Article
Medicine, General & Internal
Jean-Yves Blay, Yoon-Koo Kang, Toshiroo Nishida, Margaret von Mehren
Summary: Gastrointestinal stromal tumours (GIST) are rare malignancies with 80% of cases having KIT or PDGFRA activating mutations. Localized GIST can be cured through surgery, while advanced resistant GIST with resistance mutations require treatment with new drugs.
NATURE REVIEWS DISEASE PRIMERS
(2021)
Review
Oncology
Tiffany Foo, David Goldstein, Eva Segelov, Jeremy Shapiro, Nick Pavlakis, Jayesh Desai, Desmond Yip, John Zalcberg, Timothy J. Price, Adnan Nagrial, Lorraine Chantrill, Matt Burge, Christos S. Karapetis, Niall Tebbutt, Amitesh C. Roy
Summary: TKIs have transformed the management of advanced GIST, and there are now five approved targeted therapy options for the treatment of unresectable, advanced GISTs.
Review
Pharmacology & Pharmacy
Simon Fung, Matt Shirley
Summary: Ripretinib is a small molecule inhibitor that targets a wide range of mutations in gastrointestinal stromal tumors, leading to an increase in progression-free survival. It has acceptable tolerability and is a valuable treatment option for managing this disease.
Article
Chemistry, Medicinal
Andreas Blum, Dieter Dorsch, Nina Linde, Susanne Brandstetter, Hans-Peter Buchstaller, Michael Busch, Nina Glaser, Ulrich Graedler, Aaron Ruff, Carl Petersson, Hanno Schieferstein, Eva Sherbetjian, Christina Esdar
Summary: The treatment of gastrointestinal stromal tumors (GISTs) driven by activating mutations in the KIT gene is a successful example of targeted therapy. However, there is still a need for KIT inhibitors with high selectivity and broad coverage of all clinically relevant KIT mutants.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Oncology
Yoichi Naito, Toshirou Nishida, Toshihiko Doi
Summary: Gastrointestinal stromal tumours (GISTs) are treated with surgery, but the risk of relapse and progression is high. Targeted therapies like imatinib, sunitinib, and regorafenib have been developed, but resistance is common. Other TKIs and alternative treatments have been explored, but the development of new therapies for advanced GIST remains crucial.
Review
Oncology
Marin Golcic, Robin L. Jones, Paul Huang, Andrea Napolitano
Summary: Gastrointestinal stromal tumours (GIST) is the most common mesenchymal tumour of the gastrointestinal tract. Surgical treatment is recommended for localised GIST, while systemic treatment is the main approach for metastatic or unresectable disease. The duration of neoadjuvant treatment with imatinib is not clearly recommended, but it is usually given for 4 to 12 months. Personalized treatment options based on the molecular profile of GIST, patient characteristics, and medication adverse events are possible with the development of various systemic treatment options.
Review
Oncology
Lillian R. Klug, Homma M. Khosroyani, Jason D. Kent, Michael C. Heinrich
Summary: When Gastrointestinal Stromal Tumour (GIST) was identified as a distinct pathological entity, effective medical therapies were lacking, leading to poor prognosis. However, the discovery of KIT mutations and the development of TKIs revolutionized GIST treatment. Although there are approved drugs for treating advanced-stage GIST, challenges still remain and new therapeutic approaches are needed.
NATURE REVIEWS CLINICAL ONCOLOGY
(2022)
Article
Oncology
Yoon-Koo Kang, Suzanne George, Robin L. Jones, Piotr Rutkowski, Lin Shen, Olivier Mir, Shreyaskumar Patel, Yongjian Zhou, Margaret von Mehren, Peter Hohenberger, Victor Villalobos, Mehdi Brahmi, William D. Tap, Jonathan Trent, Maria A. Pantaleo, Patrick Schoeffski, Kevin He, Paggy Hew, Kate Newberry, Maria Roche, Michael C. Heinrich, Sebastian Bauer
Summary: Avapritinib, a potent inhibitor of KIT and PDGFRA mutant kinases, showed clinical activity in GISTs with specific mutations. The VOYAGER study comparing avapritinib and regorafenib in advanced GIST patients did not find a significant difference in median progression-free survival, but showed similar overall survival and safety profiles between the two treatments.
