Pub Date : 2025-01-17DOI: 10.1158/1078-0432.ccr-24-2311
Eudocia Q. Lee, Brian M. Alexander, Carlos G. Romo, Jeffrey G. Supko, Nathalie Y.R. Agar, Zahra Talebi, Manmeet S. Ahluwalia, Arati S. Desai, Jorg Dietrich, Thomas J. Kaley, David M. Peereboom, Jennifer Gantchev, Gerard Baquer, Sandro Santagata, Naoko Takebe, Serena Desideri, Joy D. Fisher, Megan Sims, Xiaobu Ye, Keith L. Ligon, Louis B. Nabors, Stuart A. Grossman, Patrick Y. Wen
PURPOSE: Adavosertib is an oral small molecular inhibitor of Wee1. The Adult Brain Tumor Consortium performed a phase I study of adavosertib, radiation (RT) and temozolomide (TMZ) in newly diagnosed glioblastoma (GBM) as well as a surgical window of opportunity study in recurrent GBM. PATIENTS AND METHODS: The maximum tolerated dose (MTD) of adavosertib was determined in adult patients with newly diagnosed GBM using a standard 3+3 design in 2 separate cohorts: with concurrent RT/TMZ or with adjuvant TMZ. A combination cohort with both concurrent and adjuvant adavosertib at MTD followed. We also performed intratumoral drug distribution studies in recurrent GBM patients undergoing surgery. RESULTS: As separate cohorts, MTD for concurrent adavosertib with RT/TMZ was 200 mg daily M-F x 6 weeks during RT and for adjuvant adavosertib with TMZ was 425 mg daily for 5 days of each 28-day cycle. However, 6/12 patients experienced DLTs in the combination cohort. The mean ratio of the intratumoral-to-plasma concentration of adavosertib was 4.18 ± 3.36 for contrast-enhancing tissue and 0.74 ± 0.63 in non-enhancing tissue. CONCLUSIONS: Adavosertib 200 mg daily M-F x 6 weeks with RT/TMZ and 425 mg daily on a 5d/28d cycle with TMZ had an unacceptable DLT rate. Additional dose levels in combination cohorts resulted in DLTs and we deemed concurrent adavosertib too toxic for further examination. Adavosertib 425 mg daily on a 5d/28d cycle with adjuvant TMZ is the recommended phase II dose. Tissue PK in tissue homogenates and by microdialysis provided complementary information about drug penetration.
目的：Adavosertib是一种口服小分子Wee1抑制剂。成人脑肿瘤协会（Adult Brain Tumor Consortium）对新诊断的胶质母细胞瘤（GBM）进行了阿avosertib、放疗（RT）和替莫唑胺（TMZ）的I期研究，并对复发性GBM进行了手术机会窗口研究。患者和方法：采用标准的3+3设计，在2个单独的队列中确定adavosertib在新诊断的GBM成年患者中的最大耐受剂量（MTD）：同时使用RT/TMZ或辅助TMZ。随后是在MTD中同时使用和辅助使用阿伏替尼的联合队列。我们还对复发性GBM手术患者进行了肿瘤内药物分布研究。结果：作为单独的队列，阿avosertib与RT/TMZ同时治疗的MTD为每日200 mg M-F x 6周，辅助阿avosertib与TMZ治疗的MTD为每日425 mg，每28天一个周期，持续5天。然而，在联合队列中，6/12的患者经历了dlt。对比增强组adavosertib瘤内浓度与血浆浓度之比为4.18±3.36，非增强组为0.74±0.63。结论：Adavosertib每日200mg M-F x 6周与RT/TMZ联合使用，425 mg每日5d/28d与TMZ联合使用，其DLT率不可接受。在联合队列中，额外的剂量水平导致了dlt，我们认为并发的阿avosertib毒性太大，不宜进一步检查。Adavosertib 425 mg /天，5d/28d周期，辅助TMZ是推荐的II期剂量。组织匀浆中的组织PK和微透析提供了药物渗透的补充信息。
{"title":"Phase I study of adavosertib with radiation therapy and temozolomide in newly diagnosed glioblastoma and intratumoral drug levels in recurrent glioblastoma","authors":"Eudocia Q. Lee, Brian M. Alexander, Carlos G. Romo, Jeffrey G. Supko, Nathalie Y.R. Agar, Zahra Talebi, Manmeet S. Ahluwalia, Arati S. Desai, Jorg Dietrich, Thomas J. Kaley, David M. Peereboom, Jennifer Gantchev, Gerard Baquer, Sandro Santagata, Naoko Takebe, Serena Desideri, Joy D. Fisher, Megan Sims, Xiaobu Ye, Keith L. Ligon, Louis B. Nabors, Stuart A. Grossman, Patrick Y. Wen","doi":"10.1158/1078-0432.ccr-24-2311","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2311","url":null,"abstract":"PURPOSE: Adavosertib is an oral small molecular inhibitor of Wee1. The Adult Brain Tumor Consortium performed a phase I study of adavosertib, radiation (RT) and temozolomide (TMZ) in newly diagnosed glioblastoma (GBM) as well