can regulate the functions of AURKA substrates, some of which are mitosis regulators, tumor suppressors or oncogenes. In addition, enrichment of AURKA-interacting proteins with KEGG pathway and GO analysis have demonstrated that these proteins are involved in classic oncogenic pathways. All of this evidence favors the idea of AURKA as a target for cancer therapy, and some small molecules targeting AURKA have been discovered. These AURKA inhibitors (AKIs) have been tested in preclinical studies, and some of them have been subjected to clinical trials as monotherapies or in combination with classic chemotherapy or other targeted therapies.

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Enhance the Immune Checkpoint Inhibitors Efficacy with Radiotherapy Induced Immunogenic Cell Death: A Comprehensive Review and Latest Developments

Cancers ◽

10.3390/cancers13040678 ◽

2021 ◽

Vol 13 (4) ◽

pp. 678 ◽

Cited By ~ 1

Author(s):

Adrien Procureur ◽

Audrey Simonaggio ◽

Jean-Emmanuel Bibault ◽

Stéphane Oudard ◽

Yann-Alexandre Vano

Keyword(s):

Cell Death ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Tumor Antigens ◽

Checkpoint Inhibitors ◽

Mitotic Cell ◽

Immunogenic Cell Death ◽

Dna Damages ◽

Multiple Tumor ◽

Tumor Types

The immunogenic cell death (ICD) is defined as a regulated cell death able to induce an adaptive immunity. It depends on different parameters including sufficient antigenicity, adjuvanticity and favorable microenvironment conditions. Radiation therapy (RT), a pillar of modern cancer treatment, is being used in many tumor types in curative, (neo) adjuvant, as well as metastatic settings. The anti-tumor effects of RT have been traditionally attributed to the mitotic cell death resulting from the DNA damages triggered by the release of reactive oxygen species. Recent evidence suggests that RT may also exert its anti-tumor effect by recruiting tumor-specific immunity. RT is able to induce the release of tumor antigens, to act as an immune adjuvant and thus to synergize with the anti-tumor immunity. The advent of new efficient immunotherapeutic agents, such as immune checkpoint inhibitors (ICI), in multiple tumor types sheds new light on the opportunity of combining RT and ICI. Here, we will describe the biological and radiobiological rationale of the RT-induced ICD. We will then focus on the interest to combine RT and ICI, from bench to bedside, and summarize the clinical data existing with this combination. Finally, RT technical adaptations to optimize the ICD induction will be discussed.

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Development and Performance of a CD8 Gene Signature for Characterizing Inflammation in the Tumor Microenvironment Across Multiple Tumor Types

Journal of Molecular Diagnostics ◽

10.1016/j.jmoldx.2021.06.002 ◽

2021 ◽

Author(s):

Peter M. Szabo ◽

Saumya Pant ◽

Scott Ely ◽

Keyur Desai ◽

Esperanza Anguiano ◽

...

Keyword(s):

Tumor Microenvironment ◽

Gene Signature ◽

Multiple Tumor ◽

And Performance ◽

Tumor Types

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Is There a Place for Immune Checkpoint Inhibitors in Vulvar Neoplasms? A State of the Art Review

International Journal of Molecular Sciences ◽

10.3390/ijms22010190 ◽

2020 ◽

Vol 22 (1) ◽

pp. 190

Author(s):

Fulvio Borella ◽

Mario Preti ◽

Luca Bertero ◽

Giammarco Collemi ◽

Isabella Castellano ◽

...

Keyword(s):

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

State Of The Art ◽

Checkpoint Inhibitors ◽

Early Stage ◽

Survival Rates ◽

Younger Women ◽

Multiple Tumor ◽

Tumor Types

Vulvar cancer (VC) is a rare neoplasm, usually arising in postmenopausal women, although human papilloma virus (HPV)-associated VC usually develop in younger women. Incidences of VCs are rising in many countries. Surgery is the cornerstone of early-stage VC management, whereas therapies for advanced VC are multimodal and not standardized, combining chemotherapy and radiotherapy to avoid exenterative surgery. Randomized controlled trials (RCTs) are scarce due to the rarity of the disease and prognosis has not improved. Hence, new therapies are needed to improve the outcomes of these patients. In recent years, improved knowledge regarding the crosstalk between neoplastic and tumor cells has allowed researchers to develop a novel therapeutic approach exploiting these molecular interactions. Both the innate and adaptive immune systems play a key role in anti-tumor immunesurveillance. Immune checkpoint inhibitors (ICIs) have demonstrated efficacy in multiple tumor types, improving survival rates and disease outcomes. In some gynecologic cancers (e.g., cervical cancer), many studies are showing promising results and a growing interest is emerging about the potential use of ICIs in VC. The aim of this manuscript is to summarize the latest developments in the field of VC immunoncology, to present the role of state-of-the-art ICIs in VC management and to discuss new potential immunotherapeutic approaches.

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Abstract 2778: Comparative multiplex digital phenotyping of the tumor microenvironment across multiple tumor types using a well characterized multi-tumor tissue microarray

10.1158/1538-7445.am2021-2778 ◽

2021 ◽

Author(s):

Marie Cumberbatch ◽

Douglas Wood ◽

Christopher Womack ◽

Milan Bhagat ◽

Mael Manesse ◽

...

Keyword(s):

Tumor Microenvironment ◽

Tissue Microarray ◽

Tumor Tissue ◽

Multiple Tumor ◽

Digital Phenotyping ◽

Tumor Types

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Radioembolization for Rare Metastatic Disease

Digestive Disease Interventions ◽

10.1055/s-0041-1729875 ◽

2021 ◽

Author(s):

Andrew S. Niekamp ◽

Govindarajan Narayanan ◽

Brian J. Schiro ◽

Constantino Pena ◽

Alex Powell ◽

...

Keyword(s):

Colorectal Cancer ◽

Hepatocellular Carcinoma ◽

Metastatic Colorectal Cancer ◽

Treatment Modality ◽

Treatment Options ◽

Efficacy And Safety ◽

Multiple Tumor ◽

Tumor Types ◽

Hepatic Malignancies ◽

Yttrium 90

AbstractRadioembolization has become a widespread treatment modality for both primary and metastatic hepatic malignancies. Although the majority of data and indication for yttrium-90 radioembolization have been for hepatocellular carcinoma and metastatic colorectal cancer, radioembolization with yttrium-90 has rapidly expanded into the treatment options for multiple tumor types with metastases to the liver. This article reviews the clinical data and expanding utilization of radioembolization for rare metastatic diseases with an emphasis on efficacy and safety.

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