Target-Driven Tissue-Agnostic Drug Approvals; a New Path of Drug Development DOI Open Access
Kyaw Zin Thein,

Yin Mon Myat,

Byung Park

et al.

Published: June 3, 2024

The regulatory approvals of tumor agnostic therapies have led to reevaluation the drug development process. Conventional models are histology-based. On other hand, a new (or combination) focuses on targeting common genomic biomarker in multiple cancers, regardless histology. Basket-like clinical trials with cohorts allow clinicians evaluate pan-cancer efficacy and toxicity. There currently 8 granted by Food Drug Administration (FDA). This includes two immune checkpoint inhibitors, 5 targeted therapy agents. Pembrolizumab is an anti-PD-1 antibody that was first FDA approved treatment for unresectable or metastatic microsatellite instability-high (MSI-H) deficient mismatch repair (dMMR) solid tumors 2017. It later mutational burden-high (TMB-H) tumors, although TMB cut-off used still debated. Subsequently, 2021, another antibody, Dostarlimab also dMMR refractory setting. Patients fusion-positive cancers typically difficult treat due their rare prevalence distribution. Gene rearrangements fusions present variety tumors. neurotrophic tyrosine kinase (NTRK) range pediatric adult varying frequency. Larotrectinib entrectinib were cancers. Similarly, selpercatinib Rearranged During Transfection (RET) combination dabrafenib, B-Raf Proto-Oncogene Serine/Threonine Kinase (BRAF) inhibitor, plus trametinib, mitogen-activated protein (MEK) inhibitor patients 6 months older (except colorectal cancer) carrying BRAFV600E mutation. most recent approval fam-trastuzumab deruxtecan-nxki (T-Dxd) HER2-positive important identify expeditiously develop drugs potential provide benefit across types.

Language: Английский

Final Results for Adjuvant Dabrafenib plus Trametinib in Stage III Melanoma DOI
Georgina V. Long, Axel Hauschild, Mario Santinami

et al.

New England Journal of Medicine, Journal Year: 2024, Volume and Issue: 391(18), P. 1709 - 1720

Published: June 19, 2024

The 5-year results of this trial showed that adjuvant therapy with dabrafenib plus trametinib resulted in longer relapse-free survival and distant metastasis-free than placebo among patients

Language: Английский

Citations

33
Next-generation therapies for pancreatic cancer DOI Creative Commons
Conor Buckley, Eileen M. O’Reilly

Expert Review of Gastroenterology & Hepatology, Journal Year: 2024, Volume and Issue: 18(1-3), P. 55 - 72

Published: Feb. 28, 2024

Introduction Pancreas ductal adenocarcinoma (PDAC) is a frequently lethal malignancy that poses unique therapeutic challenges. The current mainstay of therapy for metastatic PDAC (mPDAC) cytotoxic chemotherapy. NALIRIFOX (liposomal irinotecan, fluorouracil, leucovorin, oxaliplatin) an emerging standard care in the setting. An evolving understanding pathogenesis driving shift toward targeted therapy. Olaparib, poly-ADP-ribose polymerase (PARP) inhibitor, has regulatory approval maintenance BRCA-mutated mPDAC along with other agents receiving disease-agnostic approvals including rare fusions and mismatch repair deficiency. Ongoing research continues to identify evaluate expanding array therapies PDAC.

Language: Английский

Citations

15
GD2-targeting therapy: a comparative analysis of approaches and promising directions DOI Creative Commons
Julia Philippova, Julia Shevchenko, С. В. Сенников

et al.

