Pub Date : 2026-03-04DOI: 10.1158/1078-0432.ccr-25-3052
Susan Slovin, Xin Gao, Xiao X. Wei, David Y. Oh, Rana R. McKay, Gerald Falchook, Arif Hussain, Meredith McKean, Andreas Wibmer, Alan Ho, Jeff D. Eskew, Rajesh Belani, Julia Coronella, Sabrina Haag, Christopher E. Martin, Joanne McCaigue, June Mendoza, Ann Murphy, Hamid Namini, Matthew A. Spear, Devon J. Shedlock, Tanya B. Dorff
Purpose: Chimeric antigen receptor (CAR)-T cell therapies have potential in solid tumors. A higher proportion of stem cell-like memory T cells (TSCM) in CAR-T products could enhance engraftment, persistence, and prolong immune activity. This phase 1 trial (NCT04249947) evaluated the safety and efficacy of P-PSMA-101, an autologous TSCM-rich bone tropic CAR-T therapy targeting prostate-specific membrane antigen (PSMA), in metastatic castrate-resistant prostate carcinoma (mCRPC) patients. Secondary endpoints included objective response rate, PSA response, radiographic progression-free survival (PFS). Patients and Methods: P-PSMA-101 was produced from leukapheresis using the piggyBac® DNA transposon-based platform, which integrates a multi-cistronic transgene encoding an iCasp9 safety switch in addition to the CAR, generating TSCM-rich CAR-T cells. Results: Among 33 treated patients, 18% (n=6) had dose-limiting toxicities (DLTs). Cytokine release syndrome (CRS) occurred in 61% (n=20), with Grade ≥ 3 CRS in 9% (n=3). Activation of the iCasp9-based safety switch was required in 24% (n=8) of cases including one fatal toxicity, and successful resolution in the other seven. P-PSMA-101 yielded ≥50% PSA decline in 21% (n=7) of patients. Among 13 RECIST evaluable patients, one partial response was observed. Stable disease occurred in 61% (n=20), with 21% (n=7) maintaining stability for ≥3 months. Two patients' remissions exceeded 12 months characterized by PSA declines > 90%, corroborated by pharmacokinetic, biomarker, and PSMA-PET imaging data. Conclusions: Robust expansion of P-PSMA-101 CAR T cells resulted in toxicity but also durable responses in patients with mCRPC. Future trials of CAR T may be informed by the results with this nonviral engineering, TSCM cell-enriched approach.
目的：嵌合抗原受体(CAR)-T细胞治疗实体瘤有潜力。CAR-T产品中较高比例的干细胞样记忆T细胞（stem cell-like memory T cells， TSCM）可以增强植入性、持久性和延长免疫活性。这项i期试验（NCT04249947）评估了P-PSMA-101治疗转移性去势抵抗性前列腺癌（mCRPC）患者的安全性和有效性。P-PSMA-101是一种针对前列腺特异性膜抗原（PSMA）的自体富含tscm的骨致性CAR-T疗法。次要终点包括客观缓解率、PSA反应、放射学无进展生存期（PFS）。患者和方法：P-PSMA-101是利用基于piggyBac®DNA转座子的平台从白细胞分离中产生的，该平台除了CAR外，还集成了编码iCasp9安全开关的多顺反子转基因，产生富含tscm的CAR- t细胞。结果：在33名接受治疗的患者中，18% （n=6）出现剂量限制性毒性（dlt）。细胞因子释放综合征（CRS）发生率为61% (n=20)， CRS≥3级发生率为9% （n=3）。24% （n=8）的病例需要激活基于icasp9的安全开关，其中包括1例致命毒性，其他7例成功解决。P-PSMA-101使21% （n=7）患者的PSA下降≥50%。在13例可评估的RECIST患者中，观察到1例部分缓解。61% （n=20）患者病情稳定，21% （n=7）患者病情稳定≥3个月。2例患者缓解超过12个月，以PSA下降为特征；90%，经药代动力学、生物标志物和PSMA-PET成像数据证实。结论：P-PSMA-101 CAR - T细胞的强大扩增在mCRPC患者中产生毒性，但也产生持久的反应。这种非病毒工程、TSCM细胞富集方法的结果可能会为CAR - T的未来试验提供信息。
{"title":"Phase 1 Trial of P-PSMA-101 CAR-T Cells in Patients with Metastatic Castration Resistant Prostate Cancer (mCRPC)","authors":"Susan Slovin, Xin Gao, Xiao X. Wei, David Y. Oh, Rana R. McKay, Gerald Falchook, Arif Hussain, Meredith McKean, Andreas Wibmer, Alan Ho, Jeff D. Eskew, Rajesh Belani, Julia Coronella, Sabrina Haag, Christopher E. Martin, Joanne McCaigue, June Mendoza, Ann Murphy, Hamid Namini, Matthew A. Spear, Devon J. Shedlock, Tanya B. Dorff","doi":"10.1158/1078-0432.ccr-25-3052","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-3052","url":null,"abstract":"Purpose: Chimeric antigen receptor (CAR)-T cell therapies have potential in solid tumors. A higher proportion of stem cell-like memory T cells (TSCM) in CAR-T products could enhance engraftment, persistence, and prolong immune activity. This phase 1 trial (NCT04249947) evaluated the safety and efficacy of P-PSMA-101, an autologous TSCM-rich bone tropic CAR-T therapy targeting prostate-specific membrane antigen (PSMA), in metastatic castrate-resistant prostate carcinoma (mCRPC) patients. Secondary endpoints included objective response rate, PSA response, radiographic progression-free survival (PFS). Patients and Methods: P-PSMA-101 was produced from leukapheresis using the piggyBac® DNA transposon-based platform, which integrates a multi-cistronic transgene encoding an iCasp9 safety switch in addition to the CAR, generating TSCM-rich CAR-T cells. Results: Among 33 treated patients, 18% (n=6) had dose-limiting toxicities (DLTs). Cytokine release syndrome (CRS) occurred in 61% (n=20), with Grade ≥ 3 CRS in 9% (n=3). Activation of the iCasp9-based safety switch was required in 24% (n=8) of cases including one fatal toxicity, and successful resolution in the other seven. P-PSMA-101 yielded ≥50% PSA decline in 21% (n=7) of patients. Among 13 RECIST evaluable patients, one partial response was observed. Stable disease occurred in 61% (n=20), with 21% (n=7) maintaining stability for ≥3 months. Two patients' remissions exceeded 12 months characterized by PSA declines > 90%, corroborated by pharmacokinetic, biomarker, and PSMA-PET imaging data. Conclusions: Robust expansion of P-PSMA-101 CAR T cells resulted in toxicity but also durable responses in patients with mCRPC. Future trials of CAR T may be informed by the results with this nonviral engineering, TSCM cell-enriched approach.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"53 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350487","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}
Pub Date : 2026-03-04DOI: 10.1158/1078-0432.ccr-25-4600
Chang Liu, Jiarui Li, Dan Liu, Panpan Zhang, Miao Zhang, Ran Xue, Jifang Gong, Lian Liu, Min Tao, Siyuan Cheng, Ting Xu, Jiajia Yuan, Yanshuo Cao, Zhenghang Wang, Yakun Wang, Jun Zhou, Ming Lu, Zhi Peng, Zhihao Lu, Jian Li, Xiaotian Zhang, Tian Wang, Min Wang, Licui Jiang, Huimin Meng, Lin Yang, Changsong Qi, Lin Shen