as a surgical window of opportunity study in recurrent GBM. PATIENTS AND METHODS: The maximum tolerated dose (MTD) of adavosertib was determined in adult patients with newly diagnosed GBM using a standard 3+3 design in 2 separate cohorts: with concurrent RT/TMZ or with adjuvant TMZ. A combination cohort with both concurrent and adjuvant adavosertib at MTD followed. We also performed intratumoral drug distribution studies in recurrent GBM patients undergoing surgery. RESULTS: As separate cohorts, MTD for concurrent adavosertib with RT/TMZ was 200 mg daily M-F x 6 weeks during RT and for adjuvant adavosertib with TMZ was 425 mg daily for 5 days of each 28-day cycle. However, 6/12 patients experienced DLTs in the combination cohort. The mean ratio of the intratumoral-to-plasma concentration of adavosertib was 4.18 ± 3.36 for contrast-enhancing tissue and 0.74 ± 0.63 in non-enhancing tissue. CONCLUSIONS: Adavosertib 200 mg daily M-F x 6 weeks with RT/TMZ and 425 mg daily on a 5d/28d cycle with TMZ had an unacceptable DLT rate. Additional dose levels in combination cohorts resulted in DLTs and we deemed concurrent adavosertib too toxic for further examination. Adavosertib 425 mg daily on a 5d/28d cycle with adjuvant TMZ is the recommended phase II dose. Tissue PK in tissue homogenates and by microdialysis provided complementary information about drug penetration.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"98 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142988519","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 : 2025-01-17DOI: 10.1158/1078-0432.ccr-24-3476
Michiel M. Smeenk, Judi N.A. van Diessen, Thierry N. Boellaard, Koen J. Hartemink, Jeltje F. de Vries, Vincent van der Noort, Sushil K. Badrising, Emilia C. Owers, Kim Monkhorst, Michel M. van den Heuvel, Willemijn S.M.E. Theelen
Background: The phase I Induction trial (NCT04287894) assessed the feasibility and safety of induction immunotherapy (IIT) prior to concurrent chemoradiotherapy (cCRT) in patients with locally advanced non-small cell lung cancer (NSCLC). Methods: Patients with unresectable stage II/III NSCLC were eligible for inclusion. Patients received either one cycle of tremelimumab (75mg) with two cycles of durvalumab (1500mg) in cohort I, one cycle of tremelimumab (300mg) with two cycles of durvalumab in cohort II or one cycle of tremelimumab (300mg) with one cycle of durvalumab in cohort III. After IIT, a comprehensive radiological and pathological restaging was performed followed by cCRT. The combined primary endpoint was feasibility and safety of IIT-cCRT. Results: Fifteen of seventeen included patients were treated per-protocol. IIT-cCRT was completed in 13/15 of the patients within the predefined feasibility criteria. Grade ≥3 immune-related adverse events (irAEs) occurred in 7/15 patients, of which 6 were treated in the high-dose tremelimumab cohorts, thereby violating the safety criteria in cohorts II and III. The low-dose tremelimumab cohort (I) complied with safety criteria. Eleven patients had multilevel N2 or N3 disease at baseline, eight of these patients were downstaged to either N0/1 or single level N2 after IIT. Multiparametric MRI accurately identified nodal downstaging in 7/7 patients. Conclusion: Induction with high-dose tremelimumab plus durvalumab prior to cCRT in unresectable locally advanced NSCLC was associated with unacceptable toxicity, although ITT resulted in clinically relevant nodal downstaging in 8/11 of patients with baseline multilevel N2 or N3 disease. Multiparametric MRI showed potential evaluating treatment response.
