Clinical Cancer Research最新文献

{"title":"FDA Approval Summary: Belzutifan for Patients with Advanced Renal Cell Carcinoma.","authors":"Jaleh Fallah, Brian L Heiss, Hee-Koung Joeng, Chana Weinstock, Xin Gao, William F Pierce, Benjamin Chukwurah, Vishal Bhatnagar, Mallorie H Fiero, Laleh Amiri-Kordestani, Richard Pazdur, Paul G Kluetz, Daniel L Suzman","doi":"10.1158/1078-0432.CCR-24-1199","DOIUrl":"10.1158/1078-0432.CCR-24-1199","url":null,"abstract":"<p><p>On December 14, 2023, the U.S. FDA approved belzutifan (Welireg, Merck & Co., Inc.) for patients with advanced renal cell carcinoma (RCC) following treatment with a PD-1/PD-L1 inhibitor and a VEGF tyrosine kinase inhibitor. The FDA granted traditional approval based on LITESPARK-005 (NCT04195750), an open-label, randomized, head-to-head trial of 746 patients with advanced RCC that progressed following treatment with both a PD-1/PD-L1 inhibitor and a VEGF tyrosine kinase inhibitor. Patients were randomized (1:1) to receive belzutifan or everolimus. The primary endpoints were progression-free survival (PFS) assessed by blinded independent central review and overall survival. A statistically significant improvement in PFS was demonstrated for belzutifan compared with everolimus [HR = 0.75; 95% confidence interval (CI), 0.63-0.90; one-sided P value = 0.0008]. Kaplan-Meier curves reflected nonproportional hazards with similar median PFS estimates of 5.6 months (95% CI, 3.9-7.0) in the belzutifan arm and 5.6 months (95% CI, 4.8-5.8) in the everolimus arm. Although not reaching full maturity, the overall survival results seemed to show a favorable trend in the belzutifan arm compared with the everolimus arm (HR, 0.88; 95% CI, 0.73-1.07). The confirmed objective response rate by blinded independent central review was 22% and 3.6% in the belzutifan and everolimus arms, respectively. Observed toxicities differed between treatment arms, but drug discontinuations and interruptions due to treatment-emergent adverse events were lower in the belzutifan arm compared with the everolimus arm, and a descriptive analysis of patient-reported symptom and functional outcomes was suggestive of favorable tolerability for belzutifan compared with everolimus.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"5003-5008"},"PeriodicalIF":12.7,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11567780/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142153268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chemoradiotherapy and Subsequent Immunochemotherapy as Conversion Therapy in Unresectable Locally Advanced Esophageal Squamous Cell Carcinoma: A Phase II NEXUS-1 Trial.","authors":"Xin Wang, Xiaozheng Kang, Ruixiang Zhang, Liyan Xue, Jiaqi Xu, Xiaotian Zhao, Qiuxiang Ou, Nuo Yu, Guojie Feng, Jiao Li, Ziyu Zheng, Xiankai Chen, Zhen Wang, Qingfeng Zheng, Yong Li, Jianjun Qin, Nan Bi, Yin Li","doi":"10.1158/1078-0432.CCR-24-1236","DOIUrl":"10.1158/1078-0432.CCR-24-1236","url":null,"abstract":"<p><strong>Purpose: </strong>This phase II trial investigated the safety and efficacy of chemoradiotherapy (CRT) followed by immunochemotherapy (iCT) and surgery in unresectable locally advanced esophageal squamous cell carcinoma (ESCC).</p><p><strong>Patients and methods: </strong>Patients with unresectable locally advanced ESCC received radiotherapy (50 Gy/25f, 5 days/week) and nab-paclitaxel (100 mg on day 1/week) plus cisplatin (25 mg/m2 on day 1/week) for 5 weeks, followed by tislelizumab (200 mg on day 1/cycle) plus chemotherapy (nab-paclitaxel 150 mg/m2 and cisplatin 75 mg/m2 on day 2/cycle) for two 21-day cycles. Patients who converted to resectable underwent surgery 2 to 4 weeks afterward. The primary endpoint was a 1-year progression-free survival (PFS) rate.