Pub Date : 2025-03-05DOI: 10.1158/1078-0432.ccr-24-2618
Sumanta K. Pal, Alice Bernard-Tessier, Peter Grell, Xin Gao, Ritesh R. Kotecha, Joel Picus, Filippo de Braud, Shunji Takahashi, Alvin Wong, Cristina Suárez, Javier A. Otero, Nicole Kundamal, Xin Yang, Sherif Sharaby, Mike Roy, Patrizia Barzaghi-Rinaudo, Nizar M. Tannir
Background: Mutations or silencing of the von Hippel Lindau (VHL) tumor suppressor gene accumulates hypoxia-inducible factors (HIFs). HIF-2α is implicated in the oncogenesis of ~50% of patients with clear cell renal cell carcinoma (ccRCC) but, has been considered “undruggable”. DFF332, an orally administered novel allosteric inhibitor of HIF-2α showed dose-dependent antitumor efficacy in preclinical models of ccRCC. Methods: This first-in-human study evaluated the safety, tolerability, antitumor activity, pharmacokinetics, and pharmacodynamics of DFF332 in patients with heavily pretreated advanced ccRCC. Preliminary data from the dose escalation of DFF332 monotherapy, administered orally at 50 or 100 mg weekly or 25, 50, 100, or 150 mg once daily in 28-day treatment cycles is reported. Results: As of January 15, 2024, 40 patients (median age, 62.5 years) received DFF332 for a median duration of 12.1 weeks. Overall, 2 patients (5%) achieved a partial response and 19 (48%) achieved stable disease as the best overall response. DFF332 showed a favorable safety profile, with treatment-related adverse events (TRAEs) occurring in 25 patients (63%). Only 5 patients (13%) experienced treatment-related anemia, and no hypoxia was observed. The only serious TRAE, hypertension, was reported in 1 patient. The maximum tolerated dose wasn’t reached. Conclusions: While clinical responses were limited in the doses evaluated, dose exploration halted prematurely, making it difficult to draw definitive conclusions about the efficacy of DFF332. Further investigation is required to establish a recommended dose regimen, assess its efficacy and safety, and evaluate its full potential as a partner in combination studies.
{"title":"A phase I dose escalation study of the HIF-2 alpha inhibitor DFF332 in patients with advanced clear cell renal cell carcinoma","authors":"Sumanta K. Pal, Alice Bernard-Tessier, Peter Grell, Xin Gao, Ritesh R. Kotecha, Joel Picus, Filippo de Braud, Shunji Takahashi, Alvin Wong, Cristina Suárez, Javier A. Otero, Nicole Kundamal, Xin Yang, Sherif Sharaby, Mike Roy, Patrizia Barzaghi-Rinaudo, Nizar M. Tannir","doi":"10.1158/1078-0432.ccr-24-2618","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2618","url":null,"abstract":"Background: Mutations or silencing of the von Hippel Lindau (VHL) tumor suppressor gene accumulates hypoxia-inducible factors (HIFs). HIF-2α is implicated in the oncogenesis of ~50% of patients with clear cell renal cell carcinoma (ccRCC) but, has been considered “undruggable”. DFF332, an orally administered novel allosteric inhibitor of HIF-2α showed dose-dependent antitumor efficacy in preclinical models of ccRCC. Methods: This first-in-human study evaluated the safety, tolerability, antitumor activity, pharmacokinetics, and pharmacodynamics of DFF332 in patients with heavily pretreated advanced ccRCC. Preliminary data from the dose escalation of DFF332 monotherapy, administered orally at 50 or 100 mg weekly or 25, 50, 100, or 150 mg once daily in 28-day treatment cycles is reported. Results: As of January 15, 2024, 40 patients (median age, 62.5 years) received DFF332 for a median duration of 12.1 weeks. Overall, 2 patients (5%) achieved a partial response and 19 (48%) achieved stable disease as the best overall response. DFF332 showed a favorable safety profile, with treatment-related adverse events (TRAEs) occurring in 25 patients (63%). Only 5 patients (13%) experienced treatment-related anemia, and no hypoxia was observed. The only serious TRAE, hypertension, was reported in 1 patient. The maximum tolerated dose wasn’t reached. Conclusions: While clinical responses were limited in the doses evaluated, dose exploration halted prematurely, making it difficult to draw definitive conclusions about the efficacy of DFF332. Further investigation is required to establish a recommended dose regimen, assess its efficacy and safety, and evaluate its full potential as a partner in combination studies.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"15 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143560642","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 : 2025-03-05DOI: 10.1158/1078-0432.ccr-24-3753
Junsik Park, Je-Gun Joung, Myong Cheol Lim, Jungbok Lee, Byoung-Gie Kim, Jae-Weon Kim, So Jin Shin, Sunghoon Kim, Eunhyang Park, Chel Hun Choi, Hee Seung Kim, Sang Yoon Park, Jung-Yun Lee
Purpose: This open-label, investigator-initiated, phase II study was conducted to evaluate the safety, survival and neoadjuvant outcomes of NAC combined with dual immune checkpoint inhibitors in advanced-stage EOC. Patients and Methods: Between June 2019 and July 2021, 45 patients with unresectable stage III–IV EOC were enrolled. The patients received three cycles of NAC combined with durvalumab and tremelimumab. All patients underwent interval debulking surgery and received three cycles of durvalumab and adjuvant chemotherapy, followed by 12 cycles of durvalumab as maintenance therapy. The primary endpoint was the 12-month progression-free survival (PFS) rate; the secondary endpoints were the objective response rate (ORR) after NAC, a chemotherapy response score (CRS), pathologic complete response (pCR), overall survival (OS), and safety. The pre-planned exploratory analyses assessed the lymphocyte infiltration, PD-L1 expression, and genomic profiles of pre-treatment tumors. Results: The 12-month PFS rate was 65.9% (95% CI, 52.8–NE), while the 24- and 30-month PFS rates were 38.6% (95% CI, 26.7–NE) and 36.4% (95% CI, 24.7–NE), respectively. After NAC, the ORR was 86.7%, while 14 patients (31.1%) had a CRS 3, and five (11.1%) achieved pCR. The 30-month OS rate was 87.7%. The most common grade ≥ 3 adverse events was neutropenia (26.7%). In an exploratory analysis, patients with pre-NAC tumors showing PD-L1 (CPS) ≥1, high Mutation Signature 3, and a high extracellular matrix signature demonstrated improved PFS outcomes. Conclusions: NAC combined with dual immune checkpoint inhibitors is feasible for advanced-stage EOC and shows promising activity with a durable clinical response.