{"title":"Tremelimumab plus durvalumab prior to chemoradiotherapy in unresectable, locally advanced non-small cell lung cancer: the Induction trial.","authors":"Michiel M. Smeenk, Judi N.A. van Diessen, Thierry N. Boellaard, Koen J. Hartemink, Jeltje F. de Vries, Vincent van der Noort, Sushil K. Badrising, Emilia C. Owers, Kim Monkhorst, Michel M. van den Heuvel, Willemijn S.M.E. Theelen","doi":"10.1158/1078-0432.ccr-24-3476","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3476","url":null,"abstract":"Background: The phase I Induction trial (NCT04287894) assessed the feasibility and safety of induction immunotherapy (IIT) prior to concurrent chemoradiotherapy (cCRT) in patients with locally advanced non-small cell lung cancer (NSCLC). Methods: Patients with unresectable stage II/III NSCLC were eligible for inclusion. Patients received either one cycle of tremelimumab (75mg) with two cycles of durvalumab (1500mg) in cohort I, one cycle of tremelimumab (300mg) with two cycles of durvalumab in cohort II or one cycle of tremelimumab (300mg) with one cycle of durvalumab in cohort III. After IIT, a comprehensive radiological and pathological restaging was performed followed by cCRT. The combined primary endpoint was feasibility and safety of IIT-cCRT. Results: Fifteen of seventeen included patients were treated per-protocol. IIT-cCRT was completed in 13/15 of the patients within the predefined feasibility criteria. Grade ≥3 immune-related adverse events (irAEs) occurred in 7/15 patients, of which 6 were treated in the high-dose tremelimumab cohorts, thereby violating the safety criteria in cohorts II and III. The low-dose tremelimumab cohort (I) complied with safety criteria. Eleven patients had multilevel N2 or N3 disease at baseline, eight of these patients were downstaged to either N0/1 or single level N2 after IIT. Multiparametric MRI accurately identified nodal downstaging in 7/7 patients. Conclusion: Induction with high-dose tremelimumab plus durvalumab prior to cCRT in unresectable locally advanced NSCLC was associated with unacceptable toxicity, although ITT resulted in clinically relevant nodal downstaging in 8/11 of patients with baseline multilevel N2 or N3 disease. Multiparametric MRI showed potential evaluating treatment response.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"30 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142988520","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 : 2025-01-17DOI: 10.1158/1078-0432.ccr-24-1934
Caiming Xu, Alessandro Mannucci, Francis Esposito, Helena Oliveres, Vicente Alonso Orduña, Alfonso Yubero, Carlos Fernández-Martos, Antonieta Salud, Javier Gallego, Marta Martin-Richard, Julen Fernández-Plana, Monica Guillot, Jorge Aparicio, Marwan Fakih, Scott Kopetz, Jaime Feliu, Joan Maurel, Ajay Goel
PURPOSE EXONERATE (EXOsome and cell-free micro-RNAs of anti-EGFR ResistAnce) was an open-label, biomarker interventional study designed to develop, test, and validate a liquid biopsy predictive of progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) for first-line EGFR inhibitors in metastatic colorectal cancer (mCRC). PATIENTS AND METHODS Patients with newly diagnosed RAS-WT, chemotherapy-naïve mCRC, both right- and left-sided, were enrolled in 2-nationwide trials to receive cetuximab or panitumumab along with chemotherapy. The primary endpoint was 12-month PFS, which was hierarchically tested in left- and right-sided mCRC to predict PFS, OS, and ORR. RESULTS Genome-wide small-RNA sequencing identified 12 cell-free and 14 exosomal candidates that were differentially expressed in both plasma and tumor tissue of good vs. poor responders (based on PFS <12 months). The 8 and 9 best-performing candidates, respectively, were used to generate the EXONERATE assay. In left-sided mCRC, 65% were EXONERATE-high, correlating with shorter mPFS (9.5 vs. 18.5 months, p<0.001). In the independent right-sided mCRC cohort, 80.8% were EXONERATE-high and experienced a similarly shorter mPFS (8.6 vs. 41.2 months, p=0.0004). In the right-sided group, EXONERATE predicted PFS≥12 months with 100% sensitivity. A linear relationship existed between EXONERATE values and response depth. Multivariate analysis revealed that EXONERATE predicts PFS and OS independently of tumor-sidedness. CONCLUSION The EXONERATE assay robustly predicted PFS and OS outcomes in patients with mCRC, both right- and left-sided, before they received either panitumumab or cetuximab. It stratified PFS, OS, and ORR better than a right vs. left approach.
{"title":"An exosome-based liquid biopsy predicts depth of response and survival outcomes to cetuximab and panitumumab in metastatic colorectal cancer: The EXONERATE Study.","authors":"Caiming Xu, Alessandro Mannucci, Francis Esposito, Helena Oliveres, Vicente Alonso Orduña, Alfonso Yubero, Carlos Fernández-Martos, Antonieta Salud, Javier Gallego, Marta Martin-Richard, Julen Fernández-Plana, Monica Guillot, Jorge Aparicio, Marwan Fakih, Scott Kopetz, Jaime Feliu, Joan Maurel, Ajay Goel","doi":"10.1158/1078-0432.ccr-24-1934","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1934","url":null,"abstract":"PURPOSE EXONERATE (EXOsome and cell-free micro-RNAs of anti-EGFR ResistAnce) was an open-label, biomarker interventional study designed to develop, test, and validate a liquid biopsy predictive of progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) for first-line EGFR inhibitors in metastatic colorectal cancer (mCRC). PATIENTS AND METHODS Patients with newly diagnosed RAS-WT, chemotherapy-naïve mCRC, both right- and left-sided, were enrolled in 2-nationwide trials to receive cetuximab or panitumumab along with chemotherapy. The primary endpoint was 12-month PFS, which was hierarchically tested in left- and right-sided mCRC to predict PFS, OS, and ORR. RESULTS Genome-wide