JOURNAL OF CLINICAL ONCOLOGY
(2021)
Article
Oncology
Michael C. Heinrich, Christopher L. Corless, George D. Demetri, Charles D. Blanke, Margaret von Mehren, Heikki Joensuu, Laura S. Mcgreevey, Chang-Jie Chen, Annick D. van den Abbeele, Brian J. Druker, Beate Kiese, Burton Eisenberg, Peter J. Roberts, Samuel Singer, Christopher D. M. Fletcher, Sandra Silberman, Sasa Dimitrijevic, Jonathan A. Fletcher
Summary: This study found that most GISTs have activating mutations in KIT or PDGFRA, and the occurrence of these mutations is related to clinical response to imatinib. PDGFRA mutations can explain the response and sensitivity to imatinib in some GISTs without KIT mutations.
JOURNAL OF CLINICAL ONCOLOGY
(2023)
Article
Oncology
Suzanne George, Margaret von Mehren, Jonathan A. Fletcher, Jichao Sun, Sen Zhang, Justin R. Pritchard, John Graeme Hodgson, David Kerstein, Victor M. Rivera, Frank G. Haluska, Michael C. Heinrich
Summary: The study evaluated the efficacy of ponatinib for advanced gastrointestinal stromal tumors (GIST) and found that ponatinib demonstrated activity, particularly in KIT ex11-positive disease. There was a strong concordance of primary KIT mutations between plasma and tumor. Resistance was associated with the emergence of secondary mutations. Ponatinib was ineffective in patients with KIT exon 9 primary mutations. The safety profile was consistent with previous studies.
CLINICAL CANCER RESEARCH
(2022)
Article
Oncology
Thomas L. Sutton, Brett S. Walker, Kevin G. Billingsley, Christopher L. Corless, Brett C. Sheppard, Michael C. Heinrich, Skye C. Mayo
Summary: This study aimed to evaluate predictors of 10-year metastatic survivorship in patients with gastrointestinal stromal tumors (GIST) treated with tyrosine kinase inhibitor therapy. The results showed that 10-year survivorship is achievable in GIST patients in the era of tyrosine kinase inhibitors, and it is associated with younger age and longer time to first progression.
ANNALS OF SURGICAL ONCOLOGY
(2022)
Article
Oncology
Vaibhav Kumar, Leslie Doros, Margaret Thompson, Sirisha L. Mushti, Rosane Charlab, Elizabeth I. Spehalski, Hong Zhao, Matthew D. Thompson, Shenghui Tang, Richard Pazdur, Steven J. Lemery, Marc R. Theoret, Lola A. Fashoyin-Aje
Summary: On May 15, 2020, the FDA approved ripretinib for adult patients with advanced gastrointestinal stromal tumor who have received prior treatment with three or more kinase inhibitors, including imatinib. The approval was based on results from the INVICTUS trial, which showed a significant improvement in progression-free survival for patients in the ripretinib group compared to the placebo group. The median overall survival was also longer in the ripretinib group.
CLINICAL CANCER RESEARCH
(2023)
Article
Oncology
Eline L. Giraud, Loek A. W. de Jong, Erik van den Hombergh, Suzanne E. J. Kaal, Nielka P. van Erp, Ingrid M. E. Desar
Summary: This study aimed to investigate the distribution of imatinib within gastrointestinal stromal tumours (GISTs) and its correlation with plasma concentrations. The results showed that imatinib accumulated in tumour tissue with higher concentrations compared to plasma, but no clear distribution pattern within the tumour could be identified. The variability in tumour concentration was higher than that in plasma concentration. There was no correlation between imatinib concentrations in tumour tissue and treatment response.