{"title":"Neoadjuvant Chemotherapy with Dual Immune Checkpoint Inhibitors for Advanced-Stage Ovarian Cancer: Final Analysis of TRU-D Phase II Nonrandomized Clinical Trial","authors":"Junsik Park, Je-Gun Joung, Myong Cheol Lim, Jungbok Lee, Byoung-Gie Kim, Jae-Weon Kim, So Jin Shin, Sunghoon Kim, Eunhyang Park, Chel Hun Choi, Hee Seung Kim, Sang Yoon Park, Jung-Yun Lee","doi":"10.1158/1078-0432.ccr-24-3753","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3753","url":null,"abstract":"Purpose: This open-label, investigator-initiated, phase II study was conducted to evaluate the safety, survival and neoadjuvant outcomes of NAC combined with dual immune checkpoint inhibitors in advanced-stage EOC. Patients and Methods: Between June 2019 and July 2021, 45 patients with unresectable stage III–IV EOC were enrolled. The patients received three cycles of NAC combined with durvalumab and tremelimumab. All patients underwent interval debulking surgery and received three cycles of durvalumab and adjuvant chemotherapy, followed by 12 cycles of durvalumab as maintenance therapy. The primary endpoint was the 12-month progression-free survival (PFS) rate; the secondary endpoints were the objective response rate (ORR) after NAC, a chemotherapy response score (CRS), pathologic complete response (pCR), overall survival (OS), and safety. The pre-planned exploratory analyses assessed the lymphocyte infiltration, PD-L1 expression, and genomic profiles of pre-treatment tumors. Results: The 12-month PFS rate was 65.9% (95% CI, 52.8–NE), while the 24- and 30-month PFS rates were 38.6% (95% CI, 26.7–NE) and 36.4% (95% CI, 24.7–NE), respectively. After NAC, the ORR was 86.7%, while 14 patients (31.1%) had a CRS 3, and five (11.1%) achieved pCR. The 30-month OS rate was 87.7%. The most common grade ≥ 3 adverse events was neutropenia (26.7%). In an exploratory analysis, patients with pre-NAC tumors showing PD-L1 (CPS) ≥1, high Mutation Signature 3, and a high extracellular matrix signature demonstrated improved PFS outcomes. Conclusions: NAC combined with dual immune checkpoint inhibitors is feasible for advanced-stage EOC and shows promising activity with a durable clinical response.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"303 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143560643","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 : 2025-03-04DOI: 10.1158/1078-0432.CCR-24-4368
Hao Yuan, Qun Chen, Kuirong Jiang, Courtney W Houchen, Yuqing Zhang, Min Li
The shared HLA-bound neoepitopes in pancreatic ductal adenocarcinoma (PDAC) represent a novel class of non-canonical antigens with single amino acid substitutions, resulting from translational errors. These peptides, shared across PDAC patients, showed higher immunogenicity than wild-type counterparts, offering potential candidates for specific immunotherapy development in PDAC.