small-RNA sequencing identified 12 cell-free and 14 exosomal candidates that were differentially expressed in both plasma and tumor tissue of good vs. poor responders (based on PFS &lt;12 months). The 8 and 9 best-performing candidates, respectively, were used to generate the EXONERATE assay. In left-sided mCRC, 65% were EXONERATE-high, correlating with shorter mPFS (9.5 vs. 18.5 months, p&lt;0.001). In the independent right-sided mCRC cohort, 80.8% were EXONERATE-high and experienced a similarly shorter mPFS (8.6 vs. 41.2 months, p=0.0004). In the right-sided group, EXONERATE predicted PFS≥12 months with 100% sensitivity. A linear relationship existed between EXONERATE values and response depth. Multivariate analysis revealed that EXONERATE predicts PFS and OS independently of tumor-sidedness. CONCLUSION The EXONERATE assay robustly predicted PFS and OS outcomes in patients with mCRC, both right- and left-sided, before they received either panitumumab or cetuximab. It stratified PFS, OS, and ORR better than a right vs. left approach.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"205 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142988521","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 : 2025-01-17DOI: 10.1158/1078-0432.CCR-24-2247
Kendra K Radtke, Brendan C Bender, Zao Li, David C Turner, Sumedha Roy, Anton Belousov, Chi-Chung Li
Cytokine release syndrome (CRS) is a common acute toxicity in T-cell therapies, including T-cell-engaging bispecific antibodies (T-BiSp). Effective CRS management and prevention are crucial in T-BiSp development. Required hospitalization for seven of the nine approved T-BiSp and the need for clinical intervention in severe cases highlight the importance of mitigation strategies to reduce health care burden and improve patient outcomes. In this review, we discuss the emerging evidence on CRS mitigation, management, and prediction. We cover different strategies for dose optimization, current and emerging (pre) treatment strategies, quantitative pharmacology tools used during drug development, and biomarkers and predictive factors. Insights are gleaned on step-up dosing and formulation effects on CRS and CRS relationships with cytokine dynamics and drug levels gathered through a review of T-BiSp licensing applications and emerging data from conferences and publications.
{"title":"Clinical Pharmacology of Cytokine Release Syndrome with T-Cell-Engaging Bispecific Antibodies: Current Insights and Drug Development Strategies.","authors":"Kendra K Radtke, Brendan C Bender, Zao Li, David C Turner, Sumedha Roy, Anton Belousov, Chi-Chung Li","doi":"10.1158/1078-0432.CCR-24-2247","DOIUrl":"10.1158/1078-0432.CCR-24-2247","url":null,"abstract":"<p><p>Cytokine release syndrome (CRS) is a common acute toxicity in T-cell therapies, including T-cell-engaging bispecific antibodies (T-BiSp). Effective CRS management and prevention are crucial in T-BiSp development. Required hospitalization for seven of the nine approved T-BiSp and the need for clinical intervention in severe cases highlight the importance of mitigation strategies to reduce health care burden and improve patient outcomes. In this review, we discuss the emerging evidence on CRS mitigation, management, and prediction. We cover different strategies for dose optimization, current and emerging (pre) treatment strategies, quantitative pharmacology tools used during drug development, and biomarkers and predictive factors. Insights are gleaned on step-up dosing and formulation effects on CRS and CRS relationships with cytokine dynamics and drug levels gathered through a review of T-BiSp licensing applications and emerging data from conferences and publications.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"245-257"},"PeriodicalIF":10.0,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739781/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667404","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 : 2025-01-17DOI: 10.1158/1078-0432.CCR-24-1728
Randy F Sweis, Gurkamal S Chatta, Rohit K Jain, Helen Moon, Scott Edward Delacroix, Alana Fang, Leonard D'Amico, Angela Shaulov Kask, Martin A Cheever, Steven Fling, Elad Sharon, Andreanne Lacroix, Judith C Kaiser, Russell K Pachynski, Evan Y Yu
Purpose: Advanced urothelial cancer generally has high mortality despite modern anti-PD-1/L1 antibody-based combinations. Augmenting checkpoint inhibitor-mediated immune responses with lymphocyte growth factors may improve outcomes. We conducted a randomized phase II study (Cancer Immunotherapy Trials Network-14) in 47 patients to explore whether human recombinant IL-7 (CYT107) could be safely combined with PD-L1 inhibition to enhance responses.
Patients and methods: Patients with urothelial cancer after platinum chemotherapy were randomized to atezolizumab alone or with CYT107 weekly for four doses. The primary objective was clinical efficacy by the objective response rate (ORR). Secondary objectives included safety, toxicity, and other clinical outcomes. Correlative endpoints included peripheral immunophenotyping and quantification of cytokines.
Results: CYT107 plus atezolizumab was well-tolerated, without dose-limiting toxicities and lower grade 3 to 4 treatment-related adverse events compared with atezolizumab monotherapy. The ORR was 26.3% for the combination therapy versus 23.8% for atezolizumab alone (P = 0.428). The complete response rate was 10.5% for the combination therapy versus 4.8% for monotherapy. Three patients on combination therapy had responses >21 months versus one with monotherapy. CD4+ and CD8+ T-lymphocyte expansion occurred in patients with response to combination therapy, with the greatest effect in T memory stem cells. Patients who responded to treatment exhibited elevated baseline levels of CCL4 and reduced levels of VEGFA and TNF.
