Clinical Cancer Research最新文献

{"title":"Synergistic Effects of Transarterial Chemoembolization and Lenvatinib on HIF-1α Ubiquitination and Prognosis Improvement in Hepatocellular Carcinoma.","authors":"Sung Won Chung, Jin Sun Kim, Won-Mook Choi, Jonggi Choi, Danbi Lee, Ju Hyun Shim, Young-Suk Lim, Han Chu Lee, Kang Mo Kim","doi":"10.1158/1078-0432.CCR-24-1228","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-1228","url":null,"abstract":"<p><strong>Purpose: </strong>A recent trial has shown that adding transarterial chemoembolization (TACE) to lenvatinib therapy results in enhanced therapeutic efficacy in hepatocellular carcinoma (HCC). We aimed to assess the effectiveness of the lenvatinib and TACE combination in a real-world clinical context for managing HCC and to elucidate the molecular pathways involved.</p><p><strong>Experimental design: </strong>This retrospective analysis included 199 patients diagnosed with HCC and having intrahepatic lesions between 2018 and 2021. The cohort was divided into those who received lenvatinib plus TACE (n=62, combination group) and those who received lenvatinib monotherapy (n=137, monotherapy group). To further explore the underlying mechanisms, Huh-7 cells were exposed to lenvatinib or a vehicle for 48 hours under normoxic or hypoxic condition.</p><p><strong>Results: </strong>Propensity score-matched analysis revealed a significant improvement in both overall survival (adjusted hazard ratio [aHR], 0.38; 95% CI, 0.24-0.59; P<0.001) and progression-free survival (aHR, 0.41; 95% CI, 0.26-0.64; P<0.001) in the combination group compared to the monotherapy group. In laboratory experiments, under hypoxic conditions, lenvatinib notably attenuated hypoxia-inducible factor-1 alpha (HIF-1α) protein levels in Huh-7 cells without altering its mRNA levels. Intriguingly, lenvatinib facilitated the MDM2-mediated ubiquitination and subsequent degradation of HIF-1α. Additionally, cell viability assays confirmed a significant decrease in Huh-7 cell survival following lenvatinib treatment under hypoxic conditions.</p><p><strong>Conclusions: </strong>The combination of lenvatinib and TACE significantly improved survival in HCC patients. The mechanistic foundation appears to be the lenvatinib-triggered degradation of HIF-1α via the MDM2-dependent ubiquitination pathway, highlighting a potential therapeutic target in HCC treatment.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482244","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":"Validation of a digital pathology-based multimodal artificial intelligence biomarker in a prospective, real-world prostate cancer cohort treated with prostatectomy","authors":"Anders Bjartell, Agnieszka Krzyzanowska, Vinnie Y.T. Liu, Meghan Tierney, Trevor J. Royce, Martin Sjöström, Marisol Macarena Palominos-Rivera, Emmalyn Chen, Alexandra Kraft, Andre Esteva, Felix Y. Feng","doi":"10.1158/1078-0432.ccr-24-3656","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3656","url":null,"abstract":"Purpose: A multimodal artificial intelligence (MMAI) biomarker was developed using clinical trial data from North American men with localized prostate cancer (PCa) treated with definitive radiation, using biopsy digital pathology images and key clinical information (age, PSA, T-stage) to generate prognostic scores. This study externally validates the biomarker in a prospective, real-world dataset of men who underwent radical prostatectomy (RP) for localized PCa at a tertiary referral center in Sweden. Experimental Design: Association between the MMAI scores (continuously and categorically) and endpoints of interest were performed with Fine-Gray and cumulative incidence analyses for biochemical recurrence (BCR) and logistic regression for adverse pathology (AP) at RP. Results: The analysis included 143 patients with evaluable biopsy pathology images and complete clinical data to generate MMAI scores. Median follow-up was 8.8 years. At diagnosis, median PSA was 7.5 ng/mL, median age 64 years, 29% had Gleason grade group ≥3, and 88 men were evaluable for AP at RP. MMAI was significantly associated with BCR (subdistribution HR 2.45 [95% CI 1.77-3.38], p&amp;lt;0.001) and AP at RP (OR 4.85 [95% CI 2.54-10.78], p&amp;lt;0.001). Estimated 5-yr BCR rates for MMAI Intermediate-High vs Low were 25% (95% CI 16%-36%) vs 4% (95% CI 1%-11%), respectively. Conclusions: The MMAI biomarker, previously shown to be prognostic for distant metastasis and prostate cancer-specific mortality in men receiving definitive radiation, was prognostic for post-RP endpoints: BCR and AP. This biomarker validation study further supports the use of MMAI biomarkers in men with PCa outside North America and those treated with RP.