</p><p><strong>Results: </strong>Thirty patients were enrolled and underwent CRT (median follow-up: 21 months), of whom 24 received iCT. Twenty (66.7%) patients achieved resectability (R0: 95.2%; pathologic complete response: 65.0%; major pathologic response: 90.0%). One-year PFS and overall survival (OS) rates were 79.4% and 89.6%, respectively. The R0 resection group exhibited longer PFS (median, not reached vs. 8.4 months; HR = 0.28; 95% confidence interval, 0.08-0.84; P = 0.02) and OS (median, not reached vs. 19.2 months; HR = 0.18; 95% confidence interval, 0.04-0.73; P < 0.01) than the nonsurgery group. Grade 3 to 4 adverse events were observed in 11 (11/30, 36.7%) patients, and immune-related pneumonitis was observed in 5 (5/24, 20.8%) patients. Post-CRT minimal residual disease before surgery was associated with unfavorable PFS and OS.</p><p><strong>Conclusions: </strong>Our study met the primary endpoint. Conversion CRT and subsequent iCT followed by surgery was a promising treatment strategy for unresectable locally advanced ESCC.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"30 22","pages":"5061-5072"},"PeriodicalIF":10.0,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High Mechanical Conditioning by Tumor Extracellular Matrix Stiffness Is a Predictive Biomarker for Antifibrotic Therapy in HER2-Negative Breast Cancer.","authors":"Miguel Quintela-Fandino, Begoña Bermejo, Esther Zamora, Fernando Moreno, José Ángel García-Saenz, Sonia Pernas, Noelia Martínez-Jañez, Desirée Jiménez, Encarna Adrover, Raquel de Andrés, Silvana Mourón, Maria J Bueno, Luis Manso, Gemma Viñas, Emilio Alba, Antonio Llombart-Cussac, Javier Cortés, Cristina Tebar, Denise J Roe, Adam Grant, Adam Watson, Ramon Colomer, Ghassan Mouneimne","doi":"10.1158/1078-0432.CCR-24-1518","DOIUrl":"10.1158/1078-0432.CCR-24-1518","url":null,"abstract":"<p><strong>Purpose: </strong>Tumor progression has been linked to stiffening of the extracellular matrix caused by fibrosis. Cancer cells can be mechanically conditioned by stiff extracellular matrix, exhibiting a 1,004-gene signature [mechanical conditioning (MeCo) score]. Nintedanib has demonstrated antifibrotic activity in idiopathic pulmonary fibrosis. This study explores nintedanib's antifibrotic effect on breast cancer outcomes.</p><p><strong>Experimental design: </strong>We present long-term follow-up and analysis of a neoadjuvant randomized phase II trial in early HER2-negative breast cancer. Patients (N = 130) underwent a baseline biopsy and received 12 paclitaxel courses alone (control arm) or in combination with nintedanib (experimental arm). The tumor MeCo score was determined by RNA sequencing. The primary aim was to assess nintedanib's impact on event-free survival based on MeCo scores.</p><p><strong>Results: </strong>Follow-up data were retrieved from 111 patients; 75 baseline and 24 post-run-in phase samples were sequenced. After median follow-up of 9.67 years, median event-free survival was not statistically different between arms (P = 0.37). However, in the control arm, high- versus low-MeCo patients had a statistically higher relapse risk: HR = 0.21; P = 0.0075. This risk was corrected by nintedanib in the experimental arm: HR = 0.37; P = 0.16. Nintedanib demonstrated pharmacodynamic engagement, reducing the MeCo score by 25% during the run-in phase (P < 0.01). Patients with low MeCo after run-in had the best long-term prognosis (HR = 0.087; P = 0.03).</p><p><strong>Conclusions: </strong>High MeCo is predictive of poor outcomes in HER2-negative early breast cancer, although this risk can be mitigated by nintedanib, which is able to specifically reduce MeCo.