Purpose: To evaluate the safety, pharmacokinetics, and preliminary clinical activity of UTAA06, an "off-the-shelf" allogeneic B7-H3-targeted chimeric antigen receptor (CAR)-Vδ1T cell therapy, in patients with pretreated, advanced B7-H3-positive solid tumors. Patients and Methods: In this first-in-human, phase I, dose-escalation study (NCT06372236), ten patients with advanced solid tumors (including gastric, colorectal, hepatocellular, ovarian, and neuroendocrine cancers) were enrolled. Following lymphodepletion chemotherapy (cyclophosphamide and fludarabine), patients received UTAA06 infusion across three dose levels (5×10⁸, 8×10⁸, or 1×10⁹ cells). The primary endpoint was safety. Secondary endpoints included pharmacokinetics and anti-tumor efficacy. Results: UTAA06 demonstrated a manageable safety profile; no graft-versus-host disease (GvHD) was observed, and cytokine release syndrome (CRS) was limited to two transient Grade 1 events. A single dose-limiting toxicity (Grade 3 pneumonitis) was reported in one patient at the 5×10⁸ cells dose level. While UTAA06 demonstrated signals of biological activity, including transient reductions in serum tumor markers in 50% of patients, no objective response by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria was observed. Further analysis identified that the limited CAR-T cell persistence was likely driven by subclinical host-versus-graft rejection (HvGR). Conclusions: This study provides clinical proof-of-concept for allogeneic B7-H3-targeted CAR-Vδ1T cells as a safe platform with low risk of GvHD and demonstrable biological activity in solid tumors. However, clinical efficacy was constrained by limited cellular persistence caused by host immune rejection. Future strategies are required to enhance the durability and therapeutic potential of this allogeneic approach.
{"title":"Allogeneic B7-H3-targeted CAR-Vδ1T cell therapy in advanced solid tumors: A phase I study","authors":"Chang Liu, Jiarui Li, Dan Liu, Panpan Zhang, Miao Zhang, Ran Xue, Jifang Gong, Lian Liu, Min Tao, Siyuan Cheng, Ting Xu, Jiajia Yuan, Yanshuo Cao, Zhenghang Wang, Yakun Wang, Jun Zhou, Ming Lu, Zhi Peng, Zhihao Lu, Jian Li, Xiaotian Zhang, Tian Wang, Min Wang, Licui Jiang, Huimin Meng, Lin Yang, Changsong Qi, Lin Shen","doi":"10.1158/1078-0432.ccr-25-4600","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-4600","url":null,"abstract":"Purpose: To evaluate the safety, pharmacokinetics, and preliminary clinical activity of UTAA06, an \"off-the-shelf\" allogeneic B7-H3-targeted chimeric antigen receptor (CAR)-Vδ1T cell therapy, in patients with pretreated, advanced B7-H3-positive solid tumors. Patients and Methods: In this first-in-human, phase I, dose-escalation study (NCT06372236), ten patients with advanced solid tumors (including gastric, colorectal, hepatocellular, ovarian, and neuroendocrine cancers) were enrolled. Following lymphodepletion chemotherapy (cyclophosphamide and fludarabine), patients received UTAA06 infusion across three dose levels (5×10⁸, 8×10⁸, or 1×10⁹ cells). The primary endpoint was safety. Secondary endpoints included pharmacokinetics and anti-tumor efficacy. Results: UTAA06 demonstrated a manageable safety profile; no graft-versus-host disease (GvHD) was observed, and cytokine release syndrome (CRS) was limited to two transient Grade 1 events. A single dose-limiting toxicity (Grade 3 pneumonitis) was reported in one patient at the 5×10⁸ cells dose level. While UTAA06 demonstrated signals of biological activity, including transient reductions in serum tumor markers in 50% of patients, no objective response by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria was observed. Further analysis identified that the limited CAR-T cell persistence was likely driven by subclinical host-versus-graft rejection (HvGR). Conclusions: This study provides clinical proof-of-concept for allogeneic B7-H3-targeted CAR-Vδ1T cells as a safe platform with low risk of GvHD and demonstrable biological activity in solid tumors. However, clinical efficacy was constrained by limited cellular persistence caused by host immune rejection. Future strategies are required to enhance the durability and therapeutic potential of this allogeneic approach.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"42 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350489","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}
Pub Date : 2026-03-04DOI: 10.1158/1078-0432.ccr-25-3953
Zhi Lin, Cheng Tang, Tong Liu, Xingyi Wang, Zaijie Wu, Fan Hu, Yongkang Gai, Weiwei Ruan, Xiao Zhang, Xiaoli Lan
Purpose: The study aims to compare the diagnostic performance of the novel melanin-targeted [18F]PFPN PET and [18F]FDG PET in mucosal melanoma, evaluate their impact on clinical staging, and assess correlations between imaging metrics and molecular markers. Experimental Design: This prospective study enrolled 65 participants with histologically confirmed mucosal melanoma from February 2021 to January 2025. All participants underwent both [18F]FDG PET and [18F]PFPN PET within one week. Lesion-based and participant-based analyses compared detection sensitivity, false-positive rate, and staging concordance. Quantitative PET parameters were analyzed, and correlations with HMB45, SOX10, MelanA, S100, and mutation status (BRAF, CKIT, NRAS) were evaluated using nonparametric tests, correlation analysis with Bonferroni correction. Decision curve analysis was used to evaluate clinical benefit. Results: Sixty-five participants were included. [18F]PFPN PET showed higher lesion-based sensitivity than [18F]FDG PET (363/399 [91.0%] vs 332/399 [83.2%]) and no false positives (0/363 [0%] vs 4/336 [1.2%]). Normalized SUVmax was significantly higher for [18F]PFPN across all lesion types (P < 0.05). PFPN-based staging was more consistent with clinical staging (6.2% vs 18.5% discordant cases). [18F]PFPN uptake showed significant positive correlations with HMB45 and SOX10 expression, while [18F]FDG parameters showed no such associations. Conclusion: [18F]PFPN PET outperforms [18F]FDG PET in lesion detection and clinical staging in mucosal melanoma, especially for liver and bone metastases. Its association with melanin differentiation markers may support its use in personalized imaging strategies.
