Clinical Cancer Research最新文献

{"title":"Sacituzumab Govitecan in Patients With Relapsed/Refractory Advanced Head and Neck Squamous Cell Carcinoma: Results From the Phase 2 TROPiCS-03 Basket Study.","authors":"Loren Michel, Antonio Jimeno, Ammar Sukari, J Thaddeus Beck, Joanne Chiu, Elizabeth Ahern, John Hilton, Caroline Even, Sylvie Zanetta, Sabeen Mekan, Jilpa Patel, Tia Wu, Ecaterina E Dumbrava","doi":"10.1158/1078-0432.CCR-24-2523","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-2523","url":null,"abstract":"<p><strong>Purpose: </strong>Treatment options for advanced head and neck squamous cell carcinoma (HNSCC) previously treated with platinum-based chemotherapy and a programmed death-1 (PD-1) inhibitor are limited. Trophoblast cell-surface antigen 2 (Trop-2) is highly expressed in HNSCC. Sacituzumab govitecan (SG) is a Trop-2-directed antibody-drug conjugate approved for patients with certain previously treated solid tumors.</p><p><strong>Methods: </strong>TROPiCS-03 (NCT03964727) is an open-label, multicohort, phase 2 study evaluating SG in advanced solid tumors, including HNSCC. Adults with locally advanced or metastatic HNSCC that progressed following platinum-based chemotherapy and anti-PD-(ligand)1 therapy (given sequentially [either order] or in combination) were administered SG 10 mg/kg on days 1 and 8 of a 21-day cycle. The primary endpoint was investigator-assessed objective response rate (ORR). Secondary endpoints included duration of response (DoR), clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), and safety.</p><p><strong>Results: </strong>Patients (N=43) received a median of 3 (range, 2-9) prior anticancer regimens. ORR was 16% (95% confidence interval [CI], 7-31%), with 7 confirmed partial responses. CBR was 28% (95% CI, 15-44%). Median (95% CI) DoR, PFS, and OS were 4.2 (2.6-not reached), 4.1 (2.6-5.8), and 9.0 (7.1-10.5) months, respectively. The most common treatment-emergent adverse events (TEAEs) were diarrhea (47%), nausea (47%), and neutropenia (47%). Grade ≥3 TEAEs occurred in 58% of patients. Three patients died owing to TEAEs, with one event (septic shock) considered related to SG.</p><p><strong>Conclusions: </strong>These data demonstrate the clinical potential of Trop-2-directed therapy in managing heavily pretreated patients with advanced HNSCC.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142812233","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 1 Study of FHD-609, a Heterobifunctional Degrader of Bromodomain-Containing Protein 9, in Patients With Advanced Synovial Sarcoma or SMARCB1-Deficient Tumors.","authors":"J Andrew Livingston, Jean-Yves Blay, Jonathan Trent, Claudia Valverde, Mark Agulnik, Mrinal Gounder, Axel Le Cesne, Meredith McKean, Michael J Wagner, Silvia Stacchiotti, Samuel Agresta, Alfonso Quintás-Cardama, Sarah A Reilly, Kathleen Healy, Denice Hickman, Tina Zhao, Alex Ballesteros-Perez, Alexis Khalil, Michael P Collins, Jessica Piel, Kim Horrigan, Ariel Lefkovith, Scott Innis, Alexander J Lazar, Gregory M Cote, Andrew J Wagner","doi":"10.1158/1078-0432.CCR-24-2583","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-2583","url":null,"abstract":"<p><strong>Purpose: </strong>FHD-609, a potent, selective, heterobifunctional degrader of bromodomain-containing protein 9 (BRD9), was evaluated for treatment of patients with advanced synovial sarcoma (SS) or SMARCB1-deficient tumors.</p><p><strong>Patients and methods: </strong>In this multinational, open-label, phase 1 study (NCT04965753), patients received FHD609 intravenously at escalating doses either twice weekly (BIW) (5 to 80 mg; n=40) or once weekly (QW) (40 to 120 mg; n=15).