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"5094-5104"},"PeriodicalIF":10.0,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142281267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aberrant activation of wound healing programs within the metastatic niche facilitates lung colonization by osteosarcoma cells","authors":"James B. Reinecke, Leyre Jimenez Garcia, Amy C. Gross, Maren Cam, Matthew V. Cannon, Matthew J. Gust, Jeffrey P. Sheridan, Berkley E. Gryder, Ruben Dries, Ryan D. Roberts","doi":"10.1158/1078-0432.ccr-24-0049","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-0049","url":null,"abstract":"Purpose: Lung metastasis is responsible for most deaths caused by osteosarcoma. How malignant bone cells coerce the lung microenvironment to support metastatic growth remains unclear. We sought to identify metastasis-specific therapeutic vulnerabilities by delineating the cellular and molecular mechanisms essential to metastatic niche formation in the lung. Experimental design: We used single-cell transcriptomics (scRNA-seq) to characterize molecular changes induced within lung tissues by disseminated osteosarcoma cells. We then evaluated the ability of nintedanib to reverse metastasis-specific changes in both immunocompetent mouse and immunodeficient xenograft models. Molecular pharmacodynamic studies used single-nucleus and spatial transcriptomics to define the tumor-intrinsic and -extrinsic changes induced by the drug. Results: Osteosarcoma cells induced acute alveolar epithelial injury upon lung dissemination. scRNA-seq demonstrated that the surrounding lung stroma adopts a chronic, non-resolving wound-healing phenotype similar to diseases associated with lung injury. Accordingly, metastasis-associated lung demonstrated marked fibrosis, likely due to the accumulation of pathogenic, pro-fibrotic, partially differentiated epithelial intermediates and macrophages. Our data suggested that nintedanib prevented metastatic progression in multiple murine and human xenograft models by inhibiting osteosarcoma-induced fibrosis. Conclusions: Fibrosis is essential to osteosarcoma lung metastasis and represents a targetable vulnerability. Our data support a model where interactions between osteosarcoma and epithelial cells induce the deposition of extracellular matrix proteins—a reaction disrupted by the anti-fibrotic TKI nintedanib. Our data shed light on the non-cell autonomous effects of TKIs on metastasis and provide a roadmap for using single-cell and spatial transcriptomics to define the mechanism of action of TKIs on metastases in animal models.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"6 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142610297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CD40 agonist on patient-derived xenograft mice for the treatment of B-cell acute lymphoblastic leukemia","authors":"Pierre-Simon Bellaye, Aleksandra Georgievski, Paola Ballerini, Boutheina Bouslama, Corentin Richard, Romain Boidot, Guillaume Chevreux, Véronique Legros, Julien Guy, Jessica Racine, Bertrand Collin, Carmen Garrido, Ronan Quéré","doi":"10.1158/1078-0432.ccr-24-1391","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1391","url":null,"abstract":"Purpose: Cluster of differentiation 40 (CD40) is expressed on B-cell acute lymphoblastic leukemia (B-ALL) cases. However, the effect of CD40 activation on B-ALL cells has never been tested in vivo. Experimental Design: The aim of our preclinical study was to investigate the therapeutic potential of a CD40 agonist in the treatment of B-ALL using patient-derived xenograft (PDX) mouse models. Results: Intravenous administration of the CD40 agonist significantly impeded B-ALL cell proliferation and growth in vivo, accompanied by rapid activation of the extracellular signal-regulated kinase (ERK) pathway, leading to the induction of apoptosis and disruption of cell cycle progression. Co-treatment with a specific inhibitor of ERK further demonstrated that CD40 stimulation induced the pro-apoptosis of B-ALL cells in an ERK-dependent manner. Proteomic analysis revealed alterations in key signaling pathways associated with B-ALL expansion and maintenance. Moreover, the CD40 agonist markedly reduced the frequency of leukemia-initiating cells and leukemia development in PDX mice. Our study showed that the CD40 agonist can be associated with chemotherapeutic agents such as vincristine and dexamethasone, and this combination showed improved effectiveness. Additionally, the CD40 agonist was more effective on pre-B-ALL (EGIL B-III) that expressed CD40, than on common B-ALL (EGIL B-II) that lacked CD40 expression. Conclusion: These findings suggest that CD40 agonists are promising immunotherapeutic candidates for pediatric B-ALL, warranting further clinical investigations to improve patient outcomes in CD40-expressing B-ALL.