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"50 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143470665","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":"Timing of circulating tumor DNA analysis aimed at guiding adjuvant treatment in colorectal cancer.","authors":"Tenna V Henriksen, Christina Demuth, Amanda Frydendahl, Jesper Nors, Marijana Nesic, Mads H Rasmussen, Ole H Larsen, Claudia Jaensch, Uffe S Løve, Per V Andersen, Thomas Kolbro, Ole Thorlacius-Ussing, Alessio Monti, Jeppe Kildsig, Peter Bondeven, Nis H Schlesinger, Lene H Iversen, Kåre A Gotschalck, Claus L Andersen","doi":"10.1158/1078-0432.CCR-24-3200","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-3200","url":null,"abstract":"<p><strong>Background: </strong>Multiple clinical trials investigate circulating tumor DNA (ctDNA) to guide adjuvant chemotherapy (ACT) in colorectal cancer. Timely ACT initiation necessitates early ctDNA testing, but the impact of postoperative cell-free DNA (cfDNA) and ctDNA dynamics remains unclear, particularly with cost-reducing input caps employed in some assays. This study investigates ctDNA detection at day14 versus day30, comparing whole-sample analysis with capping the cfDNA input, and evaluates single and dual timepoint assessments for ACT allocation.</p><p><strong>Patients and methods: </strong>In 2019-2023, 611 stage I-III colorectal cancer patients were enrolled. Blood was collected preoperatively, and postoperatively ~day14 and ~day30. The cfDNA levels were assessed using digital PCR, and ctDNA using tumor-informed digital PCR or targeted sequencing analyzing all cfDNA from 8mL of plasma.</p><p><strong>Results: </strong>Despite elevated cfDNA in 85% of day14 samples, performance was comparable between the two timepoints (sensitivity 31% vs 32%; specificity both 98%). A 50ng cfDNA input cap reduced ctDNA detection probability, impacting 78% of day14 samples and 65% of day30 samples. At both timepoints, ctDNA detection was prognostic of recurrence (day14: HR=9.0, 95%CI 5.5-14.8; day30: HR=12.5, 95%CI 7.6-20.4). In 74% of ctDNA-positive recurrence patients, both samples had ctDNA detected. An increase in ctDNA level from day14 to day30 was associated with shorter time to recurrence (Pearson R=-0.63, P=0.003). Combining the timepoints would increase sensitivity (36%) and allow earlier ACT start in 80% of patients.</p><p><strong>Conclusion: </strong>Early ctDNA sampling is feasible and highly prognostic. Supplemental later testing may improve sensitivity while allowing early ACT initiation for most ctDNA positive patients.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457075","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":"Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms Reveals Divergent Indolent and Malignant States.","authors":"Matthew K Iyer, Ashley Fletcher, Jude Ogechukwu Okoye, Chanjuan Shi, Fengming Chen, Elishama Kanu, Austin M Eckhoff, Matthew Bao, Marina Pasca di Magliano, Timothy L Frankel, Arul M Chinnaiyan, Daniel P Nussbaum, Peter J Allen","doi":"10.1158/1078-0432.CCR-24-1529","DOIUrl":"10.1158/1078-0432.CCR-24-1529","url":null,"abstract":"<p><strong>Purpose: </strong>Intraductal papillary mucinous neoplasms (IPMN) occur in 5-10% of the population, but only a small minority progress to pancreatic ductal adenocarcinoma (PDAC). The lack of accurate predictors of high-risk disease leads both to unnecessary operations for indolent neoplasms as well as missed diagnoses of PDAC. Digital spatial RNA profiling (DSP-RNA) provides an opportunity to define and associate transcriptomic states with cancer risk.</p><p><strong>Experimental design: </strong>We performed whole-transcriptome DSP-RNA profiling on 10 IPMN specimens encompassing the spectrum of dysplastic changes from normal duct to cancer. Epithelial regions within each tissue were annotated as normal duct (NL), low-grade dysplasia (LGD), high-grade dysplasia (HGD), or invasive carcinoma (INV). The resulting digital gene expression data were analyzed with R/Bioconductor.