Pub Date : 2024-10-28DOI: 10.1158/1078-0432.CCR-24-2488
Jack J Brzezinski, Kerri D Becktell, Gaëlle Bougeard, Garrett M Brodeur, Lisa R Diller, Andrea S Doria, Jordan R Hansford, Wendy K Kohlmann, Christian P Kratz, Suzanne P MacFarland, Kristian W Pajtler, Surya P Rednam, Jaclyn Schienda, Lisa J States, Anita Villani, Rosanna Weksberg, Kristin Zelley, Gail E Tomlinson, Jennifer M Kalish
Wilms tumors are commonly associated with predisposition syndromes. Many of these syndromes are associated with specific phenotypic features and are discussed in the related paper from the AACR Pediatric Cancer Working Group. Guidelines for surveillance in this population were published in 2017 but since then several studies have identified new genes with recurrent pathogenic variants associated with increased risk for Wilms tumor development. In general, variants in these genes are less likely to be associated with other phenotypic features. Recently, members of the AACR Pediatric Cancer Working Group met to update surveillance guidelines for patients with a predisposition to Wilms tumors with a review of recently published evidence and risk estimates. Risk estimates for Wilms tumor for the more recently described genes are discussed here along with suggested surveillance guidelines for these populations. Several other emerging clinical scenarios associated with Wilms tumor predisposition are also discussed including patients with family histories of Wilms tumor and no identified causative gene, patients with bilateral tumors, and patients with somatic mosaicism for chromosome 11p15.5 alterations. This perspective serves to update pediatric oncologists, geneticists, radiologists, counselors and other healthcare professionals on emerging evidence and harmonize updated surveillance recommendations in the North American and Australian context for patients with emerging forms of Wilms tumor predisposition.
{"title":"Update on surveillance guidelines in emerging Wilms tumor predisposition syndromes.","authors":"Jack J Brzezinski, Kerri D Becktell, Gaëlle Bougeard, Garrett M Brodeur, Lisa R Diller, Andrea S Doria, Jordan R Hansford, Wendy K Kohlmann, Christian P Kratz, Suzanne P MacFarland, Kristian W Pajtler, Surya P Rednam, Jaclyn Schienda, Lisa J States, Anita Villani, Rosanna Weksberg, Kristin Zelley, Gail E Tomlinson, Jennifer M Kalish","doi":"10.1158/1078-0432.CCR-24-2488","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-2488","url":null,"abstract":"<p><p>Wilms tumors are commonly associated with predisposition syndromes. Many of these syndromes are associated with specific phenotypic features and are discussed in the related paper from the AACR Pediatric Cancer Working Group. Guidelines for surveillance in this population were published in 2017 but since then several studies have identified new genes with recurrent pathogenic variants associated with increased risk for Wilms tumor development. In general, variants in these genes are less likely to be associated with other phenotypic features. Recently, members of the AACR Pediatric Cancer Working Group met to update surveillance guidelines for patients with a predisposition to Wilms tumors with a review of recently published evidence and risk estimates. Risk estimates for Wilms tumor for the more recently described genes are discussed here along with suggested surveillance guidelines for these populations. Several other emerging clinical scenarios associated with Wilms tumor predisposition are also discussed including patients with family histories of Wilms tumor and no identified causative gene, patients with bilateral tumors, and patients with somatic mosaicism for chromosome 11p15.5 alterations. This perspective serves to update pediatric oncologists, geneticists, radiologists, counselors and other healthcare professionals on emerging evidence and harmonize updated surveillance recommendations in the North American and Australian context for patients with emerging forms of Wilms tumor predisposition.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496192","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 : 2024-10-28DOI: 10.1158/1078-0432.CCR-24-2172
Carla A Jaeger-Ruckstuhl, Jennifer M Specht, Jenna M Voutsinas, Hugh R MacMillan, Qian Vicky Wu, Vishaka Muhunthan, Carolina Berger, Shalini Pullarkat, Jocelyn H Wright, Cecilia C S Yeung, Teresa S Hyun, Brandon Seaton, Lauri D Aicher, Xiaoling Song, Robert H Pierce, Yun Lo, Gabriel O Cole, Sylvia M Lee, Evan W Newell, David G Maloney, Stanley R Riddell
Purpose: The receptor tyrosine kinase-like orphan receptor 1 (ROR1) is expressed in hematopoietic and epithelial cancers but has limited expression on normal adult tissues. This phase 1 study evaluated the safety of targeting ROR1 with autologous T-lymphocytes engineered to express a ROR1 chimeric antigen receptor (CAR). Secondary objectives evaluated persistence, trafficking, and antitumor activity of CAR T cells.
Patients & methods: Twenty-one patients with ROR1+ tumors received CAR T cells at one of four dose levels (DL): 3.3x105/1x106/3.3x106/1x107 cells/kg, administered after lymphodepletion with Cyclophosphamide/Fludarabine (Cy/Flu) or Oxaliplatin/Cyclophosphamide (Ox/Cy). Cohort A included patients with chronic lymphocytic leukemia (CLL, n=3); cohort B included patients with triple-negative breast cancer (TNBC, n=10) or non-small-cell lung cancer (NSCLC, n=8). A second infusion was administered to one patient in cohort A with residual CLL in the marrow and three patients in cohort B with stable disease after first infusion.
Results: Treatment was well tolerated apart from one dose limiting toxicity at DL4 in a patient with advanced NSCLC. Two of the three (67%) CLL patients showed robust CAR T expansion and a rapid antitumor response. In patients with NSCLC and TNBC, CAR T cells expanded to variable levels, infiltrated tumor poorly, and one of eighteen patients (5.5%) achieved partial response by RECIST 1.1.
Conclusion: ROR1 CAR T cells were well tolerated in most patients. Antitumor activity was observed in CLL but was limited in TNBC and NSCLC. Immunogenicity of the CAR and lack of sustained tumor infiltration were identified as limitations.