Article
Oncology
Cissimol P. Joseph, Sarah N. Abaricia, Michelle A. Angelis, Kathleen Polson, Robin L. Jones, Yoon-Koo Kang, Richard F. Riedel, Patrick Schoffski, Cesar Serrano, Jonathan Trent, Eric D. Tetzlaff, Tuan Dong Si, Teresa Zhou, Ashley Doyle, Sebastian Bauer, Maria Roche, Tracy Havnaer
Summary: Avapritinib, a novel inhibitor approved for U/M GISTs, showed common treatment-related AEs including nausea, fatigue, and anemia. Cognitive effects were observed in a significant percentage of patients, particularly in older patients, but improved faster with dose modification. Utilizing tolerability-guided dose modification may be an effective strategy in managing AEs and maintaining patients on avapritinib treatment.
Article
Oncology
Juan Liu, Jingjing Gao, Aoli Wang, Zongru Jiang, Shuang Qi, Ziping Qi, Feiyang Liu, Kailin Yu, Jiangyan Cao, Cheng Chen, Chen Hu, Hong Wu, Li Wang, Wenchao Wang, Qingsong Liu, Jing Liu
Summary: Drug resistance is a major challenge in the treatment of gastrointestinal stromal tumours (GISTs). A study has found that nintedanib can overcome resistance caused by mutations in the KIT gene and upregulation of fibroblast growth factor (FGF) activity. Nintedanib also showed inhibitory effects on cell proliferation and ERK phosphorylation in preclinical GIST models.
MOLECULAR ONCOLOGY
(2022)
Article
Oncology
Pawel Sobczuk, Huber Batruk, Paulina Wojcik, Krzysztof Iwaniak, Katarzyna Kozak, Piotr Rutkowski
Summary: The current landscape of phase II studies in soft tissue sarcomas (STS) is analyzed in this study, and the impact of statistical design on the results is evaluated. The study finds high heterogeneity in the design of STS phase II trials, mainly in terms of primary endpoints and hypotheses used for sample size calculation. There is a need for standardization that takes into account factors associated with the rarity of the disease, outcomes detected in previous trials and real-life studies, and specific characteristics of new therapeutic agents.
JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY
(2023)
Editorial Material
Oncology
Piotr Rutkowski, Sylvie Bonvalot
Article
Oncology
Jason A. Chesney, Antoni Ribas, Georgina Long, John M. Kirkwood, Reinhard Dummer, Igor Puzanov, Christoph Hoeller, Thomas F. Gajewski, Ralf Gutzmer, Piotr Rutkowski, Lev Demidov, Petr Arenberger, Sang Joon Shin, Pier Francesco Ferrucci, Andrew Haydon, John Hyngstrom, Johannes van Thienen, Sebastian Haferkamp, Josep Malvehy Guilera, Bernardo Leon Rapoport, Ari VanderWalde, Scott J. Diede, James R. Anderson, Sheryl Treichel, Edward L. Chan, Sumita Bhatta, Jennifer Gansert, Frank Stephen Hodi, Helen Gogas
Summary: In this phase III study, the combination of T-VEC and pembrolizumab did not significantly improve progression-free survival or overall survival in patients with advanced melanoma. These findings indicate that this combination therapy is not effective in this patient population.
JOURNAL OF CLINICAL ONCOLOGY
(2023)
Article
Oncology
Paolo A. A. Ascierto, Mario Mandala, Pier Francesso Ferrucci, Massimo Guidoboni, Piotr Rutkowski, Virginia Ferraresi, Ana Arance, Michele Guida, Evaristo Maiello, Helen Gogas, Erika Richtig, Maria Teresa Fierro, Celeste Lebbe, Hildur Helgadottir, Paola Queirolo, Francesco Spagnolo, Marco Tucci, Michele Del Vecchio, Maria Gonzales Cao, Alessandro Marco Minisini, Sabino De Placido, Miguel F. F. Sanmamed, Domenico Mallardo, Marcello Curvietto, Ignacio Melero, Giuseppe Palmieri, Antonio M. Grimaldi, Diana Giannarelli, Reinhard Dummer, Vanna Chiarion Sileni
Summary: This study is a randomized, three-arm, noncomparative phase II trial that aims to explore sequential immunotherapy and BRAF/MEK inhibition for patients with BRAFV600-mutant metastatic melanoma. The results show that sequential immunotherapy and targeted therapy provide clinically meaningful survival benefits for patients.