</p><p><strong>Results: </strong>Our analysis uncovered three distinct epithelial transcriptomic states - \"normal-like\" (cNL), \"low-risk\" (cLR), and \"high-risk\" (cHR) - which were significantly associated with pathologic grade. Furthermore, the three states were significantly correlated with the exocrine, classical, and basal-like molecular subtypes described in PDAC. Specifically, exocrine function diminished in cHR, classical activation distinguished neoplasia (cLR and cHR) from cNL, and basal-like genes were specifically upregulated in cHR. Intriguingly, markers of cHR were detected in NL and LGD regions from specimens with PDAC but not low-grade IPMN.</p><p><strong>Conclusions: </strong>DSP-RNA of IPMN revealed low-risk (indolent) and high-risk (malignant) expression programs that correlated with the activity of exocrine and basal-like PDAC signatures, respectively, and distinguished pathologically low-grade from malignant specimens. These findings contextualize IPMN pathogenesis and have the potential to improve risk stratification.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448133","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":"Spatially resolved, multi-region proteomics for prediction of immunotherapy outcome in deficient mismatch repair metastatic colorectal cancer.","authors":"Bahar Saberzadeh-Ardestani, Zhenglong Liu, Mariam I Stein, Will A Sherman, Christy E Trussoni, Charles W Abbott, Dongyao Yan, Skyler Smith, Kandavel Shanmugam, Rondell P Graham, Alos Diallo, Joshua J Levy, Tamas Ordog, Frank A Sinicrope","doi":"10.1158/1078-0432.CCR-24-0853","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-0853","url":null,"abstract":"<p><strong>Purpose: </strong>Digital proteomic profiling was performed to identify spatial context in relationship to patient response and survival after anti-PD-1 therapy in metastatic colorectal cancer (CRC).</p><p><strong>Experimental design: </strong>Primary CRCs with deficient mismatch repair (d-MMR) from patients treated with anti-PD-1 antibodies were analyzed (N=30) using Digital Spatial Profiling (GeoMx® nCounter). At the invasive margin, 71 proteins were profiled in 10 regions of interest /slide that were segmented into 3 compartments labeled with pan-cytokeratin (PanCK; epithelia), CD45 (stromal cells) and SYTO13 (nuclei). In an independent cohort (n=13), DSP data and single cell transcriptomic data were analyzed. Differential protein abundance, after Benjamini-Hochberg correction, was examined by response and progression-free survival (PFS) using multivariable Cox regression.</p><p><strong>Results: </strong>Protein abundance varied significantly between epithelial and stromal compartments. Nonresponders (NR) to anti-PD-1 showed higher fibronectin and smooth muscle actin (SMA) abundance in the epithelial compartment that were associated with significantly shorter PFS (HRadj: 6.49 and 4.52, respectively; p < 0.05). In CD45+ stroma, increased expression of proteins related to T-cells (CD3, CD4), NK cells (CD56), antigen presentation (CD40), immune activation (CD27, ICOS), and apoptosis (GZMA) were found in responders (vs NR) to anti-PD-1; each marker was significantly associated with longer patient PFS (0.02 <HRadj < 0.17; p < 0.05). In a separate cohort, consistent results by compartment were found for fibronectin and CD56. Gene expression data revealed that fibronectin and SMA were primarily derived from cancer-associated fibroblasts.</p><p><strong>Conclusions: </strong>Spatially resolved protein profiles within microenvironments of d-MMR CRCs can influence patient response and survival after anti-PD-1 highlighting their potential clinical significance.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448136","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 and Translational Results from PORTER, a Multi-cohort Phase 1 Platform Trial of Combination Immunotherapy in Metastatic Castration-Resistant Prostate Cancer.","authors":"Matthew D Galsky, Karen A Autio, Christopher R Cabanski, Kristopher Wentzel, Julie N Graff, Terence W Friedlander, Timothy R Howes, Kristin M Shotts, Julie Densmore, Marko Spasic, Diane M Da Silva, Richard O Chen, Jennifer Lata, Jeffrey Skolnik, Tibor Keler, Michael J Yellin, Theresa M LaVallee, Justin Fairchild, Silvia Boffo, Jill O'Donnell-Tormey, Ute Dugan, Nina Bhardwaj, Sumit K Subudhi, Lawrence Fong","doi":"10.1158/1078-0432.CCR-24-3693","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-3693","url":null,"abstract":"<p><strong>Purpose: </strong>Current immune checkpoint therapies offer limited benefits for metastatic castration-resistant prostate cancer (mCRPC). Novel combinations may enhance immunotherapy efficacy.