目的：受体酪氨酸激酶样孤儿受体1（ROR1）在造血癌和上皮癌中表达，但在正常成人组织中表达有限。这项1期研究评估了用表达ROR1嵌合抗原受体（CAR）的自体T淋巴细胞靶向ROR1的安全性。次要目标是评估CAR T细胞的持久性、贩运和抗肿瘤活性：21名ROR1+肿瘤患者接受了四种剂量水平（DL）之一的CAR T细胞：3.3x105/1x106/3.3x106/1x107细胞/千克，在使用环磷酰胺/氟达拉滨（Cy/Flu）或奥沙利铂/环磷酰胺（Ox/Cy）进行淋巴清除后给药。队列 A 包括慢性淋巴细胞白血病（CLL，n=3）患者；队列 B 包括三阴性乳腺癌（TNBC，n=10）或非小细胞肺癌（NSCLC，n=8）患者。A组中有1名患者骨髓中残留CLL，B组中有3名患者第一次输液后病情稳定，对这些患者进行了第二次输液：治疗耐受性良好，只有一名晚期 NSCLC 患者在 DL4 出现剂量限制性毒性反应。3名CLL患者中有2名（67%）表现出强劲的CAR T扩增和快速的抗肿瘤反应。在NSCLC和TNBC患者中，CAR T细胞的扩增水平不一，对肿瘤的浸润较差，18名患者中有1名（5.5%）获得了RECIST 1.1标准的部分反应：大多数患者对 ROR1 CAR T 细胞耐受性良好。结论：大多数患者对 ROR1 CAR T 细胞的耐受性良好，在 CLL 中观察到了抗肿瘤活性，但在 TNBC 和 NSCLC 中的活性有限。CAR 的免疫原性和缺乏持续的肿瘤浸润被认为是其局限性。
{"title":"Phase 1 Study of ROR1 Specific CAR T Cells in Advanced Hematopoietic and Epithelial Malignancies.","authors":"Carla A Jaeger-Ruckstuhl, Jennifer M Specht, Jenna M Voutsinas, Hugh R MacMillan, Qian Vicky Wu, Vishaka Muhunthan, Carolina Berger, Shalini Pullarkat, Jocelyn H Wright, Cecilia C S Yeung, Teresa S Hyun, Brandon Seaton, Lauri D Aicher, Xiaoling Song, Robert H Pierce, Yun Lo, Gabriel O Cole, Sylvia M Lee, Evan W Newell, David G Maloney, Stanley R Riddell","doi":"10.1158/1078-0432.CCR-24-2172","DOIUrl":"10.1158/1078-0432.CCR-24-2172","url":null,"abstract":"<p><strong>Purpose: </strong>The receptor tyrosine kinase-like orphan receptor 1 (ROR1) is expressed in hematopoietic and epithelial cancers but has limited expression on normal adult tissues. This phase 1 study evaluated the safety of targeting ROR1 with autologous T-lymphocytes engineered to express a ROR1 chimeric antigen receptor (CAR). Secondary objectives evaluated persistence, trafficking, and antitumor activity of CAR T cells.</p><p><strong>Patients & methods: </strong>Twenty-one patients with ROR1+ tumors received CAR T cells at one of four dose levels (DL): 3.3x105/1x106/3.3x106/1x107 cells/kg, administered after lymphodepletion with Cyclophosphamide/Fludarabine (Cy/Flu) or Oxaliplatin/Cyclophosphamide (Ox/Cy). Cohort A included patients with chronic lymphocytic leukemia (CLL, n=3); cohort B included patients with triple-negative breast cancer (TNBC, n=10) or non-small-cell lung cancer (NSCLC, n=8). A second infusion was administered to one patient in cohort A with residual CLL in the marrow and three patients in cohort B with stable disease after first infusion.</p><p><strong>Results: </strong>Treatment was well tolerated apart from one dose limiting toxicity at DL4 in a patient with advanced NSCLC. Two of the three (67%) CLL patients showed robust CAR T expansion and a rapid antitumor response. In patients with NSCLC and TNBC, CAR T cells expanded to variable levels, infiltrated tumor poorly, and one of eighteen patients (5.5%) achieved partial response by RECIST 1.1.</p><p><strong>Conclusion: </strong>ROR1 CAR T cells were well tolerated in most patients. Antitumor activity was observed in CLL but was limited in TNBC and NSCLC. Immunogenicity of the CAR and lack of sustained tumor infiltration were identified as limitations.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496191","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 : 2024-10-25DOI: 10.1158/1078-0432.ccr-24-2483
Konrad H. Stopsack, Joseph Vijai, Michael Conry, Jacob E. Berchuck, Yelena Kemel, Samantha E. Vasselman, Dory A. Freeman, Gwo-Shu M. Lee, Diana Mandelker, David B. Solit, Michael J. Morris, Kathryn L. Penney, Wassim Abida, Kenneth Offit, Lorelei A. Mucci, Philip W. Kantoff, Mark M. Pomerantz
Purpose: Deleterious germline variants in certain DNA repair genes are risk factors for developing aggressive prostate cancer. The objective was to quantify their prognostic impact after prostate cancer diagnosis. Methods: Men with prostate cancer, predominantly of European ancestry, were included from four cohorts with long-term follow-up. Pathogenic or likely pathogenic germline variants in 26 DNA repair genes were assessed in relation to metastasis-free survival in high-risk, localized prostate cancer and to overall survival in metastatic castration-sensitive prostate cancer (mCSPC) and metastatic castration-resistant prostate cancer (mCRPC). Results: Among 3,525 patients initially diagnosed with non-metastatic prostate cancer, 2,594 had high-risk localized prostate cancer, 429 mCSPC, and 502 mCRPC at inclusion. BRCA2 variant carriers did not have worse metastasis-free survival in high-risk localized prostate cancer (hazard ratio [HR] 1.01, 95% confidence interval [CI] 0.69, 1.46) or overall survival in mCSPC (HR 0.46, 95% CI 0.14, 1.45) or mCRPC (HR 0.60, 95% CI 0.31, 1.17) compared to non-carriers of DNA repair variants. Among 868 additional patients with de novo metastatic (M1) prostate cancer, BRCA2 variant carriers tended to have worse overall survival (HR 1.59, 95% CI 1.01, 2.51). BRCA2 prognostic associations were not explained by radiation, PARP inhibitor, or platinum therapy. Results for other genes were limited in precision because variants were less common. Conclusions: Among patients with high-risk or metastatic prostate cancer who were initially diagnosed with and treated for non-metastatic tumors, germline DNA repair variants in BRCA2 do not confer a substantially worse prognosis.