</p><p><strong>Results: </strong>Fifty-five patients received FHD-609 for a median of 43 days. The maximum tolerated doses (MTDs) were 40 mg BIW and the equivalent weekly dose, 80 mg QW. Dose-limiting toxicities of QTc prolongation and syncope were observed at 40 and 60 mg BIW. Treatment-related adverse events were predominantly Grade 1-2 in severity, most commonly dysgeusia (40%), dry mouth (29.1%), fatigue (27.3%), and anemia (25.5%). Eleven (20%) patients had treatment-emergent QTcF prolongation preceded by T-wave inversions; 21 (38.2%) patients had T-wave inversions without further cardiac events or ECG abnormalities. FHD-609 showed dose-dependent increases in pharmacokinetic exposure, with no substantial accumulation. Extensive BRD9 degradation in tumor tissue corresponded to downregulation of cancer cell proliferation gene sets. One (2%) patient achieved a partial response; 8 (15%) patients achieved stable disease, which lasted longer than 6 months in 2 patients.</p><p><strong>Conclusions: </strong>FHD-609 showed dose-dependent increases in systemic FHD-609 exposure and pharmacodynamic response profiles. The MTDs were identified (40 mg BIW/80 mg QW) and preliminary clinical activity was observed. Future studies of BRD9 degraders will require strict cardiac monitoring given the QTc prolongation observed in this study.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142806286","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":"Association between Locoregional Failure and NFE2L2/KEAP1/CUL3 Mutations in NRG/RTOG 9512: A Randomized Trial of Radiation Fractionation in T2N0 Glottic Cancer","authors":"Li Guan, Pedro A. Torres-Saavedra, Xiaobei Zhao, Michael B. Major, Brittany J. Holmes, Ngan K. Nguyen, Parasakthy Kumaravelu, Tim Hodge, Maximilian Diehn, Jose P. Zevallos, F. Christopher Holsinger, Bahman Emami, Richard C. Jordan, Michele C. Hayward, Stephen M. Sagar, William Morrison, Christopher Schultz, Jimmy J. Caudell, Christopher U. Jones, Scott V. Bratman, Thomas J. Galloway, Daniel J. Ma, Sue S. Yom, Mahesh Kudrimoti, Harold E. Kim, Jonathan Harris, Quynh-Thu Le, D. Neil. Hayes","doi":"10.1158/1078-0432.ccr-24-2334","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2334","url":null,"abstract":"Purpose: NFE2L2/KEAP1/CUL3 mutations have been validated for radiation resistance in cell-based assays and animal models. However, clinical validation of these biomarkers has been challenging due to multimodality treatment regimens. This study aims to investigate the association between NFE2L2/KEAP1/CUL3 mutations and patient outcomes, including local failure (LF), locoregional failures (LRF), disease-free survival (DFS) and overall survival (OS), using samples from a phase III trial in which patients were treated with radiation monotherapy at 2 controlled doses. Experimental Design: We investigated NFE2L2/KEAP1/CUL3 mutations in 250 randomized patients with T2N0 glottic SCC receiving definitive RT in NRG/RTOG 9512 trial, 119 had available biospecimens that were subjected to amplicon-based next-generation sequencing to assess for presence of NFE2L2/KEAP1/CUL3 mutations without regard to outcomes. Mutations in NFE2L2/KEAP1/CUL3 were assessed blinded to clinical outcomes. Cox models (2-sided alpha = 0.05) were used to evaluate the association with clinical outcomes, performed by an independent statistical team. Results: Nineteen of 119 patients (16.0%) had NFE2L2/KEAP1/CUL3 mutations. Patient, treatment, and tumor characteristics were similar between those with and without mutations. Patients with mutation compared to those without had significantly more LF [HR 3.50 (95% CI 1.56, 7.89), p=0.0025] and LRF [HR 3.80 (95% CI 1.80, 8.03), p=0.0005]. DFS was significantly worse for the mutated compared to the non-mutated group in the first two years [HR 2.88 (95% CI 1.46, 5.66), p=0.0022]. Median DFS was shorter in the mutation group (10.3 months) versus those with intact NFE2L2/KEAP1/CUL3 (4.2 years). Conclusion: NFE2L2/KEAP1/CUL3 mutations may predict radiation treatment failure in T2N0 glottic cancer.