Conclusions: Combining CYT107 with atezolizumab was safe and resulted in lymphocyte expansion, a doubling of the complete response rate, and durable responses exceeding 2 years. However, the ORR was similar to atezolizumab alone. Increased and sustained doses of CYT107 coupled with patient selection strategies should be further investigated.
{"title":"A Phase II Open-Label, Randomized Clinical Trial of Atezolizumab with or without Human Recombinant IL-7 (CYT107) in Advanced Urothelial Cancer.","authors":"Randy F Sweis, Gurkamal S Chatta, Rohit K Jain, Helen Moon, Scott Edward Delacroix, Alana Fang, Leonard D'Amico, Angela Shaulov Kask, Martin A Cheever, Steven Fling, Elad Sharon, Andreanne Lacroix, Judith C Kaiser, Russell K Pachynski, Evan Y Yu","doi":"10.1158/1078-0432.CCR-24-1728","DOIUrl":"10.1158/1078-0432.CCR-24-1728","url":null,"abstract":"<p><strong>Purpose: </strong>Advanced urothelial cancer generally has high mortality despite modern anti-PD-1/L1 antibody-based combinations. Augmenting checkpoint inhibitor-mediated immune responses with lymphocyte growth factors may improve outcomes. We conducted a randomized phase II study (Cancer Immunotherapy Trials Network-14) in 47 patients to explore whether human recombinant IL-7 (CYT107) could be safely combined with PD-L1 inhibition to enhance responses.</p><p><strong>Patients and methods: </strong>Patients with urothelial cancer after platinum chemotherapy were randomized to atezolizumab alone or with CYT107 weekly for four doses. The primary objective was clinical efficacy by the objective response rate (ORR). Secondary objectives included safety, toxicity, and other clinical outcomes. Correlative endpoints included peripheral immunophenotyping and quantification of cytokines.</p><p><strong>Results: </strong>CYT107 plus atezolizumab was well-tolerated, without dose-limiting toxicities and lower grade 3 to 4 treatment-related adverse events compared with atezolizumab monotherapy. The ORR was 26.3% for the combination therapy versus 23.8% for atezolizumab alone (P = 0.428). The complete response rate was 10.5% for the combination therapy versus 4.8% for monotherapy. Three patients on combination therapy had responses >21 months versus one with monotherapy. CD4+ and CD8+ T-lymphocyte expansion occurred in patients with response to combination therapy, with the greatest effect in T memory stem cells. Patients who responded to treatment exhibited elevated baseline levels of CCL4 and reduced levels of VEGFA and TNF.</p><p><strong>Conclusions: </strong>Combining CYT107 with atezolizumab was safe and resulted in lymphocyte expansion, a doubling of the complete response rate, and durable responses exceeding 2 years. However, the ORR was similar to atezolizumab alone. Increased and sustained doses of CYT107 coupled with patient selection strategies should be further investigated.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"299-307"},"PeriodicalIF":10.0,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11747792/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142686251","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 : 2025-01-17DOI: 10.1158/1078-0432.ccr-24-3460
David E. Gerber, Claire R. Wynters, Tanushree Prasad, Ronny K. Schnel, Song Zhang, Thomas E. Stinchcombe, Liza C. Villaruz, Joshua M. Bauml, Wade T. Iams, Tejas Patil, Stephen V. Liu, Leora Horn, John M. Hudak, D. Ross. Camidge
Background: Investigator-initiated trials (IITs) may address important biological and clinical questions that may not be prioritized by pharmaceutical sponsors. However, little is known about the process by which IIT proposals are evaluated and activated. Methods: We performed a retrospective study of IIT concepts submitted through the Academic Thoracic Oncology Medical Investigators Consortium (ATOMIC), which comprises 13 institutions in the U.S. and Canada, from 2014 (consortium inception) to 2024. We compared approved and disapproved concepts using chi-squared tests, Fisher’s exact tests, and Wilcoxon Rank-Sum tests. Results: Among a total of 68 presented IIT concepts, 60 (88%) received consortium approval a median of 30 days (interquartile range [IQR] 31-59 days) after submission. Concepts submitted by junior faculty were more likely to be approved than those from full professors (P=0.003). Of the 60 concepts subsequently submitted to pharmaceutical sponsors, 15 (25%) were approved, 43 (72%) were disapproved, and 2 (3%) remain under review. The median time between concept submission to a sponsor and the sponsor’s decision was 61 days (IQR 31-183 days). Concepts with shorter projected durations were more likely to be approved by the pharmaceutical sponsor (P=0.05). For sponsor-approved IIT concepts, median overall time from initial submission to trial activation was 18 months. Conclusions: Only a small proportion of proposed investigator-initiated cancer clinical trials are successfully activated following a prolonged development process. Given the importance of IITs in addressing real-world, practical questions and the growing professional challenges facing clinical research physician faculty, further attention to IIT development facilitators and barriers is warranted.