目的：某些 DNA 修复基因中的畸变种系变异是罹患侵袭性前列腺癌的风险因素。我们的目的是量化它们在前列腺癌确诊后对预后的影响。研究方法研究人员从四个长期随访的队列中选取了患有前列腺癌的男性患者，他们主要来自欧洲血统。评估了 26 个 DNA 修复基因中的致病性或可能致病性种系变异与高危局部前列腺癌无转移生存率的关系，以及与转移性阉割敏感性前列腺癌（mCSPC）和转移性阉割耐药前列腺癌（mCRPC）总生存率的关系。研究结果在3525名初步诊断为非转移性前列腺癌的患者中，2594人患有高风险局部前列腺癌，429人患有mCSPC，502人患有mCRPC。与DNA修复变异体非携带者相比，BRCA2变异体携带者的高危局部前列腺癌无转移生存率（危险比[HR]1.01，95%置信区间[CI]0.69，1.46）或mCSPC（HR 0.46，95% CI 0.14，1.45）或mCRPC（HR 0.60，95% CI 0.31，1.17）不比非携带者差。在另外868例新发转移性（M1）前列腺癌患者中，BRCA2变异携带者的总生存率往往较低（HR 1.59，95% CI 1.01，2.51）。放射治疗、PARP抑制剂或铂类治疗无法解释BRCA2与预后的关系。由于变异较不常见，其他基因的结果在精确性上受到限制。结论在最初被诊断为非转移性肿瘤并接受治疗的高危或转移性前列腺癌患者中，BRCA2的种系DNA修复变异并不会导致预后大大降低。
{"title":"Germline DNA damage repair variants and prognosis of patients with high-risk or metastatic prostate cancer","authors":"Konrad H. Stopsack, Joseph Vijai, Michael Conry, Jacob E. Berchuck, Yelena Kemel, Samantha E. Vasselman, Dory A. Freeman, Gwo-Shu M. Lee, Diana Mandelker, David B. Solit, Michael J. Morris, Kathryn L. Penney, Wassim Abida, Kenneth Offit, Lorelei A. Mucci, Philip W. Kantoff, Mark M. Pomerantz","doi":"10.1158/1078-0432.ccr-24-2483","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2483","url":null,"abstract":"Purpose: Deleterious germline variants in certain DNA repair genes are risk factors for developing aggressive prostate cancer. The objective was to quantify their prognostic impact after prostate cancer diagnosis. Methods: Men with prostate cancer, predominantly of European ancestry, were included from four cohorts with long-term follow-up. Pathogenic or likely pathogenic germline variants in 26 DNA repair genes were assessed in relation to metastasis-free survival in high-risk, localized prostate cancer and to overall survival in metastatic castration-sensitive prostate cancer (mCSPC) and metastatic castration-resistant prostate cancer (mCRPC). Results: Among 3,525 patients initially diagnosed with non-metastatic prostate cancer, 2,594 had high-risk localized prostate cancer, 429 mCSPC, and 502 mCRPC at inclusion. BRCA2 variant carriers did not have worse metastasis-free survival in high-risk localized prostate cancer (hazard ratio [HR] 1.01, 95% confidence interval [CI] 0.69, 1.46) or overall survival in mCSPC (HR 0.46, 95% CI 0.14, 1.45) or mCRPC (HR 0.60, 95% CI 0.31, 1.17) compared to non-carriers of DNA repair variants. Among 868 additional patients with de novo metastatic (M1) prostate cancer, BRCA2 variant carriers tended to have worse overall survival (HR 1.59, 95% CI 1.01, 2.51). BRCA2 prognostic associations were not explained by radiation, PARP inhibitor, or platinum therapy. Results for other genes were limited in precision because variants were less common. Conclusions: Among patients with high-risk or metastatic prostate cancer who were initially diagnosed with and treated for non-metastatic tumors, germline DNA repair variants in BRCA2 do not confer a substantially worse prognosis.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"14 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489810","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: Angiogenesis inhibitors are known to modify tumor immunity. Combination of angiogenesis inhibitors with immune checkpoint inhibitors (ICIs) has shown efficacy against many types of cancers, including non-small cell lung cancer (NSCLC). We investigated the feasibility of neoadjuvant therapy with pembrolizumab and ramucirumab, a vascular endothelial growth factor (VEGF) receptor-2 antagonist for patients with PD-L1-positive NSCLC and its influence on the tumor microenvironment (TME). Patients and Methods: Patients with pathologically proven NSCLC with PD-L1-positive, clinical stage IB-IIIA were eligible. Patients received two cycles of pembrolizumab (200 mg/body) and ramucirumab (10 mg/kg) every three weeks. Surgery was scheduled 4 to 8 weeks after the last dose. The primary endpoint was the major pathologic response (MPR) rate by a blinded independent pathology review. The sample size was 24 patients. Exploratory endpoints were evaluated to elucidate the effects of neoadjuvant therapy on TME. Results: The 24 eligible patients were enrolled between July 2019 and April 2022. The MPR rate was 50.0% (90% confidence interval, 31.9-68.1%). Six patients showed pathological complete response. Grade 3 adverse events (AEs) occurred in 9 patients (37.5%), including 3 immune-related AEs (acute tubulointerstitial nephritis in 2 cases and polymyalgia rheumatica in one). There were no grade 4 or 5 AEs. The transcriptome and multiplexed immunohistochemistry results suggested that tumors with greater CD8+ T-cell infiltration and higher expression of effector molecules at the baseline could show better sensitivity to treatment. Conclusions:This new neoadjuvant combination of pembrolizumab plus ramucirumab was feasible and anti-VEGF agents may enhance the effects of ICIs.