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"216 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142610294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Phase III Randomized Trial of Integrated Genomics and Avatar Models for Personalized Treatment of Pancreatic Cancer: the AVATAR Trial","authors":"Francesca Sarno, Jair Tenorio, Sofia Perea, Laura Medina, Roberto Pazo-Cid, Ignacio Juez, Rocio Garcia-Carbonero, Jaime Feliu, Carmen Guillen-Ponce, Pedro P. Lopez-Casas, Carmen Guerra, Yolanda Duran, Jose Francisco López-Acosta, Carolina Alonso, Estrella Esquivel, Ana Dopazo, Dipikaa Akshinthala, Senthil K. Muthuswamy, Pablo Lapunzina, Bruno Bockorny, Manuel Hidalgo","doi":"10.1158/1078-0432.ccr-23-4026","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-23-4026","url":null,"abstract":"Purpose: Pancreatic adenocarcinoma (PDAC) has limited treatment options. We compared the efficacy of comprehensive precision medicine against the conventional treatment in PDAC. Methods: Phase III trial of advanced PDAC where patients were randomized (1:2) to a conventional treatment treated at physician’s discretion (arm A), or to precision medicine (arm B). Subjects randomized to arm B underwent a tumor biopsy for whole exome sequencing (WES) and to generate avatar mouse models and patient derived organoids for phenotypic drug screening, with final treatment recommended by molecular tumor board. The primary objective was median overall survival (OS). Results: 137 patients were enrolled with 125 randomized, 44 to arm A and 81 to Arm B. WES was performed in 80.3% (65/81) patients of arm B, with potentially actionable mutations detected in 21.5% (14/65). Experimental models were generated in 16/81 patients (19.8%). Second-line treatment was administered to 39 patients in the experimental arm, but only 4 (10.2%) received personalized treatment, while 35 could not be receive matched therapy due to rapid clinical deterioration, delays in obtaining study results or absence of actionable targets. Median OS was 8.7 and 8.6 months (p=0.849) and median progression-free survival was 3.8 and 4.3 months (p=0.563) for the conventional and experimental arms, respectively. Notably, the four patients who received personalized treatment had median OS of 19.3 months. Conclusions: Personalized medicine was challenging to implement in most patients with PDAC, limiting the interpretation of intention to treat analysis. Survival was improved in the subset of patients who did receive matched therapy.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"5 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142610295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Update on Pediatric Surveillance Recommendations for PTEN Hamartoma Tumor Syndrome, DICER1-Related Tumor Predisposition, and Tuberous Sclerosis Complex.","authors":"Kris Ann P Schultz, Suzanne P MacFarland, Melissa R Perrino, Sarah G Mitchell, Junne Kamihara, Alexander T Nelson, Paige H R Mallinger, Jack J Brzezinski, Kara N Maxwell, Emma R Woodward, Bailey Gallinger, Sun Young Kim, Mary-Louise C Greer, Kami Wolfe Schneider, Sarah R Scollon, Anirban Das, Jonathan D Wasserman, Charis Eng, David Malkin, William D Foulkes, Orli Michaeli, Andrew J Bauer, Douglas R Stewart","doi":"10.1158/1078-0432.CCR-24-1947","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-1947","url":null,"abstract":"<p><p>PTEN hamartoma tumor syndrome (PHTS), DICER1-related tumor predisposition (DICER1) and tuberous sclerosis complex (TSC) are rare conditions which each increase risk for distinct spectra of benign and malignant neoplasms throughout childhood and adulthood. Surveillance considerations for each of these conditions focus on patient and family education, early detection and multidisciplinary care. In this manuscript, we present updated surveillance recommendations and considerations for children and adolescents with PHTS, DICER1 and TSC and provide suggestions for further research in each of these conditions.