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: March 15, 2024

Disialoganglioside GD2 is a promising target for immunotherapy with expression primarily restricted to neuroectodermal and epithelial tumor cells. Although its role in the maintenance repair of neural tissue well-established, functions during normal organism development remain understudied. Meanwhile, studies have shown that plays an important tumorigenesis. Its include proliferation, invasion, motility, metastasis, high ability transform microenvironment may be associated malignant phenotype. Structurally, glycosphingolipid stably expressed on surface cells, making it suitable candidate targeting by antibodies or chimeric antigen receptors. Based mouse monoclonal antibodies, humanized their combinations cytokines, toxins, drugs, radionuclides, nanoparticles as well receptor been developed. Furthermore, vaccines photoimmunotherapy are being used treat GD2-positive tumors, aptamers can targeting. In field cell therapy, allogeneic immunocompetent cells also utilized enhance therapy. Efforts currently made optimize modifying design transducing not only αβ T but γδ NK NKT macrophages. addition, combine both diagnostic therapeutic methods, allowing early detection disease minimal residual disease. This review discusses each method strategy, advantages disadvantages, highlights future directions

Language: Английский

Citations

13
If it’s a target, it’s a pan-cancer target: Tissue is not the issue DOI Creative Commons
Jacob J. Adashek, Shumei Kato, Jason K. Sicklick

et al.

Cancer Treatment Reviews, Journal Year: 2024, Volume and Issue: 125, P. 102721 - 102721

Published: March 21, 2024

Cancer is traditionally diagnosed and treated on the basis of its organ origin (e.g., lung or colon cancer). However, organ-of-origin diagnostics does not reveal underlying oncogenic drivers. Fortunately, molecular have advanced at a breathtaking pace, it increasingly apparent that cancer disease genome. Hence, we now multiple genomic biomarker-based, tissue-agnostic Food Drug Administration approvals for both gene- immune-targeted therapies (larotrectinib/entrectinib, NTRK fusions; selpercatinib, RET dabrafenib plus trametinib, BRAF

Language: Английский

Citations

12
Liquid biopsy guides successful molecular targeted therapy of an inoperable pediatric brainstem neoplasm DOI Creative Commons
Cecilia Arthur,

Lena-Maria Carlson,

J Svoboda

et al.

npj Precision Oncology, Journal Year: 2024, Volume and Issue: 8(1)

Published: Feb. 22, 2024

Abstract Midline CNS tumors are occasionally inaccessible for surgical biopsies. In these instances, cell-free DNA (cfDNA) may serve as a viable alternative molecular analysis and identification of targetable mutations. Here, we report young child with an inoperable brainstem tumor in whom stereotactic biopsy was deemed unsafe. The progressed on steroids after radiotherapy the patient developed hydrocephalus received ventriculoperitoneal shunt. Droplet digital PCR cfDNA from intraoperative cerebrospinal fluid liquid revealed BRAF V600 mutation enabling targeted treatment MEK inhibitors. patient, now trametinib dabrafenib 1 year, has had substantial volume regression reduction contrast enhancement MRIs is making remarkable clinical progress. This case highlights that subset tumors, access to be crucial identify actionable therapeutic targets would otherwise go undiscovered.

Language: Английский

Citations

9
Importance of EQA/PT for the detection of genetic variants in comprehensive cancer genome testing DOI Creative Commons
Kazuyuki Matsushita, Takayuki Ishige, Kousuke Watanabe

et al.

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: Jan. 7, 2025

Comprehensive genomic profiling (CGP) is increasingly used as a clinical laboratory test and being applied to cancer treatment; however, standardization external quality assessments (EQA) have not been fully developed. This study performed cost-effective EQA proficiency tests (PT) for CGP testing among multiple institutions those belong the working group of Japan Association Clinical Laboratory Science (JACLS). revealed that preanalytical processes, such derived nucleic acids (NA) extraction from formalin fixed paraffine embedded (FFPE) samples, are critical. First, with extracted DNA cell lines showed detection rate 100% (9 out 9) in KRAS (c.38G > A; p.G13D), PIK3CA (p.H1047R), B-Raf proto-oncogene, serine/threonine kinase (BRAF) (c.1799 T p.V600E) cases 10% variant allele frequency (VAF). However, BRAF decreased 67% (6 VAF 4.9%. Second, when was FFPE pathogenic variants companion diagnostic indications were detected all 10 participating laboratories. Each had < 20% VAFs on average (8.1–19.1%) wide variability laboratories observed (relative standard deviation, 13–60%). Nonetheless, (c.1798_1799delinsAA; p.V600K) 8.1% VAF, EGFR (c.2235_2249del; p.E746_A750del) 9.7% (c.2254_2277del; p.S752_I759del) 9.8% 70% (7/10), 60% (6/10) frequency, respectively. Therefore, pre-analytic processing critical analysis. Further, incorrect results reported case independent calling BRAF; c.1798_1799delinsAA (p.V600K) mistakenly interpreted c.1798G A, c.1799 A other strand. In conclusion, EQA/PT institutes common samples importance pre-analysis helped us understand significance pipeline pitfalls usually ignored by internal control single institute.