{"title":"Efficacy, Safety, and Influence on Tumor Microenvironment of Neoadjuvant Pembrolizumab plus Ramucirumab for PD-L1 Positive NSCLC: A Phase 2 Trial (EAST ENERGY)","authors":"Keiju Aokage, Shohei Koyama, Shogo Kumagai, Kotaro Nomura, Yoshihisa Shimada, Kiyotaka Yoh, Masashi Wakabayashi, Miki Fukutani, Hideki Furuya, Tomohiro Miyoshi, Kenta Tane, Joji Samejima, Tetsuro Taki, Takuo Hayashi, Jun Matsubayashi, Genichiro Ishii, Hiroyoshi Nishikawa, Norihiko Ikeda, Masahiro Tsuboi","doi":"10.1158/1078-0432.ccr-24-1561","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1561","url":null,"abstract":"Purpose: Angiogenesis inhibitors are known to modify tumor immunity. Combination of angiogenesis inhibitors with immune checkpoint inhibitors (ICIs) has shown efficacy against many types of cancers, including non-small cell lung cancer (NSCLC). We investigated the feasibility of neoadjuvant therapy with pembrolizumab and ramucirumab, a vascular endothelial growth factor (VEGF) receptor-2 antagonist for patients with PD-L1-positive NSCLC and its influence on the tumor microenvironment (TME). Patients and Methods: Patients with pathologically proven NSCLC with PD-L1-positive, clinical stage IB-IIIA were eligible. Patients received two cycles of pembrolizumab (200 mg/body) and ramucirumab (10 mg/kg) every three weeks. Surgery was scheduled 4 to 8 weeks after the last dose. The primary endpoint was the major pathologic response (MPR) rate by a blinded independent pathology review. The sample size was 24 patients. Exploratory endpoints were evaluated to elucidate the effects of neoadjuvant therapy on TME. Results: The 24 eligible patients were enrolled between July 2019 and April 2022. The MPR rate was 50.0% (90% confidence interval, 31.9-68.1%). Six patients showed pathological complete response. Grade 3 adverse events (AEs) occurred in 9 patients (37.5%), including 3 immune-related AEs (acute tubulointerstitial nephritis in 2 cases and polymyalgia rheumatica in one). There were no grade 4 or 5 AEs. The transcriptome and multiplexed immunohistochemistry results suggested that tumors with greater CD8+ T-cell infiltration and higher expression of effector molecules at the baseline could show better sensitivity to treatment. Conclusions:This new neoadjuvant combination of pembrolizumab plus ramucirumab was feasible and anti-VEGF agents may enhance the effects of ICIs.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"7 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142490293","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 : 2024-10-25DOI: 10.1158/1078-0432.ccr-24-1875
Qing H. Meng, Thorvardur R. Halfdanarson, Joshua A. Bornhorst, Henning Jann, Shagufta Shaheen, Run Zhang Shi, Andrej Schwabe, Katrin Stade, Daniel M. Halperin
Purpose: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are relatively indolent but can be more aggressive. The current recommendations for the use of serum CgA for GEP-NET patients are equivocal. This study was designed to validate an automated CgA immunofluorescence assay for monitoring disease progression in GEP-NET patients. Patients and Methods: A prospective, multi-center blinded observational study was designed to validate an automated chromogranin A (CgA) immunofluorescence assay for monitoring disease progression in GEP-NET patients. Tumor progression was evaluated with Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 by CT/MRI. An increase ≥ 50% above the prior CgA concentration to a value > 100 ng/mL in the following CgA concentration was considered positive. Results: 153 GEP-NET patients were enrolled. Using the pre-specified cut-off of CgA change for tumor progression, specificity was 93·4% (95%-CI: 90·4%—95·5%, p < 0·001), sensitivity 34·4% (25·6%—44·3%), positive predictive value 57·9% (45·0—69·8), negative predictive value (NPV) 84·3% (80·5—87·6), and area under the curve 0·73 (0·67—0·79). Conclusions: Changes in serial measurements of serum CgA had a favorable specificity and NPV, making this test a useful adjunct to routine radiographic monitoring.