目的：本研究旨在比较新型黑色素靶向[18F]PFPN PET和[18F]FDG PET在粘膜黑色素瘤中的诊断性能，评估其对临床分期的影响，并评估影像学指标与分子标志物之间的相关性。实验设计：本前瞻性研究于2021年2月至2025年1月招募了65名组织学证实的粘膜黑色素瘤患者。所有参与者在一周内都接受了[18F]FDG PET和[18F]PFPN PET检查。基于病变和基于参与者的分析比较了检测灵敏度、假阳性率和分期一致性。定量分析PET参数，并使用非参数检验、Bonferroni校正相关分析评估与HMB45、SOX10、MelanA、S100和突变状态（BRAF、CKIT、NRAS）的相关性。采用决策曲线分析法评价临床获益。结果：共纳入65名受试者。[18F]PFPN PET的病变敏感性高于[18F]FDG PET (363/399 [91.0%] vs 332/399[83.2%])，无假阳性（0/363 [0%]vs 4/336[1.2%]）。归一化SUVmax在所有病变类型中均显著高于[18F]PFPN （P < 0.05）。基于pfpn的分期与临床分期更为一致（6.2% vs 18.5%不一致的病例）。[18F]PFPN摄取与HMB45和SOX10表达呈显著正相关，而[18F]FDG参数未显示出这种相关性。结论：[18F]PFPN PET在粘膜黑色素瘤的病变检测和临床分期方面优于[18F]FDG PET，尤其是在肝脏和骨转移方面。它与黑色素分化标志物的关联可能支持其在个性化成像策略中的应用。
{"title":"Comparison of [18F]PFPN and [18F]FDG PET in mucosal melanoma: diagnostic performance, staging impact, and correlation with molecular markers","authors":"Zhi Lin, Cheng Tang, Tong Liu, Xingyi Wang, Zaijie Wu, Fan Hu, Yongkang Gai, Weiwei Ruan, Xiao Zhang, Xiaoli Lan","doi":"10.1158/1078-0432.ccr-25-3953","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-3953","url":null,"abstract":"Purpose: The study aims to compare the diagnostic performance of the novel melanin-targeted [18F]PFPN PET and [18F]FDG PET in mucosal melanoma, evaluate their impact on clinical staging, and assess correlations between imaging metrics and molecular markers. Experimental Design: This prospective study enrolled 65 participants with histologically confirmed mucosal melanoma from February 2021 to January 2025. All participants underwent both [18F]FDG PET and [18F]PFPN PET within one week. Lesion-based and participant-based analyses compared detection sensitivity, false-positive rate, and staging concordance. Quantitative PET parameters were analyzed, and correlations with HMB45, SOX10, MelanA, S100, and mutation status (BRAF, CKIT, NRAS) were evaluated using nonparametric tests, correlation analysis with Bonferroni correction. Decision curve analysis was used to evaluate clinical benefit. Results: Sixty-five participants were included. [18F]PFPN PET showed higher lesion-based sensitivity than [18F]FDG PET (363/399 [91.0%] vs 332/399 [83.2%]) and no false positives (0/363 [0%] vs 4/336 [1.2%]). Normalized SUVmax was significantly higher for [18F]PFPN across all lesion types (P &lt; 0.05). PFPN-based staging was more consistent with clinical staging (6.2% vs 18.5% discordant cases). [18F]PFPN uptake showed significant positive correlations with HMB45 and SOX10 expression, while [18F]FDG parameters showed no such associations. Conclusion: [18F]PFPN PET outperforms [18F]FDG PET in lesion detection and clinical staging in mucosal melanoma, especially for liver and bone metastases. Its association with melanin differentiation markers may support its use in personalized imaging strategies.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"227 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350578","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}
Pub Date : 2026-03-04DOI: 10.1158/1078-0432.ccr-25-3846
Ehsan Irajizad, Johannes F. Fahrmann, Ranran Wu, Hamid Rudsari, Jennifer B. Dennison, Edwin Ostrin, Jaffer Ajani, Samir Hanash
Purpose: Recent evidence suggests a significant association between microplastic (MPs), forever chemicals, and plasticizers and various diseases including cancer. Here, we evaluated the circulating levels of plastic-associated chemicals for lung cancer incidence and mortality among smokers in the Prostate Lung Colorectal and Ovarian (PLCO) study. Experimental Design: Using mass spectrometry, we screened for 29 known MPs, forever plastics (per- and polyfluoroalkyl substances [PFAS]), and plasticizers chemicals in 245 sera collected preceding a lung cancer diagnosis and 1,200 non-case sera from participants in the PLCO study who had a history of smoking. Five PFAS and 3 plasticizers were detected and quantified in sera. A PFAP model, consisting of PFOS + PFHA + mono-iso-nonyl-phthalate, was developed for predicting lung cancer mortality and risk strata based on quantiles established. Results: Higher circulating levels of PFOS, PFHA, and mono-iso-nonyl-phthalate were associated (p<0.05) with increased risk of lung cancer death but not incidence. Compared to the lowest quantile (reference), individuals with PFAP scores in the highest quantile were at markedly higher risk of death from lung cancer (p<0.0001), with respective cause-specific and sub-distributional HRs of 1.86 (95% CI: 1.18-2.93) and 1.82 (95% CI: 1.15 - 2.88). Sub-stratified analyses confirmed that the PFAP model remained an independent predictor of lung cancer–specific mortality (p < 0.05) across strata defined by age, sex, smoking history, histologic subtype, and stage at diagnosis. Conclusions: In the PLCO cohort elevated levels of PFOS, PFHA, and mono-iso-nonyl-phthalate were associated with increased lung cancer mortality among ever smokers across disease subgroups.