</p><p><strong>Patients and methods: </strong>We conducted an open-label, non-comparative platform trial (NCT03835533) in mCRPC to assess nivolumab-based combinations. The cohorts were: A) bempegaldesleukin 0.006 mg/kg and nivolumab 360 mg intravenously Q3W, B) stereotactic body radiation therapy 30-50 Gray, CDX-301 75 μg/kg subcutaneously for 5 days, poly-ICLC 1 mg intramuscularly twice weekly for 3 weeks, and nivolumab 480 mg Q4W, and C) CDX-301 75 μg/kg for 10 days, INO-5151 3 mg intramuscularly on Lead-in Day 8, Day 1 of Cycles 1-3, then Q12W, and nivolumab 480 mg Q4W. The primary endpoint was safety; secondary endpoints included composite response rate (radiographic, PSA, or circulating tumor cell responses), 6-month disease control rate, progression-free survival, and overall survival. Serial blood and tissue samples were analyzed for pharmacodynamics and association with disease control.</p><p><strong>Results: </strong>43 patients enrolled (N = 14, 15, 14 in Cohorts A, B, C). Grade 3-4 treatment-related adverse events (TRAEs) occurred in 10 (71%), 2 (13%), and 2 (14%) patients, respectively, with one Grade 5 TRAE in Cohort A. Composite response rates were 7% (1/14), 33% (5/15), and 7% (1/14). Across cohorts, 6-month disease control was associated with pre-existing memory/regulatory T cells, TNFα, and other inflammatory pathways.</p><p><strong>Conclusions: </strong>Cohort B, which combined radiation therapy with CDX-301, poly-ICLC, and nivolumab, demonstrated encouraging clinical activity. Pre-existing rather than treatment-induced immune activation was associated with clinical benefit across cohorts, highlighting the importance of baseline immune fitness.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440021","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":"Increased interaction between B cells and CD3+ T cells in non-progressors with human papillomavirus-associated oropharyngeal squamous cell carcinoma.","authors":"Kathleen R Bartemes, Raymond M Moore, Brenna C Novotny, Kevin D Pavelko, Will A Sherman, Michael Rivera, Joaquin J Garcia, Linda X Yin, Daniel J Ma, Eric J Moore, Kathryn M Van Abel, David M Routman","doi":"10.1158/1078-0432.CCR-24-2425","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-2425","url":null,"abstract":"<p><strong>Background: </strong>Tumor-infiltrating lymphocytes (TILs) are associated with decreased risk of recurrence in human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV(+)OPSCC). The composition and spatial distribution of TILs and tumor-infiltrating immune cells is not well characterized.</p><p><strong>Methods: </strong>Formalin-fixed paraffin-embedded primary and lymph node (LN) tumor tissues from ten progressors (cases) and ten matched non-progressors (controls) were interrogated by imaging mass cytometry. Immune, stromal, and tumor cells were quantified from selected regions of interest (ROIs) using machine learning. Nearest neighbors, cell-cell interactions, and niche analyses were performed.</p><p><strong>Results: </strong>In primary ROIs, immune cell, lymphocyte, T cell, CD8+ T cell, and innate cell prevalence was significantly greater in controls. High prevalence of immune cells, lymphocytes, innate cells, and CD4+ T cells in primary tissues was significantly associated with increased time to event (TTE). Although primary and LN prevalence of T cells, CD4+ T cells, CD8+ T cells, macrophages, and tumor cells were significantly correlated, differences in LNs were neither significant nor associated with TTE. Average distances between T cells and nearest B cells, and between lymphocytes and nearest tumor cells were decreased in control primary tissues. Interactions between B cells and T cells were less organized in primary tissues from cases. A niche predominantly comprising lymphocytes was associated with longer TTE.