{"title":"Shared HLA-Bound Neoepitopes Are New Targets for Pancreatic Cancer Immunotherapy.","authors":"Hao Yuan, Qun Chen, Kuirong Jiang, Courtney W Houchen, Yuqing Zhang, Min Li","doi":"10.1158/1078-0432.CCR-24-4368","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-4368","url":null,"abstract":"<p><p>The shared HLA-bound neoepitopes in pancreatic ductal adenocarcinoma (PDAC) represent a novel class of non-canonical antigens with single amino acid substitutions, resulting from translational errors. These peptides, shared across PDAC patients, showed higher immunogenicity than wild-type counterparts, offering potential candidates for specific immunotherapy development in PDAC.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143540408","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}
Purpose: Neoadjuvant anti-PD-1 immunotherapy combined with chemotherapy has shown promising pathological responses in various cancers, including oral squamous cell carcinoma (OSCC). However, the pathological response of lymph node (LN) metastases remains poorly understood. This study aims to systematically evaluate the pathological response rates (pRRs) of LN metastases in OSCC patients and identify potential targets to improve therapeutic outcomes. Experimental design: We assessed the pRRs of LN metastases and matched primary tumors (PTs) in OSCC patients enrolled in a randomized, two-arm, phase II clinical trial (NCT04649476). Single-cell and spatial transcriptomics and multiplex immunohistochemistry were performed to analyze the tumor microenvironment and identify potential therapeutic targets in LN metastases. A neoadjuvant orthotopic OSCC mouse model was established to evaluate the therapeutic potential of these targets. Results: We observed significant heterogeneity in pathological regression of LN metastases, with lower pRRs compared to PTs. pRRs in LN metastases were correlated with overall and disease-free survival in OSCC patients. We identified an abundance of macrophages in LN metastases exhibiting an unfolded protein response and activated PERK signaling. These macrophages contributed to an extracellular matrix-enriched microenvironment through interactions with fibroblasts, which hindered T cell-mediated cytotoxicity. Pharmacological inhibition of the PERK pathway significantly enhanced anti-PD-1 therapy in LN metastases and PTs in the mouse model. Conclusions: Our study confirms that the pathological response of LN metastases in OSCC patients undergoing neoadjuvant immunotherapy or immunochemotherapy is inferior to that of PTs. It suggests targeting the PERK pathway in macrophages could be a potential strategy to enhance treatment outcomes.
{"title":"PERK+ macrophages drive immunotherapy resistance in lymph node metastases of oral squamous cell carcinoma","authors":"Wei Zhang, Jin-Bang Li, Hai-Ming Liu, Kui-Ming Wang, Bo-Lin Xiao, Yi-Man Wang, Jia-Jie Liang, Jun Zeng, Lin-Zhou Zhang, Yang-Ying-Fan Feng, Qiu-Yun Fu, Xin-Xin Wang, Yu-Tong Liu, Xiao-Xia Cheng, Jing Li, Yu-Ying Zhang, Gao Zhang, Jia-Li Zhang, Zi-Li Yu, Zhe Shao, Xue-Peng Xiong, Jun Jia, Bing Liu, Gang Chen","doi":"10.1158/1078-0432.ccr-24-3135","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3135","url":null,"abstract":"Purpose: Neoadjuvant anti-PD-1 immunotherapy combined with chemotherapy has shown promising pathological responses in various cancers, including oral squamous cell carcinoma (OSCC). However, the pathological response of lymph node (LN) metastases remains poorly understood. This study aims to systematically evaluate the pathological response rates (pRRs) of LN metastases in OSCC patients and identify potential targets to improve therapeutic outcomes. Experimental design: We assessed the pRRs of LN metastases and matched primary tumors (PTs) in OSCC patients enrolled in a randomized, two-arm, phase II clinical trial (NCT04649476). Single-cell and spatial transcriptomics and multiplex immunohistochemistry were performed to analyze the tumor microenvironment and identify potential therapeutic targets in LN metastases. A neoadjuvant orthotopic OSCC mouse model was established to evaluate the therapeutic potential of these targets. Results: We observed significant heterogeneity in pathological regression of LN metastases, with lower pRRs compared to PTs. pRRs in LN metastases were correlated with overall and disease-free survival in OSCC patients. We identified an abundance of macrophages in LN metastases exhibiting an unfolded protein response and activated PERK signaling. These macrophages contributed to an extracellular matrix-enriched microenvironment through interactions with fibroblasts, which hindered T cell-mediated cytotoxicity. Pharmacological inhibition of the PERK pathway significantly enhanced anti-PD-1 therapy in LN metastases and PTs in the mouse model. Conclusions: Our study confirms that the pathological response of LN metastases in OSCC patients undergoing neoadjuvant immunotherapy or immunochemotherapy is inferior to that of PTs. It suggests targeting the PERK pathway in macrophages could be a potential strategy to enhance treatment outcomes.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"35 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143546207","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 : 2025-03-04DOI: 10.1158/1078-0432.ccr-24-3357
Timil H. Patel, Amy Corneli, Pamela Balcazar, Craig Lipset, Sara B. Calvert, Sabrena Mervin-Blake, Vinit Nalawade, Paul G. Kluetz
The COVID-19 pandemic disrupted cancer clinical trials, prompting sponsors to adopt decentralized clinical trial (DCT) elements to ensure patient safety and trial continuity. Supported by FDA emergency guidance, the FDA Oncology Center of Excellence, in collaboration with the Clinical Trials Transformation Initiative (CTTI), conducted an assessment of DCT elements in cancer trials leading to FDA approval during the pandemic. Between December 6, 2022, and January 17, 2023, CTTI collected survey data from trial sponsors about DCT elements used in response to the pandemic, implementation challenges, and anticipated future use. Out of 52 eligible trials, 19 responses were received from 13 sponsors, predominantly large pharmaceutical companies. The majority of trials (89%) included both U.S. and international sites, and nearly all sponsors (95%) adopted at least one DCT element during the pandemic. Key DCT elements included remote site monitoring (89%), telemedicine (68%), remote laboratory assessments (63%), and remote distribution of investigational products (58%). Main challenges encountered included institutional policies (83%), technology adoption (61%), and regulatory restrictions (56%). Despite challenges, sponsors showed strong intent to continue DCT use, especially for remote monitoring, patient-reported outcomes collection, and telemedicine. This study demonstrates the viability of DCT elements for generating FDA-approvable data, suggesting potential for expanded trial access and reduced patient burden. Continued attention to site-level challenges is needed to sustain DCT adoption in cancer clinical trials.
