Clinical Cancer Research最新文献

{"title":"Safety, Efficacy, and Biomarker Analysis of Crizotinib in MET-Mutated Non-Small Cell Lung Cancer-Results from the Drug Rediscovery Protocol.","authors":"Karlijn Verkerk, Tijmen J W T van der Wel, Laurien J Zeverijn, Birgit S Geurts, Ilse A C Spiekman, Gijs F de Wit, Paul Roepman, Anne M L Jansen, Vincent van der Noort, Egbert F Smit, Ann Hoeben, Lizza E L Hendriks, Michel M van den Heuvel, Berber Piet, Gerarda J M Herder, Sayed M S Hashemi, Hans Gelderblom, Henk M W Verheul, Emile E Voest, Adrianus J de Langen","doi":"10.1158/1078-0432.CCR-24-1925","DOIUrl":"10.1158/1078-0432.CCR-24-1925","url":null,"abstract":"<p><strong>Purpose: </strong>To provide patients with MET-mutated advanced non-small cell lung cancer (METmut aNSCLC) access to crizotinib, further substantiate evidence of its efficacy and safety in this setting, and find potential biomarkers for nonresponse.</p><p><strong>Patients and methods: </strong>In the Drug Rediscovery Protocol (NCT0295234), patients with an actionable molecular profile are treated with off-label registered drugs. Both treated and untreated patients with aNSCLC harboring MET exon 14 skipping or other MET mutations received crizotinib 250 mg BID until disease progression or intolerable toxicity. Primary endpoints were clinical benefit [CB: RECIST v1.1 confirmed partial response, complete response (CR), or stable disease ≥16 weeks] and safety. Patients were enrolled using a Simon-like two-stage design, with eight patients in stage I and if ≥1/8 patients had CB, 24 patients in stage II. Whole-genome sequencing and RNA sequencing were performed on baseline biopsies.</p><p><strong>Results: </strong>Between September 2018 and October 2022, 30 patients started treatment, and 24 were response-evaluable after completing ≥1 full treatment cycle. Two patients (8.3%) achieved CR, 13 (54.2%) partial response, and two (8.3%) stable disease. The CB rate was 70.8% [95% confidence interval (CI), 48.9-87.4], and the objective response rate was 62.5% (95% CI, 40.6-81.2). After 21.2-month median follow-up, median duration of response, progression-free survival, and overall survival were 9.3 (95% CI, 6.5-not available), 10.2 (95% CI, 6.0-20.1), and 13.0 months (95% CI, 9.0-not available), respectively. Twenty-three treatment-related grade ≥ 3 adverse events occurred in 12/30 patients (40%), causing treatment discontinuation in three (10%). One patient (achieving CR) had a tyrosine kinase domain mutation (p.H1094Y), and all other patients had MET exon 14 skipping mutations.</p><p><strong>Conclusions: </strong>Crizotinib is a valuable treatment option in METmut aNSCLC.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"5323-5332"},"PeriodicalIF":10.0,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342743","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":"Editor's Note: Deciphering the Mechanisms of Tumorigenesis in Human Pancreatic Ductal Epithelial Cells.","authors":"Zhe Chang, Zhongkui Li, Xiaoyang Wang, Ya'an Kang, Yuhui Yuan, Jiangong Niu, Huamin Wang, Deyali Chatterjee, Jason B Fleming, Min Li, James L Abbruzzese, Paul J Chiao","doi":"10.1158/1078-0432.CCR-24-3479","DOIUrl":"10.1158/1078-0432.CCR-24-3479","url":null,"abstract":"","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"30 23","pages":"5495"},"PeriodicalIF":10.0,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766768","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 Gemcitabine and Nab-Paclitaxel for Recurrent Osteosarcoma with Serial Monitoring Using Liquid Biopsy: A Report from the National Pediatric Cancer Foundation.","authors":"Aditi Dhir, Masanori Hayashi, Avery Bodlak, Javier Oesterheld, David M Loeb, Leo Mascarenhas, Michael S Isakoff, Eric S Sandler, Scott C Borinstein, Matteo Trucco, Joanne P Lagmay, Bhuvana A Setty, Christine A Pratilas, Emi Caywood, Jonathan Metts, Hong Yin, Brooke Fridley, Jun Yin, Jose Laborde, Damon R Reed, Daniel L Adams, Lars M Wagner","doi":"10.1158/1078-0432.CCR-24-1339","DOIUrl":"10.1158/1078-0432.CCR-24-1339","url":null,"abstract":"<p><strong>Purpose: </strong>The combination of gemcitabine and docetaxel is often used to treat patients with recurrent osteosarcoma. Nab-paclitaxel has preclinical activity against osteosarcoma and is potentially less myelosuppressive than docetaxel. We conducted a prospective multi-institutional phase II trial combining gemcitabine and nab-paclitaxel for patients aged 12 to 30 years with recurrent osteosarcoma and measurable disease.