{"title":"Development, review, and activation of thoracic oncology investigator-initiated trials","authors":"David E. Gerber, Claire R. Wynters, Tanushree Prasad, Ronny K. Schnel, Song Zhang, Thomas E. Stinchcombe, Liza C. Villaruz, Joshua M. Bauml, Wade T. Iams, Tejas Patil, Stephen V. Liu, Leora Horn, John M. Hudak, D. Ross. Camidge","doi":"10.1158/1078-0432.ccr-24-3460","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3460","url":null,"abstract":"Background: Investigator-initiated trials (IITs) may address important biological and clinical questions that may not be prioritized by pharmaceutical sponsors. However, little is known about the process by which IIT proposals are evaluated and activated. Methods: We performed a retrospective study of IIT concepts submitted through the Academic Thoracic Oncology Medical Investigators Consortium (ATOMIC), which comprises 13 institutions in the U.S. and Canada, from 2014 (consortium inception) to 2024. We compared approved and disapproved concepts using chi-squared tests, Fisher’s exact tests, and Wilcoxon Rank-Sum tests. Results: Among a total of 68 presented IIT concepts, 60 (88%) received consortium approval a median of 30 days (interquartile range [IQR] 31-59 days) after submission. Concepts submitted by junior faculty were more likely to be approved than those from full professors (P=0.003). Of the 60 concepts subsequently submitted to pharmaceutical sponsors, 15 (25%) were approved, 43 (72%) were disapproved, and 2 (3%) remain under review. The median time between concept submission to a sponsor and the sponsor’s decision was 61 days (IQR 31-183 days). Concepts with shorter projected durations were more likely to be approved by the pharmaceutical sponsor (P=0.05). For sponsor-approved IIT concepts, median overall time from initial submission to trial activation was 18 months. Conclusions: Only a small proportion of proposed investigator-initiated cancer clinical trials are successfully activated following a prolonged development process. Given the importance of IITs in addressing real-world, practical questions and the growing professional challenges facing clinical research physician faculty, further attention to IIT development facilitators and barriers is warranted.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"30 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142988518","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 : 2025-01-17DOI: 10.1158/1078-0432.ccr-24-3277
Igor Odintsov, David J. Papke, Suzanne George, Robert F. Padera, Jason L. Hornick, Stephanie E. Siegmund
Purpose: Cardiac angiosarcoma (CAS) is a rare, aggressive malignancy with limited treatment options. Both sporadic and familial cases occur, with recent links to germline POT1 mutations. The genomic landscape of this disease is poorly understood. Experimental Design: We conducted comprehensive genomic profiling of CAS to assess the burden of germline predisposition and identify other recurrent genomic alterations of clinical significance. Results: Six patients were female and four were male. The median age at presentation was 40 years (range 21– 69 years). All cases with available follow up exhibited an aggressive clinical course (6/8 patients died of disease). KDR alterations, including novel structural variants, were found in 9/11 cases, at a rate significantly higher than in non-cardiac angiosarcomas. POT1 mutations were present in 45.5% of CAS cases. In three of five POT1-mutant cases, the germline status was confirmed through testing of normal tissue and in one additional case, the germline status was inferred with high probability through allele frequency analysis. Additionally, we identified novel recurrent MED12 exon 2 mutations in POT1-wild type CAS, suggesting an alternative path to CAS oncogenesis. Conclusions: CAS demonstrate unique genetic profile, distinct from non-cardiac angiosarcoma. This study highlights the role of germline POT1 burden on CAS development and demonstrates recurrent MED12 alterations for the first time. The reported KDR variants provide a potential avenue for treatment of this aggressive disease. Given the prevalence of germline POT1 mutations reported herein, germline genetic testing should be considered in patients diagnosed with CAS.