</p><p><strong>Conclusion: </strong>In HPV(+)OPSCC, immune cell subset prevalence in primary tumors differs with outcome and is associated with TTE. Interactions between B cells and both T cell subsets are associated with longer TTE, underscoring the importance of active intratumoral immune responses in outcomes.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440043","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":"Biomarkers of radioresistance in head and neck cancer: a new beginning.","authors":"Yuan James Rao","doi":"10.1158/1078-0432.CCR-24-4223","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-4223","url":null,"abstract":"<p><p>The development of biomarkers of radioresistance in head and neck cancer may help personalize treatment. This commentary puts in context the findings of a secondary analysis of NRG/RTOG 9512, a trial of fractionation in T2N0 glottic cancer, which observed that NFE2L2/KEAP1/CUL3 mutations are correlated with local recurrence and disease-free survival.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440018","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":"Correction: Targeting the Phosphoinositide 3-Kinase p110-α Isoform Impairs Cell Proliferation, Survival, and Tumor Growth in Small Cell Lung Cancer.","authors":"Anna Wojtalla, Barbara Fischer, Nataliya Kotelevets, Francesco A Mauri, Jens Sobek, Hubert Rehrauer, Carlos Wotzkow, Mario P Tschan, Michael J Seckl, Uwe Zangemeister-Wittke, Alexandre Arcaro","doi":"10.1158/1078-0432.CCR-25-0031","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-25-0031","url":null,"abstract":"","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"31 4","pages":"787"},"PeriodicalIF":10.0,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143432722","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":"Determinants of Response to Sequential Pembrolizumab with Trastuzumab Plus Platinum/5FU in HER2-positive Gastric Cancer: A Phase II Chemoimmunotherapy Trial","authors":"Sung Hee Lim, Minae An, Hyuk Lee, You Jeong Heo, Byung-Hoon Min, Arnav Mehta, Samuel Wright, Kyoung-Mee Kim, Seung Tae Kim, Samuel J. Klempner, Jeeyun Lee","doi":"10.1158/1078-0432.ccr-24-3528","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3528","url":null,"abstract":"Purpose: Adding pembrolizumab to first-line 5FU/platinum chemotherapy plus trastuzumab improves outcomes in advanced HER2+ gastroesophageal adenocarcinomas, but the benefit is largely confined to dual HER2+ and PD-L1+ patients. To assess the contributions of components, we conducted a phase II trial evaluating 5FU/platinum/trastuzumab and added pembrolizumab in cycle 2 in patients with metastatic HER2+ disease. Patients and Methods: Treatment naive advanced HER2+ gastroesophageal cancer patients underwent a baseline biopsy, and received a single dose of 5FU/platinum with trastuzumab followed by repeat biopsy. Pembrolizumab was added, and a third biopsy was performed after 6 cycles. The primary endpoint was the objective response rate (ORR). Secondary endpoints included progression free (PFS), and overall survival. Exploratory biomarker analysis and dynamic changes in HER2 and PD-L1 were prespecified. Results: Sixteen patients were enrolled. The ORR was 69%, and the median PFS was 11.9 months. Serial whole-exome, single-cell RNA, T-cell receptor sequencing and spatial transcriptomics from pre-treatment and on-treatment samples revealed early trastuzumab-induced natural killer cell infiltration in HER2+ tumor beds and an increase in Fc receptor (FcR) gamma III expression in macrophages, suggesting that trastuzumab directs FcR-mediated antibody-dependent cytotoxicity. This favorable remodeling was enhanced by the addition of pembrolizumab, primarily in PD-L1+ samples. We observed TGF-β signaling in HER2-negative tumor regions, which was associated with non-responder status. Conclusions: These data highlight the biology of intratumoral heterogeneity, and the impact of tumor and immune cell features on clinical outcomes and may partly explain the lesser magnitude of pembrolizumab benefit in HER2+ and PD-L1 negative subgroups.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"64 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143435291","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}