{"title":"Adoption of Decentralized Trial Elements in Cancer Clinical Trials Supporting FDA Approvals During COVID-19","authors":"Timil H. Patel, Amy Corneli, Pamela Balcazar, Craig Lipset, Sara B. Calvert, Sabrena Mervin-Blake, Vinit Nalawade, Paul G. Kluetz","doi":"10.1158/1078-0432.ccr-24-3357","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3357","url":null,"abstract":"The COVID-19 pandemic disrupted cancer clinical trials, prompting sponsors to adopt decentralized clinical trial (DCT) elements to ensure patient safety and trial continuity. Supported by FDA emergency guidance, the FDA Oncology Center of Excellence, in collaboration with the Clinical Trials Transformation Initiative (CTTI), conducted an assessment of DCT elements in cancer trials leading to FDA approval during the pandemic. Between December 6, 2022, and January 17, 2023, CTTI collected survey data from trial sponsors about DCT elements used in response to the pandemic, implementation challenges, and anticipated future use. Out of 52 eligible trials, 19 responses were received from 13 sponsors, predominantly large pharmaceutical companies. The majority of trials (89%) included both U.S. and international sites, and nearly all sponsors (95%) adopted at least one DCT element during the pandemic. Key DCT elements included remote site monitoring (89%), telemedicine (68%), remote laboratory assessments (63%), and remote distribution of investigational products (58%). Main challenges encountered included institutional policies (83%), technology adoption (61%), and regulatory restrictions (56%). Despite challenges, sponsors showed strong intent to continue DCT use, especially for remote monitoring, patient-reported outcomes collection, and telemedicine. This study demonstrates the viability of DCT elements for generating FDA-approvable data, suggesting potential for expanded trial access and reduced patient burden. Continued attention to site-level challenges is needed to sustain DCT adoption in cancer clinical trials.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"16 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143546206","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 : 2025-03-03DOI: 10.1158/1078-0432.ccr-24-2449
Raghida A. Bukhalid, Jeremy R. Duvall, Kelly Lancaster, Kalli C. Catcott, Naniye Malli Cetinbas, Travis Monnell, Caitlin Routhier, Joshua D. Thomas, Keith W. Bentley, Scott D. Collins, Elizabeth Ditty, Timothy K. Eitas, Eugene W. Kelleher, Pamela Shaw, Jahna Soomer-James, Elena Ter-Ovanesyan, Ling Xu, Jeffrey Zurita, Dorin Toader, Marc Damelin, Timothy B. Lowinger
Purpose: Targeted tumor delivery may be required to potentiate the clinical benefit of innate immune modulators. The objective of the study was to apply an antibody-drug conjugate approach to STING agonism and develop a clinical candidate. Methods: XMT-2056, a HER2-directed STING-agonist antibody-drug conjugate (ADC), was designed, built, and tested in pharmacology and toxicology studies. The ADC was compared to a clinical benchmark intravenously administered STING agonist. Results: XMT-2056 achieved tumor-targeted delivery of the STING agonist upon systemic administration in mice and induced innate anti-tumor immune responses; single dose administration of XMT-2056 induced tumor regression in a variety of tumor models with high and low HER2 expression. Notably, XMT-2056 demonstrated superior efficacy and reduced systemic inflammation compared to a free STING agonist. XMT-2056 exhibited concomitant immune-mediated killing of HER2-negative cells specifically in the presence of HER2-positive cancer cells, supporting the potential for activity against tumors with heterogenous HER2 expression. The antibody does not compete for binding with trastuzumab or pertuzumab, and a benefit was observed when combining XMT-2056 with each of these therapies as well as with trastuzumab-deruxtecan (T-Dxd) ADC. The combination of XMT-2056 with anti-PD-1 conferred benefit on anti-tumor activity and induced immunological memory. XMT-2056 was well tolerated in nonclinical toxicology studies. Conclusion: These data provide a robust preclinical characterization of XMT-2056 and provide rationale and strategy for its clinical testing.