{"title":"Circulating Chromogranin A as Surveillance Biomarker in Patients with Carcinoids – The CASPAR Study","authors":"Qing H. Meng, Thorvardur R. Halfdanarson, Joshua A. Bornhorst, Henning Jann, Shagufta Shaheen, Run Zhang Shi, Andrej Schwabe, Katrin Stade, Daniel M. Halperin","doi":"10.1158/1078-0432.ccr-24-1875","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1875","url":null,"abstract":"Purpose: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are relatively indolent but can be more aggressive. The current recommendations for the use of serum CgA for GEP-NET patients are equivocal. This study was designed to validate an automated CgA immunofluorescence assay for monitoring disease progression in GEP-NET patients. Patients and Methods: A prospective, multi-center blinded observational study was designed to validate an automated chromogranin A (CgA) immunofluorescence assay for monitoring disease progression in GEP-NET patients. Tumor progression was evaluated with Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 by CT/MRI. An increase ≥ 50% above the prior CgA concentration to a value &gt; 100 ng/mL in the following CgA concentration was considered positive. Results: 153 GEP-NET patients were enrolled. Using the pre-specified cut-off of CgA change for tumor progression, specificity was 93·4% (95%-CI: 90·4%—95·5%, p &lt; 0·001), sensitivity 34·4% (25·6%—44·3%), positive predictive value 57·9% (45·0—69·8), negative predictive value (NPV) 84·3% (80·5—87·6), and area under the curve 0·73 (0·67—0·79). Conclusions: Changes in serial measurements of serum CgA had a favorable specificity and NPV, making this test a useful adjunct to routine radiographic monitoring.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"236 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142490634","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 : 2024-10-25DOI: 10.1158/1078-0432.ccr-24-2444
Zhichao Tan, Yan Wu, Zhengfu Fan, Tian Gao, Wei Guo, Chujie Bai, Ruifeng Xue, Shu Li, Lu Zhang, Xinyu Wang, Ling Jia, Jiayong Liu
Purpose: Alveolar soft part sarcoma (ASPS) is an ultra-rare soft-tissue sarcoma with a high rate of metastasis and no established treatment. This study aimed to explore the efficacy and safety of anlotinib (a tyrosine-kinase inhibitor) and TQB2450 (a PD-L1 inhibitor) in ASPS patients. Methods: This single-arm, phase 2 study evaluated the efficacy of TQB2450, an anti-programmed death ligand 1 (PD-L1) agent, combined with anlotinib, a TKI, in adults with advanced ASPS. TQB2450 was given intravenously (1,200 mg) on day 1, and anlotinib (12 mg/day) was taken orally from day 1 to day 14 every 3 weeks. The primary endpoint was overall response rate, with secondary endpoints including duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Lymphocyte infiltration and tertiary lymphoid structure (TLS) were also analyzed as potential prognostic biomarkers. Results: The study enrolled 29 patients, with 28 evaluable (one withdrew due to acute pancreatitis). An objective response was achieved in 82.1% of patients, including 4 complete and 19 partial responses. The median time to response was 2.8 months, and the DOR was not reached, with an estimated median PFS of 35.2 months. Grade 3-4 treatment-related adverse events occurred in 44.8% of patients, with no study-related deaths. Responders had a higher proportion of TLS area, density, and CD20-positive immune cells. Conclusions: The combination of anlotinib and TQB2450 is effective and tolerable in ASPS patients. TLS may serve as a prognostic biomarker, meriting further investigation.
{"title":"Anlotinib plus TQB2450, a PD-L1 Antibody, in Patients with Advanced Alveolar Soft Part Sarcoma: a single-arm, phase 2 trial","authors":"Zhichao Tan, Yan Wu, Zhengfu Fan, Tian Gao, Wei Guo, Chujie Bai, Ruifeng Xue, Shu Li, Lu Zhang, Xinyu Wang, Ling Jia, Jiayong Liu","doi":"10.1158/1078-0432.ccr-24-2444","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2444","url":null,"abstract":"Purpose: Alveolar soft part sarcoma (ASPS) is an ultra-rare soft-tissue sarcoma with a high rate of metastasis and no established treatment. This study aimed to explore the efficacy and safety of anlotinib (a tyrosine-kinase inhibitor) and TQB2450 (a PD-L1 inhibitor) in ASPS patients. Methods: This single-arm, phase 2 study evaluated the efficacy of TQB2450, an anti-programmed death ligand 1 (PD-L1) agent, combined with anlotinib, a TKI, in adults with advanced ASPS. TQB2450 was given intravenously (1,200 mg) on day 1, and anlotinib (12 mg/day) was taken orally from day 1 to day 14 every 3 weeks. The primary endpoint was overall response rate, with secondary endpoints including duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Lymphocyte infiltration and tertiary lymphoid structure (TLS) were also analyzed as potential prognostic biomarkers. Results: The study enrolled 29 patients, with 28 evaluable (one withdrew due to acute pancreatitis). An objective response was achieved in 82.1% of patients, including 4 complete and 19 partial responses. The median time to response was 2.8 months, and the DOR was not reached, with an estimated median PFS of 35.2 months. Grade 3-4 treatment-related adverse events occurred in 44.8% of patients, with no study-related deaths. Responders had a higher proportion of TLS area, density, and CD20-positive immune cells. Conclusions: The combination of anlotinib and TQB2450 is effective and tolerable in ASPS patients. TLS may serve as a prognostic biomarker, meriting further investigation.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"48 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142490545","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 : 2024-10-25DOI: 10.1158/1078-0432.ccr-24-1867
Gregory M. Cote, Bose S. Kochupurakkal, Khanh Do, Andrea Bullock, Michael L. Cheng, Alona Muzikansky, Daniel E. McLoughlin, James M. Cleary, Xin Gao, Aparna Parikh, Jong Chul Park, Colin D. Weekes, Oladapo Yeku, Lee Zou, Geoffrey I. Shapiro
Background: Preclinical studies have identified molecular correlates of sensitivity to ATR inhibition. This translational study was designed to test the ATR inhibitor berzosertib in patients with advanced solid tumors carrying alterations in ATRX, ATM, genes conferring replication stress (RS), or SDH. Methods: Patients were recruited to 4 cohorts: T1: ATRX-mutant leiomyosarcoma; T2: ATM-mutant solid tumors; T3: solid tumors with mutations in RS-associated genes; and T4: SDH-deficient GIST. Patients were treated with berzosertib 240 mg/m2 IV twice per week. Pre and on-treatment biopsies were obtained in cohorts T1-T3. Results: Patients with SDH-mutant GIST had the longest median progression-free survival (PFS) (229 days) with stable disease as the best response. Patients in the other cohorts experienced progressive disease within 4 months. There was no significant difference in PFS comparing outcomes in patients with/without mutations in ATM or RS genes. Decreased pS345-CHK1 in on-treatment biopsies indicated target engagement by berzosertib and were accompanied by substantial increases in levels of DNA damage (g-H2AX) and RS (pKAP1) markers in a subset of patients. However, these biomarker changes did not translate to clinical benefit. In contrast, in cohorts T1-T3, increased expression of SFLN11 on treatment correlated with clinical benefit (HR = 0.045; 95%CI 0.005-0.400). Conclusions: Across cohorts, only SDH-mutant GIST patients experienced prolonged disease control. Despite evidence of target engagement, patients enrolled to all other cohorts had short PFS, suggesting rapid adaptation to ATR inhibitor monotherapy. Among these patients, those with tumors expressing SLFN11 during berzosertib exposure derived the most clinical benefit.