</p><p><strong>Patients and methods: </strong>A Simon's two-stage design was used to test a 4-month progression-free survival (PFS-4) of 10% vs. 35%. Patients received nab-paclitaxel 125 mg/m2 and gemcitabine 1,000 mg/m2 weekly × 3 in 4-week cycles. Immunohistochemical analysis of archival tissue and serial assessment of circulating tumor cells (CTC) and circulating tumor DNA (ctDNA) using ultralow passage whole-genome sequencing were performed to identify potential biomarkers of response.</p><p><strong>Results: </strong>Eighteen patients received 56 total cycles (median 2, range 1-12). Two patients (11%) experienced confirmed partial response and six (33%) received >2 cycles. The PFS-4 was 28% (95% confidence interval, 13%-59%). Six patients required dose reductions and three patients were removed due to toxicities. All 18 patients had detectable CTCs and 10 had ctDNA identified. All eight patients with MYC amplification at study entry experienced disease progression.</p><p><strong>Conclusions: </strong>Gemcitabine and nab-paclitaxel demonstrated similar clinical activity and toxicity compared to previous retrospective reports utilizing gemcitabine and docetaxel in patients with recurrent osteosarcoma. Serial analysis of CTC and ctDNA was feasible in this prospective multi-institution study and provides preliminary data on the use of these assays in patients with relapsed disease.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"5314-5322"},"PeriodicalIF":10.0,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364636","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":"Efficacy and Safety of the Anti-IL1RAP Antibody Nadunolimab (CAN04) in Combination with Gemcitabine and Nab-Paclitaxel in Patients with Advanced/Metastatic Pancreatic Cancer.","authors":"Eric Van Cutsem, Joelle Collignon, Rikke L Eefsen, Sebastian Ochsenreither, Zanete Zvirbule, Audrius Ivanauskas, Dirk Arnold, Edita Baltruskeviciene, Per Pfeiffer, Jeffrey Yachnin, Susanne Magnusson, Camilla Rydberg Millrud, Annika Sanfridson, Nedjad Losic, Ignacio Garcia-Ribas, Dominique Tersago, Ahmad Awada","doi":"10.1158/1078-0432.CCR-24-0645","DOIUrl":"10.1158/1078-0432.CCR-24-0645","url":null,"abstract":"<p><strong>Purpose: </strong>IL1 pathway upregulation is implicated in pancreatic ductal adenocarcinoma (PDAC) progression, therapy resistance, and survival. Nadunolimab is an IL1 receptor accessory protein (IL1RAP)-targeting antibody with enhanced antibody-dependent cellular cytotoxicity that blocks IL1α/IL1β signaling. We investigated efficacy and safety of nadunolimab in PDAC, in combination with gemcitabine/nab-paclitaxel (GN).</p><p><strong>Patients and methods: </strong>Patients with previously untreated locally advanced/metastatic PDAC received nadunolimab (1.0-7.5 mg/kg) every 2 weeks with standard GN. The primary objective was safety; secondary objectives were antitumor response, progression-free survival, and overall survival (OS). Correlations between serum and tumor biomarkers and clinical response were explored.</p><p><strong>Results: </strong>Seventy-six patients were enrolled; the median age was 63 years (range, 43-89), 42% were female, 97% had metastatic disease, and 9% had received adjuvant chemotherapy. The most frequent grade ≥3 adverse event was neutropenia (66%), typically during cycle 1. Infusion-related reactions occurred in 29% (grade 3, 3%). Only 1 of the 76 patients had grade 3 or above peripheral neuropathy. No marked dose-dependent differences in safety or efficacy were observed among the four dose groups. The median OS was 13.2 months (95% confidence interval, 11.0-15.6), and the 1-year survival rate was 58%. The median immune PFS (immune Response Evaluation Criteria in Solid Tumours) was 7.1 months (95% confidence interval, 5.2-7.4). Treatment efficacy was higher in patients with high versus low tumor baseline IL1RAP expression (OS 14.2 vs. 10.6 months; P = 0.012). A reduction in serum IL8 on treatment correlated with prolonged OS.