JOURNAL OF CLINICAL ONCOLOGY
(2023)
Article
Oncology
Philip Heesen, Gabriela Studer, Beata Bode, Hubi Windegger, Benjamin Staeheli, Paul Aliu, Javier Martin-Broto, Alessandro Gronchi, Jean-Yves Blay, Axel Le Cesne, Bruno Fuchs
Summary: This article presents a comprehensive analysis of quality indicators for sarcoma care and introduces a novel interoperable digital platform that gathers information from physicians and patients consecutively and instantly. The platform provides evidence of care quality by analyzing real-time world information, enabling predictive modeling and value-based health care. The lack of global data harmonization and quality standards, as well as discipline, institution, and network fragmentation, hinder the progress in sarcoma care. To improve quality, a common definition of quality indicators and the assessment of longitudinal real-time data are required. An international advisory board defined six categories of quality indicators, which were programmed into the digital platform for analysis and visualization. Standardized quality indicators and their real-time assessment are critical to improving the quality of sarcoma care.
Article
Oncology
Elodie Darbo, Gaelle Perot, Lucie Darmusey, Sophie Le Guellec, Laura Leroy, Laetitia Gaston, Nelly Desplat, Noemie Thebault, Candice Merle, Philippe Rochaix, Thibaud Valentin, Gwenael Ferron, Christine Chevreau, Binh Bui, Eberhard Stoeckle, Dominique Ranchere-Vince, Pierre Meeus, Philippe Terrier, Sophie Piperno-Neumann, Francoise Collin, Gonzague De Pinieux, Florence Duffaud, Jean-Michel Coindre, Jean-Yves Blay, Frederic Chibon
Summary: Leiomyosarcomas are aggressive diseases mainly treated by surgical resection with or without conventional chemotherapy. Two specifically deregulated pathways (MYOCD/SRF and E2F1/RB1) were identified in a subgroup of well-differentiated vascular smooth muscle cell-derived leiomyosarcomas. Targeting the MYOCD/SRF pathway has the potential to be a therapeutic target for leiomyosarcoma.
Editorial Material
Oncology
Piotr Rutkowski, Hanna Kosela-Paterczyk
ANNALS OF SURGICAL ONCOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Michal Bereza, Mateusz Dembinski, Agnieszka E. E. Zajac, Jakub Piatkowski, Monika Dudzisz-Sledz, Piotr Rutkowski, Anna M. Czarnecka
Summary: In recent years, there has been significant progress in understanding the role of epigenetic mechanisms in tumor pathology. Various modifications to DNA and histones can impact gene expression and contribute to the development of tumors. MicroRNAs also play a role in regulating gene expression at a post-transcriptional level. This review focuses on the specific case of chondrosarcoma, a rare bone tumor, and summarizes the current understanding of how epigenetic alterations contribute to its pathogenesis and potential therapeutic approaches that target these modifications.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Oncology
Florence Duffaud, Jean-Yves Blay, Axel Le Cesne, Christine Chevreau, Pascaline Boudou-Rouquette, Elsa Kalbacher, Nicolas Penel, Christophe Perrin, Valerie Laurence, Emmanuelle Bompas, Esma Saada-Bouzid, Corinne Delcambre, Francois Bertucci, Mathilde Cancel, Camille Schiffler, Laure Monard, Corinne Bouvier, Vincent Vidal, Nathalie Gaspar, Sylvie Chabaud
Summary: Although the primary endpoint was not met statistically in this randomised cohort, there is evidence to suggest that regorafenib might modestly delay tumour progression in relapsed ES after failure of prior chemotherapy.
BRITISH JOURNAL OF CANCER
(2023)
Article
Oncology
Piotr Rutkowski, Anna M. Czarnecka
Summary: Up to 30% of stage IIB and 50% of stage IIC melanoma patients experience recurrence within 5 years after radical surgery. Pembrolizumab treatment significantly reduces the risk of recurrence and distant metastases in resected stage II melanoma, showing important efficacy for stage IIB/C patients.