{"title":"A Translational Study of the ATR Inhibitor Berzosertib as Monotherapy in Four Molecularly Defined Cohorts of Advanced Solid Tumors","authors":"Gregory M. Cote, Bose S. Kochupurakkal, Khanh Do, Andrea Bullock, Michael L. Cheng, Alona Muzikansky, Daniel E. McLoughlin, James M. Cleary, Xin Gao, Aparna Parikh, Jong Chul Park, Colin D. Weekes, Oladapo Yeku, Lee Zou, Geoffrey I. Shapiro","doi":"10.1158/1078-0432.ccr-24-1867","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1867","url":null,"abstract":"Background: Preclinical studies have identified molecular correlates of sensitivity to ATR inhibition. This translational study was designed to test the ATR inhibitor berzosertib in patients with advanced solid tumors carrying alterations in ATRX, ATM, genes conferring replication stress (RS), or SDH. Methods: Patients were recruited to 4 cohorts: T1: ATRX-mutant leiomyosarcoma; T2: ATM-mutant solid tumors; T3: solid tumors with mutations in RS-associated genes; and T4: SDH-deficient GIST. Patients were treated with berzosertib 240 mg/m2 IV twice per week. Pre and on-treatment biopsies were obtained in cohorts T1-T3. Results: Patients with SDH-mutant GIST had the longest median progression-free survival (PFS) (229 days) with stable disease as the best response. Patients in the other cohorts experienced progressive disease within 4 months. There was no significant difference in PFS comparing outcomes in patients with/without mutations in ATM or RS genes. Decreased pS345-CHK1 in on-treatment biopsies indicated target engagement by berzosertib and were accompanied by substantial increases in levels of DNA damage (g-H2AX) and RS (pKAP1) markers in a subset of patients. However, these biomarker changes did not translate to clinical benefit. In contrast, in cohorts T1-T3, increased expression of SFLN11 on treatment correlated with clinical benefit (HR = 0.045; 95%CI 0.005-0.400). Conclusions: Across cohorts, only SDH-mutant GIST patients experienced prolonged disease control. Despite evidence of target engagement, patients enrolled to all other cohorts had short PFS, suggesting rapid adaptation to ATR inhibitor monotherapy. Among these patients, those with tumors expressing SLFN11 during berzosertib exposure derived the most clinical benefit.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"35 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142490635","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 : 2024-10-22DOI: 10.1158/1078-0432.ccr-24-2713
Kyriakos P. Papadopoulos, Meredith McKean, Silvia Goldoni, Isabelle Genvresse, Marine F. Garrido, Rui Li, Gary Wilkinson, Christoph Kneip, Timothy A. Yap
Purpose: To evaluate the safety, tolerability, and pharmacokinetics of BAY 2666605, a velcrin that induces complex formation between the phosphodiesterase PDE3A and the protein Schlafen 12 (SLFN12) leading to a cytotoxic response in cancer cells. Patients and methods: This was a first-in-human phase I study of BAY 2666605 (NCT04809805), an oral, potent first-in-class PDE3A-SLFN12 complex inducer, with reduced PDE3A inhibition. Adults with advanced solid tumors that co-express SLFN12 and PDE3A received BAY 2666605 at escalating doses starting at 5 mg once daily in 28-day cycles. Forty-seven patients were pre-screened for SLFN12 and PDE3A overexpression, and 5 biomarker-positive patients received ≥ 1 BAY 2666605 dose. Results: The most common adverse event was grade 3-4 thrombocytopenia in 3 of the 5 patients treated. The long half-life (> 360 hours) and associated accumulation of BAY 2666605 led to the selection of an alternative schedule consisting of a loading dose with QD maintenance dose. The maximum tolerated dose was not established as the highest doses of both schedules were intolerable. No objective responses were observed. Due to the high expression of PDE3A in platelets compared to tumor tissues, the ex vivo dose-dependent inhibitory effect of BAY 2666605 on megakaryocytes, and the pharmacokinetic profile of the compound, alternative schedules were not predicted to ameliorate the mechanism-based thrombocytopenia. Conclusions: Despite the decreased PDE3A enzymatic inhibition profile of BAY 2666605, the occurrence of thrombocytopenia in treated patients, an on-target effect of the compound, precluded the achievement of a therapeutic window, consequently leading to trial termination.