{"title":"XMT-2056, a HER2-Directed STING Agonist Antibody-Drug Conjugate, Induces Innate Anti-Tumor Immune Responses by Acting on Cancer Cells and Tumor-Resident Immune Cells","authors":"Raghida A. Bukhalid, Jeremy R. Duvall, Kelly Lancaster, Kalli C. Catcott, Naniye Malli Cetinbas, Travis Monnell, Caitlin Routhier, Joshua D. Thomas, Keith W. Bentley, Scott D. Collins, Elizabeth Ditty, Timothy K. Eitas, Eugene W. Kelleher, Pamela Shaw, Jahna Soomer-James, Elena Ter-Ovanesyan, Ling Xu, Jeffrey Zurita, Dorin Toader, Marc Damelin, Timothy B. Lowinger","doi":"10.1158/1078-0432.ccr-24-2449","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2449","url":null,"abstract":"Purpose: Targeted tumor delivery may be required to potentiate the clinical benefit of innate immune modulators. The objective of the study was to apply an antibody-drug conjugate approach to STING agonism and develop a clinical candidate. Methods: XMT-2056, a HER2-directed STING-agonist antibody-drug conjugate (ADC), was designed, built, and tested in pharmacology and toxicology studies. The ADC was compared to a clinical benchmark intravenously administered STING agonist. Results: XMT-2056 achieved tumor-targeted delivery of the STING agonist upon systemic administration in mice and induced innate anti-tumor immune responses; single dose administration of XMT-2056 induced tumor regression in a variety of tumor models with high and low HER2 expression. Notably, XMT-2056 demonstrated superior efficacy and reduced systemic inflammation compared to a free STING agonist. XMT-2056 exhibited concomitant immune-mediated killing of HER2-negative cells specifically in the presence of HER2-positive cancer cells, supporting the potential for activity against tumors with heterogenous HER2 expression. The antibody does not compete for binding with trastuzumab or pertuzumab, and a benefit was observed when combining XMT-2056 with each of these therapies as well as with trastuzumab-deruxtecan (T-Dxd) ADC. The combination of XMT-2056 with anti-PD-1 conferred benefit on anti-tumor activity and induced immunological memory. XMT-2056 was well tolerated in nonclinical toxicology studies. Conclusion: These data provide a robust preclinical characterization of XMT-2056 and provide rationale and strategy for its clinical testing.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"23 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538608","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 : 2025-03-03DOI: 10.1158/1078-0432.CCR-24-2948
Khalid Jazieh, Jill Tsai, Sheila Solomon, Mojun Zhu, Frank A Sinicrope, Katrina S Pedersen, Martin E Fernandez-Zapico, Hao Xie
Purpose: KRAS G12C inhibitors can treat KRASG12C-mutant advanced colorectal cancers and pancreatic ductal adenocarcinomas (PDAC), but alterations in Kirsten rat sarcoma (KRAS), EGFR, BRAF, MAP2K1, and other genes bypass KRAS inhibition and reduce therapy efficacy. Our study evaluates the genetic landscape of candidate primary resistance alterations relevant to KRAS targeting in KRASG12C-mutant colorectal cancer and PDAC.
Experimental design: We analyzed two cohorts (national database and Mayo) of patients with advanced colorectal cancer or PDAC tested with next-generation sequencing of ctDNA via Guardant360. Cohorts were divided into three groups: KRASG12C alone (KRASG12C without a resistance gene), KRASG12C with resistance (KRASG12C and ≥1 candidate resistance gene), and KRAS not detected. Candidate resistance mutations were inferred from the reported literature.
Results: Among the national (13,603 colorectal cancer and 5,016 PDAC cases) and Mayo (741 colorectal cancer and 422 PDAC cases) cohorts, resistance alterations were identified in a considerable number of KRASG12C cases (46.5% of national colorectal cancer, 16.4% of national PDAC, 53.8% of Mayo colorectal cancer, and 36.4% of Mayo PDAC). The presence of resistance alterations was associated with a trend toward worse overall survival in KRASG12C colorectal cancer (P = 0.05).
Conclusions: Putative resistance alterations are prevalent in PDAC and colorectal cancer and may limit monotherapy efficacy. Identifying these alterations has potential implications in optimal patient selection for targeted therapies and the development of combination therapy strategies to overcome primary resistance.
{"title":"Identification of Candidate Alterations Mediating KRASG12C Inhibitor Resistance in Advanced Colorectal and Pancreatic Cancers.","authors":"Khalid Jazieh, Jill Tsai, Sheila Solomon, Mojun Zhu, Frank A Sinicrope, Katrina S Pedersen, Martin E Fernandez-Zapico, Hao Xie","doi":"10.1158/1078-0432.CCR-24-2948","DOIUrl":"10.1158/1078-0432.CCR-24-2948","url":null,"abstract":"<p><strong>Purpose: </strong>KRAS G12C inhibitors can treat KRASG12C-mutant advanced colorectal cancers and pancreatic ductal adenocarcinomas (PDAC), but alterations in Kirsten rat sarcoma (KRAS), EGFR, BRAF, MAP2K1, and other genes bypass KRAS inhibition and reduce therapy efficacy. Our study evaluates the genetic landscape of candidate primary resistance alterations relevant to KRAS targeting in KRASG12C-mutant colorectal cancer and PDAC.</p><p><strong>Experimental design: </strong>We analyzed two cohorts (national database and Mayo) of patients with advanced colorectal cancer or PDAC tested with next-generation sequencing of ctDNA via Guardant360. Cohorts were divided into three groups: KRASG12C alone (KRASG12C without a resistance gene), KRASG12C with resistance (KRASG12C and ≥1 candidate resistance gene), and KRAS not detected. Candidate resistance mutations were inferred from the reported literature.</p><p><strong>Results: </strong>Among the national (13,603 colorectal cancer and 5,016 PDAC cases) and Mayo (741 colorectal cancer and 422 PDAC cases) cohorts, resistance alterations were identified in a considerable number of KRASG12C cases (46.5% of national colorectal cancer, 16.4% of national PDAC, 53.8% of Mayo colorectal cancer, and 36.4% of Mayo PDAC). The presence of resistance alterations was associated with a trend toward worse overall survival in KRASG12C colorectal cancer (P = 0.05).</p><p><strong>Conclusions: </strong>Putative resistance alterations are prevalent in PDAC and colorectal cancer and may limit monotherapy efficacy. Identifying these alterations has potential implications in optimal patient selection for targeted therapies and the development of combination therapy strategies to overcome primary resistance.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"31 5","pages":"899-906"},"PeriodicalIF":10.0,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11879249/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536681","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}
Pub Date : 2025-03-03DOI: 10.1158/1078-0432.CCR-24-1977
Shailendra Kumar Maurya, Jenny A Jaramillo-Gómez, Asad Ur Rehman, Shailendra Kumar Gautam, Mahek Fatima, Md Arafat Khan, Mohd Ali Abbas Zaidi, Parvez Khan, Laiba Anwar, Zahraa Wajih Alsafwani, Ranjana K Kanchan, Sameer Mohiuddin, Ramesh Pothuraju, Raghupathy Vengoji, Ramakanth Chirravuri Venkata, Gopalakrishnan Natarajan, Rakesh Bhatia, Pranita Atri, NaveenKumar Perumal, Sanjib Chaudhary, Imayavaramban Lakshmanan, Sidharth Mahapatra, Geoffrey A Talmon, Jesse L Cox, Lynette M Smith, Juan A Santamaria-Barria, Apar Kishor Ganti, Jawed Akhtar Siddiqui, Diana M Cittelly, Surinder Kumar Batra, Mohd Wasim Nasser
Purpose: Breast cancer brain metastasis remains a significant clinical problem. Mucins have been implicated in metastasis; however, whether they are also involved in breast cancer brain metastasis remains unknown. We queried databases of patients with brain metastasis and found mucin 5AC (MUC5AC) to be upregulated and therefore sought to define the role of MUC5AC in breast cancer brain metastasis.