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"9 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142804735","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":"Multi-omics reveals the immunological features and the immune checkpoint blockade potential of colorectal medullary carcinoma","authors":"Chao Liu, Haoyi Zou, Yuli Ruan, Lin Fang, Bojun Wang, Luying Cui, Tong Wu, Zhuo Chen, Tianjiao Dang, Ya Lan, Wenyuan Zhao, Chunhui Zhang, Hongxue Meng, Yanqiao Zhang","doi":"10.1158/1078-0432.ccr-24-2505","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2505","url":null,"abstract":"Purpose: Colorectal medullary carcinoma is extensive lymphocyte infiltration and associated with an active immune response. However, studies to comprehensively explore the immune landscape and efficacy of immune checkpoint blockade therapy in MeC are limited. Experimental Design: We screened 47 cases of MeC from Harbin Medical University Cancer Hospital cohort. The immunological characteristics of MeC were analyzed by targeted exon sequencing, NanoString nCounter gene expression sequencing, immunohistochemistry, multiplexed immunofluorescence and T cell antigen receptor-sequencing. An additional 47 MeC patients received ICB therapy were included in the retrospective analysis to verify the efficacy of immunotherapy. Results: Genomically, MeC tend to have a higher proportion of mismatch repair protein deficiency/microsatellite instability, ARID1A mutation, and ASCL2 amplification. Gene expression shows enriched immune response-related pathways while down-regulated oncogenic pathways, such as Glycolysis, Epithelial mesenchymal transition, and Wnt beta catenin signaling. Further immune-characterization showed that MeC showed advantages in antigen presentation, co-stimulatory molecules, effector molecules, immune checkpoints, and immune cell abundance. More importantly, both MSI and microsatellite stable type MeC showed a similar state of high infiltration of immune cells, even better than MSI-nMeC. MeC infiltrated massive highly clonal immune cells, especially intraepithelial CD8+T cells. In the retrospective cohort, there were 30 patients with MeC received ICB achieved complete or partial response with an objective response rate of 63.8%, especially including 16 patients with MSS-CRC. Conclusion: MeC is a pathological subtype with an active immune response and is a promising group for ICB therapy. This heightened immune response was not limited to the patient's microsatellite status.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"19 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142796992","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 1/2 trial of XPO1 inhibitor selinexor plus docetaxel in previously treated, advanced KRAS mutant non-small cell lung cancer","authors":"Mitchell S. von Itzstein, Timothy F. Burns, Jonathan E. Dowell, Leora Horn, D. Ross. Camidge, Sally J. York, Keith D. Eaton, Kelly Kyle, Farjana J. Fattah, Jialiang Liu, Hong Mu-Mosley, Arjun Gupta, Urooba Nadeem, Ang Gao, Song Zhang, David E. Gerber","doi":"10.1158/1078-0432.ccr-24-1722","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1722","url":null,"abstract":"Purpose: Patients with KRAS mutant non-small cell lung cancer (NSCLC) have limited therapeutic options. Based on activity of nuclear export inhibition in preclinical models, we evaluated this strategy in previously treated advanced KRAS mutant NSCLC. Patients and Methods: The primary outcome of this multi-center phase 1/2 dose escalation trial of selinexor plus docetaxel was safety and tolerability. Selinexor was started one week before docetaxel to permit monotherapy pharmacodynamic assessment. Results: Among 40 enrolled patients, median age was 66 years, 55% were female, and 85% were white. Maximum tolerated dose was selinexor 60 mg orally weekly plus docetaxel 75 mg/m2 every three weeks. The most common adverse events were nausea (73%, 8% Gr ≥3), fatigue (70%, 5% Gr ≥3), neutropenia (65%, 60% Gr ≥3), and diarrhea (58%, 10% Gr ≥3). Of 32 efficacy evaluable patients, 7 (22%) had partial responses and 18 (56%) had stable disease. Outcomes were not associated with KRAS mutation type but were significantly better in cases with wild type TP53 (42%), including disease control and response rates (27% and 80%, vs. 9% and 27%, respectively; P=0.03) and progression-free survival (median 7.4 vs. 1.8 months; HR, 0.2; 95% CI, 0.07-0.67; P=0.003). Post-selinexor / pre-docetaxel, serum LDH levels increased an average 51 U/L in TP53 altered and decreased an average 48 U/L in TP53 wild type cases (P=0.06). Conclusions: Selinexor plus docetaxel was relatively well tolerated in patients with advanced KRAS mutant NSCLC. The regimen has promising efficacy in TP53 wild type cases, where selinexor monotherapy may also have activity.