{"title":"Association of blood levels of forever plastics with lung cancer mortality among ever smokers in the Prostate Lung Colorectal and Ovarian (PLCO) cohort study.","authors":"Ehsan Irajizad, Johannes F. Fahrmann, Ranran Wu, Hamid Rudsari, Jennifer B. Dennison, Edwin Ostrin, Jaffer Ajani, Samir Hanash","doi":"10.1158/1078-0432.ccr-25-3846","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-3846","url":null,"abstract":"Purpose: Recent evidence suggests a significant association between microplastic (MPs), forever chemicals, and plasticizers and various diseases including cancer. Here, we evaluated the circulating levels of plastic-associated chemicals for lung cancer incidence and mortality among smokers in the Prostate Lung Colorectal and Ovarian (PLCO) study. Experimental Design: Using mass spectrometry, we screened for 29 known MPs, forever plastics (per- and polyfluoroalkyl substances [PFAS]), and plasticizers chemicals in 245 sera collected preceding a lung cancer diagnosis and 1,200 non-case sera from participants in the PLCO study who had a history of smoking. Five PFAS and 3 plasticizers were detected and quantified in sera. A PFAP model, consisting of PFOS + PFHA + mono-iso-nonyl-phthalate, was developed for predicting lung cancer mortality and risk strata based on quantiles established. Results: Higher circulating levels of PFOS, PFHA, and mono-iso-nonyl-phthalate were associated (p&lt;0.05) with increased risk of lung cancer death but not incidence. Compared to the lowest quantile (reference), individuals with PFAP scores in the highest quantile were at markedly higher risk of death from lung cancer (p&lt;0.0001), with respective cause-specific and sub-distributional HRs of 1.86 (95% CI: 1.18-2.93) and 1.82 (95% CI: 1.15 - 2.88). Sub-stratified analyses confirmed that the PFAP model remained an independent predictor of lung cancer–specific mortality (p &lt; 0.05) across strata defined by age, sex, smoking history, histologic subtype, and stage at diagnosis. Conclusions: In the PLCO cohort elevated levels of PFOS, PFHA, and mono-iso-nonyl-phthalate were associated with increased lung cancer mortality among ever smokers across disease subgroups.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"32 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350774","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}
Pub Date : 2026-03-04DOI: 10.1158/1078-0432.ccr-25-2854
Akitada Yogo, Naoki Akanuma, Grace E. Kim, Netta Mäkinen, Chrissie Thirlwell, Eric K. Nakakura
Purpose: Small intestinal neuroendocrine tumors (SI-NETs) frequently present as multifocal lesions, but the molecular mechanisms underlying their development and heterogeneity remain unclear. This study aimed to characterize the phenotypes of tumor cell populations across anatomical sites in multifocal SI-NET patients and identify local microenvironmental factors influencing tumor development. Experimental Design: Spatial transcriptomics was performed on 72 tissue microarray cores derived from four patients with multifocal SI-NETs that included tumoral and non-tumoral tissues from various anatomical layers of the small intestine and regional metastatic sites. Unsupervised clustering, over-representation analysis (ORA), and ligand-receptor (L-R) pair analysis were used to define the tumor cell subtypes and associated signaling networks. External datasets were used for validation. Protein expression of selected genes was evaluated by immunohistochemistry and immunofluorescence. Results: Unsupervised clustering revealed four major tumor cell subtypes, ‘mucosal’, ‘mesenteric’, ‘lymphatic’, and ‘deep’, based on their anatomical location and transcriptomic profiles. Each subtype exhibited distinct gene expression patterns and L-R interactions. The ‘mesenteric’ and ‘lymphatic’ subtypes exhibited distinct L-R pairs, such as NRG1 - ERBB3 (HER3) and CXCL12 - CXCR4, respectively. 5HT - HTR1D was found in all subtypes except ‘mucosal’. Across the four subtypes, SST - SSTR1/2,PTN - NCL, MDK - NCL and GJD2 - GJD2 were consistently detected, suggesting fundamental roles in SI-NET biology. Conclusions: While further validation is needed, our findings indicate that multifocal SI-NETs consist of spatially distinct tumor cell subtypes affected by local cellular interactions, providing insight into SI-NET intra-tumoral heterogeneity, possible microenvironmental-triggered tumorigenesis, and potential subtype-targeted therapeutic strategies.
{"title":"Spatial Transcriptomics Reveals Location-Specific Tumor Cell Subtypes and Signaling within Multifocal Small Intestinal Neuroendocrine Tumors","authors":"Akitada Yogo, Naoki Akanuma, Grace E. Kim, Netta Mäkinen, Chrissie Thirlwell, Eric K. Nakakura","doi":"10.1158/1078-0432.ccr-25-2854","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-2854","url":null,"abstract":"Purpose: Small intestinal neuroendocrine tumors (SI-NETs) frequently present as multifocal lesions, but the molecular mechanisms underlying their development and heterogeneity remain unclear. This study aimed to characterize the phenotypes of tumor cell populations across anatomical sites in multifocal SI-NET patients and identify local microenvironmental factors influencing tumor development. Experimental Design: Spatial transcriptomics was performed on 72 tissue microarray cores derived from four patients with multifocal SI-NETs that included tumoral and non-tumoral tissues from various anatomical layers of the small intestine and regional metastatic sites. Unsupervised clustering, over-representation analysis (ORA), and ligand-receptor (L-R) pair analysis were used to define the tumor cell subtypes and associated signaling networks. External datasets were used for validation. Protein expression of selected genes was evaluated by immunohistochemistry and immunofluorescence. Results: Unsupervised clustering revealed four major tumor cell subtypes, ‘mucosal’, ‘mesenteric’, ‘lymphatic’, and ‘deep’, based on their anatomical location and transcriptomic profiles. Each subtype exhibited distinct gene expression patterns and L-R interactions. The ‘mesenteric’ and ‘lymphatic’ subtypes exhibited distinct L-R pairs, such as NRG1 - ERBB3 (HER3) and CXCL12 - CXCR4, respectively. 