</p><p><strong>Conclusions: </strong>Nadunolimab combined with GN shows promising efficacy and manageable safety in locally advanced/metastatic PDAC. Higher tumor baseline IL1RAP expression correlated with better outcome.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"5293-5303"},"PeriodicalIF":10.0,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11609625/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142388484","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":"Phase 2 Trial of Regorafenib in Recurrent/Metastatic Adenoid Cystic Carcinoma.","authors":"Antoine Desilets, Joris L Vos, Nora Katabi, Fengshen Kuo, Zaineb Nadeem, Maximilian Linxweiler, Irina Ostrovnaya, Shrujal Baxi, Lara A Dunn, Eric J Sherman, David G Pfister, Luc G T Morris, Alan L Ho","doi":"10.1158/1078-0432.CCR-24-1064","DOIUrl":"10.1158/1078-0432.CCR-24-1064","url":null,"abstract":"<p><strong>Purpose: </strong>There is a significant need for effective therapies to treat recurrent/metastatic (R/M) adenoid cystic carcinoma (ACC). This study evaluated the multitargeted VEGFR tyrosine kinase inhibitor (TKI) regorafenib in patients with R/M ACC.</p><p><strong>Patients and methods: </strong>Patients with progressive R/M ACC were treated with regorafenib until disease progression, consent withdrawal, or excessive toxicity. The co-primary endpoints were best overall response and 6-month progression-free survival (PFS). Genomic and transcriptomic biomarker analyses were performed in tumors from trial participants.</p><p><strong>Results: </strong>Thirty-eight patients were enrolled, including 7 (18%) patients with prior VEGFR TKIs. No objective responses were observed. The 6-month PFS was 45%, and the median PFS was 7.2 months (95% confidence interval, 5.2-11.9 months). The presence of either activating NOTCH1 (22%) or KDM6A alterations (24%) was associated with decreased PFS [HR 2.6; 95% confidence interval (CI), 1.1-6.1; P = 0.03]. Bulk RNA sequencing of pretreatment tumors revealed that regorafenib clinical benefit (CB; PFS ≥ 6 months; n = 11) was associated with the native enrichment of immune-related signatures. Immune deconvolution revealed a greater degree of macrophage and T-cell infiltration in CB tumors. Tumors from patients with no clinical benefit (NCB; PFS < 6 months; n = 9) had greater expression of signatures related to cell-cycle progression (E2F targets, G2-M checkpoint).</p><p><strong>Conclusions: </strong>The trial failed to meet the prespecified 6-month PFS and best overall response targets. We hypothesize that TKI efficacy may be reliant upon an interplay between kinase inhibition and the ACC immune microenvironment, whereas programs promoting cell-cycle progression may contribute to TKI resistance. These observations suggest that trials evaluating CDK4/6 inhibition plus a VEGFR TKI should be considered.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"5281-5292"},"PeriodicalIF":10.0,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11611652/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342742","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":"Update on cancer screening in children with syndromes of bone lesions, hereditary leiomyoma and renal cell carcinoma syndrome, and other rare syndromes.","authors":"Orli Michaeli, Sun Young Kim, Sarah G Mitchell, Marjolijn C J Jongmans, Jonathan D Wasserman, Melissa R Perrino, Anirban Das, Suzanne P MacFarland, Sarah R Scollon, Mary-Louise C Greer, Nara Sobreira, Bailey Gallinger, Philip J Lupo, David Malkin, Kami Wolfe Schneider, Kris Ann P Schultz, William D Foulkes, Emma R