Experimental design: In silico dataset analysis, RNA-sequence profiling of patient samples and cell lines, analysis of patient serum samples, and in vitro/in vivo knockdown experiments were performed to determine the function of MUC5AC in breast cancer brain metastasis. Coimmunoprecipitation was used to unravel the interactions that can be therapeutically targeted.
Results: Global in silico transcriptomic analysis showed that MUC5AC is significantly higher in patients with breast cancer brain metastasis. Analysis of archived breast cancer brain metastasis tissue further revealed significantly higher expression of MUC5AC in all breast cancer subtypes, and high MUC5AC expression predicted poor survival in HER2+ breast cancer brain metastasis. We validated these observations in breast cancer brain metastatic cell lines and tissue samples. Interestingly, elevated levels of MUC5AC were detected in the sera of patients with breast cancer brain metastasis. MUC5AC silencing in breast cancer brain metastatic cells reduced their migration and adhesion in vitro and in brain metastasis in the intracardiac injection mouse model. We found high expression of cMET and CD44v6 in breast cancer brain metastasis, which increased MUC5AC expression via hepatocyte growth factor signaling. In addition, MUC5AC interacts with cMET and CD44v6, suggesting that MUC5AC promotes breast cancer brain metastasis via the cMET/CD44v6 axis. Inhibition of the MUC5AC/cMET/CD44v6 axis with the blood-brain barrier-permeable cMET inhibitor bozitinib (PLB1001) effectively inhibits breast cancer brain metastasis.
Conclusions: Our study establishes that the MUC5AC/cMET/CD44v6 axis is critical for breast cancer brain metastasis, and blocking this axis will be a novel therapeutic approach for breast cancer brain metastasis.
{"title":"Mucin 5AC Promotes Breast Cancer Brain Metastasis through cMET/CD44v6.","authors":"Shailendra Kumar Maurya, Jenny A Jaramillo-Gómez, Asad Ur Rehman, Shailendra Kumar Gautam, Mahek Fatima, Md Arafat Khan, Mohd Ali Abbas Zaidi, Parvez Khan, Laiba Anwar, Zahraa Wajih Alsafwani, Ranjana K Kanchan, Sameer Mohiuddin, Ramesh Pothuraju, Raghupathy Vengoji, Ramakanth Chirravuri Venkata, Gopalakrishnan Natarajan, Rakesh Bhatia, Pranita Atri, NaveenKumar Perumal, Sanjib Chaudhary, Imayavaramban Lakshmanan, Sidharth Mahapatra, Geoffrey A Talmon, Jesse L Cox, Lynette M Smith, Juan A Santamaria-Barria, Apar Kishor Ganti, Jawed Akhtar Siddiqui, Diana M Cittelly, Surinder Kumar Batra, Mohd Wasim Nasser","doi":"10.1158/1078-0432.CCR-24-1977","DOIUrl":"10.1158/1078-0432.CCR-24-1977","url":null,"abstract":"<p><strong>Purpose: </strong>Breast cancer brain metastasis remains a significant clinical problem. Mucins have been implicated in metastasis; however, whether they are also involved in breast cancer brain metastasis remains unknown. We queried databases of patients with brain metastasis and found mucin 5AC (MUC5AC) to be upregulated and therefore sought to define the role of MUC5AC in breast cancer brain metastasis.</p><p><strong>Experimental design: </strong>In silico dataset analysis, RNA-sequence profiling of patient samples and cell lines, analysis of patient serum samples, and in vitro/in vivo knockdown experiments were performed to determine the function of MUC5AC in breast cancer brain metastasis. Coimmunoprecipitation was used to unravel the interactions that can be therapeutically targeted.</p><p><strong>Results: </strong>Global in silico transcriptomic analysis showed that MUC5AC is significantly higher in patients with breast cancer brain metastasis. Analysis of archived breast cancer brain metastasis tissue further revealed significantly higher expression of MUC5AC in all breast cancer subtypes, and high MUC5AC expression predicted poor survival in HER2+ breast cancer brain metastasis. We validated these observations in breast cancer brain metastatic cell lines and tissue samples. Interestingly, elevated levels of MUC5AC were detected in the sera of patients with breast cancer brain metastasis. MUC5AC silencing in breast cancer brain metastatic cells reduced their migration and adhesion in vitro and in brain metastasis in the intracardiac injection mouse model. We found high expression of cMET and CD44v6 in breast cancer brain metastasis, which increased MUC5AC expression via hepatocyte growth factor signaling. In addition, MUC5AC interacts with cMET and CD44v6, suggesting that MUC5AC promotes breast cancer brain metastasis via the cMET/CD44v6 axis. Inhibition of the MUC5AC/cMET/CD44v6 axis with the blood-brain barrier-permeable cMET inhibitor bozitinib (PLB1001) effectively inhibits breast cancer brain metastasis.</p><p><strong>Conclusions: </strong>Our study establishes that the MUC5AC/cMET/CD44v6 axis is critical for breast cancer brain metastasis, and blocking this axis will be a novel therapeutic approach for breast cancer brain metastasis.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"921-935"},"PeriodicalIF":10.0,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11882111/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142930719","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}