5HT - HTR1D was found in all subtypes except ‘mucosal’. Across the four subtypes, SST - SSTR1/2,PTN - NCL, MDK - NCL and GJD2 - GJD2 were consistently detected, suggesting fundamental roles in SI-NET biology. Conclusions: While further validation is needed, our findings indicate that multifocal SI-NETs consist of spatially distinct tumor cell subtypes affected by local cellular interactions, providing insight into SI-NET intra-tumoral heterogeneity, possible microenvironmental-triggered tumorigenesis, and potential subtype-targeted therapeutic strategies.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"1 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350777","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}
Pub Date : 2026-03-04DOI: 10.1158/1078-0432.ccr-25-4948
Evan Y. Yu, Vivek Narayan, Giuseppe Esposito, Russell Szmulewitz, Yang Lu, Michael B. Lilly, Jeremie Calais, Gennady Bratslavsky, Yusuf Menda, Minal Vasanawala, Frédéric Pouliot, David Laidley, Neil Fleshner, Fred Saad, Jean-Claude Provost, Iryna Teslenko, Nand Kishore. Rawat, Gary Ulaner
Purpose: The phase 2 ARROW study was designed to evaluate radioligand therapy with 131I-LNTH-1095, an iodine-131–labeled small molecule targeting PSMA, in combination with enzalutamide in subjects with metastatic castration-resistant prostate cancer after progression on prior abiraterone therapy. Patients and Methods: Men ≥18 years with PSMA-positive prostate cancer (PSMA PET tracer uptake >1× liver SUVmean in all CT-measurable lesions) were randomized 2:1 to 131I-LNTH-1095 (4 cycles of 3.7 GBq/dose every 8 weeks)+enzalutamide (160 mg po qd) vs. enzalutamide alone. The primary endpoint was PSA50 response. Secondary endpoints included rPFS, ORR, OS, and safety. Results: Of 177 screened subjects, 120 were randomized (80: 131I-LNTH-1095+enzalutamide; 40: enzalutamide-monotherapy). PSA50 response was 62.9% (95% CI, 50.5-74.1) for 131I-LNTH-1095+enzalutamide vs. 31.3% (16.1-50.0) for enzalutamide alone (P=.003). Median rPFS was 14.0 months (95% CI: 8.64-18.20) for 131I-LNTH-1095+enzalutamide vs. 11.5 months (2.79–18.43) for enzalutamide alone (P=.10). Incidence of grade ≥3 treatment-emergent adverse events (TEAEs) was 65.8% for 131I-095+enzalutamide vs. 41.0% for enzalutamide-monotherapy; the most frequent TEAEs were fatigue (75.0 vs. 53.8%), nausea (59.2 vs. 33.3%), thrombocytopenia (51.3 vs. 0%), and decreased appetite (48.7 vs. 17.9%), respectively. Two deaths in the 131I-LNTH-1095+enzalutamide group were considered treatment-related. The study was not powered to detect rPFS and OS differences. Conclusions: 131I-LNTH-1095+enzalutamide was associated with a statistically significant improvement in PSA50 response compared to enzalutamide alone despite a lower dosing schedule (4 cycles of 3.7 GBq/dose every 8 weeks) than the other approved PSMA RLT agents. Grade ≥3 adverse events were more frequent with combination therapy, particularly hematologic toxicity. NCT03939689
目的：2期ARROW研究旨在评估131I-LNTH-1095（一种碘-131标记的靶向PSMA的小分子）联合恩杂鲁胺在既往阿比特龙治疗进展后转移性去势抵抗性前列腺癌患者中的放射配体治疗。患者和方法：年龄≥18岁的男性PSMA阳性前列腺癌（PSMA PET示踪剂摄取率为所有ct可测量病变的1倍肝脏SUVmean）随机分为2:1至131I-LNTH-1095（4个周期，每8周3.7 GBq/剂）+恩杂鲁胺（160 mg /次）vs单独恩杂鲁胺。主要终点为PSA50反应。次要终点包括rPFS、ORR、OS和安全性。结果：在177名筛选的受试者中，120名被随机分配（80名：131I-LNTH-1095+enzalutamide； 40名：enzalutamide单药治疗）。131I-LNTH-1095+enzalutamide的PSA50应答率为62.9% (95% CI, 50.5-74.1)，而单独enzalutamide的PSA50应答率为31.3% (16.1-50.0)（P= 0.003）。131I-LNTH-1095+enzalutamide的中位rPFS为14.0个月（95% CI: 8.64-18.20），而单独enzalutamide的中位rPFS为11.5个月（2.79-18.43）（P= 0.10）。131I-095+enzalutamide治疗后出现的≥3级不良事件（teae）的发生率为65.8%，而enzalutamide单药治疗为41.0%；最常见的teae分别是疲劳（75.0 vs. 53.8%）、恶心（59.2 vs. 33.3%）、血小板减少（51.3 vs. 0%）和食欲下降（48.7 vs. 17.9%）。131I-LNTH-1095+enzalutamide组中有2例死亡被认为与治疗有关。该研究没有检测rPFS和OS的差异。结论：与单独使用enzalutamide相比，131I-LNTH-1095+enzalutamide与PSA50反应的统计学显著改善相关，尽管其给药计划较低（每8周4个周期3.7 GBq/剂），但与其他批准的PSMA RLT药物相比。≥3级不良事件在联合治疗中更为常见，尤其是血液毒性。NCT03939689
{"title":"131I-LNTH-1095 Radioligand Therapy Plus Enzalutamide vs. Enzalutamide Alone in Men With PSMA-Avid Metastatic Castration-Resistant Prostate Cancer: A Phase 2 Study","authors":"Evan Y. Yu, Vivek Narayan, Giuseppe Esposito, Russell Szmulewitz, Yang Lu, Michael B. Lilly, Jeremie Calais, Gennady Bratslavsky, Yusuf Menda, Minal Vasanawala, Frédéric Pouliot, David Laidley, Neil Fleshner, Fred Saad, Jean-Claude Provost, Iryna Teslenko, Nand Kishore. Rawat, Gary Ulaner","doi":"10.1158/1078-0432.ccr-25-4948","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-4948","url":null,"abstract":"Purpose: The phase 2 ARROW study was designed to evaluate radioligand therapy with 131I-LNTH-1095, an iodine-131–labeled small molecule targeting PSMA, in combination with enzalutamide in subjects with metastatic castration-resistant prostate cancer after progression on prior abiraterone therapy. Patients and Methods: Men ≥18 years with PSMA-positive prostate cancer (PSMA PET tracer uptake &gt;1× liver SUVmean in all CT-measurable lesions) were randomized 2:1 to 131I-LNTH-1095 (4 cycles of 3.7 GBq/dose every 8 weeks)+enzalutamide (160 mg po qd) vs. enzalutamide alone. The primary endpoint was PSA50 response. Secondary endpoints included rPFS, ORR, OS, and safety. Results: Of 177 screened subjects, 120 were randomized (80: 131I-LNTH-1095+enzalutamide; 40: enzalutamide-monotherapy). PSA50 response was 62.9% (95% CI, 50.5-74.1) for 131I-LNTH-1095+enzalutamide vs. 31.3% (16.1-50.0) for enzalutamide alone (P=.003). Median rPFS was 14.0 months (95% CI: 8.64-18.20) for 131I-LNTH-1095+enzalutamide vs. 11.5 months (2.79–18.43) for enzalutamide alone (P=.10). Incidence of grade ≥3 treatment-emergent adverse