Woodward, Douglas R Stewart","doi":"10.1158/1078-0432.CCR-24-2171","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-2171","url":null,"abstract":"<p><p>The management of children with syndromes associated with an increased risk of benign and malignant neoplasms is a complex challenge for healthcare professionals. The 2023 AACR Childhood Cancer Predisposition Workshop provided updated consensus guidelines on cancer surveillance in these syndromes, aiming to improve early detection, intervention, and reduce morbidity associated with such neoplasms. In this paper, we review several of the rare conditions discussed in this workshop. Ollier disease and Maffucci syndrome are enchondromatoses (disorders featuring benign bone lesions) with up to 50% risk of malignancy, including chondrosarcoma. These patients require surveillance with baseline whole-body MRI and routine monitoring of potential malignant transformation of bony lesions. Hereditary Multiple Osteochondromas carry a lower risk of chondrosarcoma (<6%) but still require lifelong surveillance and baseline imaging. Related syndromes of benign bone lesions are also described. Hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC), associated with fumarate hydratase pathogenic variants, is discussed in detail. Surveillance for RCC in pediatric age is recommended, as well as prompt intervention when a lesion is detected. Schinzel-Giedion Syndrome and Rubinstein-Taybi Syndrome are described for their associated malignancies and other complications, as well as expert consensus on the need for childhood cancer surveillance. Clinical recommendations, including imaging modalities and frequency of screenings, were proposed and are tailored to each syndrome's age-specific tumor risk profile. In all syndromes, patients and their families should be educated about the potential malignancy risk and advised to seek medical care for rapid growth of a mass, persistent pain, or other unexplained symptoms.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142726504","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":"Framework for the Pathology Workup of Metastatic Castration-Resistant Prostate Cancer Biopsies.","authors":"Michael C Haffner, Michael J Morris, Chien-Kuang C Ding, Erolcan Sayar, Rohit Mehra, Brian Robinson, Lawrence D True, Martin Gleave, Tamara L Lotan, Rahul Aggarwal, Jiaoti Huang, Massimo Loda, Peter S Nelson, Mark A Rubin, Himisha Beltran","doi":"10.1158/1078-0432.CCR-24-2061","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-2061","url":null,"abstract":"<p><p>Lineage plasticity and histologic transformation from prostate adenocarcinoma to neuroendocrine prostate cancer (NEPC) occurs in up to 15-20% of patients with castration-resistant prostate cancer (CRPC) as mechanism of treatment resistance and is associated with aggressive disease and poor prognosis. NEPC tumors typically display small cell carcinoma morphology with loss of androgen receptor (AR) expression and gain of neuroendocrine (NE) lineage markers. However, there is a spectrum of phenotypes that are observed during the lineage plasticity process, and the clinical significance of mixed histologies or those that co-express AR and NE markers or lack all markers is not well defined. Translational research studies investigating NEPC have used variable definitions making clinical trial design challenging. Here we discuss the diagnostic workup of metastatic biopsies to help guide the reproducible classification of phenotypic CRPC subtypes. We recommend classifying CRPC tumors based on histomorphology (adenocarcinoma, small cell carcinoma, poorly differentiated carcinoma, other morphologic variant, or mixed morphology) and immunohistochemical markers with a priority for AR, NKX3.1, INSM1, synaptophysin and cell proliferation based on Ki-67 positivity, with additional markers to be considered based on the clinical context. Ultimately, a unified workup of metastatic CRPC biopsies can improve clinical trial design and eventually practice.