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616047","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An AI-driven preoperative radiomic subtype for predicting the prognosis and treatment response of patients with papillary thyroid carcinoma","authors":"Qiang Li, Weituo Zhang, Tian Liao, Yi Gao, Yanzhi Zhang, Anqi Jin, Ben Ma, Ning Qu, Huan Zhang, Xiangqian Zheng, Dapeng Li, Xinwei Yun, Jingzhu Zhao, Herbert Yu, Ming Gao, Yu Wang, Biyun Qian","doi":"10.1158/1078-0432.ccr-24-2356","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2356","url":null,"abstract":"Purpose: 8-28% of Papillary thyroid carcinoma (PTC) experience recurrence, complicating risk stratification and treatment. We previously identified an inflammatory molecular subtype of PTC associated with poor prognosis. Based on this subtype, we aimed to develop and validate a noninvasive radiomic signature to predict prognosis and treatment response in PTC patients. Experimental Design: We collected preoperative ultrasound images from two large independent centers (n=2506) to develop and validate a Deep Learning Radiomics signature of Inflammation (DLRI) for predicting the inflammatory subtype of PTC, including its correlation with prognosis and anti-inflammatory traditional Chinese medicine (TCM) treatment. Training set 1 (n=64) and internal validation set 2 (n=1108) were from Tianjin Medical University Cancer Institute and Hospital. External validation set 1 (n=76) and 2 (n=1258) were from Fudan University Shanghai Cancer Center. Results: We developed DLRI to accurately predict PTC's inflammatory subtype (AUC=0.97 in the training set 1 and AUC=0.82 in the external validation set 1). High-risk DLRI was significantly associated with poor disease-free survival in the first cohort (HR=16.49, 95% CI: 7.92-34.35, P&amp;lt;0.001) and second cohort (HR=5.42, 95%: 3.67-8.02, P&amp;lt;0.001). DLRI independently predicted disease-free survival, irrespective of clinicopathological variables (P&amp;lt;0.001 for all). Furthermore, patients with high-risk DLRI were likely to benefit from anti-inflammatory TCM treatment (HR=0.19, 95% CI: 0.06-0.55, P=0.002), whereas those in low-risk DLRI did not. Conclusions: DLRI is a reliable noninvasive tool for evaluating prognosis and guiding anti-inflammatory TCM treatment in PTC patients. Prospective studies are needed to confirm these findings.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"11 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142610299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Homoharringtonine Added to Venetoclax and Azacitidine Improves Outcome and Mitigates Genetic Impact in Relapsed/Refractory AML: A Multi-center Cohort Study","authors":"Guopan Yu, Yu Zhang, Sijian Yu, Zhao Yin, Guangyang Weng, Na Xu, Xin Du, Dongjun Lin, Jie Xiao, Zhiqiang Sun, Hongyu Zhang, Xinquan Liang, Ziwen Guo, Weihua Zhao, Min Dai, Zhiping Fan, Li Xuan, Hui Liu, Dan Xu, Jieyu Ye, Xuejie Jiang, Pengcheng Shi, Hua Jin, Qifa Liu","doi":"10.1158/1078-0432.ccr-24-1332","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1332","url":null,"abstract":"Purpose: We investigated whether homoharringtonine (HHT) added to venetoclax (VEN) plus azacitidine (VA) could improve outcomes and counteract the negative effects of genetic patterns in patients with relapsed/refractory acute myeloid