{"title":"Genomic Profiling of Cardiac Angiosarcoma Reveals Novel Targetable KDR Variants, Recurrent MED12 Mutations and a High Burden of Germline POT1Alterations","authors":"Igor Odintsov, David J. Papke, Suzanne George, Robert F. Padera, Jason L. Hornick, Stephanie E. Siegmund","doi":"10.1158/1078-0432.ccr-24-3277","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3277","url":null,"abstract":"Purpose: Cardiac angiosarcoma (CAS) is a rare, aggressive malignancy with limited treatment options. Both sporadic and familial cases occur, with recent links to germline POT1 mutations. The genomic landscape of this disease is poorly understood. Experimental Design: We conducted comprehensive genomic profiling of CAS to assess the burden of germline predisposition and identify other recurrent genomic alterations of clinical significance. Results: Six patients were female and four were male. The median age at presentation was 40 years (range 21– 69 years). All cases with available follow up exhibited an aggressive clinical course (6/8 patients died of disease). KDR alterations, including novel structural variants, were found in 9/11 cases, at a rate significantly higher than in non-cardiac angiosarcomas. POT1 mutations were present in 45.5% of CAS cases. In three of five POT1-mutant cases, the germline status was confirmed through testing of normal tissue and in one additional case, the germline status was inferred with high probability through allele frequency analysis. Additionally, we identified novel recurrent MED12 exon 2 mutations in POT1-wild type CAS, suggesting an alternative path to CAS oncogenesis. Conclusions: CAS demonstrate unique genetic profile, distinct from non-cardiac angiosarcoma. This study highlights the role of germline POT1 burden on CAS development and demonstrates recurrent MED12 alterations for the first time. The reported KDR variants provide a potential avenue for treatment of this aggressive disease. Given the prevalence of germline POT1 mutations reported herein, germline genetic testing should be considered in patients diagnosed with CAS.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"23 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142988896","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 : 2025-01-17DOI: 10.1158/1078-0432.CCR-24-1947
Kris Ann P Schultz, Suzanne P MacFarland, Melissa R Perrino, Sarah G Mitchell, Junne Kamihara, Alexander T Nelson, Paige H R Mallinger, Jack J Brzezinski, Kara N Maxwell, Emma R Woodward, Bailey Gallinger, Sun Young Kim, Mary-Louise C Greer, Kami Wolfe Schneider, Sarah R Scollon, Anirban Das, Jonathan D Wasserman, Charis Eng, David Malkin, William D Foulkes, Orli Michaeli, Andrew J Bauer, Douglas R Stewart
Phosphate and tensin homolog hamartoma tumor syndrome, DICER1-related tumor predisposition, and tuberous sclerosis complex are rare conditions, which each increases risk for distinct spectra of benign and malignant neoplasms throughout childhood and adulthood. Surveillance considerations for each of these conditions focus on patient and family education, early detection, and multidisciplinary care. In this article, we present updated surveillance recommendations and considerations for children and adolescents with phosphate and tensin homolog hamartoma tumor syndrome, DICER1-related tumor predisposition, and tuberous sclerosis complex and provide suggestions for further research in each of these conditions.
{"title":"Update on Pediatric Surveillance Recommendations for PTEN Hamartoma Tumor Syndrome, DICER1-Related Tumor Predisposition, and Tuberous Sclerosis Complex.","authors":"Kris Ann P Schultz, Suzanne P MacFarland, Melissa R Perrino, Sarah G Mitchell, Junne Kamihara, Alexander T Nelson, Paige H R Mallinger, Jack J Brzezinski, Kara N Maxwell, Emma R Woodward, Bailey Gallinger, Sun Young Kim, Mary-Louise C Greer, Kami Wolfe Schneider, Sarah R Scollon, Anirban Das, Jonathan D Wasserman, Charis Eng, David Malkin, William D Foulkes, Orli Michaeli, Andrew J Bauer, Douglas R Stewart","doi":"10.1158/1078-0432.CCR-24-1947","DOIUrl":"10.1158/1078-0432.CCR-24-1947","url":null,"abstract":"<p><p>Phosphate and tensin homolog hamartoma tumor syndrome, DICER1-related tumor predisposition, and tuberous sclerosis complex are rare conditions, which each increases risk for distinct spectra of benign and malignant neoplasms throughout childhood and adulthood. Surveillance considerations for each of these conditions focus on patient and family education, early detection, and multidisciplinary care. In this article, we present updated surveillance recommendations and considerations for children and adolescents with phosphate and tensin homolog hamartoma tumor syndrome, DICER1-related tumor predisposition, and tuberous sclerosis complex and provide suggestions for further research in each of these conditions.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"234-244"},"PeriodicalIF":10.0,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11747828/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616047","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 : 2025-01-16DOI: 10.1158/1078-0432.ccr-24-3149
Bach Ardalan, Aaron Ciner, Yasmine Baca, Andrew Hinton, Sourat Darabi, Anup Kasi, Emil Lou, Jose Ignacio. Azqueta, Joanne Xiu, Jashodeep Datta, Anthony F. Shields, Andrew Aguirre, Harshabad Singh, Rachna T. Shroff, Michael J. Pishvaian, Sanjay Goel
PURPOSE Oncogenic mutations in KRAS have been identified in > 85% of pancreatic ductal adenocarcinoma (PDAC) cases. G12D, G12V, and G12R are the most frequent variants. Using large clinical and genomic databases, this study characterizes prognostic and molecular differences between KRAS variants, focusing on KRAS G12D and G12R. METHODS PDAC samples were tested using DNA and RNA sequencing. MAPK activation score and tumor microenvironment were analyzed from RNA expression data. Real-world overall survival (OS) obtained from insurance claims data was calculated from tissue collection to last contact. Significance was determined by X2 and Fisher-Exact tests. RESULTS 3,755 PDAC patients harboring KRAS G12D (n = 1,766), G12V (n = 1,294) G12R (n = 621) or G12C (n = 74) variants were identified. Patients with G12R mutations had longer OS compared to G12D overall (12.7 vs 10.1 months, p-value=0.0001), with similar trends in patients treated with gemcitabine/nab-paclitaxel (13.5 vs 10.4 months, p-value=0.0002) or FOLFIRINOX (18.3 vs 14.0 months, p-value<0.001). ARID1A and KMT2D mutations were more frequent in the G12D subgroup. Several glucose and glutamine metabolism genes were less expressed in G12R vs G12D. PD-L1 expression was lower in G12R vs G12D (13% vs 19%). CONCLUSION KRAS G12D tumors exhibited a distinct molecular profile compared to G12R tumors, including genes involved in the MAPK pathway, immune activation, and glucose and glutamine metabolism. Patients with G12D mutations had lower OS compared to G12R. Based on this data, future studies should address the KRAS mutation status and explore distinct therapeutic vulnerabilities.