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715500","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 Study of the Aurora Kinase A Inhibitor Alisertib and Pembrolizumab in Refractory, Rb-Deficient Head and Neck Squamous Cell Carcinomas.","authors":"Faye M Johnson, Madison P O'Hara, Lacin Yapindi, Peixin Jiang, Hai T Tran, Alexandre Reuben, Weihong Xiao, Maura Gillison, Xiaowen Sun, Alexander Khalaf, J Jack Lee, Jagannadha K Sastry, Soma Ghosh","doi":"10.1158/1078-0432.CCR-24-2290","DOIUrl":"10.1158/1078-0432.CCR-24-2290","url":null,"abstract":"<p><strong>Purpose: </strong>Effective therapy for recurrent head and neck squamous cell carcinoma (HNSCC) that is refractory to chemotherapy and immunotherapy is a considerable need. Aurora kinase A inhibition leads to apoptosis and immunogenic cell death in preclinical models of human papilloma virus (HPV)-driven cancers.</p><p><strong>Experimental design: </strong>Alisertib was administered orally twice daily on days 1-7 and pembrolizumab on day 1 of a 21-day cycle to adults with advanced solid tumors (phase 1) or with immunotherapy- and platinum-resistant, HPV-positive HNSCC (phase 2).</p><p><strong>Results: </strong>The recommended phase 2 alisertib dose was 40 mg which had only the expected toxicity including cytopenia that led to dose reductions in two phase 2 patients at cycles 13 and 16. We saw no objective responses, but the combination led to prolonged stable disease (SD) in several patients, including 2 of 10 phase 1 patients (8 and 27 months). Eight of the 15 HPV-positive patients had SD; four of them (heavily pretreated) for ≥6 months, with median overall and progression-free survival durations of 16.8 and 1.4 months, respectively. In circulating immune cells and plasma patients with SD had markedly higher levels of HLA-DR-expressing natural killer cells than did progressive disease patients who demonstrated a more immunosuppressive and inflammatory profile. Pharmacokinetics did not indicate any significant drug-drug interactions between pembrolizumab and alisertib.</p><p><strong>Conclusions: </strong>The combination of alisertib and pembrolizumab was well tolerated and led to prolonged SD in some immunotherapy-resistant patients, supporting our hypothesis that Aurora kinase A inhibition can reverse immunotherapy resistance of retinoblastoma protein-deficient HNSCC.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715503","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":"Anti-tumor activity and biomarker analysis for TROP2-antibody drug conjugate Datopotamab deruxtecan in patient-derived breast cancer xenograft models.","authors":"Funda Meric-Bernstam, Erkan Yuca, Kurt W Evans, Ming Zhao, Takanori Maejima, Tsuyoshi Karibe, Maria Gabriela Raso, Ximing Tang, Xiaofeng Zheng, Yasmeen Qamar Rizvi, Argun Akcakanat, Stephen S Scott, Bailiang Wang, Lauren A Byers, Debu Tripathy, Daisuke Okajima, Senthil Damodaran","doi":"10.1158/1078-0432.CCR-24-1948","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-1948","url":null,"abstract":"<p><strong>Background: </strong>Datopotamab deruxtecan (Dato-DXd), is a humanized anti-TROP2 IgG1 monoclonal antibody linked to a potent topoisomerase I inhibitor payload (DXd). Dato-DXd has already shown antitumor activity in breast cancer; however, the determinants of response, including the importance of TROP2 expression, remain unclear. We tested the activity of Dato-DXd in a panel of breast cancer patient-derived xenografts (BCXs) varying in TROP2 expression.</p><p><strong>Methods: </strong>The antitumor activity of Dato-DXd and isotype-control-DXd (IgG-DXd) was assessed against 11 BCXs varying in TROP2 expression, 10 representing tumors post-neoadjuvant chemotherapy. Pharmacodynamic effects were assessed at 24 and 72 hours. The effects of TROP2 expression on Dato-DXd activity was assessed in vitro and in vivo using viral overexpression in BCX-derived cell lines.