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"20 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142796991","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":"Human pancreatic cancer single cell atlas reveals association of CXCL10+ fibroblasts and basal subtype tumor cells.","authors":"Ian M Loveless, Samantha B Kemp, Kailee M Hartway, Jacob T Mitchell, Yuesong Wu, Samuel D Zwernik, Daniel James Salas-Escabillas, Sydney Brender, Madison George, Yetunde Makinwa, Thais Stockdale, Kendyll Gartrelle, Rohit G Reddy, Daniel W Long, Allison Wombwell, Julie M Clark, Albert M Levin, David Kwon, Ling Huang, Ralph Francescone, Debora B Vendramini-Costa, Ben Stanger, Adam Alessio, Andrew M Waters, Yuehua Cui, Elana J Fertig, Luciane T Kagohara, Brian Theisen, Howard C Crawford, Nina G Steele","doi":"10.1158/1078-0432.CCR-24-2183","DOIUrl":"10.1158/1078-0432.CCR-24-2183","url":null,"abstract":"<p><strong>Purpose: </strong>Pancreatic ductal adenocarcinoma (PDAC) patients with tumors enriched for the basal-like molecular subtype exhibit enhanced resistance to standard of care treatments and have significantly worse overall survival (OS) compared to patients with classical subtype enriched tumors. It is important to develop genomic resources, enabling identification of novel putative targets in a statistically rigorous manner.</p><p><strong>Experimental design: </strong>We compiled a single cell RNA sequencing (scRNAseq) atlas of the human pancreas with 229 patient samples, aggregated from publicly available raw data. We mapped cell-type specific scRNAseq gene signatures in bulk RNAseq (n=744) and spatial transcriptomics (ST) (n=22) and performed validation using multiplex immunostaining.</p><p><strong>Results: </strong>Analysis of tumor cells from our scRNAseq atlas revealed nine distinct populations, two of which aligned with the basal subtype, correlating with worse OS in bulk RNAseq. Deconvolution identified one of the basal populations to be the predominant tumor subtype in non-dissociated ST tissues and in vitro tumor cell and patient-derived organoid lines. We discovered a novel enrichment and spatial association of CXCL10+ cancer associated fibroblasts (CAFs) with basal tumor cells. We identified that besides immune cells, ductal cells also express CXCR3, the receptor for CXCL10, suggesting a relationship between these cell types in PDAC tumor microenvironment.</p><p><strong>Conclusions: </strong>We show that our scRNAseq atlas (700,000 cells), integrated with ST data, has increased statistical power and is a powerful resource, allowing for expansion of current subtyping paradigms in PDAC. We uncovered a novel signaling niche marked by CXCL10+ CAFs and basal tumor cells that could be explored for future targeted therapies.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142784327","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":"Aberrantly Expressed Mitochondrial Lipid Kinase, AGK Activates JAK2-Histone H3 Axis and BCR Signal: A Mechanistic Study with Implication in CLL Therapy","authors":"Murali K. Mamidi, Sutapa Sinha, Mariana T. Mendez, Tapojyoti Sanyal, Hasan Mahmud, Neil E. Kay, Mamta Gupta, Chao Xu, Sara K. Vesely, Priyabrata Mukherjee, Jennifer Holter Chakrabarty, Asish K. Ghosh","doi":"10.1158/1078-0432.ccr-24-1192","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1192","url":null,"abstract":"Purpose: Although the B-cell receptor (BCR) signal plays a critical role in CLL cell survival and a target of current therapies (ibrutinib targets Bruton’s tyrosine kinase; idelalisib targets PI3Kδ), contribution of the cytokine-driven JAK2 pathway to the “CLL cell-survival signaling network” is largely undefined. Experimental Design: CLL patients were enrolled to investigate expression/activation of JAK2 and acylglycerol kinase (AGK), and their functional implication in primary CLL cell survival. A series of biochemical and molecular biology assays were employed to uncover the underlying mechanism. Results: We detected that compared to normal B-cells, CLL cells aberrantly express constitutively active JAK2. Mechanistically, HSP90 forms a chaperoning complex with JAK2, resulting in its aberrant accumulation in CLL cells. We also discovered aberrant upregulation of a novel mitochondrial lipid kinase, AGK, which remains complexed with HSP90 in CLL cells activating JAK2. Although AGK is typically mitochondrial, we detected its nuclear localization in association with JAK2 in some CLL cells. Functionally, JAK2 phosphorylates its non-canonical substrate, histone H3(Y41), but not STAT3, activating transcription of diverse sets of genes in a patient-specific manner. Additionally, JAK2 activates the BCR-signal in CLL cells via LYN/BTK axis. Targeted inhibition of JAK2 as monotherapy, or in combination with the BCR-inhibitors or venetoclax (a BCL2-inhibitor) induced apoptosis synergistically in CLL cells. Conclusions: These findings suggest that aberrantly expressed AGK activates JAK2, independent of cytokine, leading to activation of diverse sets of gene transcription in CLL cells. Combined targeting of JAK2 and BCR signals or BCL2 may be effective in some CLL patients.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"10 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142782450","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":"RORing CAR T cells in solid and hematological cancers: same but different","authors":"Sebastian Kobold","doi":"10.1158/1078-0432.ccr-24-3688","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3688","url":null,"abstract":"A recent phase I clinical study tested anti-ROR1 CAR T cells in patients with CLL, NSCLC, and TNBC. The product could be safely administered and had activity in CLL but less so in NSCLC and TNBC.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"37 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142763426","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":"Duvelisib with docetaxel for patients with anti-PD-1 refractory, recurrent or metastatic head and neck squamous cell carcinoma","authors":"G. J. Hanna, L. B. Oakley, R. Shi, A. ONeill, K.Y. Shin, N. Scarfo, K/ Sehgal, M. J. Dennis, N. Quinn, V. Y. Jo, K. Wong, A. Shvyrkova, V. Kushnarev, B. U. Shanthappa, A. Tkachuk, K. Kryukov, A. Sarachakov, V. Svekolkin, J. Lennerz, S. Waters, R. I. Haddad","doi":"10.1158/1078-0432.ccr-24-2262","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2262","url":null,"abstract":"Background: Treatments after anti-PD-1 therapy for patients with recurrent, metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) are limited. Blocking phosphatidylinositol 3-kinase (PI3K) signaling may lead to tumor immunomodulation and enhanced taxane sensitivity. This phase 2 trial evaluated dual, selective PI3Kδ/γ inhibition with docetaxel in patients with anti-PD-1 refractory R/M HNSCC. Design: Patients received duvelisib (25 mg orally twice daily) with docetaxel (75 mg/m2 IV) every 21-days. The primary endpoint was overall response rate (ORR) (RECISTv1.1), employing a Simon two-stage design. Secondary endpoints: safety, progression-free survival (PFS), overall survival (OS); exploratory endpoints: correlating immunologic and genomic parameters with outcomes. Results: From 11/1/21 to 10/10/23, 26 patients enrolled (median age: 64, 96% men, 54% with HPV+ disease; primary site: 12 oropharynx, 11 oral cavity, 3 larynx/hypopharynx. Best