Tumor-Agnostic Drug Development.
Ontology highlight
ABSTRACT:
SUBMITTER: Offin M
PROVIDER: S-EPMC7506519 | biostudies-literature | 2018 May
REPOSITORIES: biostudies-literature
Publications
Tumor-Agnostic Drug Development.
Offin Michael M Liu Dazhi D Drilon Alexander A
American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting 20180501
Therapies designed to target cancers that harbor specific molecular signatures have reshaped the landscape of oncologic drug development, and advances in next generation sequencing have led to an increase in the identification of these alterations across tumor types. Tumor-agnostic trial designs, such as the "basket trial," have been developed as an approach to study the efficacy of these treatments and increase patient access, especially for patients whose tumors carry these alterations infrequ ...[more]
Similar Datasets
Project description:A better understanding of cancer biology has led to the development of targeted therapies specifically designed to modulate an altered molecular pathway in the cancer cells or their microenvironment. Despite the identification of molecular targets across cancer types, most of targeted therapies were developed per cancer type. In this ancestral paradigm, randomization was the gold-standard approach for market access. Randomization of large patient populations was feasible for drugs developed in common cancer types but more challenging in rare cancer types. The traditional paradigm of drug development in oncology was further challenged by the ever-expanding molecular segmentation of cancer with ever-smaller subgroups of patients who might benefit from specific targeted therapies or immunotherapies and the identification of molecular alterations against which drugs may be effective across cancer types. In this novel drug development paradigm, novel ways of evaluating the efficacy of drugs are highly needed in these small patient populations. One approach is to use each patient as his/her own control by comparing the efficacy of a drug to the efficacy of prior treatments received. This approach allows to overcome patient heterogeneity, especially in a tissue-agnostic drug development paradigm.
| S-EPMC8199632 | biostudies-literature
Project description:Precision medicine just witnessed two breakthroughs in oncology in 2017. Pembrolizumab (Keytruda), Merck's anti-programmed cell death-1 (PD-1) monoclonal antibody (mAb), received accelerated approval in May 2017 by the US Food and Drug Administration for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors that have been identified as having microsatellite instability-high (MSI-H) or deficient DNA mismatch repair (dMMR). Shortly after, nivolumab (Opdivo), Bristol-Myers Squibb's anti-PD-1 mAb, gained an accelerated approval in August 2017 for adult and pediatric patients with MSI-H or dMMR metastatic colorectal cancer that has progressed after standard chemotherapy. These regulatory approvals marked an important milestone that a cancer treatment may be approved based on a common biomarker rather than the anatomic location in the body where the tumor originated, and therefore established a precedent for tumor type-agnostic therapy. In the 2017 American Society for Clinical Oncology annual meeting, larotrectinib (LOXO-101), Loxooncology's oral, potent, and selective inhibitor of tropomyosin receptor kinases (TRK), demonstrated unprecedented efficacy on unresectable or metastatic solid tumors with neurotrophic tropomyosin receptor kinase (NTRK)-fusion proteins in adult and pediatric patients. Both the anti-PD-1 mAbs and the TRK-targeting therapies share some basic features: (a) biomarker-based, well-defined rare patient population; (b) exceptionally high clinical efficacy, e.g., near 40% overall response rate (ORR) for pembrolizumab across 15 tumor types with MSI-H/dMMR and 75% ORR for larotrectinib across more than 12 tumor types with NTRK-fusion proteins; (c) durable responses lasting at least 6 months with complete responses observed; and (d) parallel development in adult and pediatric populations. With increasing accessibility to genetic analysis tools such as next-generation sequencing, tumor type-agnostic therapy has become a reality, both during clinical development and in clinical practice. Adjustments in our approaches to developing new anti-cancer drugs and to adopting these new cancer treatments in clinical practice need to occur in order to prepare ourselves for the new era of precision medicine.
| S-EPMC5953403 | biostudies-literature
Project description:Circulating tumor DNA (ctDNA) has recently emerged as a real-time prognostic and predictive biomarker for monitoring cancer patients. Here, we aimed to ascertain whether tumor-agnostic ctDNA testing would be a feasible strategy to monitor disease progression and therapeutic response in muscle-invasive bladder cancer (MIBC) patients after radical cystectomy (RC). Forty-two MIBC patients who underwent RC were prospectively included. Blood samples from these patients were collected at different follow-up time points. Two specific mutations (TERT c.1-124C>T and ATM c.1236-2A>T) were analyzed in the patients' plasma samples by droplet digital PCR to determine their ctDNA status. During a median follow-up of 21 months, 24% of patients progressed in a median of six months. ctDNA status was identified as a prognostic biomarker of tumor progression before RC and 4 and 12 months later (HR 6.774, HR 3.673, and HR 30.865, respectively; p < 0.05). Lastly, dynamic changes in ctDNA status between baseline and four months later were significantly associated with patient outcomes (p = 0.045). In conclusion, longitudinal ctDNA analysis using a tumor-agnostic approach is a potential tool for monitoring MIBC patients after RC. The implementation of this testing in a clinical setting could improve disease management and patients' outcomes.