{"title":"First-in-human dose escalation study of the first-in-class PDE3A-SLFN12 complex inducer BAY 2666605 in patients with advanced solid tumors co-expressing SLFN12 and PDE3A.","authors":"Kyriakos P. Papadopoulos, Meredith McKean, Silvia Goldoni, Isabelle Genvresse, Marine F. Garrido, Rui Li, Gary Wilkinson, Christoph Kneip, Timothy A. Yap","doi":"10.1158/1078-0432.ccr-24-2713","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2713","url":null,"abstract":"Purpose: To evaluate the safety, tolerability, and pharmacokinetics of BAY 2666605, a velcrin that induces complex formation between the phosphodiesterase PDE3A and the protein Schlafen 12 (SLFN12) leading to a cytotoxic response in cancer cells. Patients and methods: This was a first-in-human phase I study of BAY 2666605 (NCT04809805), an oral, potent first-in-class PDE3A-SLFN12 complex inducer, with reduced PDE3A inhibition. Adults with advanced solid tumors that co-express SLFN12 and PDE3A received BAY 2666605 at escalating doses starting at 5 mg once daily in 28-day cycles. Forty-seven patients were pre-screened for SLFN12 and PDE3A overexpression, and 5 biomarker-positive patients received ≥ 1 BAY 2666605 dose. Results: The most common adverse event was grade 3-4 thrombocytopenia in 3 of the 5 patients treated. The long half-life (&gt; 360 hours) and associated accumulation of BAY 2666605 led to the selection of an alternative schedule consisting of a loading dose with QD maintenance dose. The maximum tolerated dose was not established as the highest doses of both schedules were intolerable. No objective responses were observed. Due to the high expression of PDE3A in platelets compared to tumor tissues, the ex vivo dose-dependent inhibitory effect of BAY 2666605 on megakaryocytes, and the pharmacokinetic profile of the compound, alternative schedules were not predicted to ameliorate the mechanism-based thrombocytopenia. Conclusions: Despite the decreased PDE3A enzymatic inhibition profile of BAY 2666605, the occurrence of thrombocytopenia in treated patients, an on-target effect of the compound, precluded the achievement of a therapeutic window, consequently leading to trial termination.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"34 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142487548","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 : 2024-10-22DOI: 10.1158/1078-0432.ccr-24-0036
Mark H. O'Hara, Opeyemi Jegede, Mark A. Dickson, Angela M. DeMichele, Richard Piekarz, Robert J. Gray, Victoria Wang, Lisa M. McShane, Lawrence V. Rubinstein, David R. Patton, P. Mickey Williams, Stanley R. Hamilton, Adedayo Onitilo, James V. Tricoli, Barbara A. Conley, Carlos L. Arteaga, Lyndsay N. Harris, Peter J. O'Dwyer, Alice P. Chen, Keith T. Flaherty
Purpose: Amplification of CDK4 and CDK6 is a feature of a variety of malignancies, and preclinical evidence suggests inhibition of CDK4/6 is a plausible treatment strategy in these tumors. Subprotocol Z1C of the NCI-MATCH trial was designed to evaluate the CDK4/6 inhibitor palbociclib in CDK4- or CDK6-amplified tumors. Patients and Methods: Patients had a solid malignancy with progression on at least one systemic therapy for advanced disease. Tumors with ≥ 7 copies of CDK4 or CDK6 were considered amplified and molecularly eligible. Enrolled patients were treated with palbociclib 125 mg daily on days 1-21 of a 28-day cycle. The primary endpoint was ORR. Results: Forty-three patients were enrolled on subprotocol Z1C, and 38 patients were deemed eligible, treated, and included in analyses; 25 patients were eligible, treated, and centrally confirmed to have CDK4 or CDK6 amplification and comprised the primary analysis cohort for ORR endpoint. Among the 25 patients in the primary cohort, one patient had a PR, 4 patients had SD, and 16 patients had PD as best response. Four patients were not evaluable due to lack of follow-up scans. Among the 38 evaluable patients, one patient had a PR, 10 patients had SD, and 21 patients had PD as best response. Partial response and stable disease were only seen in patients with CDK4 amplification. Median progression-free survival was 2.0 months, and median overall survival was 8.8 months. Conclusions: Palbociclib showed limited activity in histology-agnostic CDK4- or CDK6-amplified tumors, though CNS tumors may be worthy of future investigation.
{"title":"Phase 2 Study of Palbociclib in Patients with Tumors with CDK4 or CDK6 Amplification: Results from the NCI-MATCH ECOG-ACRIN Trial (EAY131) Sub-protocol Z1C","authors":"Mark H. O'Hara, Opeyemi Jegede, Mark A. Dickson, Angela M. DeMichele, Richard Piekarz, Robert J. Gray, Victoria Wang, Lisa M. McShane, Lawrence V. Rubinstein, David R. Patton, P. Mickey Williams, Stanley R. Hamilton, Adedayo Onitilo, James V. Tricoli, Barbara A. Conley, Carlos L. Arteaga, Lyndsay N. Harris, Peter J. O'Dwyer, Alice P. Chen, Keith T. Flaherty","doi":"10.1158/1078-0432.ccr-24-0036","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-0036","url":null,"abstract":"Purpose: Amplification of CDK4 and CDK6 is a feature of a variety of malignancies, and preclinical evidence suggests inhibition of CDK4/6 is a plausible treatment strategy in these tumors. Subprotocol Z1C of the NCI-MATCH trial was designed to evaluate the CDK4/6 inhibitor palbociclib in CDK4- or CDK6-amplified tumors. Patients and Methods: Patients had a solid malignancy with progression on at least one systemic therapy for advanced disease. Tumors with ≥ 7 copies of CDK4 or CDK6 were considered amplified and molecularly eligible. Enrolled patients were treated with palbociclib 125 mg daily on days 1-21 of a 28-day cycle. The primary endpoint was ORR. Results: Forty-three patients were enrolled on subprotocol Z1C, and 38 patients were deemed eligible, treated, and included in analyses; 25 patients were eligible, treated, and centrally confirmed to have CDK4 or CDK6 amplification and comprised the primary analysis cohort for ORR endpoint. Among the 25 patients in the primary cohort, one patient had a PR, 4 patients had SD, and 16 patients had PD as best response. Four patients were not evaluable due to lack of follow-up scans. Among the 38 evaluable patients, one patient had a PR, 10 patients had SD, and 21 patients had PD as best response. Partial response and stable disease were only seen in patients with CDK4 amplification. Median progression-free survival was 2.0 months, and median overall survival was 8.8 months. Conclusions: Palbociclib showed limited activity in histology-agnostic CDK4- or CDK6-amplified tumors, though CNS tumors may be worthy of future investigation.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"25 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142487505","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 : 2024-10-22DOI: 10.1158/1078-0432.ccr-24-1993