Pub Date : 2025-03-03DOI: 10.1158/1078-0432.CCR-24-2523
Loren Michel, Antonio Jimeno, Ammar Sukari, J Thaddeus Beck, Joanne Chiu, Elizabeth Ahern, John Hilton, Caroline Even, Sylvie Zanetta, Sabeen Mekan, Jilpa Patel, Tia Wu, Ecaterina E Dumbrava
Purpose: Treatment options for advanced head and neck squamous cell carcinoma (HNSCC) previously treated with platinum-based chemotherapy and a PD-1 inhibitor are limited. Trophoblast cell-surface antigen 2 (Trop-2) is highly expressed in HNSCC. Sacituzumab govitecan (SG) is a Trop-2-directed antibody-drug conjugate approved for patients with certain previously treated solid tumors.
Patients and methods: TROPiCS-03 (NCT03964727) is an open-label, multicohort, phase II study evaluating SG in advanced solid tumors, including HNSCC. Adults with locally advanced or metastatic HNSCC that progressed following platinum-based chemotherapy and anti-PD-(L)1 therapy [given sequentially (either order) or in combination] were administered SG 10 mg/kg on days 1 and 8 of a 21-day cycle. The primary endpoint was the investigator-assessed objective response rate. Secondary endpoints included duration of response, clinical benefit rate, progression-free survival, overall survival, and safety.
Results: Patients (N = 43) received a median of 3 (range, 2-9) prior anticancer regimens. The objective response rate was 16% [95% confidence interval (CI), 7%-31%], with seven confirmed partial responses. The clinical benefit rate was 28% (95% CI, 15%-44%). The median (95% CI) duration of response, progression-free survival, and overall survival were 4.2 (2.6-not reached), 4.1 (2.6-5.8), and 9.0 (7.1-10.5) months, respectively. The most common treatment-emergent adverse events (TEAE) were diarrhea (47%), nausea (47%), and neutropenia (47%). Grade ≥3 TEAE occurred in 58% of patients. Three patients died from TEAE, with one event (septic shock) considered related to SG.
Conclusions: These data demonstrate the clinical potential of Trop-2-directed therapy in managing heavily pretreated patients with advanced HNSCC.
{"title":"Sacituzumab Govitecan in Patients with Relapsed/Refractory Advanced Head and Neck Squamous Cell Carcinoma: Results from the Phase II TROPiCS-03 Basket Study.","authors":"Loren Michel, Antonio Jimeno, Ammar Sukari, J Thaddeus Beck, Joanne Chiu, Elizabeth Ahern, John Hilton, Caroline Even, Sylvie Zanetta, Sabeen Mekan, Jilpa Patel, Tia Wu, Ecaterina E Dumbrava","doi":"10.1158/1078-0432.CCR-24-2523","DOIUrl":"10.1158/1078-0432.CCR-24-2523","url":null,"abstract":"<p><strong>Purpose: </strong>Treatment options for advanced head and neck squamous cell carcinoma (HNSCC) previously treated with platinum-based chemotherapy and a PD-1 inhibitor are limited. Trophoblast cell-surface antigen 2 (Trop-2) is highly expressed in HNSCC. Sacituzumab govitecan (SG) is a Trop-2-directed antibody-drug conjugate approved for patients with certain previously treated solid tumors.</p><p><strong>Patients and methods: </strong>TROPiCS-03 (NCT03964727) is an open-label, multicohort, phase II study evaluating SG in advanced solid tumors, including HNSCC. Adults with locally advanced or metastatic HNSCC that progressed following platinum-based chemotherapy and anti-PD-(L)1 therapy [given sequentially (either order) or in combination] were administered SG 10 mg/kg on days 1 and 8 of a 21-day cycle. The primary endpoint was the investigator-assessed objective response rate. Secondary endpoints included duration of response, clinical benefit rate, progression-free survival, overall survival, and safety.</p><p><strong>Results: </strong>Patients (N = 43) received a median of 3 (range, 2-9) prior anticancer regimens. The objective response rate was 16% [95% confidence interval (CI), 7%-31%], with seven confirmed partial responses. The clinical benefit rate was 28% (95% CI, 15%-44%). The median (95% CI) duration of response, progression-free survival, and overall survival were 4.2 (2.6-not reached), 4.1 (2.6-5.8), and 9.0 (7.1-10.5) months, respectively. The most common treatment-emergent adverse events (TEAE) were diarrhea (47%), nausea (47%), and neutropenia (47%). Grade ≥3 TEAE occurred in 58% of patients. Three patients died from TEAE, with one event (septic shock) considered related to SG.</p><p><strong>Conclusions: </strong>These data demonstrate the clinical potential of Trop-2-directed therapy in managing heavily pretreated patients with advanced HNSCC.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"832-838"},"PeriodicalIF":10.0,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142812233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-03DOI: 10.1158/1078-0432.CCR-23-2073
Vivek M Shastri, Lata Chauhan, Mohammed Gbadamosi, Todd A Alonzo, Yi-Cheng Wang, Richard Aplenc, Betsy A Hirsch, Edward A Kolb, Alan S Gamis, Soheil Meshinchi, Jatinder K Lamba
Purpose: Comprehensive pharmacogenomics (PGx) evaluation of calicheamicin pathway to identify predictive PGx markers of response to gemtuzumab ozogamicin (GO) treatment in acute myeloid leukemia (AML).