| S-EPMC10706140 | biostudies-literature
Project description:Molecular similarities between embryonic and malignant cells can be exploited to target tumors through specific signatures absent in healthy adult tissues. One such embryonic signature tumors express is oncofetal chondroitin sulfate (ofCS), which supports disease progression and dissemination in cancer. Here, we report the identification and characterization of phage display-derived antibody fragments recognizing two distinct ofCS epitopes. These antibody fragments show binding affinity to ofCS in the low nanomolar range across a broad selection of solid tumor types in vitro and in vivo with minimal binding to normal, inflamed, or benign tumor tissues. Anti-ofCS antibody drug conjugates and bispecific immune cell engagers based on these targeting moieties disrupt tumor progression in animal models of human and murine cancers. Thus, anti-ofCS antibody fragments hold promise for the development of broadly effective therapeutic and diagnostic applications targeting human malignancies.
| S-EPMC11364678 | biostudies-literature
Project description:Comprehensive genomic profiling examinations (CGPs) have recently been developed, and a variety of tumor-agnostic mutations have been detected, leading to the development of new molecular-targetable therapies across solid tumors. In addition, the elucidation of hereditary tumors, such as breast and ovarian cancer, has pioneered a new age marked by the development of new treatments and lifetime management strategies required for patients with potential or presented hereditary cancers. In acute myeloid leukemia (AML), however, few tumor-agnostic or hereditary mutations have been the focus of investigation, with associated molecular-targeted therapies remaining poorly developed. We focused on representative tumor-agnostic mutations such as the TP53, KIT, KRAS, BRCA1, ATM, JAK2, NTRK3, FGFR3 and EGFR genes, referring to a CGP study conducted in Japan, and we considered the possibility of developing molecular-targeted therapies for AML with tumor-agnostic mutations. We summarized the frequency, the prognosis, the structure and the function of these mutations as well as the current treatment strategies in solid tumors, revealed the genetical relationships between solid tumors and AML and developed tumor-agnostic molecular-targeted therapies and lifetime management strategies in AML.
| S-EPMC9775249 | biostudies-literature
Project description:Biomarker-driven cancer therapy has revolutionized precision oncology. With a better understanding of tumor biology, tissue-agnostic targets have been characterized and explored, which ultimately led to therapeutics with pan-cancer efficacy. To date, five molecular biomarkers have obtained FDA tissue-agnostic approval for targeted therapies and immunotherapies. Those include BRAFV600E mutations, RET fusions, NTRK fusions, high tumor mutation burden (TMB), and deficient mismatch repair/high microsatellite instability (dMMR/MSI-High). Herein, we have used data from AACR project GENIE to explore the clinico-genomic landscape of these alterations. AACR GENIE is a publicly accessible registry of genomic data from multiple collaborating cancer centers. Current database (version 13.0) includes sequencing data of 168,423 samples collected from patients with different cancers. We were able to identify BRAFV600E, RET fusions, NTRK fusions, and high TMB in 2.9%, 1.6%, 1.5%, and 15.2% of pan-cancer samples, respectively. In this article, we describe the distribution of those tissue-agnostic targets among different cancer types. In addition, we summarize the current prospect on the biology of these alterations and evidence on approved drugs, including pembrolizumab, dostarilmab, larotrectinib, entrectinib, selpercatinib, and dabrafenib/trametinib combination.
| S-EPMC10390861 | biostudies-literature
Project description:Anaplastic lymphoma kinase (ALK) alterations (activating mutations, amplifications, and fusions/rearrangements) occur in ~3.3% of cancers. ALK fusions/rearrangements are discerned in >50% of inflammatory myofibroblastic tumors (IMTs) and anaplastic large cell lymphomas (ALCLs), but only in ~0.2% of other cancers outside of non-small cell lung cancer (NSCLC), a rate that may be below the viability threshold of even large-scale treatment trials. Five ALK inhibitors -alectinib, brigatinib, ceritinb, crizotinib, and lorlatinib-are FDA approved for ALK-aberrant NSCLCs, and crizotinib is also approved for ALK-aberrant IMTs and ALCL, including in children. Herein, we review the pharmacologic tractability of ALK alterations, focusing beyond NSCLC. Importantly, the hallmark of approved indications is the presence of ALK fusions/rearrangements, and response rates of ~50-85%. Moreover, there are numerous reports of ALK inhibitor activity in multiple solid and hematologic tumors (e.g., histiocytosis, leiomyosarcoma, lymphoma, myeloma, and colorectal, neuroendocrine, ovarian, pancreatic, renal, and thyroid cancer) bearing ALK fusions/rearrangements. Many reports used crizotinib or alectinib, but each of the approved ALK inhibitors have shown activity. ALK inhibitor activity is also seen in neuroblastoma, which bear ALK mutations (rather than fusions/rearrangements), but response rates are lower (~10-20%). Current data suggests that ALK inhibitors have tissue-agnostic activity in neoplasms bearing ALK fusions/rearrangements.