events (TEAEs) was 65.8% for 131I-095+enzalutamide vs. 41.0% for enzalutamide-monotherapy; the most frequent TEAEs were fatigue (75.0 vs. 53.8%), nausea (59.2 vs. 33.3%), thrombocytopenia (51.3 vs. 0%), and decreased appetite (48.7 vs. 17.9%), respectively. Two deaths in the 131I-LNTH-1095+enzalutamide group were considered treatment-related. The study was not powered to detect rPFS and OS differences. Conclusions: 131I-LNTH-1095+enzalutamide was associated with a statistically significant improvement in PSA50 response compared to enzalutamide alone despite a lower dosing schedule (4 cycles of 3.7 GBq/dose every 8 weeks) than the other approved PSMA RLT agents. Grade ≥3 adverse events were more frequent with combination therapy, particularly hematologic toxicity. NCT03939689","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"27 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350353","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}
Pub Date : 2026-03-02DOI: 10.1158/1078-0432.CCR-25-3216
Rakesh Popat, Bradley Augustson, Paul Cannell, Keith Stockerl-Goldstein, Andrew Spencer, Amit Khot, Ajay Nooka, Nashita Patel, Ravi S Kasinathan, Astrid McKeown, Amy Curry, Rachel Rogers, Mehreen Shaikh, Fernando Carreno, Sumita Roy-Ghanta, Joanna Opalinska, Hang Quach
Purpose: The Phase 1/2 DREAMM-6 Arm B study (NCT03544281) explored belantamab mafodotin combined with bortezomib/dexamethasone (BVd) in relapsed/ refractory multiple myeloma (RRMM).
Patients and methods: Adults with RRMM were enrolled sequentially in two belantamab mafodotin (intravenous) dose-escalation (DE) cohorts (2.5 then 3.4 mg/kg every 3 weeks [Q3W]). Additional patients enrolled sequentially to eight dose-expansion cohorts: 1.9, 2.5, or 3.4 mg/kg Q3W; 2.5 or 3.4 mg/kg Q3W split dose (Days 1 and 8); 1.9 or 2.5 mg/kg Q6W; or 2.5 mg/kg in cycle 1 stepped down to 1.9 mg/kg Q6W thereafter. Patients received bortezomib twice weekly and dexamethasone four times weekly. Endpoints were dose-limiting toxicities (DLT; DE), adverse events (AEs), serious AEs (SAEs; DE and expansion), overall response rate (ORR; expansion), and pharmacokinetics.
Results: 107 patients (median 4 prior lines of therapy) received BVd (n=12-18/ cohort). Median follow-up was 15.2-25.4 months. No DLTs occurred during DE. The most common Grade 3/4 AE was keratopathy (53%). Protocol-defined ocular events (change in best corrected visual acuity and/or corneal examination findings) were reported in 93% of patients (Grade 3/4: 77%). Twenty-eight (26%) patients experienced any study treatment-related SAEs; 3 of 7 fatal SAEs had a treatment-related primary cause. ORR was 70% (95% CI: 60.5, 78.6). Higher initial exposures had higher probabilities of response and ocular events; lower exposures resulted in fewer deep responses, with small differences in ocular events.
Conclusion: BVd demonstrated manageable safety and clinical activity across all dosing cohorts in heavily pretreated RRMM, supporting the 2.5 mg/kg Q3W dose.
{"title":"Efficacy and Safety of Belantamab Mafodotin with Bortezomib Plus Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma: the DREAMM-6 Arm B Trial.","authors":"Rakesh Popat, Bradley Augustson, Paul Cannell, Keith Stockerl-Goldstein, Andrew Spencer, Amit Khot, Ajay Nooka, Nashita Patel, Ravi S Kasinathan, Astrid McKeown, Amy Curry, Rachel Rogers, Mehreen Shaikh, Fernando Carreno, Sumita Roy-Ghanta, Joanna Opalinska, Hang Quach","doi":"10.1158/1078-0432.CCR-25-3216","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-25-3216","url":null,"abstract":"<p><strong>Purpose: </strong>The Phase 1/2 DREAMM-6 Arm B study (NCT03544281) explored belantamab mafodotin combined with bortezomib/dexamethasone (BVd) in relapsed/ refractory multiple myeloma (RRMM).</p><p><strong>Patients and methods: </strong>Adults with RRMM were enrolled sequentially in two belantamab mafodotin (intravenous) dose-escalation (DE) cohorts (2.5 then 3.4 mg/kg every 3 weeks [Q3W]). Additional patients enrolled sequentially to eight dose-expansion cohorts: 1.9, 2.5, or 3.4 mg/kg Q3W; 2.5 or 3.4 mg/kg Q3W split dose (Days 1 and 8); 1.9 or 2.5 mg/kg Q6W; or 2.5 mg/kg in cycle 1 stepped down to 1.9 mg/kg Q6W thereafter. Patients received bortezomib twice weekly and dexamethasone four times weekly. Endpoints were dose-limiting toxicities (DLT; DE), adverse events (AEs), serious AEs (SAEs; DE and expansion), overall response rate (ORR; expansion), and pharmacokinetics.</p><p><strong>Results: </strong>107 patients (median 4 prior lines of therapy) received BVd (n=12-18/ cohort). Median follow-up was 15.2-25.4 months. No DLTs occurred during DE. The most common Grade 3/4 AE was keratopathy (53%). Protocol-defined ocular events (change in best corrected visual acuity and/or corneal examination findings) were reported in 93% of patients (Grade 3/4: 77%). Twenty-eight (26%) patients experienced any study treatment-related SAEs; 3 of 7 fatal SAEs had a treatment-related primary cause. ORR was 70% (95% CI: 60.5, 78.6). Higher initial exposures had higher probabilities of response and ocular events; lower exposures resulted in fewer deep responses, with small differences in ocular events.</p><p><strong>Conclusion: </strong>BVd demonstrated manageable safety and clinical activity across all dosing cohorts in heavily pretreated RRMM, supporting the 2.5 mg/kg Q3W dose.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147324903","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}
Pub Date : 2026-03-02DOI: 10.1158/1078-0432.CCR-25-2367
Yushang Yang, Xiaolong Yan, Hongjing Jiang, Mingqiang Kang, Xinyu Mei, Lijie Tan, Junfeng Liu, Wenting Du, Yang Shi, Zhang Zhang, Lei Liang, Yongde Liao, Longqi Chen
Purpose: To assess positron emission tomography/computed tomography (PET/CT)-guided neoadjuvant treatment with tislelizumab plus chemotherapy/chemoradiotherapy in patients with resectable esophageal squamous cell carcinoma (ESCC).