Language: Английский

Citations

1
Revolutionizing cancer drug development: Harnessing the potential of basket trials DOI
Vivek Subbiah, Howard A. Burris, Razelle Kurzrock

et al.

Cancer, Journal Year: 2023, Volume and Issue: 130(2), P. 186 - 200

Published: Nov. 7, 2023

Abstract The landscape of cancer therapy has been transformed by advances in clinical next‐generation sequencing, genomically targeted therapies, and immunotherapies. Well designed trials efficient trial conduct are crucial for advancing our understanding cancer, improving patient outcomes, identifying personalized treatments. Basket have emerged as one the modern designs that evaluate efficacy these therapies across multiple types based on specific molecular alterations or biomarkers, irrespective histology anatomic location. This review delves into evolution basket drug development, highlighting their potential prospects current obstacles. design involves screening patients biomarkers enrolling them to receive under investigation. Statistical considerations play a role design, analysis, interpretation trials. Several notable examples led US Food Drug Administration approval uncommon (e.g., NTRK fusions, BRAF mutations, RET FGFR1 alterations) discussed, including LOXO‐TRK (ClinicalTrials.gov identifier NCT02122913)/SCOUT NCT02637687)/NAVIGATE NCT02576431)/STARTRK identifiers NT02097810, NT02568267), VE‐BASKET NCT01524978), ROAR NCT02034110), LIBRETTO‐001 NCT03157128), ARROW NCT03037385), FIGHT‐203 NCT03011372), National Cancer Institute‐Molecular Analysis Therapy Choice NCT02465060). revolutionize treatment effective rather than traditional histology‐based approaches. Plain Language Summary To gain more knowledge about improve discover treatments, it is efficiently. One type called . In trials, new treatments tested various regardless location body; instead, researchers focus abnormalities cells. offer hope we can find each individual battling cancer.

Language: Английский

Citations

19
Update on current diagnosis and management of anaplastic thyroid carcinoma DOI Open Access
T. Pavlidis, I. Galanis, T. Pavlidis

et al.

World Journal of Clinical Oncology, Journal Year: 2023, Volume and Issue: 14(12), P. 570 - 583

Published: Dec. 21, 2023

Well-differentiated thyroid carcinoma has a favorable prognosis with 5-year survival rate of over 95%. However, the undifferentiated or anaplastic type accounting for < 0.2%, usually in elderly individuals, exhibits dismal rapid growth and disappointing outcomes. It is most aggressive form carcinoma, median 5 mo poor quality life (airway obstruction, dysphagia, hoarseness, persistent pain). Early diagnosis staging are crucial. Diagnostic tools include biopsy (fine needle aspiration, core needle, open surgery), high-resolution ultrasound, computed tomography, magnetic resonance imaging, [(18)F]fluoro-D-glucose positron emission tomo-graphy/computed liquid microRNAs. The

Language: Английский

Citations

12
Heterogeneity in precision oncology DOI Creative Commons
Bartłomiej Tomasik, Filip Garbicz, Marcin Braun

et al.

Cambridge Prisms Precision Medicine, Journal Year: 2023, Volume and Issue: unknown, P. 1 - 37

Published: Oct. 5, 2023

An abstract is not available for this content so a preview has been provided. As you have access to content, full PDF via the ‘Save PDF’ action button.

Language: Английский

Citations

11
Trametinib for a child with refractory Rosai–Dorfman–Destombes disease harboring a novel somatic mutation in MAP2K1 DOI
Yuichi Taneyama, Akira Morimoto,

Hidemasa Ochiai

et al.

International Journal of Hematology, Journal Year: 2024, Volume and Issue: 120(4), P. 520 - 524

Published: July 14, 2024

Language: Английский

Citations

4