| S-EPMC10542332 | biostudies-literature
Project description:Circulating tumor cells (CTC) isolated from the peripheral blood of cancer patients by a minimally invasive procedure provide surrogate markers of the tumor that can be repeatedly sampled. However, the selection and enumeration of CTCs by traditional methods based on surface proteins like EPCAM may not detect CTCs with a mesenchymal phenotype. Here, we employed an antibody-agnostic platform, the Parsortix® PR1 system, which enriches CTCs based on cell size and membrane deformability. We evaluated the linearity, sensitivity, and specificity of the Parsortix PR1 system in tandem with 3 downstream molecular characterization techniques using healthy donor blood spiked with cultured cell lines. Signal amplification of mRNA using a QuantiGene 25-gene assay was able to quantitate multiple epithelial genes, including CDH1, EGFR, ERBB2, KRT18, and MUC1, from high numbers of spiked cells and was able to detect KRT18 when only 50 MCF-7 or SUM190 cells were spiked into healthy donor blood. However, target amplification of mRNA by quantitative polymerase chain reaction (qPCR) showed better sensitivity; qPCR without pre-amplification was able to detect CTC-related genes in Parsortix PR1-enriched cells when as few as 5 SKBR3 cells were spiked into blood. Finally, the HTG EdgeSeq nuclease protection assay was able to profile mRNA expression of over 2,560 cancer-related genes from Parsortix PR1 enriched cells, showing enrichment in cancer signaling pathways and ERBB2, KRT19, and KRT7. Overall, the Parsortix PR1 platform may be amenable to transition into routine clinical workflows.
| S-EPMC7584183 | biostudies-literature
Project description:BackgroundLarotrectinib is a precision oncology treatment for solid tumors with neurotrophic tyrosine receptor kinase (NTRK) gene fusions. Larotrectinib efficacy has been evaluated in single-arm basket trials with limited follow-up and sample sizes at the initial regulatory approval due to the rarity of solid tumors with NTRK gene fusion.ObjectivesWe aim to demonstrate that trends in progression-free survival (PFS) and overall survival (OS) in survival data with longer follow-up may be predicted from long-term survival estimates from survival data with shorter follow-up, including predictions for median survival when it is not observed in the trial.MethodsPatient-level data were pooled from 3 clinical trials (NCT02122913, NCT02576431, and NCT02637687) using the 2018 and 2020 data cuts for the same subset of pediatric and adult patients. The Weibull distribution was selected for survival models. Survival predictions using 2018 data were compared to 2020 Kaplan-Meier (KM) curves.ResultsA total of 102 patients representing 15 tumor types were included in the analysis, with a mean age of 37 years. When comparing PFS from the 2018 survival prediction to observed 2020 KM data, the 12-month PFS rate was identical (66.6%). The 36-month PFS rate was lower for the 2018 prediction (35.3%) compared to 2020 KM data (44.4%). The median OS had not yet been reached in either data cut but was predicted to be 90 months using the 2018 data. When comparing OS from the 2018 survival prediction to the observed 2020 KM data, the 12-month OS rate was 89.0% and 86.6% and the 48-month OS rate was 67.2% and 63.0%, respectively.ConclusionLong-term PFS predictions deviated from observed PFS rates due to response differences across tumor types and heavy censoring towards the end of the survival curve. However, for OS, the 48-month survival prediction was consistent with the observed 2020 KM estimate.
| S-EPMC8820422 | biostudies-literature
Project description:Systemic pan-tumor analyses may reveal the significance of common features implicated in cancer immunogenicity and patient survival. Here, we provide a comprehensive multi-omics data set for 32 patients across 25 tumor types for proteogenomic-based discovery of neoantigens. By using an optimized computational approach, we discover a large number of tumor-specific and tumor-associated antigens. To create a pipeline for the identification of neoantigens in our cohort, we combine DNA and RNA sequencing with MS-based immunopeptidomics of tumor specimens, followed by the assessment of their immunogenicity and an in-depth validation process. We detect a broad variety of non-canonical HLA-binding peptides in the majority of patients demonstrating partially immunogenicity. Our validation process allows for the selection of 32 potential neoantigen candidates. The majority of neoantigen candidates originates from variants identified in the RNA data set, illustrating the relevance of RNA as a still understudied source of cancer antigens. This study underlines the importance of RNA-centered variant detection for the identification of shared biomarkers and potentially relevant neoantigen candidates.
| S-EPMC10397250 | biostudies-literature