</p><p><strong>Results: </strong>Models differed in their sensitivity to both Dato-DXd and IgG-DXd. Dato-DXd (10 mg/kg) led to objective response in 4 (36%) models and statistically significant prolongation of event-free survival (EFS) in 8 (73%) models while IgG-DXd (10 mg/kg) led to response in 1 (9%) and prolonged EFS in 3 (27%) models. TROP2 RNA and protein was significantly higher in Dato-DXd-sensitive models. In isogenic cell lines derived from Dato-DXd-resistant BCXs, overexpression of TROP2 conferred Dato-DXd antitumor activity in vitro and in vivo. Dato-DXd increased γH2AX and phospho-KAP1 in the 2 Dato-DXd-sensitive BCXs but not in a Dato-DXd-resistant BCX. In Dato-DXd-sensitive models, antitumor activity was enhanced in combination with PARP inhibitor, olaparib.</p><p><strong>Conclusion: </strong>Dato-DXd is active in breast cancer models. Dato-DXd has TROP2 dependent and independent mediators of activity; however, high TROP2 expression enhances Dato-DXd antitumor activity.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142709620","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":"Response-Adaptive Surgical Timing in neoadjuvant immunotherapy demonstrates enhanced pathologic treatment response in Head and Neck Squamous Cell Carcinoma.","authors":"Eric V Mastrolonardo, Kathryn L Nunes, Pablo Llerena, Anastasia Nikitina, Anastasia Sobol, E Reilly Scott, Madalina Tuluc, Christopher J H Davitt, Jessica Scher, Sruti Tekumalla, Derek Mann, Camilo Henao, Victor Jegede, Stacey Gargano, Larry A Harshyne, Angela Alnemri, Andrey Tyshevich, Vladimir Kushnarev, Madison Chasse, Danielle Sookiasian, Rita Axelrod, Tingting Zhan, Benjamin E Leiby, Matthew Old, Nolan Seim, My G Mahoney, Ubaldo Martinez-Outschoorn, David M Cognetti, Joseph M Curry, George Prendergast, Athanassios Argiris, Andrew P South, Alban J Linnenbach, Jennifer M Johnson, Adam J Luginbuhl","doi":"10.1158/1078-0432.CCR-24-0037","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-0037","url":null,"abstract":"<p><strong>Purpose: </strong>We evaluated whether IDO-inhibitor BMS986205 (IDOi) + PD-1 inhibitor nivolumab enhanced T-cell activity and augmented immune-mediated antitumor responses in untreated, resectable HNSCC. We employed response-adaptive surgical timing to identify responders to immunotherapy and enhance their response.</p><p><strong>Patients and methods: </strong>Patients with HNSCC were 3:1 randomized to receive nivolumab with or without BMS986205 PO daily (NCT03854032). In the combination arm, BMS986205 was initiated 7 days prior to nivolumab. Patients were stratified by HPV status. Response-adaptive surgical timing involved response assessment by radiographic criteria 4 weeks after nivolumab in both arms. Non-responders underwent surgical resection, while responders received 4 more weeks of randomized therapy before surgery. Biomarker analysis utilized pathologic treatment response (pTR) and RNA sequencing.</p><p><strong>Results: </strong>Forty-two patients were enrolled, and the addition of IDOi to nivolumab did not result in greater rate of radiographic response (p=0.909). Treatment was well-tolerated with only 2 (5%) patients experiencing grade 3 immune-related adverse events. The addition of IDO-inhibitor augmented rates of pTR in patients with high baseline IDO RNA expression (p<0.05). Response-adaptive surgical timing demonstrated reliability in differentiating pathologic responders versus non-responders (p=0.009). A pretreatment NK cell signature, PD-L1 status, and IFN-g expression in the HPV- cohort correlated with response. HPV+ cohort found B-cell and CAF signatures predictive of response/non-response.</p><p><strong>Conclusions: </strong>Response-adaptive surgical timing enhanced treatment response. IDO-inhibitor BMS986205 augmented pTR in patients with high IDO1-expression in baseline samples, indicating a need for identifying and targeting resistant nodes to immunotherapy. HPV-status-dependent signatures predicting response to immunotherapy in HNSCC warrant further study.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142709626","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}