Patients and methods: RATIONALE-213, a multicenter, open-label, two-cohort phase II study, enrolled 70 patients with resectable ESCC. After one induction chemotherapy cycle, patients were categorized as PET responders (PET maximum standardized uptake value decrease ≥35%) or PET nonresponders (<35%). Subsequently, all patients received three cycles of tislelizumab 200 mg intravenously. In addition, PET responders received chemotherapy and PET nonresponders received chemoradiotherapy as neoadjuvant treatment followed by surgery. The primary endpoint was pathological complete response (pCR) rate.
Results: As of October 25, 2024 (median follow-up 25.5 months), pCR rates were 30.0% (95% CI, 11.9-54.3) in PET responders and 34.4% (95% CI, 18.6-53.2) in PET nonresponders. Higher pCR rates associated with higher baseline programmed cell death ligand 1 (PD-L1) Tumor Area Positivity (TAP) scores in both cohorts. One-year disease-free survival rates were 79.0% and 74.2%, and event-free survival rates were 87.1% and 67.8% respectively. Any-grade and grade ≥3 treatment-related adverse events (TRAEs) occurred in 93.3% and 50.0% of PET responders and 97.5% and 82.5% of PET nonresponders, with no new safety signals. The most common grade ≥3 TRAE was decreased neutrophil count (36.7% and 70.0%, respectively).
Conclusions: Tislelizumab with chemotherapy/chemoradiotherapy as neoadjuvant treatment for resectable ESCC yielded promising pCR rates and favorable survival outcomes with a tolerable safety profile in both PET-/CT-guided responders and PET nonresponders.
{"title":"PET/CT-Guided Neoadjuvant Tislelizumab Plus Chemotherapy/Chemoradiotherapy for Resectable Esophageal Squamous Cell Carcinoma: RATIONALE-213 Final Analysis.","authors":"Yushang Yang, Xiaolong Yan, Hongjing Jiang, Mingqiang Kang, Xinyu Mei, Lijie Tan, Junfeng Liu, Wenting Du, Yang Shi, Zhang Zhang, Lei Liang, Yongde Liao, Longqi Chen","doi":"10.1158/1078-0432.CCR-25-2367","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-25-2367","url":null,"abstract":"<p><strong>Purpose: </strong>To assess positron emission tomography/computed tomography (PET/CT)-guided neoadjuvant treatment with tislelizumab plus chemotherapy/chemoradiotherapy in patients with resectable esophageal squamous cell carcinoma (ESCC).</p><p><strong>Patients and methods: </strong>RATIONALE-213, a multicenter, open-label, two-cohort phase II study, enrolled 70 patients with resectable ESCC. After one induction chemotherapy cycle, patients were categorized as PET responders (PET maximum standardized uptake value decrease ≥35%) or PET nonresponders (<35%). Subsequently, all patients received three cycles of tislelizumab 200 mg intravenously. In addition, PET responders received chemotherapy and PET nonresponders received chemoradiotherapy as neoadjuvant treatment followed by surgery. The primary endpoint was pathological complete response (pCR) rate.</p><p><strong>Results: </strong>As of October 25, 2024 (median follow-up 25.5 months), pCR rates were 30.0% (95% CI, 11.9-54.3) in PET responders and 34.4% (95% CI, 18.6-53.2) in PET nonresponders. Higher pCR rates associated with higher baseline programmed cell death ligand 1 (PD-L1) Tumor Area Positivity (TAP) scores in both cohorts. One-year disease-free survival rates were 79.0% and 74.2%, and event-free survival rates were 87.1% and 67.8% respectively. Any-grade and grade ≥3 treatment-related adverse events (TRAEs) occurred in 93.3% and 50.0% of PET responders and 97.5% and 82.5% of PET nonresponders, with no new safety signals. The most common grade ≥3 TRAE was decreased neutrophil count (36.7% and 70.0%, respectively).</p><p><strong>Conclusions: </strong>Tislelizumab with chemotherapy/chemoradiotherapy as neoadjuvant treatment for resectable ESCC yielded promising pCR rates and favorable survival outcomes with a tolerable safety profile in both PET-/CT-guided responders and PET nonresponders.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147324134","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}
Pub Date : 2026-03-02DOI: 10.1158/1078-0432.CCR-25-3528
Richard S Finn, Masatoshi Kudo, Ivan Borbath, Julien Edeline, Stephane Cattan, Hans van Vlierberghe, Chris Verslype, Daniel Palmer, Per Stål, Sadahisa Ogasawara, Arndt Vogel, Stephen L Chan, Jennifer J Knox, Bruno Daniele, Amos Odeleye-Ajakaye, Ken Hatogai, Abby B Siegel, Ann-Lii Cheng, Jean-Luc Van Laethem
Purpose: In the phase 2 KEYNOTE-224 study, pembrolizumab showed durable antitumor activity and manageable safety in participants with sorafenib-treated (cohort 1) or treatment-naive (cohort 2) advanced hepatocellular carcinoma (HCC). We present data after a median follow-up of ~7 years for cohort 1 and ~5 years for cohort 2.
Participants and methods: Adults with advanced HCC received pembrolizumab 200 mg intravenously every 3 weeks until disease progression or unacceptable toxicity for ≤35 cycles. Primary end point was objective response rate (ORR) per RECIST v1.1 by blinded independent central review (BICR). Secondary end points included overall survival (OS), progression-free survival (PFS), and safety.