ORR was 19% (5/26) (95%CI: 6.8-40.7%), all were partial responses (median duration: 5.1 months [0.7-15.5]); 46% (12/26) exhibited stable disease and 32% (8/26) progression (1 unevaluable). Two patients remain on-treatment at data cutoff; 25% (6/24) came off for toxicity. Grade 3+ treatment-related adverse events were observed in 50% (13/26), most often elevated liver function tests (6, 23%). No deaths were treatment related. At median follow-up of 6.5 months (0.7-26), median PFS: 2.8 months (95%CI: 1.9-7.0); 17/26 patients had died. Median OS: 10.2 months (95%CI: 6.7-15.9), favoring HPV-negative patients. Greater tumor CD3+/CD8+ T cell infiltration trended with improved outcomes. Conclusion(s): We report a favorable response rate when combining a selective PI3K pathway inhibitor and taxane in patients with anti-PD-1 refractory HNSCC. ClinicalTrials.gov: NCT05057247","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"26 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142763431","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":"Clinical characteristics and outcome of central nervous system tumors harboring NTRK gene fusions","authors":"Audrey-Anne Lamoureux, Michael J. Fisher, Lauriane Lemelle, Elke Pfaff, Pouneh Amir-Yazdani, Christof Kramm, Bram De Wilde, Bernarda Kazanowska, Caroline Hutter, Stefan M. Pfister, Dominik Sturm, David T.W. Jones, Daniel Orbach, Gaëlle Pierron, Scott Raskin, Alexander Drilon, Eli L. Diamond, Guilherme Harada, Michal Zapotocky, Josef Zamecnik, Lenka Krskova, Benjamin Ellezam, Alexander G. Weil, Dominic Venne, Marc Barritault, Pierre Leblond, Hallie Coltin, Rawan Hammad, Uri Tabori, Cynthia Hawkins, Jordan R. Hansford, Deborah Meyran, Craig Erker, Kathryn McFadden, Mariko Sato, Nicholas G. Gottardo, Hetal Dholaria, Dorte Schou. Nørøxe, Hiroaki Goto, David S. Ziegler, Frank Y. Lin, Donald Williams. Parsons, Holly Lindsay, Tai-Tong Wong, Yen-Lin Liu, Kuo-Sheng Wu, Andrea T. Franson, Eugene Hwang, Ana Aguilar-Bonilla, Sylvia Cheng, Chantel Cacciotti, Maura Massimino, Elisabetta Schiavello, Paul Wood, Lindsey M. Hoffman, Andréa Cappellano, Alvaro Lassaletta, An Van Damme, Anna Llort, Nicolas U. Gerber, Mariella Spalato Ceruso, Anne E. Bendel, Maggie Skrypek, Dima Hamideh, Naureen Mushtaq, Andrew Walter, Nada Jabado, Aysha Alsahlawi, Jean-Pierre Farmer, Christina Coleman, Sabine Mueller, Claire Mazewski, Dolly Aguilera, Nathan J. Robison, Katrina O’Halloran, Samuel Abbou, Pablo Berlanga, Birgit Geoerger, Ingrid Øra, Christopher L. Moertel, Evangelia D. Razis, Anastasia Vernadou, François Ducray, Charlotte Bronnimann, Romuald Seizeur, Matthew Clarke, Adam C. Resnick, Mélanie Alves, Chris Jones, François Doz, Theodore W. Laetsch, Sébastien Perreault","doi":"10.1158/1078-0432.ccr-24-0581","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-0581","url":null,"abstract":"Purpose: TRK fusions are detected in less than 2% of central nervous system tumors. There are limited data on the clinical course of affected patients. Experimental design: We conducted an international retrospective cohort study of patients with TRK fusion-driven CNS tumors. Results: 119 patients were identified. The median age at time of diagnosis was 4.5 years. The majority were reported to have a histology consistent with a diagnosis of high-grade glioma (HGG) (57.1%) followed by low-grade glioma (LGG) (27.7%). Pediatric patients had a better prognosis with a median overall survival of 185.5 months compared to 24.8 months in adults (p&amp;lt;.0001). Patients with LGG also had a better outcome when compared to HGG (p=0.0012). The objective response was 68.8% with larotrectinib compared to 38.1% for non-targeted treatment. Conclusions: Children with LGG glioma had a favorable outcome compared to adult and HGG. TRK inhibitors appear to improve tumor control.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"14 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142763429","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}