leukemia (RR-AML). Experimental Design: A multi-center, retrospective, cohort study of the response and genetic patterns of response to the VA plus HHT (VAH) versus the VA regimens as salvage treatment in patients with RR-AML was performed. The endpoints were the rates of composite complete remission (CRc), measurable residual disease (MRD), event-free survival (EFS), overall survival (OS), and relapse between VAH and VA groups. Results: A total of 321 patients (VAH, n=172; VA, n=149) were analyzed. Compared to VA, VAH significantly improved the rates of CRc (44.3% vs. 66.3%, P&amp;lt;0.001), MRD-negativity (34.8% vs. 59.3%, P=0.002), prolonged OS (median: 15.1 months vs. not reached, P &amp;lt;0.001), and EFS (median: 3.8 vs. 13.0 months, P&amp;lt;0.001). VAH significantly mitigated the negative impact on VA efficacy of mutated FLT3-ITD/TKD, N/KRAS, and t(8;21)/AML1-ETO, as well as the relatively unfavorable effects of the TET2 and DNMT3A mutations. VAH significantly enhanced the response of patients with non-adverse European LeukemiaNet (ELN) risk, with a trend towards improved response in those with adverse ELN risk, complex karyotype, and DNMT3A+FLT3+NPM1+. The incidence of grade 3 or higher adverse events was comparable between the two groups. Conclusions: Our findings suggest the addition of HHT to VA might enhance response and mitigate the negative impact of certain genetic patterns in RR-AML while being well tolerated.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"159 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601145","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phase II Trial of Induction Chemotherapy for Advanced Sinonasal Squamous Cell Carcinoma","authors":"Kevin J. Contrera, Renata Ferrarotto, Brandon Gunn, Shirley Y. Su, Merrill S. Kies, Bonnie S. Glisson, Adam S. Garden, Dianna Roberts, Curtis Hanba, Camilla O. Hoff, Adel El-Naggar, Michelle D. Williams, Shaan M. Raza, Franco DeMonte, Melissa M. Chen, Mark S. Chambers, Ehab Y. Hanna","doi":"10.1158/1078-0432.ccr-24-1416","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1416","url":null,"abstract":"Purpose: Outcomes after primary surgery for advanced sinonasal squamous cell carcinoma (SCC) are poor. We tested whether induction chemotherapy (IC) can improve disease control or organ preservation. Patients and Methods: A phase II trial evaluated previously untreated patients with stage II-IV, M0 sinonasal SCC. Patients received IC with docetaxel, cisplatin, and fluorouracil, followed by chemoradiotherapy (CRT) for responders and surgery with adjuvant radiotherapy or CRT for non-responders. The primary endpoints were overall response rate (ORR) and locoregional control (LRC). Secondary endpoints included progression-free survival (PFS), overall survival (OS), organ preservation, and treatment toxicity. Results: Of the 31 patients enrolled between 2008 and 2020, 28 were evaluated for efficacy. Disease was T4a, T4b, and N+ in 57%, 21%, and 36% of patients, respectively. The ORR was 82.1%; 17.9% of patients had stable disease, and 0% had progressive disease. Grade 3 and 4 adverse events (AE) occurred in 54% and 18% of patients, respectively; there were no Grade 5 AEs. The 2-year LRC and PFS rates were 64.3% (95% CI 40.4-77.6) and 52.4% (95% CI 32.3-69.0), respectively. The median PFS was 25.8 months. The median OS was 47.4 months, with a 2-year OS rate of 69.4% (95% CI 44.9-80.4). No survival difference was observed between surgery versus CRT (hazard ratio 1.07, 95% CI 0.9-3.84). Of patients alive at 2 years, 63% achieved organ preservation, avoiding maxillectomy (38%), craniotomy (13%), or orbital exenteration (38%). Conclusions: IC and response-directed treatment achieved promising disease control and added organ preservation for patients with advanced sinonasal SCC.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"32 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}