Results: Overall, 155 participants received ≥1 dose of pembrolizumab (cohort 1, n = 104; cohort 2, n = 51). Median follow-up was 83.0 months (range, 79.3-87.3) for cohort 1 and 58.8 (range, 55.3-60.8) for cohort 2. Median OS was 13.2 months (95% CI, 9.7-15.3) and 16.9 (95% CI, 8.3-23.1), respectively; 24/48-month OS rates were 31%/17% and 34%/20%. Median PFS was 4.9 months (95% CI, 3.5-7.0) and 4.3 (95% CI, 2.1-7.8), respectively. Treatment-related adverse events occurred in 76 participants (73.1%; grade 3-5, 27 [26.0%]) in cohort 1 and 28 participants (54.9%; grade 3-5, 8 [15.7%]) in cohort 2.
Conclusion: Pembrolizumab continued to show durable response and manageable safety in participants with advanced HCC with or without prior systemic therapy, with long-term effects on OS lasting beyond 48 months in some participants despite receiving study treatment for ≤2 years.
{"title":"Pembrolizumab Monotherapy in Sorafenib-Treated and Treatment-Naive Advanced Hepatocellular Carcinoma: Long-Term Follow-Up of Open-Label, Phase 2 KEYNOTE-224 Study.","authors":"Richard S Finn, Masatoshi Kudo, Ivan Borbath, Julien Edeline, Stephane Cattan, Hans van Vlierberghe, Chris Verslype, Daniel Palmer, Per Stål, Sadahisa Ogasawara, Arndt Vogel, Stephen L Chan, Jennifer J Knox, Bruno Daniele, Amos Odeleye-Ajakaye, Ken Hatogai, Abby B Siegel, Ann-Lii Cheng, Jean-Luc Van Laethem","doi":"10.1158/1078-0432.CCR-25-3528","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-25-3528","url":null,"abstract":"<p><strong>Purpose: </strong>In the phase 2 KEYNOTE-224 study, pembrolizumab showed durable antitumor activity and manageable safety in participants with sorafenib-treated (cohort 1) or treatment-naive (cohort 2) advanced hepatocellular carcinoma (HCC). We present data after a median follow-up of ~7 years for cohort 1 and ~5 years for cohort 2.</p><p><strong>Participants and methods: </strong>Adults with advanced HCC received pembrolizumab 200 mg intravenously every 3 weeks until disease progression or unacceptable toxicity for ≤35 cycles. Primary end point was objective response rate (ORR) per RECIST v1.1 by blinded independent central review (BICR). Secondary end points included overall survival (OS), progression-free survival (PFS), and safety.</p><p><strong>Results: </strong>Overall, 155 participants received ≥1 dose of pembrolizumab (cohort 1, n = 104; cohort 2, n = 51). Median follow-up was 83.0 months (range, 79.3-87.3) for cohort 1 and 58.8 (range, 55.3-60.8) for cohort 2. Median OS was 13.2 months (95% CI, 9.7-15.3) and 16.9 (95% CI, 8.3-23.1), respectively; 24/48-month OS rates were 31%/17% and 34%/20%. Median PFS was 4.9 months (95% CI, 3.5-7.0) and 4.3 (95% CI, 2.1-7.8), respectively. Treatment-related adverse events occurred in 76 participants (73.1%; grade 3-5, 27 [26.0%]) in cohort 1 and 28 participants (54.9%; grade 3-5, 8 [15.7%]) in cohort 2.</p><p><strong>Conclusion: </strong>Pembrolizumab continued to show durable response and manageable safety in participants with advanced HCC with or without prior systemic therapy, with long-term effects on OS lasting beyond 48 months in some participants despite receiving study treatment for ≤2 years.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147324895","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}
Pub Date : 2026-03-02DOI: 10.1158/1078-0432.CCR-25-3352
Avilasha Sinha, Riyad N H Seervai, Katie M Vlastelica, Molly Fisher Thomas, Noah I Hornick
Immune checkpoint inhibitors (ICI) have revolutionized cancer therapy, although their use is limited by immune-related adverse events (irAE)-off-target immune responses that can affect any organ, frequently lead to ICI discontinuation, and require immunosuppressive therapy. Barrier organs, including the skin, gastrointestinal tract, and lung, are among the tissues most frequently affected by irAEs. As barrier organs, these tissues share important functions in maintaining separation from the external environment, participating in gas and nutrient exchange, and initiating localized immune responses that balance protection with tolerance. In this review, we highlight common immunologic features of these barrier organs and how they contribute to the immunopathogenesis of tissue-specific irAEs. We specifically review the contribution of T lymphocytes, myeloid cells, interferons, interleukins, androgens, autoantibodies, oxygenation, and dysbiosis to irAE pathogenesis. Finally, we identify gaps in the understanding of shared immunologic mechanisms across barrier irAEs and highlight how an interdisciplinary approach to irAE treatment would improve the survival and quality of life of patients with cancer.
{"title":"When Checkpoint Inhibitors Break Barriers: Mechanisms and Challenges of irAEs of the Skin, Gastrointestinal Tract, and Lung.","authors":"Avilasha Sinha, Riyad N H Seervai, Katie M Vlastelica, Molly Fisher Thomas, Noah I Hornick","doi":"10.1158/1078-0432.CCR-25-3352","DOIUrl":"10.1158/1078-0432.CCR-25-3352","url":null,"abstract":"<p><p>Immune checkpoint inhibitors (ICI) have revolutionized cancer therapy, although their use is limited by immune-related adverse events (irAE)-off-target immune responses that can affect any organ, frequently lead to ICI discontinuation, and require immunosuppressive therapy. Barrier organs, including the skin, gastrointestinal tract, and lung, are among the tissues most frequently affected by irAEs. As barrier organs, these tissues share important functions in maintaining separation from the external environment, participating in gas and nutrient exchange, and initiating localized immune responses that balance protection with tolerance. In this review, we highlight common immunologic features of these barrier organs and how they contribute to the immunopathogenesis of tissue-specific irAEs. We specifically review the contribution of T lymphocytes, myeloid cells, interferons, interleukins, androgens, autoantibodies, oxygenation, and dysbiosis to irAE pathogenesis. Finally, we identify gaps in the understanding of shared immunologic mechanisms across barrier irAEs and highlight how an interdisciplinary approach to irAE treatment would improve the survival and quality of life of patients with cancer.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"835-849"},"PeriodicalIF":10.2,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12758644/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145888675","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}
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