{"title":"Distinct molecular and clinical features of specific variants of KRAS codon 12 in pancreatic adenocarcinoma","authors":"Bach Ardalan, Aaron Ciner, Yasmine Baca, Andrew Hinton, Sourat Darabi, Anup Kasi, Emil Lou, Jose Ignacio. Azqueta, Joanne Xiu, Jashodeep Datta, Anthony F. Shields, Andrew Aguirre, Harshabad Singh, Rachna T. Shroff, Michael J. Pishvaian, Sanjay Goel","doi":"10.1158/1078-0432.ccr-24-3149","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3149","url":null,"abstract":"PURPOSE Oncogenic mutations in KRAS have been identified in &gt; 85% of pancreatic ductal adenocarcinoma (PDAC) cases. G12D, G12V, and G12R are the most frequent variants. Using large clinical and genomic databases, this study characterizes prognostic and molecular differences between KRAS variants, focusing on KRAS G12D and G12R. METHODS PDAC samples were tested using DNA and RNA sequencing. MAPK activation score and tumor microenvironment were analyzed from RNA expression data. Real-world overall survival (OS) obtained from insurance claims data was calculated from tissue collection to last contact. Significance was determined by X2 and Fisher-Exact tests. RESULTS 3,755 PDAC patients harboring KRAS G12D (n = 1,766), G12V (n = 1,294) G12R (n = 621) or G12C (n = 74) variants were identified. Patients with G12R mutations had longer OS compared to G12D overall (12.7 vs 10.1 months, p-value=0.0001), with similar trends in patients treated with gemcitabine/nab-paclitaxel (13.5 vs 10.4 months, p-value=0.0002) or FOLFIRINOX (18.3 vs 14.0 months, p-value&lt;0.001). ARID1A and KMT2D mutations were more frequent in the G12D subgroup. Several glucose and glutamine metabolism genes were less expressed in G12R vs G12D. PD-L1 expression was lower in G12R vs G12D (13% vs 19%). CONCLUSION KRAS G12D tumors exhibited a distinct molecular profile compared to G12R tumors, including genes involved in the MAPK pathway, immune activation, and glucose and glutamine metabolism. Patients with G12D mutations had lower OS compared to G12R. Based on this data, future studies should address the KRAS mutation status and explore distinct therapeutic vulnerabilities.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"93 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987879","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 : 2025-01-16DOI: 10.1158/1078-0432.ccr-24-3571
Fengchao Lang, Karambir Kaur, Javeria Zaheer, Diego Luis. Ribeiro, Chunzhang Yang
Cell cycle checkpoints are stringent quality control mechanisms that regulate cell cycle progression and division. Cancer cells often develop a dependency on the G2/M cell cycle checkpoint to facilitate DNA repair and resolve intrinsic or therapy-induced DNA damage. This dependency leads to therapy resistance, continuous cell division, and disease progression. Targeting G2/M checkpoints has been heavily pursued over the past two decades and has progressed into clinical studies. Recent genome-scale functional genomic studies have revealed that Myt1 kinase, an essential but previously overlooked molecule for the G2/M checkpoint, is a promising target for multiple types of cancers. In this work, we summarize the latest discoveries in molecular targeting of Myt1 kinase and discuss the challenges and limitations in expanding its clinical application.
{"title":"Myt1 kinase: An Emerging Cell Cycle Regulator for Cancer Therapeutics","authors":"Fengchao Lang, Karambir Kaur, Javeria Zaheer, Diego Luis. Ribeiro, Chunzhang Yang","doi":"10.1158/1078-0432.ccr-24-3571","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3571","url":null,"abstract":"Cell cycle checkpoints are stringent quality control mechanisms that regulate cell cycle progression and division. Cancer cells often develop a dependency on the G2/M cell cycle checkpoint to facilitate DNA repair and resolve intrinsic or therapy-induced DNA damage. This dependency leads to therapy resistance, continuous cell division, and disease progression. Targeting G2/M checkpoints has been heavily pursued over the past two decades and has progressed into clinical studies. Recent genome-scale functional genomic studies have revealed that Myt1 kinase, an essential but previously overlooked molecule for the G2/M checkpoint, is a promising target for multiple types of cancers. In this work, we summarize the latest discoveries in molecular targeting of Myt1 kinase and discuss the challenges and limitations in expanding its clinical application.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"6 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987880","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}
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