EXPERT REVIEW OF ANTICANCER THERAPY
(2023)
Review
Oncology
Natalia Banaszek, Dominika Kurpiewska, Katarzyna Kozak, Piotr Rutkowski, Pawel Sobczuk
Summary: Sarcomas are a challenging and significant clinical problem due to their poor prognosis. The Sonic hedgehog (Shh) signaling pathway has been found to play a key role in the pathogenesis of sarcomas, and inhibition of this pathway may be a potential therapeutic strategy.
JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY
(2023)
Review
Oncology
Monika Dudzisz-Sledz, Monika Kondracka, Monika Rudzinska, Agnieszka E. Zajac, Wiktoria Firlej, Dorota Sulejczak, Aneta Borkowska, Bartlomiej Szostakowski, Anna Szumera-Cieckiewicz, Jakub Piatkowski, Piotr Rutkowski, Anna M. Czarnecka
Summary: Mesenchymal chondrosarcoma (MCS) is a rare subtype of chondrosarcoma with a poor prognosis. The pathology and therapeutic options for MCS are still unknown due to its low incidence. Potential role of PDGF/PPI3K/AKT, PKC/RAF/MEK/ERK, and pRB pathways, and BCL2 overexpression have been reported in the pathogenesis of MCS. This review summarizes the current knowledge about MCS diagnosis and treatment options, including immunological and molecular biomarkers, prognostic and predictive factors. The novel trends in targeted therapies and ongoing clinical trials using protein kinase inhibitors and DR5 agonists are discussed as possible future focus in MCS treatment studies.
Article
Oncology
Olivier Tredan, Maud Toulmonde, Christophe Le Tourneau, Laure Montane, Antoine Italiano, Isabelle Ray-Coquard, Christelle de la Fouchardiere, Francois Bertucci, Anthony Goncalves, Carlos Gomez-Roca, Benoit You, Valery Attignon, Sandrine Boyault, Philippe A. Cassier, Armelle Dufresne, Severine Tabone-Eglinger, Alain Viari, Emilie Sohier, Maud Kamal, Gwenael Garin, Jean-Yves Blay, David Perol
Summary: Using a randomized discontinuation design, sorafenib was tested on patients with advanced/metastatic solid tumors harboring sorafenib-targeted genes. Continuing sorafenib when stable disease is achieved improves progression-free rate compared to interruption. Sorafenib has tumor-agnostic efficacy in patients with tumors harboring genomic alterations in PDGFRA/B, VEGF-Rs, Flt-3, KIT, FGFR1 or the RAF/MEK/ERK pathway.
Article
Oncology
Xiaolan Feng, Laurie Tonon, Haocheng Li, Elodie Darbo, Erin Pleasance, Nicolas Macagno, Armelle Dufresne, Mehdi Brahmi, Julien Bollard, Francoise Ducimetiere, Marie Karanian, Alexandra Meurgey, Gaelle Perot, Thibaud Valentin, Frederic Chibon, Jean-Yves Blay
Summary: This study is the first comprehensive transcriptomic profiling analysis focused on the tumor immune microenvironment (TIME) in leiomyosarcoma (LMS). The study identified a subset of LMS patients with an active immune microenvironment, which is associated with validated immune signatures observed in other cancers. The study supports the further development of immune biomarkers to select the right LMS patients for immune checkpoint inhibitors (ICIs) in clinical trials.
Article
Oncology
J. Y. Blay, C. Cropet, S. Mansard, Y. Loriot, C. De La Fouchardiere, J. Haroche, D. Topart, D. Tougeron, B. You, A. Italiano, V. Le Brun-Ly, J. M. Ferrero, N. Penel, M. Fabbro, X. Troussard, D. Malka, I. Ray-Coquard, S. Leboulleux, A. Flechon, E. Maubec, J. Charles, S. Dalle, S. Taieb, G. C. T. E. Garcia, A. M. Mandache, N. Colignon, M. Gavrel, F. Nowak, N. Hoog Labouret, C. Mahier Ait Oukhatar, C. Gomez-Roca
Summary: Vemurafenib demonstrates efficacy and prolonged PFS in advanced tumors with BRAF mutations other than melanoma and NSCLC. This therapy is effective for various tumor types including HCL, ECD, ovarian carcinoma, gliomas, ganglioglioma, and sarcomas.