Experimental design: SNPs in DNA damage response (DDR) pathway genes were tested for association with event-free survival (EFS), overall survival (OS), and risk of relapse after induction 1 (RR1) in patients treated with standard chemotherapy consisting of Ara-C, daunorubicin, and etoposide (ADE) with or without addition of GO on COG-AAML03P1 and COGAAAML0531 trials (ADE+GO, n = 755; ADE n = 470). SNPs with significant association with any endpoint within ADE+GO arm but not in the ADE arm were tested using multi-SNP modeling to develop DDR_PGx7 score.
Results: Patients with low DDR_PGx7 score (<0) had significantly worse EFS [HR = 1.51, 95% confidence interval (CI: 1.21-1.89), P < 0.001], worse OS [HR = 1.59, 95% CI (1.22-2.08), P < 0.001], and higher RR1 [HR = 1.87, 95% CI (1.41-2.47), P < 0.0001] compared with patients with highDDR_PGx7 score (≥0)when treated withGO (ADE+GO cohort). However, no difference between low and high DDR_PGx7 score groups was observed for EFS, OS, and RR1 (all P > 0.3) in patients treated on ADE arm.
Conclusions: Our results suggest that DDR pathway-based pharmacogenomic score holds potential to predict outcome in patients treated with GO which consists of DNA damaging cytotoxin, calicheamicin. The potential clinical relevance for this score to personalize GO in AML requires further validation in independent and expanded cohorts.
{"title":"DNA Damage Response Pharmacogenomic (DDR_PGx) Score Predicts Response to Chemotherapy Consisting of Gemtuzumab Ozogamicin in Pediatric AML: A Report from the Children's Oncology Group.","authors":"Vivek M Shastri, Lata Chauhan, Mohammed Gbadamosi, Todd A Alonzo, Yi-Cheng Wang, Richard Aplenc, Betsy A Hirsch, Edward A Kolb, Alan S Gamis, Soheil Meshinchi, Jatinder K Lamba","doi":"10.1158/1078-0432.CCR-23-2073","DOIUrl":"10.1158/1078-0432.CCR-23-2073","url":null,"abstract":"<p><strong>Purpose: </strong>Comprehensive pharmacogenomics (PGx) evaluation of calicheamicin pathway to identify predictive PGx markers of response to gemtuzumab ozogamicin (GO) treatment in acute myeloid leukemia (AML).</p><p><strong>Experimental design: </strong>SNPs in DNA damage response (DDR) pathway genes were tested for association with event-free survival (EFS), overall survival (OS), and risk of relapse after induction 1 (RR1) in patients treated with standard chemotherapy consisting of Ara-C, daunorubicin, and etoposide (ADE) with or without addition of GO on COG-AAML03P1 and COGAAAML0531 trials (ADE+GO, n = 755; ADE n = 470). SNPs with significant association with any endpoint within ADE+GO arm but not in the ADE arm were tested using multi-SNP modeling to develop DDR_PGx7 score.</p><p><strong>Results: </strong>Patients with low DDR_PGx7 score (<0) had significantly worse EFS [HR = 1.51, 95% confidence interval (CI: 1.21-1.89), P < 0.001], worse OS [HR = 1.59, 95% CI (1.22-2.08), P < 0.001], and higher RR1 [HR = 1.87, 95% CI (1.41-2.47), P < 0.0001] compared with patients with highDDR_PGx7 score (≥0)when treated withGO (ADE+GO cohort). However, no difference between low and high DDR_PGx7 score groups was observed for EFS, OS, and RR1 (all P > 0.3) in patients treated on ADE arm.</p><p><strong>Conclusions: </strong>Our results suggest that DDR pathway-based pharmacogenomic score holds potential to predict outcome in patients treated with GO which consists of DNA damaging cytotoxin, calicheamicin. The potential clinical relevance for this score to personalize GO in AML requires further validation in independent and expanded cohorts.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"890-898"},"PeriodicalIF":10.0,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11233425/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139402047","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：