Filippo G. Dall'Olio, Wael Zrafi, Veronique Roelants, Valentina Ambrosini, Aloyse Fourquet, Cristina Mitea, Francesco Passiglia, Matteo Bauckneht, Gerald Bonardel, Nicole Conci, Jose Carlos Benitez, Vincenzo Arena, Céline Namour, Marie Naigeon, Isabelle Monnet, Kristi Beshiri, Delphine Hoton, Safiye Dursun, Francois Xavier. Danlos, Giulia Argalia, Mihaela Aldea, Guido Rovera, Lisa Derosa, Valerio Iebba, Hester A. Gietema, Valerie Gounant, Valérie Lacroix, Jordi Remon, Daniel Gautheret, Nathalie Chaput, Bastien Job, Patricia L. Kannouche, Monica Velasco-Nuño, Laurence Zitvogel, Eugenia Cella, José Reinaldo Chícharo de Freitas, Damien Vasseur, Mohamed Aymen Bettaieb, Marco Tagliamento, Lizza Hendriks, Antoine Italiano, David Planchard, Aurelien Marabelle, Fabrice Barlesi, Silvia Novello, Desiree De Andreis, Frank Aboubakar Nan, Andrea Ardizzoni, Gerard Zalcman, Camilo Garcia, Benjamin Besse
Purpose: This study aimed to explore metabolic tumor volume (tMTV) as assessed 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG-PET/CT), and understand its biological meaning in patients with NSCLC exposed to immune checkpoint blockers(ICBs). Experimental Design: In this study, patients with advanced NSCLC and a positive PET scan within 42 days of first line treatment were enrolled in 11 institutions across 4 countries. Total MTV (tMTV) was analyzed, with a 42% SUVmax threshold. Survival was analyzed according to high tMTV (≥ median). Plasma proteomic profile, whole exome, transcriptome and other analysis were performed on monocentric cohorts to explore its biological correlates. Results: Of the 518 patients included, 167 received ICBs, 257 had chemotherapy plus ICBs, and 94 had chemotherapy. Median tMTV was 99 cm3. Median overall survival (OS) for patients with high tMTV treated with ICBs was 11.4 months vs 29.6 months (P<0.0012) for those with low tMTV. In patients receiving chemotherapy-ICB tMTV did not correlate with OS (P=0.099). In patients with PD-L1≥1% and high tMTV, chemotherapy-ICB combination was associated with longer OS compared with ICBs alone (20 vs 11.4 months,p=0.026), while no survival differences observed in low tMTV group. High tMTV correlated (and its detrimental effect seems to be driven by) a specific proteomic profile and increase in genomic instability. Conclusion: Our analysis indicates high tTMV is linked to an increase in systemic inflammation, specific cytokines production and chromosomal instability. tTMV may serve as one of the biomarker to select the best upfront strategy in patients with PD-L1 positive advanced NSCLC.
{"title":"Metabolic tumor volume assessed by 18F FDG - PET CT scan as a predictive biomarker for immune checkpoint blockers in advanced NSCLC and its biological correlates","authors":"Filippo G. Dall'Olio, Wael Zrafi, Veronique Roelants, Valentina Ambrosini, Aloyse Fourquet, Cristina Mitea, Francesco Passiglia, Matteo Bauckneht, Gerald Bonardel, Nicole Conci, Jose Carlos Benitez, Vincenzo Arena, Céline Namour, Marie Naigeon, Isabelle Monnet, Kristi Beshiri, Delphine Hoton, Safiye Dursun, Francois Xavier. Danlos, Giulia Argalia, Mihaela Aldea, Guido Rovera, Lisa Derosa, Valerio Iebba, Hester A. Gietema, Valerie Gounant, Valérie Lacroix, Jordi Remon, Daniel Gautheret, Nathalie Chaput, Bastien Job, Patricia L. Kannouche, Monica Velasco-Nuño, Laurence Zitvogel, Eugenia Cella, José Reinaldo Chícharo de Freitas, Damien Vasseur, Mohamed Aymen Bettaieb, Marco Tagliamento, Lizza Hendriks, Antoine Italiano, David Planchard, Aurelien Marabelle, Fabrice Barlesi, Silvia Novello, Desiree De Andreis, Frank Aboubakar Nan, Andrea Ardizzoni, Gerard Zalcman, Camilo Garcia, Benjamin Besse","doi":"10.1158/1078-0432.ccr-24-1993","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1993","url":null,"abstract":"Purpose: This study aimed to explore metabolic tumor volume (tMTV) as assessed 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG-PET/CT), and understand its biological meaning in patients with NSCLC exposed to immune checkpoint blockers(ICBs). Experimental Design: In this study, patients with advanced NSCLC and a positive PET scan within 42 days of first line treatment were enrolled in 11 institutions across 4 countries. Total MTV (tMTV) was analyzed, with a 42% SUVmax threshold. Survival was analyzed according to high tMTV (≥ median). Plasma proteomic profile, whole exome, transcriptome and other analysis were performed on monocentric cohorts to explore its biological correlates. Results: Of the 518 patients included, 167 received ICBs, 257 had chemotherapy plus ICBs, and 94 had chemotherapy. Median tMTV was 99 cm3. Median overall survival (OS) for patients with high tMTV treated with ICBs was 11.4 months vs 29.6 months (P&lt;0.0012) for those with low tMTV. In patients receiving chemotherapy-ICB tMTV did not correlate with OS (P=0.099). In patients with PD-L1≥1% and high tMTV, chemotherapy-ICB combination was associated with longer OS compared with ICBs alone (20 vs 11.4 months,p=0.026), while no survival differences observed in low tMTV group. High tMTV correlated (and its detrimental effect seems to be driven by) a specific proteomic profile and increase in genomic instability. Conclusion: Our analysis indicates high tTMV is linked to an increase in systemic inflammation, specific cytokines production and chromosomal instability. tTMV may serve as one of the biomarker to select the best upfront strategy in patients with PD-L1 positive advanced NSCLC.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"62 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142487556","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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